GOOD MANUFACTURING PRACTICES MANUAL - FDA 91-4179

MEDICAL DEVICE
GOOD MANUFACTURING PRACTICES MANUAL

5Th EDITION -
September 1991

PREPARED BY
DIVISION OF SMALL MANUFACTURERS ASSISTANCE
OFFICE OF TRAINING AND ASSISTANCE

PROJECT OFFICERS
ANDREW LOWERY
RICHARD J. RIVERA

FPA
FOREWORD

In October 1982, the Food and Drug Administration established the

Center for Devices and Radiological Health (CDRH) by merging the
Bureau
of Medical Devices and the Bureau of Radiological Health.

CDRH develops and implements national programs to protect the

public
health in the fields of medical devices and radiological health.
These
programs are intended to assure the safety, effectiveness, and proper
labeling of medical devices; to control unnecessary human exposure to
potentially hazardous ionizing and nonionizing radiation; and to
assure
the safe, efficacious use of such radiation.

CDRH publishes the results of its work in scientific journals and

in
its own technical reports. These reports disseminate results of CDRH
and
contractor projects. These are sold by the Government Printing Office
and/or the National Technical Information Service. Their addresses
are:
U.S. Government Printing Office
Washington, D.C. 20402
202-783-3238

National Technical Information Services

 U.S. Department of Commerce
5285 Port Royal Road
Springfield, VA 22161
703-487-4650
We welcome your comments and requests for further information.

James S. Benson
Acting Director
Center for Devices and
Radiological Health
 PREFACE

Adherence to the Good Manufacturing Practices (GMP) regulation

makes
good business sense and also serves public health aims -- two very
good
reasons for the Food and Drug Administration (FDA) to encourage
compliance. However, a prerequisite to complying with a regulation is
a
clear understanding of its content. Recognizing this fact, the
Division
of Small Manufacturers Assistance (DSMA) developed this manual and
sponsors workshops to help manufacturers increase their knowledge of
medical device requirements and FDA compliance policies. In addition,
DSMA distributes a wide variety of printed materials, such as
regulations, guidelines, policy statements, question-and-answer
booklets, and other FDA documents. These documents help manufacturers
understand regulatory requirements and determine the most effective
ways
to meet them.

We include interpretations of most GMP requirements and a variety

of
model procedures and sample forms. Manufacturers may find these
procedures and forms useful in understanding how other manufacturers
have successfully complied with GMP and other quality related
requirements.

The GMP regulation outlines minimum elements of quality assurance

practices. Manufacturers of medical devices commonly find that their
quality assurance needs are broader than the basic GMP elements
because
of the additional need to meet company quality claims as required by
paragraph 501(c) of the Federal Food, Drug, and Cosmetic (FD& C) Act
and
to meet customer needs and requirements of consensus standards. Also,
analysis of recalls and adverse reaction reports shows that only
about
half of reported device failures involve traditional GMP problems. It
is
clear that proper design and understandable labeling must be taken
into
full account during development of products that will operate
effectively, be used correctly, and accomplish their intended effects.
Therefore, this manual also deals with the broader considerations
involved in establishing and maintaining total quality assurance
systems.

Congress has also recognized the need for expanded quality

assurance
 systems, and by the passage of the Safe Medical Devices Act of 1990
has
added design validation to the FD& C Act. FDA is in the process of
rewriting the GMP regulation to include design validation as well as
other revisions.

The GMP interpretations were provided by the Division of

Compliance
Programs (DCP), Office of Compliance and Surveillance. We wish to
recognize the extensive efforts of Mr. W. Fred Hooten, Director of
DCP,
and his staff in developing these interpretations for the regulated
industry.

Joseph S. Arcarese
Director
Office of Training and Assistance
Center for Devices and
Radiological Health

OPEN LETTER TO MANUFACTURERS OF MEDICAL DEVICES

 Many of you have requested from the Food and Drug Administration
(FDA) assistance in complying with the device Good Manufacturing
Practices (GMP) regulation. The Division of Small Manufacturers
Assistance (DSMA) has received many requests to provide examples of
actual quality assurance procedures and GMP records that would be
acceptable to FDA. Traditionally, FDA has resisted the temptation to
prescribe specifically how a manufacturer is to comply with the GMP
regulation. It is the manufacturer, not FDA, who bears overall
responsibility for production of high-quality products. A publication
by
FDA on restrictive GMP rules on how to produce devices would be more
likely to retard innovation, reduce efficiency, and hinder cost
control
than to foster these worthwhile goals.

We recognize, nevertheless, that manufacturers may benefit from

reviewing model GMP procedures and forms that others have developed
or
adopted in order to comply with the intent of the regulations. To
help
answer such needs, this manual contains a variety of model
procedures
and sample forms. These, however, are not meant to be official
statements of FDA policy. Rather, these represent a compilation of
examples that firms may find useful in understanding how some
manufacturers have successfully complied with GMP requirements.
Before
adopting any model procedure or form into a quality assurance program,
you should carefully examine its applicability and suitability to
your
particular device and manufacturing operation.

We also wish to emphasize that the successful development and

marketing of a medical device requires a total quality assurance
system. Therefore, this manual includes GMP and total quality
assurance
information.

FDA recognizes the continuing need to use innovative approaches,

particularly in dealing with small businesses that might find
themselves
unnecessarily adversely affected by federal regulations. We hope
that
the information contained in this manual will assist manufacturers
in
their efforts to establish and maintain quality assurance program
elements that add up to good business practices. Please contact the
Division of Compliance Programs at 301-427-1131 or call DSMA toll
free
at 1-800-638-2041 for additional assistance and further information.

Sincerely yours,
 John F. Stigi
Director
Division of Small
Manufacturers

Assistance

CONTENTS

CONTENTS

FOREWORD . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ii
 PREFACE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
iii
OPEN LETTER TO MANUFACTURERS OF MEDICAL DEVICES . . . . . . . . . .
iv
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
vi

1. THE GMP REGULATION . . . . . . . . . . . . . . . . . . . . . .

1-1

2. QUALITY ASSURANCE SYSTEMS . . . . . . . . . . . . . . . . . .

2-1

3. PREPRODUCTION QUALITY . . . . . . . . . . . . . . . . . . . .
3-1

4. BUILDINGS AND ENVIRONMENT . . . . . . . . . . . . . . . . . .

4-1

5. EQUIPMENT AND CALIBRATION . . . . . . . . . . . . . . . . . .

5-1

6. DEVICE MASTER RECORDS . . . . . . . . . . . . . . . . . . . .

6-1

7. CHANGE CONTROL . . . . . . . . . . . . . . . . . . . . . . . .
7-1

8. COMPONENTS AND MATERIALS . . . . . . . . . . . . . . . . . . .

8-1

9. PRODUCTION APPLICATIONS . . . . . . . . . . . . . . . . . . .
9-1

10. DEVICE EVALUATION . . . . . . . . . . . . . . . . . . . . . .

10-1

11. LABELING . . . . . . . . . . . . . . . . . . . . . . . . . . .
11-1

12. PACKAGING . . . . . . . . . . . . . . . . . . . . . . . . . .
12-1

13. DISTRIBUTION . . . . . . . . . . . . . . . . . . . . . . . . .
13-1

14. COMPLAINTS AND FAILURE INVESTIGATIONS . . . . . . . . . . . .

14-1

15. QA SYSTEM AUDITS . . . . . . . . . . . . . . . . . . . . . . .

15-1
 16. FACTORY INSPECTIONS . . . . . . . . . . . . . . . . . . . . .
16-1

17. APPENDIX . . . . . . . . . . . . . . . . . . . . . . . . . . .
17-1
Good Manufacturing Practices Regulation . . . . . . . . . . .
17-2
Guideline List of Critical Medical Devices . . . . . . . . . .
17-12
Good Manufacturing Practices Preamble . . . . . . . . . . . .
17-21
Summary of Requirements Spreadsheet . . . . . . . . . . . . .
17-42
Preproduction Quality Assurance Planning: Recommendations
for Medical Device Manufacturers . . . . . . . . . . . . . .
17-43
Guideline on General Principles of Process Validation . . . .
17-61
Government-Wide Quality Assurance Program . . . . . . . . . .
17-73

ABSTRACT

Department of Health and Human Services, Center for Devices and

Radiological Health. Device Good Manufacturing Practices Manual.
Fifth
Edition. HHS Publication FDA 91-???? (June 1991) (pp. ???).
This manual discusses requirements of the Good Manufacturing
Practices
(GMP) regulation that firms marketing medical devices must consider
when
they establish specifications for devices, or when they manufacture,
 contract manufacture, process, repack, or relabel finished medical
devices intended to be commercially distributed. This manual contains
articles that explain the various GMP requirements such as
calibration,
device master records, component control, etc. It also contains
examples
of forms, procedures, decals, etc. Manufacturers may use these as
guidelines when developing their GMP or quality assurance system.
The manual includes total quality assurance systems and preproduction
quality information because of their importance to anyone who
manufactures a medical device. The last chapter covers the
inspections
performed by Food and Drug investigators to determine if medical
device
firms are in compliance with the GMP requirements.
This is the manual used in the Division of Small Manufacturers
Assistance (DSMA) GMP workshops.
gmp 1.25: 4/15/91
 GMP - CHAPTER 1 - THE GMP REGULATION

CHAPTER 1 THE GMP REGULATION

INTRODUCTION
FLEXIBILITY OF THE GMP
MANUAL CONTENTS
GMP APPLICATIONS AND EXEMPTIONS
Exemptions
Component Manufacturers
Service Firms
Custom Device Manufacturers
Contract Manufacturers
Contract Testing Laboratories
Repackagers, Initial Distributors and Specification Developers
Repackers and Relabelers
Specification Developers
Initial Distributors of Imported Devices

INTRODUCTION

The Good Manufacturing Practices (GMP) regulation, promulgated

under
section 520 of the Food, Drug and Cosmetic Act, requires that
domestic
or foreign manufacturers of medical devices intended for commercial
distribution in the United States have a quality assurance (QA)
program. The regulation requires that various specifications and
controls be established for devices and that finished devices meet
these specifications. Thus, the GMP regulation helps assure that
medical devices are safe and effective for the intended use. The
Food
and Drug Administration (FDA) monitors device problem data and
inspects
the operations and records of device manufacturers to determine
compliance with the QA program requirements in the regulation.

The regulation, which is Part 820 of Title 21 of the Code of

Federal
Regulations (CFR), and its preamble appear in the appendix of this
manual. The regulation covers QA programs and organization,
buildings,
equipment, components, production and process controls, packaging and
labeling control, distribution and installation, device evaluation,
and
records. A few additional controls such as critical component
traceability are specified for critical devices. Critical devices are
defined in 820.3(f). The preamble contains the gist of public
comments
 received during the development of the GMP regulation and contains
the
FDA Commissioner's resolution of the comments. Thus, the preamble
contains valuable insight into the meaning and intent of the
regulation.

FLEXIBILITY OF THE GMP

Section 820.5 of the GMP regulation requires that, "Every

finished
device manufacturer shall prepare and implement a quality assurance
 program that is appropriate to the specific device manufactured and
meets the requirements of this part." The word "appropriate" means
that
the GMP rule is a flexible regulation. Operating within this
flexibility, it is the responsibility of each manufacturer to
establish
requirements for each type or family of devices that will result in
devices that are safe and effective, and to establish and implement
manufacturing methods and procedures to produce devices that meet the
requirements. FDA has identified in the GMP regulation the essential
elements that a quality assurance system for a manufacturing
operation
must embody, without prescribing specific ways in which to establish
them. Because the GMP regulation covers a broad spectrum of devices
and
manufacturing processes, it allows a certain amount of leeway in the
details of quality assurance programs. It is left to manufacturers
to
determine the pertinence of, or necessity for, certain quality
assurance elements and to develop and implement specific procedures
tailored to their particular manufacturing processes and devices. For
example, if it is impossible to mix up labels at a firm because
there
is only one label or one product, then there is no point in the firm
implementing all of the GMP requirements for label control.

The medical device GMP regulation requires an "umbrella" quality

assurance program intended to cover the manufacturing of all medical
devices from simple surgical hand tools to very complex computerized
axial tomography (CAT) scanners. It is not practical for a
regulation
to specify details of quality assurance programs for such a wide
range
of products. Rather, the GMP regulation specifies general objectives
such as use of calibrated equipment, process controls, etc., rather
than methods, because one method would not be applicable to all
manufacturing processes.

In most cases, it is left to the manufacturer to determine the

best
methods to attain quality assurance objectives. In some cases,
however,
the GMP regulation does specify the particular type of method to be
used, such as verification of critical operations for critical
devices
and written manufacturing procedures (instructions). This does not
mean,
however, that manufacturers cannot vary from the method specified if
the
intent of the GMP requirement can be met by another method such as
using an engineering drawing plus a model device as manufacturing
instructions. Likewise, "written procedures" may be filed and
distributed by automated data processing equipment. This flexibility
is
 allowed by section 820.5.

Typically, large manufacturers will have a GMP or QA program that

exceeds the medical device GMP regulation requirements. Small
manufacturers will have something less. (At the present time there
is
no official FDA definition of a small manufacturer, although 10 or
fewer employees is often used as the definition.) However, FDA does
not
grant special concessions to small firms simply because they are
small.
FDA recognizes: that a small firm may not need the same amount of
documentation that a large firm does in order to achieve a state-of-
control; and, that some of the GMP requirements for written
procedures
may not be necessary for a small firm.

Manufacturers must use good judgment when developing their GMP

program and apply the GMP regulation as appropriate for their
specific
products and operations (820.5).

After a firm establishes a GMP/quality assurance program, it must

be
maintained. The firm must assure that with growth and process or
product changes their QA program is still adequate. This assurance
is
 obtained through change control, day-to-day observance of operations,
and by periodic audits of the QA program. The auditor must first
identify the elements of the company's quality assurance program,
determine how well each element is functioning, and then determine
its
adequacy in light of the intent of the device GMP regulation (i.e.,
to
assure conformance to device master record specifications) and
adequacy
with respect to meeting the company's quality claims. To aid auditors,
QA managers, and others, this manual provides guidance in the
interpretation of the GMP requirements and demonstrates the
flexibility
of the GMP regulation in its application to the diversity of devices,
manufacturing processes, and manufacturers. In the absence of
guidance
from FDA, manufacturers may rely on industry, national, and
international consensus guidelines that are acceptable to FDA in
meeting GMP requirements.

MANUAL CONTENTS

This manual was also developed to aid small manufacturers in

completing, maintaining, or expanding their quality assurance
programs.
Contents include educational materials, aids and examples of how to
implement elements of a quality assurance program, together with
detailed examples of procedures, control forms, and associated data.
The
examples of typical procedures, drawings, and forms found in this
manual were derived from quality assurance programs in the device
industry. These materials are not meant to describe universally
applicable elements of a quality assurance program that can be used
unchanged by any firm. Of course, a form or aid as presented in this
manual may be suitable for direct use for a specific device and
operation; but, in general, manufacturers will need to use care in
adopting and modifying a selected form or procedure to meet the
specific
quality assurance needs of their devices and operations. This manual
is
arranged as if the reader were starting a new business. That is, as
if
an entrepreneur were sequentially:

1. obtaining information on GMP requirements and other QA

systems;
2. determining the extent of the QA system needed to control
the
development and production of the proposed device; and
training employees;
3. designing a product;
4. acquiring adequate facilities;
5. purchasing and installing processing equipment;
 6. drafting the master record (product documentation);
7. noting how to change master records;
8. procuring components and materials;
9. manufacturing devices;
10. evaluating finished devices;
11. labeling devices;
12. packaging devices;
13. distributing devices;
14. processing complaints and analyzing service and repair data;

15. auditing and correcting deficiencies in the QA system; and

16. preparing for an FDA inspection.

If firms perform these activities as required by the GMP

regulation
and as expounded in this manual, they will be prepared for a GMP
inspection of their manufacturing operations by an FDA investigator.
 Manufacturers and importers of medical devices must also comply
with
the Medical Device Reporting (MDR) regulation, 21 CFR Part 803, which
requires that serious complaints be reported to FDA. MDR is related
to
the GMP complaint and failure investigation requirements, which are
covered in chapter 14. If firms comply with the GMP regulation and
pre-
production quality assurance guidelines in this manual and in other
sources, there is a high probability that they will reduce the
frequency of events that must be reported.

GMP APPLICATIONS AND EXEMPTIONS

The GMP regulation applies to the manufacture of finished devices

intended to be commercially distributed for human use unless there is
an
approved exemption in effect.

Certain components such as blood tubing and major diagnostic x-

ray
components may be considered to be finished devices because they are
accessories to finished devices. The manufacturer of such components
or
accessories is subject to the GMP regulation when the accessory
device
is labeled and sold separately from the primary device for a health
related purpose to a hospital, physician, or other user.

The designation of a device as a "custom" device does not confer

a
GMP exemption.

Contract manufacturers and specification developers must comply

with
the sections of the GMP regulation that apply to the functions they
perform. Contract test laboratories are considered an extension of a
manufacturer's quality assurance program and presently are not
routinely scheduled for GMP inspections. Internal test laboratories,
however, that are part of a corporate firm that provides services to
individual corporation factories, are inspected as part of the FDA
GMP
inspection of the member factories.

Situations are discussed in the remainder of this chapter where

various firms are exempt from the GMP regulation or are not
routinely
inspected. However, these firms are still subject to the FD& C Act.
If
these firms render devices unsafe or ineffective, the devices are
adulterated and/or misbranded and the firms are subject to the
penalties
of the FD& C Act.
 Exemptions

FDA has determined that certain types of establishments are

exempt
from the GMP regulation; and FDA has defined GMP responsibilities for
others. Exemption from the GMP regulation does not exempt
manufacturers
of finished devices from keeping complaint files (820.198) or from
general requirements concerning records (820.180). Sterile devices
are
never exempted from the GMP regulation. A device that normally would
be
subject to the GMP regulation may be exempt if:

o FDA has issued an exemption order in response to a

citizen's
petition for exemption;

o FDA, in the absence of a petition, has exempted the device

and
published the exemption in the Federal Register;

o the device is exempted by FDA classification regulations

published in the Federal Register;
 o the device is an investigational device and meets the
requirements of the Investigational Device Exemption (IDE)
regulation;

o the device is an investigational intraocular lens (IOL) and

meets the requirements of the investigational device
exemption
(IDE) regulation for IOL's; or,

o through a policy statement, FDA may decide not to apply the

GMP regulation to some types of devices and manufacturing
processes although the devices may not have been exempted
from
the GMP regulation.

Manufacturers should keep on file records of any GMP exemption

granted to them by FDA. Upon request during a factory visit, the
exemption records need to be shown during normal business hours to
the
FDA investigator in order to verify that an exemption has been
granted.

Component Manufacturers

A "component" is defined by 820.3(c) as "any material, substance,

piece, part, or assembly used during device manufacture which is
intended to be included in the finished device." Some component
manufacturers are excluded from the GMP regulation by 820.1. This
exclusion is clarified in comment number one in the GMP preamble
(July
21, 1978 Federal Register). Excluded are those component
manufacturers
who supply only a fraction of their production to finished device
manufacturers and who do not manufacture exclusively for use in
medical
devices. The GMP preamble does not specifically discuss whether the
GMP
regulation applies to manufacturers of components that are sold only
to
device manufacturers and used solely in finished devices. Current
FDA
policy, however, is to rely upon the finished device manufacturer to
assure that components are acceptable for use. Component
manufacturers
are not routinely scheduled for GMP inspections; however, FDA
encourages
them to use the GMP regulation as a guideline for the manufacturing
portion of their quality assurance program.

When finished device manufacturers produce components

specifically
for use in medical devices they produce, whether in the same
building
 or another location, such production of components is considered
part
of the device manufacturing operations, and the production must
comply
with the GMP regulation.

Accessory devices, such as hemodialysis tubing or major

diagnostic
x-ray components, that are packaged, labeled, and distributed
separately to a hospital, physician, etc., for health-related
purposes
are sometimes referred to as components. However, FDA considers them
finished devices in that they are "suitable for use" and the GMP
regulation applies to their manufacture. Similarly, a device or
component including software that is sold as an addition to a
finished
medical device to augment or supplement its performance is also
termed
an accessory. An accessory to a medical device is considered a
finished
device and therefore subject to the GMP regulation (820.3(j)).

Service Firms

"Service firms" dispense devices to consumers or render a service

necessary to provide consumers with devices or with the benefits to
be
derived from the use of devices. These firms do not have to comply
with
the GMP regulation in performing these service operations. Examples
of
 service firms include hearing-aid dispensers, opticians, optical
laboratories, clinical laboratories, assemblers of diagnostic x-ray
systems, hospitals, clinics, dental laboratories, and orthotic or
prosthetic retail facilities. In these examples, the primary
responsibility is to dispense a device or provide a service through
the
use of a previously manufactured device.

In contrast to hearing aid dispensers who are not subject to the

GMP
regulation, manufacturers that prepare hearing-aid kits containing
the
parts to be assembled by the purchaser must comply with applicable
parts
of the GMP regulation. Firms that assemble, repack, and label these
kits
also must comply.

The GMP regulation applies to firms that manufacture and

distribute
devices such as alloys, resins, and other dental materials. The
Center
for Devices and Radiological Health's (CDRH) present policy is not
to
require dental laboratories to comply with the GMP regulation.
Optical
laboratories that perform functions such as processing, surfacing,
edging, finishing, heat treating, tempering, and assembling
previously
manufactured lenses or frames are not normally expected to comply
with
the GMP regulation.

Remanufacturing, rebuilding, reconditioning, and updating are

manufacturing operations. Thus, persons who take ownership of
previously
owned medical devices and rebuild or recondition these for
commercial
distribution are processing finished devices and are considered
manufacturers. As such, these firms are subject to inspection by FDA
and
must meet the applicable requirements of the medical device GMP
regulation. (See Compliance Policy Guide 7124.28) These firms must
establish and implement quality assurance programs adequate to assure
the safety and effectiveness of the rebuilt devices. Such activities
include drafting of master records, rebuilding per the master records,
inspection and testing, removal of reconditioning materials,
calibration of measurement equipment, control of components, and
processing of complaints.

These remanufacturing, rebuilding, reconditioning, and updating

firms are also required to comply with the labeling requirements of
21
 CFR 801.1(c). This labeling regulation requires that where the
person
or firm named on the label of the device is not the original
manufacturer, the name must be qualified by an appropriate phrase
which
reveals the connection that person has with the device.

In the case of a rebuilder or reconditioner, an appropriate

qualification phrase would be, "rebuilt by ", or
"reconditioned by ".

Shops that repair devices as a service to the owner of the device

are not expected to comply with the GMP regulation, although they
are
required to register if they resell the devices. (The terms "repair",
"refurbish", and "recondition" are used to refer to refinishing or
replacement of broken or worn-out parts.)

Firms that only lease devices to practitioners or patients, and

that
may perform routine maintenance, or make repairs to these devices
for
their customers, are not required to comply with the GMP regulation.
If
they significantly modify (update) devices, however, these firms
become
manufacturers (see rebuilding, etc., above).

Custom Device Manufacturers

 Section 520(b) of the Act and the IDE regulation (21 CFR Part 812)
define a custom device. Custom devices are exempt from certain
statutory requirements. For example, manufacturers of custom devices
are
not required to comply with Performance Standards (Section 514 of
the
Act) or Premarket Approval requirements (Section 515) and are exempt
from Premarket Notification requirements [Section 510(k)]. Custom
devices are NOT exempt from the GMP regulation. Current FDA policy,
however, is not to inspect manufacturers of custom devices.
Manufacturers of custom devices should comply with the GMP
requirements
while keeping in mind the flexibility allowed.

Contract Manufacturers

A firm that manufactures a finished device under the terms of a

contract with another firm is a contract manufacturer. The agreement
between the firms should be documented in a written contract.
Contract
manufacturers of finished devices must comply with applicable
requirements of the GMP regulation and must register their
establishment
with FDA. Depending on the circumstances, both the contractor and
manufacturer may be held jointly responsible for the manufacturing
processes performed.

Contract Testing Laboratories

Contract laboratories that test components or finished devices

for a
manufacturer are considered an extension of the manufacturer's
quality
assurance program. These laboratories may provide services to a
number
of customers, many of which are not medical device manufacturers. In
such situations, these laboratories are not subject to routine GMP
inspections. Through the conduct of quality audits or other means,
the
finished device manufacturer is responsible for assuring that
equipment
and procedures used by the lab are adequate and appropriate. However,
an internal test laboratory, if part of a firm that does testing for
various facilities within the corporation, is subject to inspection
when
FDA GMP inspections are conducted at the individual manufacturing
facilities. That is, the test laboratory is simply part of a medical
device firm of which all divisions must comply with the GMP
regulation.

Repackagers, Initial Distributors and Specification Developers

Repackaging, relabeling, initial distribution of an imported

device,
 and specification development are defined as manufacturing in Part
807,
Establishment Registration and Device Listing for Manufacturers of
Devices. Some definitions from 807.3(d) are reprinted below because
they bear on applications of the GMP regulation.

(d) "Manufacture, preparation, propagating, compounding,

assembly,
or processing" of a device means the making by chemical,
physical, biological, device in Section 201(h) of the Act.
These terms include the following activities.

(1) Repackaging or otherwise changing the container, wrapper, or

labeling of any device package in furtherance of the distribution of
the
device from the original place of manufacture to the person who makes
final delivery or sale to the ultimate consumer;

(2) Initial distribution of imported devices; or

(3) Initiation of specifications for devices that are

manufactured
 by a second party for subsequent commercial distribution by the
person
initiating specifications.

Repackers and Relabelers

As defined above, repackaging and relabeling are manufacturing

operations. Further, a repacker (repackager) or relabeler is a
manufacturer per 820.3(k) and subject to the applicable requirements
of
the GMP regulation. A firm is a repacker or relabeler if it:

o packages and/or labels previously manufactured finished

devices;

o receives finished devices in bulk (e.g., surgical tubing,

syringes, media, etc.,) and repacks them into individual
packages and labels them; or,
o receives previously manufactured devices that have been
packaged and labeled by another manufacturer, and combines
them into a kit with other unpackaged devices which are
received in bulk.

A firm is not considered a repacker or relabeler or a

manufacturer
for purposes of applying the GMP regulation if it packs only
previously
packaged and labeled individual devices into convenience packages.
(Note that this activity is essentially the same as a drug store
employee placing packaged items into a bag.)

A distributor who only adds a label bearing their name and

address
is exempt from the GMP requirements. A firm simply affixing a
sticker
label bearing the distributor's name and address would not require
record keeping demonstrating compliance with GMP labeling controls.

Specification Developers

Specification developers provide specifications to contract

manufacturers who produce devices to meet the specifications. The
contract manufacturer may package and label the device, or the
finished
device may be shipped to the specification developer for packaging
and
labeling.

A specification developer is considered a manufacturer and is

subject to the GMP requirements that apply to the activities they
conduct, such as correct transfer of the design information to a
contract manufacturer (820.100). This activity, in turn, requires an
adequate device master record (820.181, 820.182) and adequate change
 control. Further, if the product carries the specification
developer's
label, the developer is responsible for maintaining a complaint file
and processing complaints, plus maintaining the specifications and
other
appropriate device master records.

Initial Distributors of Imported Devices

As noted above, initial distributors are defined as manufacturers

and must comply with applicable GMP requirements such as complaint
handling which is discussed in chapter 14.

If initial distributors (importers) repackage, relabel, or

develop
device specifications, then they are subject to the requirements
described above for repackagers and relabelers, or specifications
developers.
gmp 1-23: 7/15/91
 GMP - CHAPTER 2 - QUALITY ASSURANCE SYSTEMS

CHAPTER 2 QUALITY ASSURANCE SYSTEMS

INTRODUCTION
QUALITY ASSURANCE SYSTEMS
QUALITY CONTROL
GOOD MANUFACTURING PRACTICES
Adequate Organization and QA Management
Formal and Documented QA Program
Approval of Materials, Components and Finished Devices
Adequate Quality Assurance Checks
Identify and Solve QA Problems
Periodic QA System Audits
Employee Training
INTERNATIONAL QA STANDARDS
TOTAL QUALITY ASSURANCE SYSTEM
Design Quality
Component Selection
Labeling Content
Process Quality
QA PROGRAM MAINTENANCE AND IMPROVEMENTS
SOME HIGHLIGHTS OF THE SAFE MEDICAL DEVICES ACT OF 1990
EXHIBIT
Example of a Standard Operating Procedure for Employee Training

INTRODUCTION

Quality assurance must be an integrated effort -- a total systems

approach to satisfy the particular safety and performance needs of a
specific manufacturer, product, and user- market. It must not simply
consist of inspection and testing, or spot solutions or "fire
fighting", no matter what the product is or how small the
manufacturer.
In all cases, quality must be considered at the earliest stages in
every significant area that has an effect on the quality, safety,
and
effectiveness of the device. These areas include product development,
design evaluation, component and/or vendor selection, documentation,
development of labeling, design transfer, process development and
validation, pilot production, routine manufacturing, test/inspection,
history record evaluation, distribution, service or repair, and
complaints. Complaints and, of course, favorable comments,
constitute
customer feedback.

Most important of all factors, management and employees must have

 the correct attitude if their quality assurance (QA) program is to
be
effective. Quality consciousness must be developed in every employee.
Each person must be made aware of the importance of his or her
individual contributions in the overall effort to achieve an
acceptable
level of quality.

After a QA program is in place and checked, it must not be

allowed
 to stagnate -- it must continue to be dynamic. A QA program remains
dynamic through continuous feedback; "big-picture" monitoring by
system
audits; and by corrective action. Sufficient personnel with
appropriate
education, background, and experience must be in all departments to
ensure that QA activities are properly and adequately performed.

The result is an organization that is operating in a known state-

of-
control for the device, manufacturing processes, and records. A
properly functioning quality assurance system results in increased
safety and effectiveness of the device, reduced liability exposure,
reduced regulatory exposure, increased customer satisfaction, less
scrap, lower costs, much less confusion, higher employee morale, and,
of course, higher profits.

QUALITY ASSURANCE SYSTEMS

There are several QA systems in common use, including: quality

control, good manufacturing practices, product assurance, the ISO
9000
series of international QA standards, and total quality assurance.
[A
special government-wide quality assurance program (GWQAP) used to
help
control the quality of goods purchased by various agencies is
described
in the Appendix.] Quality control is a minimal QA system which
emphasizes test and inspection. Good Manufacturing Practices (GMP) is
a
government mandated QA system for medical device manufacturers. It
emphasizes all aspects of production: facilities, equipment, design
and
production documentation, correct design transfer, production control,
production records and feedback. Thus, GMP systems include classical
quality control activities. Total quality assurance is a system
which
emphasizes that: all employees and vendors are responsible for their
activities; design requirements are established and met; process
requirements are established and met; all production activities are
controlled; finished product specifications are met; and feedback
results in appropriate corrections.

Product assurance is a QA system which assures that customer

needs
are determined, and that product design requirements are established
and met. Note that a total QA system is a sum of a product assurance
(design QA) system and a GMP system. The ISO 9000 series of QA
standards ranges from basic QC systems to complete design and
production
systems.

These systems will be discussed in more detail below. First,

 however, an ideal system for quality assurance is discussed in order
to
explain the concept of a system.

An ideal QA system is composed of an organization that executes a

QA
program according to documented policy and specifications in order
to
achieve stated objectives as shown in Figure 2.1.

Figure 2.1 <Elements of a Quality Assurance System>

The written policies and objectives are set by management and are
influenced by outside factors such as customer requirements,
standards,
and regulations. For example, the customer requirements and needs
and
resulting device specifications should be known to be correct as
these
are based on market research, technical and medical considerations,
consensus standards, review of existing devices, environmental and
compatibility considerations, and design review. The objectives are
to
produce safe and effective (quality) devices at a profit. Ideally,
the
organization is everyone in the company as everyone is fully
committed
 to the quality assurance program. In addition, however, organizations
such as design QA departments and production QA departments are
established to achieve specific objectives. Tasks to be performed to
meet the objectives are described in procedures and other documents.

Documentation is composed of: product-specific technical

documentation, such as engineering drawings, labels, etc.; and
general
documentation, such as standard operating procedures (SOP's). All
activities and product quality are monitored; and, any deviations
from
device and process specifications and policy are fed back into the
system where the deviations are corrected. Likewise, complaint and
repair information are processed and fed back for appropriate
corrections. If the required activities including the feedback are
performed, the system is self correcting and, thus, it is operating
in a
state-of-control. FDA requires manufacturers of medical devices to
operate in a state-of-control.

In order to fully comply with the intent of the Good

Manufacturing
Practices regulation and the Food, Drug, and Cosmetic Act,
manufacturers
will need a QA program that approaches this ideal system. The system
nearest to the ideal is the total QA system which, as noted,
incorporates design quality assurance and the requirements of the GMP
regulation.

QUALITY CONTROL

Quality control is generally considered to be the most basic or

minimum type of "quality program" that a firm can have. Typically, in
a
classical quality control system, selected employees evaluate the
quality of raw materials, in-process items, packaging, and finished
devices in order to prevent production and shipment of defective
material or product. Quality control, which consists largely of
inspection and testing, is the primary mechanism for detecting
defects,
but it represents only a part of quality assurance and does not
achieve
complete control. A quality control program generally has very
limited
provisions for feedback of information into the design and
manufacturing
process. Even in cases where inspection and testing results are
perfect, quality cannot be inspected into a product. Quality control
measures are not preventive -- they only allow products to be set
aside
when they are found to be defective during or after manufacture.

Further, mixups caused by poor manufacturing practice can result

in
 defective products being distributed, even though they were at one
time
set aside as defective. Of course, in situations where inspection
and
test results are not perfect, defective products remain undiscovered
and are shipped. The best that quality control can do is detect most
of
the raw materials, components, and products that fail to meet
specifications and keep them from being distributed. Therefore, a
quality assurance program is needed that involves considerably more
company operations as briefly described in the beginning of this
chapter.

GOOD MANUFACTURING PRACTICES

An adequate and properly implemented quality assurance program

such
as a GMP program, because of its broader scope, has a much higher
probability than a quality control program of preventing the
manufacture and shipment of defective products. Quality controls,
however, such as inspection and testing, are important parts of a
quality assurance program because they provide information that
should
 be fed back into the quality assurance program where action can then
be
taken to correct root causes of quality problems. Identifying and
solving quality problems is a core requirement of the GMP regulation.
This action is in contrast to merely applying superficial
corrections
by pass/fail quality-control inspection including rework of finished
product or in-process assemblies.

The GMP regulation requires in subpart 820.5 every finished

device
manufacturer to prepare and implement a quality assurance program
that
is appropriate to the device manufactured and that meets the
requirements of the GMP. Manufacturers who implement all applicable
requirements of the GMP regulation will have in place a significant
quality assurance program. Such a program does not completely meet a
company's needs, however, because the GMP regulation has limited
coverage of the initial product design stage and does not consider
the
needs of the user.

Adequate Organization and QA Management

A specific organizational structure for executing a QA program is

not prescribed by the GMP regulation, but the regulation states that,
where possible, one or more designated individuals not having direct
responsibility for the performance of a manufacturing operation shall
be
responsible for the quality assurance program. FDA is more concerned
with the adequacy and appropriateness of quality assurance
activities
than it is with organizational structure. Larger firms will tend to
have
independent QA management.

The GMP regulation requires quality awareness training for

manufacturing and quality assurance personnel [820.25(a)]. Personnel
involved in quality assurance activities must be properly trained,
both
by education and experience. No matter how effective quality
assurance
and production systems are as concepts, people still play the major
role
in producing a quality product. Lack of training -- as reflected in
instances of negligence, poor operating techniques, or inability of
employees to discharge their functions properly -- can lead to
defective products and, sometimes, to regulatory or liability
problems.
Management should be diligent in looking for factors that indicate a
need for employee training.

A quality assurance system should include an ongoing formal

program
 for training and motivating all personnel. All personnel should be
made
aware that product quality is not solely the responsibility of
management. Quality is the responsibility of every employee -- any
employee can potentially generate a quality problem through
negligence.
It is extremely important to understand the following points with
respect to typical quality- related functions.

o Top management sets the quality attitude for the company.

o Research and development has primary responsibility for

designing quality into the device.

o Technical services or an equivalent functional group has

primary responsibility for documenting the design.

o Manufacturing, process or "scale-up" engineering has

primary
responsibility for designing quality into the manufacturing
processes.
 o Manufacturing personnel have primary responsibility for
producing devices that have the maximum level of quality
that
can be achieved based on the product and process designs.

o Quality assurance has primary responsibility for QA program

management, status reports, audits, problem identification,
data analysis, etc., as described in the GMP regulation and
this manual.

A medical device manufacturer must NEVER try to operate on the

basis
that the quality assurance organization has primary and direct
responsibility for the quality of the products. To do so means that
quality problems will not be solved in a timely manner because
attention is directed toward the wrong organization. In reality, it
is
part of the responsibility of the quality assurance organization to
see
that attention is directed toward the correct department if a
quality
problem arises.

Where necessary, employees should be certified to perform certain

manufacturing or quality assurance procedures. Records of training
and/or certification should be maintained. Personnel performing
quality
assurance functions must:

o have sufficient, well-defined responsibilities and

authority;

o be afforded the organizational freedom to identify and

evaluate quality problems;

o be able to formulate, obtain, and recommend possible

solutions for quality assurance problems; and,

o verify implementation of solutions to quality problems.

Formal and Documented QA Program

The GMP regulation requires that each manufacturer prepare and

implement quality assurance procedures adequate to assure that a
formally established and documented quality assurance program is
performed (section 820.20). "Formally established" means not only
formal documentation, but an obvious commitment to quality from top
management. There must be manifest indications that management
recognizes the need for a quality assurance program in order to
assure quality products. In many firms, this commitment is
accomplished
through such means as: a management policy; assignment of
responsibilities and authorities; and general statements and actions
that define and support the goals of the quality assurance program.
 This policy is supported by a number of more detailed quality
assurance
documents such as qualification methods, sampling procedures,
inspection/test procedures, product audits, and records indicating
that
measurement and monitoring of quality has occurred. The number of
documents needed depends on the size and complexity of the operation
and the characteristics of the product. A firm must have the various
records required by the GMP regulation. These records include:

o device master records;

o device history records;
o maintenance schedules and records;
o complaint files and failed device/component files;
o audit reports;
o distribution records; and
 o personnel training records.

Most of these records are discussed in more detail in later

chapters. In each case, the records should be appropriate for the
device and the operation involved. Any changes to master records
must
be made by a formal procedure and be formally approved.

Among other records, the device master record contains

manufacturing
procedures and standard operating procedures (SOP's). Some firms
tend
to write an excessive number of general SOP's. This manual contains
information that should help some firms write and maintain adequate
procedures without excessive paperwork. Firms should not generate and
use procedures that are not needed. Also, standard operating
procedures
tend not to match actual operations because the operations gradually
changed as the company grew or as products were added without the
procedures keeping pace. Such procedures may require operations that
have no benefit or require excessive collection of data or collection
of
data that is never used. Thus, firms need to occasionally flow chart
and
analyze their operations to determine, among other things, if the
existing procedures are inadequate, correct, or excessive.
Flowcharting
and analyzing operations is an excellent method for improving
operations and the associated quality assurance activities. At the
end
of chapter 8, Components and Materials, an example of a flowchart is
contained in PA-1004, Procedure for Receiving and Inspection of
Material, integral page 4 of 9.

Approval of Materials, Components and Finished Devices

The quality assurance organization is also responsible for

assuring
that all components, packaging, labeling, manufacturing materials,
and
finished devices have been approved for use; and that contracted
items
and services are suitable. Likewise, the QA organization must assure
that rejected items are identified and properly disposed.
Additionally,
the QA organization should assure that production records are
reviewed
before the product is distributed. These records are part of the
device
history record. Device history records should be reviewed to verify
that the operations represented have been properly conducted and
that
the records are complete.
 Adequate Quality Assurance Checks

The quality assurance organization must determine that all tests

and
inspections are performed correctly [820.20(a)(4)]. Some of the
methods
used to accomplish this are training of test personnel, QA system
audits, review of quality assurance records, and product audits.
However, simply instituting a quality assurance control program and
checking that it is conducted correctly is not enough to satisfy the
GMP regulation. The GMP regulation also requires that quality
assurance
controls be qualified to make certain they are appropriate and
adequate
for their purpose. The qualification should be done during final
product development, pilot production, and, of course, whenever
product
and/or processes are modified. In cases where conformance to
specifications cannot be adequately measured by in-process or
finished
product testing and inspection, the qualification must include
validation of processes that have a significant bearing on product
quality.

Identify and Solve QA Problems

As set forth by the GMP regulation, one of the most important

 responsibilities of the QA organization is to identify quality
assurance problems, to recommend and provide solutions, and to verify
implementation of the solutions [820.20(a)(3)]. Other personnel are
also identifying and solving quality problems and the QA organization
must support such activities.

Typically, quality assurance identifies problems with device

quality
through review of inspection/test data, trend analysis of history
and
repair records, failure analysis, analysis of complaints, and review
of
other objective data. In this regard, reduction in productivity is
often an indicator of quality problems. Low morale and confusion are
indicators of inadequate device master records and poor management.
Also, measurement of scrap and rework is an effective method of
detecting quality problems and reducing costs. These are examples of
sources that provide feedback to the quality assurance organization.
Feedback is necessary to verify the adequacy of the manufacturing
process and the controls used. It also helps trigger corrective
action
to solve root causes of quality problems rather than just performing
rework.

Periodic QA System Audits

The GMP regulation requires (820.20) that each manufacturer must

prepare and implement quality assurance procedures adequate to
assure
that a formally established and documented quality assurance program
is
performed. Many activities are required to fulfill this requirement;
and
management is aware of the obvious aspects of the QA program as they
perform their routine duties. However, to make sure that all aspects,
obvious, hidden or subtle, of the required program exist and are
operating correctly, the GMP regulation requires [820.20(b)] planned
and periodic audits of the QA program.

Employee Training

It is not unusual for FDA investigators to conduct factory

inspections and observe employees who are clearly unaware of
situations
that can result in poor device quality. These employees have
obviously
not been properly instructed on what activities or conditions will
directly cause defective devices or that can lead to mixups,
contamination, or other problems that can cause non conforming
devices.
For example, an improperly maintained piece of manufacturing
equipment
may eventually have disastrous consequences on the finished device.
 Therefore, the employee charged with maintaining the equipment, as
well
as the operator of the equipment, must be made aware of conditions
that
reflect a need for maintenance.

FDA investigators have observed employees: handling delicate

devices
while wearing sharp-edged rings or other jewelry; wearing gloves
with
holes in them or rubbing their nose and then continuing to handle
devices which needed to comply with bioburden requirements; wearing
cleanroom clothing into uncontrolled areas; and other poor practices
such as leaving doors open in controlled environmental areas.

We at FDA are always advised that it is the firm's policy not to

allow these situations to occur; but, are these employees originally
and
then periodically reminded of the reason for the no wearing of rings,
personal cleanliness, and other employee behavior requirements?
People
respond better when they know why they are doing something - not
just
because it is company policy.
 The GMP regulation requires in section 820.25 that each
manufacturer
have sufficient personnel with the necessary education, training and
experience to assure that all operations are correctly performed. All
employees must be made aware of device defects which may occur from
improper performance of their specific jobs; and, quality assurance
personnel must be made aware of defects and errors likely to be found
in
defective components and devices. This section requires that
personnel
in contact with a device or its environment shall be clean, healthy,
and
suitably attired where lack of cleanliness, good health, or suitable
attire could adversely affect the device. Personnel who, by medical
examination or supervisory observation, appear to have a condition
which
could adversely affect the device must be excluded from affected
operations until the adverse condition is corrected. Personnel shall
be
instructed to report such conditions to their supervisors.

As the first step in meeting these GMP personnel requirements,

manufacturers should select and hire appropriate employees.
Thereafter,
employees must be trained to perform their specific jobs and made
aware
of any defects or problems that may occur from poor hygiene, poor
health, smoking, or improper performance of their assigned tasks.

Quality assurance employees must meet the GMP personnel

requirements for manufacturing employees AND must be made aware of
defects and errors likely to be found in non-conforming components
and
devices. Usually, it is easier and more effective to teach all of the
GMP personnel requirements to all employees.

Sales personnel, representatives, phone operators, secretaries,

service personnel, and other staff may receive complaints. Thus,
most
of the company personnel need training in basic complaint handling
techniques. Also, proper job performance by employees as required by
the GMP regulation dictates that management have a good knowledge of
the
GMP regulation and resulting quality assurance program. Therefore,
management must also have appropriate education, training, and
experience. Proper job performance is also supported by correct and
complete device master records. These records must be written in such
a
manner that the intended employees can understand and properly use
them.

When training programs for line employees or management are

 conducted, they must be documented. For example, attending GMP
seminars
and reading GMP requirements or QA documents should be recorded in
the
employees personnel file.

Training for employees performing GMP related functions can be

achieved by many methods such as:

o GMP seminars;
o Individual consultations with managers, consultants, FDA
personnel, etc.;
o On-the-job training with an appropriate instructor;
o Video tapes and movies;
o Slide shows with an appropriate instructor;
o Reading GMP/QA manuals and textbooks; and
o Formal college QA courses.

To meet GMP requirements, all training must be documented as

noted
above.
 Management should diligently look for factors that indicate a
need
for additional training or retraining. Some of these factors are
excessive device defects, line down time, improper labeling or
packaging, employee confusion, customer complaints, and delayed or
no
company response to customer complaints received through unusual and,
of
course, usual channels. This information regarding training is
derived
from management observations, analysis of device history records,
analysis of complaint records, and quality assurance audits.

INTERNATIONAL QA STANDARDS

U.S. manufacturers planning to export their products should be

familiar with international QA standards. The International
Organization
for Standardization (ISO), a world-wide federation of national
standards
bodies, produced a series of quality management and quality
assurance
standards. This set of five international QA standards, known as the
ISO
9000 series (ISO 9000 to 9004 inclusive) embodies a rationalization
of
the many and various national approaches to quality management and
quality assurance. Also there is the ISO 8402 "Quality Vocabulary"
that
defines the quality terms used in the ISO 9000 series of standards.

The first of the series is ISO 9000, "Quality Management and

Quality
Assurance Standards - Guidelines for Selection and Use". ISO 9000
identifies and defines the relationships among principal quality
concepts and provides guidance for selecting the most appropriate
standard from the series ISO 9001, 9002, and 9003 to be used for
external QA purposes in particular contractual situations. ISO 9004,
"Quality Management and Quality System Elements - Guidelines",
together
with ISO 9000, gives guidance on developing and implementing a
quality
management system.

ISO 9002, "Quality Systems - Model for Quality Assurance in

Production and Installation" is closest in comparison with the
current
(1991) U.S. FDA Medical Device GMP regulation. ISO 9001 is
essentially
ISO 9002 with the addition of design and development QA controls.
When
the pre-production design validation requirements are added to the
U.S.
 FDA GMP regulation as required by the Safe Medical Devices Act of
1990,
a manufacturer complying with the updated FDA GMP regulation should
be
in substantial compliance with ISO 9001. It should be noted, however,
that the reverse is not true. The FDA GMP requires more extensive
controls for product labeling, complaint processing, and traceability.

The ISO 9000 series standards and ISO 8402 can be purchased
individually from the American National Standards Institute (ANSI)
1430 Broadway, New York, NY, 10018.

Price and availability of these standards can be obtained by phoning

ANSI at 212-642-4900.

TOTAL QUALITY ASSURANCE SYSTEM

Total quality assurance systems extend from customer requirements

through development and production and on to customer use and
feedback.
Thus total QA systems encompass the medical device law and
regulations,
particularly the GMP regulation. The Food, Drug and Cosmetic Act,
and
its implementing regulations such as those for Labeling, Premarket
Notification, Investigational Device Exemptions (IDE), Premarket
Approval (PMA), and Good Manufacturing Practices impact at various
times during the product lifecycle on the design and quality of
 devices. For a few devices, the IDE, PMA and GMP regulations with
their
preproduction and production requirements essentially constitute a
total
quality assurance program. For other devices, preproduction or
design
quality receives limited attention until after a problem occurs. For
example, Section 501(c) of the Act states that a product is
adulterated
if it does not have a quality equal to the quality stated or implied
by
the product labeling. Analysis of device recall problem data by FDA
has
shown that such problems are divided equally between design and
production.

Thus, compliance with the GMP regulation is not sufficient to

produce safe and effective devices -- design must also be covered.
Design validation (design QA) is contained in the Safe Medical
Devices
Act of 1990 and FDA will promulgate this requirement in the
forthcoming
revised GMP regulation. The revised GMP regulation will be
essentially
a total QA system. Also, the quality requirements implied by Food,
Drug,
and Cosmetic Act Section 501(c) and the history of regulatory
actions
taken thereunder are sufficient reasons for device manufacturers to
implement a total quality assurance system.

Two other reasons for having a total quality assurance system are
21
CFR Part 803, Medical Device Reporting (MDR), and product liability.
MDR requires manufacturers of medical devices to report to FDA
serious
complaints that they receive from any source. Product liability
actions
are the result of poor design, labeling, and manufacturing.
Reporting
and liability exposure are reduced by using a total quality assurance
system.

Intrinsic, or desired quality is established by the design

specifications for the product, its components, and the
manufacturing
processes. Complying with the GMP regulation assures that the
manufacturing processes can consistently achieve desired levels of
quality and that the finished device meets its design or master
record
specifications. This result is a significant quality step. However,
if
the device as designed is of poor quality, the GMP controls will
only
 assure that a poor quality device is produced. To overcome this
limitation, many firms use an overall quality assurance program which
embraces evaluation of customer needs; product design, development
and
evaluation; labeling development and control; all manufacturing and
control activities; and customer feed-back. The FDA GMP regulation
covers all of these areas except customer needs and initial product
design. (Design validation will be added to the GMP regulation in the
near future as required by the Safe Medical Devices Act.) The GMP
regulation has a significant impact on the control of product design
after production starts because of GMP requirements for changes to
master records, data feedback, complaint processing, and corrective
actions.

Design Quality

Because the intrinsic quality level is established during the

design
or preproduction phase, the quality assurance program must include
this
phase if the program is to assure overall quality, meet customer
requirements, meet company quality claims, and comply with the
intent
of the FD& C Act. The terms "product assurance" and "design QA" are
often
used to identify the quality assurance activities related to product
design. A product assurance system or design QA system combined with
a
GMP system constitutes a total QA system. (Design QA or
preproduction
quality is covered in chapter 3 and in the Appendix. The remaining
chapters cover good manufacturing practices in detail.) Quality
 assurance personnel should participate in the review, evaluation and
documentation of the components, device, and process design because
it
is from data established during this preproduction phase that all
other
activities derive: i.e., processing, purchasing, and testing.
Development and evaluation data are also useful in cases of
regulatory
or product liability actions to show that the design and
manufacturing
processes were well conceived and properly qualified, reviewed, and
documented.

Component Selection

Component and raw material specifications developed during the

design phase must be well conceived and adequate for their intended
purpose. In some cases where large quantities of components or raw
materials are involved, the specifications must include valid and
well
understood methods of sampling and acceptance. These specification
and
sampling/acceptance plans must also be accessible and acceptable to
vendors.

Labeling Content

The regulations in 21 CFR Part 801, Labeling; Part 809, In Vitro

Diagnostic Products for Human Use; and Part 812, Investigational
Device
Exemptions; are intended to control the content of labeling.
Likewise,
21 CFR Part 807, Premarket Notification; and Part 814, Premarket
Approval; help control the content of labeling through premarket
submissions. The intent of these regulations and the FD& C Act is
for
manufacturers to have a labeling control program such that their
labeling always complies with the regulations and meets the needs of
the users. Under a total QA system, clear, concise and correct
printed
and software labeling is developed during the design phase by a
formal
process. Such labeling is designed to meet customer and regulatory
requirements. Thereafter, the procurement, use of the correct label,
and correct attachment of labels is assured under a firm's GMP
program.

Process Quality

Manufacturing methods and processes to be used must be developed,

equipment selected, and processes and methods qualified. For all
significant processes such as welding, molding, lyophilization,
sterilization and packaging/sealing, the qualification must include
a
 full validation of the processes. (The FDA guideline on process
validation is reprinted in the Appendix.) Production specifications
and
methods employed in manufacturing must result in standard in-process
and
finished products without excessive sorting or reprocessing.
Inspection
and test methods must be developed that will adequately monitor
product
characteristics to make certain these are within the acceptable
specifications. These methods should be developed, verified, and
documented during the product and process development phase. The
methods must be implemented at the beginning of routine production.

Any adverse effects the manufacturing processes, manufacturing

materials, or equipment may have on device safety and performance
must
be identified. Where necessary, procedures have to be developed,
implemented, and monitored to control these characteristics. Quality
assurance personnel should participate in the timely (i.e., early)
development of special controls, test or inspection methods, or
training programs needed to insure product quality. Acceptance
methods
must be developed for accurate measurement of outgoing product
quality.
 QA PROGRAM MAINTENANCE AND IMPROVEMENTS

After the GMP program or total quality assurance program is

operational, quality assurance and other personnel must continue to
look for problem areas or factors that can have an impact on product
quality. Many factors can have an impact on the quality program such
as:

o changes in, or absence of, personnel;

o uncomfortable working conditions (e.g., breakdowns in air
conditioning);

o increases in workload or production rates;

o introduction of new production or inspection equipment;

o changes in company incentive techniques (e.g., placing

hourly
employees on piecework can cause deterioration of product
quality); and

o changes in sources for purchased components and materials,

as
well as changes in components, devices, or process
techniques.

As noted, QA system audits and flow-charting of operations are

excellent methods for determining the status of QA programs.
Correcting
problems or responding to conditions identified by audits,
operational
analyses, and customer feedback data can result in quality assurance
program improvements.

SOME HIGHLIGHTS OF THE SAFE MEDICAL DEVICES ACT OF 1990

We have reprinted below some key highlights from the Safe Medical
Devices Act of 1990 (Public Law 101-629) regarding device design and
problems with distributed devices:

Congress has amended the Federal Food, Drug, And Cosmetic (FD& C)
Act
to add new requirements and provisions concerning the regulation of
medical devices.

These requirements are described in the Safe Medical Devices Act

(SMDA) of 1990, signed into law by President Bush on November 28,
1990.
Some provisions impact on complaint handling and reporting by
manufacturers to FDA.

User Facility Reporting

o Medical device user facilities are now required to report

 incidents that reasonably suggest that there is a
probability
that a medical device has caused or contributed to:

- the death of a patient, or

- serious injury or serious illness of a patient.

The report is due as soon as possible but no later than 10

working
days after the user facility becomes aware of the incident.

o "Medical device user facility" includes hospitals,

ambulatory
surgical facilities, nursing homes, or out-patient
treatment
facilities which are not a physician's office.
 o Reports of deaths must be made to FDA and to the
manufacturer,
if known.

o Reports of serious injuries or illness must be made to the

manufacturer, or to FDA, if the manufacturer is not known.

o A semiannual report to FDA is required which summarizes the

reports.

Effective: 12 months after enactment of the SMDA or the promulgation

of
regulations, whichever occurs first.

Distributor Reports, MDRs and Certification

o FDA must promulgate regulations for distributors requiring

them to establish and maintain reports, including the
Medical
Device Reporting (MDR) reports.

o Distributors must submit MDR reports to FDA and to the

manufacturer.

o MANUFACTURERS, IMPORTERS and DISTRIBUTORS must certify to

the FDA annually the number of MDR reports they have
submitted.

Effective: FDA must propose regulations in 9 months, and issue final

regulations in 18 months, or the proposed regulations become final.

Device Tracking

o Manufacturers must adopt a method of tracking devices, the

failure of which would be reasonably likely to have serious,
adverse health consequences; and which are permanently
implanted, or a life-sustaining or a life-supporting device
used outside a device user facility.

Effective: FDA must propose regulations in 9 months, and issue final

regulations in 18 months, or the proposed regulations become final.

Reports of Removals and Corrective Actions

o Manufacturers, importers and distributors are required to

report to FDA any removals or corrections of a device to:

- reduce a risk to health posed by the device; or

- remedy a violation of the FD& C Act caused by the device

which may present a risk to health.

Note: Routine servicing is not considered a removal or a corrective

action.
 Effective: Upon promulgation of regulations.

Postmarket Surveillance

o Manufacturers are required to conduct postmarket

surveillance,
such as studies to gather data on the safety and
effectiveness of a device, for certain devices introduced
into
interstate commerce after January 1, 1991. This requirement
 includes devices that:

- are permanent implants, the failure of which may cause

serious, adverse health consequences or death;
- are intended for use in supporting or sustaining human
life;
or
- present a potential serious risk to human health.

o FDA may require postmarket surveillance for any other

devices
if deemed necessary to protect the public health.

WITHIN 30 DAYS OF INTRODUCTION of these types of devices into

interstate
commerce, manufacturers must submit a postmarket surveillance
protocol
to FDA for approval.

Effective: Immediately

Recall Authority

o After determining that there is a reasonable probability

that
a device would cause serious, adverse health consequences
or
death, FDA may order a manufacturer or other appropriate
firm
to:

- begin immediate action to cease distribution of the

device;
and
- immediately notify health professionals and device user
facilities to cease using the device.

o The order shall provide the person subject to the order

with
an opportunity for an informal hearing, to be held not
later
than 10 days after the date of the issuance of the order.

Effective: Immediately

Design Validation

o The good manufacturing practices (GMP) requirements in

section
520(f) of the FD& C Act are amended to include
preproduction
design validation, including a process to assess the
performance of a device, but not including an evaluation of
the safety and effectiveness of the device.
 Effective: Upon promulgation of a regulation.

gmp 1-22 7/16/91

EXHIBIT

Example of a Standard Operating Procedure for Employee Training

This standard operating procedure is an example of what a firm

may
use to implement and document training of their employees. Page one
outlines the company's policy, scope of training, responsibility for
this activity, actual training to be done, etc. Page two is used to
document classroom and on-the-job training for each employee. This
record will be signed by both the employee's supervisor and the
person(s) conducting the training. This form, or whatever record is
 used, must be updated after each training session.

C O M P A N Y L O G O

Title: Employee Training

|Approved: Date:
Prepared By: |Procedure No.:
Sheet: 1 of 2 Date: |Revision:
Date:
Ecn Notes:
Policy - Employees shall be trained to perform their assigned tasks
and
shall be made aware that our company produces medical devices in
accordance with various regulations.

Scope - This procedure applies to ALL employees.

Hiring - The education, background, training, and experience of

prospective employees shall be considered with respect to the
requirements of the job to be filled.

Responsibility - Managers are responsible for assuring that the

employees assigned to them are trained or otherwise qualified for
the
assigned jobs. Before assigning an employee for the first time to a
new
job, production managers shall check their training to verify that
the
employee has been trained or qualified for the new job.

Training - All inexperienced employees shall be trained to perform

their
assigned jobs. On-the-job training shall be monitored closely by a
supervisor. All employees shall be made aware of device defects that
may occur from improper performance of their jobs.

Our standard safety procedures shall be explained to all employees.

Quality Assurance Employees - QA employees shall receive the training

noted above and shall be made aware of defects and errors likely to
be
encountered as part of their quality assurance functions.

Customer Complaints - Receptionists, secretaries, managers,

representatives, salespersons, and other employees likely to receive
complaints shall be made aware of our complaint handling procedures.

Change Control - All employees are to be instructed that they are to

perform their jobs as instructed or as covered by standard operating
procedures (SOP's). They are not allowed to change cleaning,
processing, testing, packaging, labeling, or other tasks covered by
 SOP's until the change is approved according to our change control
SOP.

Documentation - All classroom and on-the-job training shall be

documented by the supervisor and trainer of the employee on the form
as
shown on page 2. A separate form for each employee with a record of
their training shall be filed and shall be updated at the end of
each
training session.

Employee Training Record for Procedure No.

Sheet
2 of 2

Employee Name:
Hire Date:
|Date
| Employee
| Present Job
| Type of Training
| Supervisor / Trainer
| Signature
| Signature
| Standard safety
| Defect awareness

gmp 1-22: 4/25/91

 GMP - CHAPTER 3 - PREPRODUCTION QUALITY

CHAPTER 3
PREPRODUCTION QUALITY

INTRODUCTION
REGULATORY REQUIREMENTS
Medical Device Reporting
Application of the GMP Regulation
PRODUCT ASSURANCE
Device, Software, and Process Specifications
Design Evaluation versus Specifications
Software Validation
Labeling Evaluation
Design Reviews
ADEQUATE MASTER RECORD
ADEQUATE MANUFACTURING PROCESS
PROCESS VALIDATION
Validation Planning and Protocol
Equipment and Process Qualification
Validation Documentation
Revalidation
PERSONNEL TRAINING
DEVICE EVALUATION AND HISTORY RECORD
FINISHED DEVICE RELEASE
EXHIBITS
Design Transfer Checklists

[Many of the recommendations herein will become requirements when

design
validation is added to the GMP regulation as required by the Safe
Medical Devices Act of 1990.]

INTRODUCTION

Developing a new device and introducing it into production are

very
complex tasks. For many new devices and associated manufacturing
processes that use software, these tasks are further complicated
because
of the importance of every minute characteristic of software, and the
possibility of subtle software errors. Without thorough planning,
program control, and design reviews, these tasks are virtually
impossible to accomplish without errors or leaving important aspects
undone. The planning exercise and execution of the plans are complex
because of the many areas and activities that must be covered. Some
of
the key activities are:

o determining and meeting the customer's requirements;

o meeting regulations and standards;
o developing specifications for the device;
o developing the device;
o evaluating prototype devices;
o developing, selecting and evaluating components and vendors;
o developing specifications for manufacturing processes;
o developing and validating manufacturing processes;
 o developing and approving labels and user instructions;
o documenting the details of the device design and processes;
and,
o if applicable, developing a service program.

Most of these topics are discussed in this chapter and in two

additional key documents in the Appendix: "Preproduction Quality
Assurance Planning: Recommendations for Medical Device Manufacturers",
and "Guideline on General Process Principles of Process Validation".
Chapter 5 covers equipment including automated production and quality
assurance equipment and thus discusses preproduction activities such
as
validation. Other topics, such as component selection, and labeling
content and approval, are covered in chapters 8 and 11, respectively.

There are various programs for assuring that appropriate

preproduction activities are correctly performed in the listed areas
that will result in the orderly development and transfer into
production
of a new or modified device. These programs include: using a product
assurance program and complying with the Good Manufacturing Practices
(GMP) regulation; using a total quality assurance program; etc. This
chapter emphasizes preproduction quality or product and process
assurance -- the first half of a total quality assurance system.
Chapter
9 of this manual has additional material on process planning and
production control.

An adequate quality assurance system requires coordination of all

quality related activities from initial concept of each specific
device
through production and postmarketing activities; hence, such a system
is
called a total quality assurance system. A product assurance system
plus
a GMP system constitutes a total QA system. The primary goal of a
total
QA system is to produce quality products by assuring both intrinsic
quality and achieved quality.

Intrinsic quality is the inherent quality designed into a device

and
the associated manufacturing processes. Intrinsic quality is
accomplished by having the design or formulation, process or process
modification, and related documentation for a new or modified device
or
process, comply with appropriate requirements of the company,
customers,
standards, and regulations. As a result, the device design has the
desired level of quality designed into it and the associated
processes
have the desired capability designed into them.

The intrinsic safety and effectiveness of a device is established

 during the design phase and is a direct function of:

o awareness of the design goal by management, research and

development, production, and quality assurance;

o review and analysis of the proposed design;

o correct selection and application of parts and materials;

and

o performance of normal and worst-case testing to evaluate

and
assure that the device and manufacturing processes will
perform as intended under all reasonable circumstances.

Worst-case testing for a device design must be reasonably and

prudently interpreted based on the anticipated use, use with other
devices, environmental conditions, and review of the literature for
past
problems with similar devices. For a manufacturing process, worst-
case
 conditions are derived from operational limits established by the
firm,
environmental conditions, process equipment capabilities, maintenance
requirements, employee changes, and the like.

Achieved quality is assured through procedures for orderly

transfer
of the design information into the production department followed by
controlled manufacturing of the new or modified device. Some key
activities are listed below and discussed later:

o adequate device master record and change control,

o process validation,
o review of total development and manufacturing programs,
o pilot production, and
o detailed review of the pilot devices.

REGULATORY REQUIREMENTS

Preproduction quality assurance activities must, as appropriate,

include the initiation and submission to FDA of a Premarket
Notification
(PMN), 21 CFR Part 807; or Premarket Approval (PMA), Part 814. The
contents of a submission, particularly a PMA submission, is very
closely
related to the intrinsic quality of a device. Likewise, compliance
with
Medical Device Reporting, Good Manufacturing Practices, and the
labeling
regulations support quality. (Please see 21 CFR Parts 800-1299, which
contains all of the medical device regulations.)

Medical Device Reporting

Achieving quality goals reduces customer complaints, product

liability exposure, recalls, and reduces the probability of reporting
to
FDA under the Medical Device Reporting regulation (MDR).
Manufacturers
and importers of medical devices must comply with the MDR regulation
(21
CFR Part 803) by reporting to FDA whenever they become aware of a
death
or serious injury that may have been caused by one of their marketed
devices and/or any malfunction in one of their devices which, if it
were
to recur, could reasonably be expected to cause a death or serious
injury. These are essentially the same complaints that the GMP
regulation requires a firm to place in a special file -- the
death/injury/hazardous complaint file [820.198(b)].

The GMP complaint and investigation requirements and the MDR

regulation play an important role in the protection of public health;
 however, both of these have the same limitation: they are after-the-
fact
requirements. They do not directly assure the safety and
effectiveness
of medical devices. In contrast, the most fundamental concepts of
quality assurance engineering require that quality problems be
prevented
from occurring. The best way to achieve this goal with its many
associated benefits is to have an active total quality assurance
system
as described herein and in chapter 2. The GMP regulation covers a
significant part of such a QA system.

Application of the GMP Regulation

The GMP regulation applies to the design and control of

facilities,
production and measurement equipment, design transfer, and to
production
processes, including controls for packaging and labeling design. A
manufacturer who follows the GMP regulation is working towards
maintaining the intrinsic safety and effectiveness established during
the design phase by using a formal QA program to assure that all
 manufacturing activities that affect quality are controlled. The GMP
regulation is intended to provide a high degree of confidence that a
manufacturing process will consistently produce finished devices that
conform to their specifications.

Manufacturers may transfer design specifications that result in

unsafe or ineffective devices if the manufacturers fail to ensure
that
the design basis for a device is correct; that is, if they adopt
design
specifications that have not been properly qualified and verified.
GMP
section 820.100(a)(1) controls transfer by requiring manufacturers to
establish procedures to make certain that:

o the approved design is accurately transferred into written

specifications;

o there are sufficient specifications, which accurately

describe
the device, its components, and packaging; and

o these specifications are adequate to assure that the design

configuration and performance requirements can be met if
the
device is manufactured and assembled according to
specifications.

Typically, assuring accuracy, sufficiency, and adequacy are

accomplished through a formal evaluation and review process, as
discussed in this chapter, to verify that the design or design change
is
adequately translated into specifications. If the design is not
adequately translated into correct specifications as needed to
procure
components and manufacture finished devices, the resulting product
may
be unsafe and ineffective. The need for a written procedure for
adequate
transfer of specifications should be determined on the basis of the
need
for communication, complexity of the activity, etc. The GMP
regulation
does not mandate a written procedure for transferring a design, but,
as
noted above, it does require that the design be correctly transferred
into production.

The GMP regulation also addresses design retrospectively through

the
Complaint File requirements, Failure Investigations, and through the
Quality Assurance Program requirements. These sections require
manufacturers to:
 o review and investigate all complaints (820.198);

o investigate failure of released devices to meet performance

specifications and take corrective action (820.162); and

o identify, recommend, or provide solutions for quality

assurance problems [820.20(a)(3)].

In context of the total GMP regulation, particularly the scope in

820.1 and QA program in 820.20, the followup (corrective) activities
in
820.162 refer to solving the quality problem regardless of its origin
or
nature. That is, design and labeling deficiencies are not excluded.

After production starts, GMP section [820.100(a)(2)] requires

manufacturers to subject all changes to the original device design to
stringent controls. Change control for devices or processes is
covered
in chapter 7 of this manual.

PRODUCT ASSURANCE
 Product assurance is a quality assurance program that assures
quality is designed into a device. Under it, manufacturers determine
customer needs and expectations or specifications, if specifications
exists. These are documented by the manufacturer in device
specifications which, to the technical and economic extent feasible,
reflect the customer needs and expectations. In addition to device
specifications, a product assurance program encompasses employee
responsibility, safety standards, component selection, label content
and
physical characteristics, design evaluation, design analysis, design
review, adequate documentation, and correct transfer into production.
Meanwhile, under the GMP regulation, employees are being trained, and
manufacturing processes are being developed and validated for the new
product. During pilot production, the product assurance and GMP
programs
work together to make certain that design and production quality
goals
have been achieved.

One of the first steps in the transfer of a design into

specifications and production is to inform the quality assurance
manager
or other designee about all new or significantly modified devices or
processes. Also, management should designate appropriate persons to
be
responsible for directing, monitoring, and reporting all activities
from
device concept through associated post-marketing activities, with
nothing left to chance (See 820.20, Organization). Preproduction
quality
planning for a specific device by the quality assurance manager and
other managers must include consideration of all significant aspects
of
that device, the manufacture of it, and its ultimate use. These
activities result in many documents, the first of which is usually a
device specification.
Device, Software, and Process Specifications

An important goal in a preproduction program is to have all of

the
involved personnel working toward developing and manufacturing the
same
device as outlined by the device, software, if any, and process
specifications. Preliminary device specifications that identify the
characteristics of the new or modified device should be drafted at
the
very beginning of the development program. A major value of
specifications is to aid communications between all of the various
departments working on the project. The major value of specifications
is
lost if they are written after the product is developed; however, the
belated device specifications are still useful for developing
accurate
catalog sheets or other marketing aids.
 At the start of the development project, performance standards,
and
general safety standards to be met should be identified by management
and included as part of the device specifications. The document,
"Preproduction Quality Assurance Planning: Recommendations for
Medical
Device Manufacturers", in the Appendix lists several standards and
books
on product development and product quality. If international sales
are
planned, then appropriate foreign standards and marketing
requirements
should be considered. For example, the International Electrotech
Commission has a draft design review standard, "Guide on Formal
Design
Review", which should be helpful to product assurance personnel.
Information about national and international standards may be
obtained
from, American National Standards Association (ANSI), 1430 Broadway,
New
York, New York, 10018. ANSI is a private organization, which monitors
most of the standards activity in the United States and foreign
activity
in which U.S. citizens "officially" participate. Thus, ANSI can
supply
addresses and other information about all well established standards
writing groups. Also, ANSI has for sale many different types of
standards.
 Designing and design evaluation are expensive and time consuming.
Therefore, to control these and increase the probability of achieving
desired safety and performance characteristics, device, software, and
process specifications should be thoroughly reviewed before
development
commences. As the hardware and software designs evolve, they should
be
evaluated versus their specifications.

Design Evaluation versus Specifications

The original design of devices and any subsequent changes should

be
evaluated by appropriate and formal laboratory, animal, and clinical
testing. The design should also be evaluated by careful and extensive
Failure Mode and Effects Analysis as discussed below.

Appropriate laboratory and animal testing followed by evaluation

of
the results must be carefully performed before clinical testing or
commercial distribution of the devices. The company must be assured
that
the design is safe and effective to the extent that can be determined
by
various scientific tests and analysis before clinical testing on
humans
or use by humans. For example, the electrical, thermal, mechanical,
chemical, radiation, etc., safety of devices usually can be
determined
by laboratory tests.

Clinical testing is not needed for many substantially equivalent

devices (See 21 CFR Part 807 Subpart E - Premarket Notification
Procedure). Where it is needed, such as for complex substantially
equivalent devices or new devices, clinical testing on humans must
meet
the applicable requirements in the Investigational Device Exemption
(IDE) regulations (21 CFR 812 and 813).

The general IDE regulation (812) exempts a manufacturer during

the
"premarketing phase" from the following provisions of the FD& C Act:

o Misbranding
o Registration of the Establishment
o Premarket Notification [510(k)]
o FDA Performance Standards
o Premarket Approval
o Good Manufacturing Practices
o Color Additives
o Banned Devices
o Restricted Devices

Don't be misled by this list of exemptions -- being exempted from

 these provisions does not mean that a company may develop a new
device
under uncontrolled conditions and then test it on humans. The
situation
is just the opposite -- development and testing must be highly
controlled (i.e., formal). Devices being clinically tested are not
exempt from section 501(c) of the FD& C Act, which states that a
device
is adulterated if it does not meet company quality claims. In
addition,
the IDE regulation has labeling requirements in section 812.5 and
quality assurance requirements in section 812.20(b)(3) that must be
met.
Further, manufacturers should remember that human subjects are also
protected through the courts via product liability laws and actions.
In
summation, protection of company interests, human test subjects,
practitioners, and patients requires that all medical devices be
developed, evaluated, and manufactured under a total quality
assurance
system.
 Laboratory testing to force a failure takes considerable time and
the "culprit" may not fail during the testing. Another evaluation
technique is Failure Mode and Effects Analysis (FMEA) in which
failures
are assumed to occur. FMEA is useful for evaluating reliability,
safety,
and general quality where, for example, the evaluator assumes that:

o each component fails;

o each subsystem or subassembly fails;
o the operator makes errors; and
o the power source is interrupted and immediately restarted.

The probability of each failure actually occurring and, if it

does,
the resulting effect are analyzed. Then, where needed and feasible,
hazards and faulty performance are designed out of the device; or
compensated or prevented/reduced by interlocks, warning signs,
explicit
instructions, alarms, etc. Risks, of course, cannot always be removed
from medical devices, but they should be known and controlled to the
extent feasible with existing technology.

Failure Mode and Effects Analysis is a very powerful and

cost-effective technique. Note that it takes very little time to
assume
that a component or subsystem is going to fail versus the time
required
to test to failure. The idea is not to promote one method above the
other because a reasonable amount of both actual testing and failure
mode and effects analysis should be done before a device is
clinically
tested and/or placed into production.

All evaluation results must be reviewed by product development

personnel who compare the test and FMEA results with specifications,
including safety and performance standards, to make certain that the
desired level of intrinsic quality has been designed into the device.

Software Validation

Software is evaluated and reviewed versus the software

specifications during the ongoing development of the device design.
When
a "final" prototype(s) is available, the software and hardware are
validated to make certain company specifications for the device and
process are met. Some aspects of hardware evaluation were discussed
above. Aspects specific to software are covered below.

Before testing the software in actual use, the detailed code

should
be visually reviewed versus the flow charts and specification. All
cases, especially decision points and error/ limit handling, should
be
 reviewed and the results documented.

In all cases, algorithms should be checked for accuracy. Recalls

have occurred because algorithms were incorrectly copied form a
source
and, in other cases, because the source algorithm was incorrect.
During
the development phase, complex algorithms may need to be checked by
using a test subprogram written in a high-order language, if the
operational program is written in a low-level language.
The validation program is planned and executed such that all
elements of the software and hardware are exercised and evaluated.
The
testing of software usually involves the use on an emulator and
should
include testing of the software in the finished device.

The testing includes normal operation of the complete device; and

this phase of the validation program may be completed first to make
certain that the device meets the fundamental performance
 specifications. Concurrently or afterward, the combined system
(hardware
and software) should be challenged with abnormal inputs and
conditions.
As appropriate, these include such items as:

o operator errors;
o induced failure of sensors;
o induced failure of output equipment;
o exposure to static electricity;
o power loss and restart;
o simultaneous inputs or interrupts; and,
o as appropriate, deliberate application of none, low, high,
positive, negative, and extremely high input values.

The results of the software and combined system validation are

included in the design reviews discussed later.

Labeling Evaluation

During evaluation, the complete device is exercised such that all

labeling, displays, and outputs are generated, reviewed, and the
results
documented. During the evaluation, all displayed prompts and
instructions are checked versus Company and FDA labeling requirements
and versus the operators manual.

Printed labeling and screen displays should be checked to see if

they are directed to the user and not to the system designers, which
is
a common fault found in labeling. Displayed text should be short and
to
the point. Because displays are brief, keywords should be carefully
selected to match system characteristics, yet transfer the maximum
information to the user. The text of references to controls or other
parts of the system must match the labeling on the device. Data,
identifications, or other key information displayed must be current,
complete, unambiguous, and accurate.

During the evaluation, all prompts and instructions should be

followed exactly by the device operators and such action must result
in
correct operation of the device. Prompts and instructions must
appropriately match the instructions in the operator's manual. The
evaluation should include verification that the screen displays meet
the
requirements of and have been approved per the company
policy/procedure
for control of labeling.

Patient and procedure data on printouts must be correct;

therefore,
printouts must undergo an evaluation similar to that performed for
the
 screen displays. In addition, the printouts should be evaluated with
respect to their "cold" information transfer characteristics. Will
the
printouts be quickly and clearly understood a few weeks later when
the
reader is not reading the screens, operating the device, or looking
at
the patient? All printouts should also meet the company
policy/procedure
requirements for labeling. Likewise, patient data or other key
information transmitted to a remote location must be correct;
therefore,
it must be checked for accuracy, completeness, and identification.

The overall device specifications usually have requirements that

cover operator error prevention and control. Along with operator
training, such errors are controlled by:

o adequate instruction manuals,

o display of adequate prompts and correct instructions,
o status (history) reports,
 o exclusion of certain erroneous inputs or actions,
o human factors, and
o ergonomics.

Also, for some devices, it may be important to control the order

in
which data can be entered by the operator. In emergency situations or
because of distractions, it may be important to present the operator
with a brief history or status report of recent actions. During the
evaluation, the listed items should be evaluated versus the
specifications, and checked for completeness and appropriateness.

Design Reviews

During the development program and especially after the device is

formally evaluated as noted above, and after associated manufacturing
processes have been developed as discussed below and in chapter 9,
progressive design reviews should be performed in a group setting by
all
affected company managers or designees. Reviews should be performed
for
all new designs or formulations and for device or process revisions
to
make certain that the following two goals are fully met.

o The desired level of intrinsic quality is in or is being

designed into the device and/or processes before the start
of
production.

o The designs are appropriately reflected by the device

master
record documentation as verified by ample evidence that the
device specifications (i.e., the company labeling claims)
are
met.

ADEQUATE MASTER RECORD

Most of the documents in the device master record should be

drafted
before process validation or pilot production begins. Of course,
these
documents may be changed later due to changes in requirements,
corrections, and results from validation, pilot production, etc. A
complete and adequate device master record, including all labeling
and
data forms, must be drafted and approved before full-scale production
and before commercial distribution of the device. Details of device
master records and their control are described in chapters 6 and 7.

A Device Master Record Document Plan, which is basically an index

or
 table of contents, should be drafted to support product
specifications
and improve communications among involved personnel. By reviewing the
document plan, one can see which drawings and procedures are
completed,
in-process, or need to be drafted. Two examples of master record
indices
are in chapter 6, Device Master Records.

ADEQUATE MANUFACTURING PROCESS

Production processes should be planned, developed, validated, and

documented to assure that they will routinely achieve the intrinsic
level of quality designed into the new or modified device.
Manufacturing, customer, and vendor problems associated with previous
device designs should be analyzed to eliminate or reduce similar
problems in new or modified devices.

The evaluation of a new design and its associated manufacturing

processes usually includes pilot production of a few units or batches.
Pilot production is recommended as it helps debug the device design
and
 overall production program. Thus, pilot production should be planned
so
that manufacturing activities are monitored, problems are discovered
and
resolved, and documentation is updated.

The adequacy of facilities and equipment for manufacturing a new

or
modified device must be determined as discussed in chapters 4 and 5.
Included in this determination should be the facilities used in, and
equipment used for: environmental control, inspection, testing,
labeling
control, device and component handling, etc.

Where finished device testing cannot adequately measure desired

attributes of a device, assurance of quality must be derived by other
means -- a method acceptable to FDA is validation of each process
used
in production and consideration of the interaction of these processes.
(Also see, "Guideline on General Principles of Process Validation,"
in
the Appendix.)

PROCESS VALIDATION

Process validation is a formal program to determine with a high

degree of assurance and document that a specific process will
consistently meet its predetermined specifications and thus produce
devices that meet their predetermined specifications and quality
attributes. Process validation is intended to be a terminal activity
because it is performed on production equipment and processes that,
along with a new or modified device design, are expected to meet
their
specifications based on previous phase-by-phase evaluations and
reviews
during their development.

Thus, the device and, as appropriate, the packaging must be

defined
in terms of the desired attributes, such as physical, chemical, and
performance characteristics. The device and packaging attributes must
then be translated into written device specifications, as discussed,
and
manufacturing specifications to assure that the finished device
conforms
to the approved design. Acceptable ranges or limits must be
established
for each attribute. The validity of the acceptance specifications
should
be verified through testing and challenge of the device, package, and
manufacturing processes during their respective development programs
and
later during pilot-production. These specifications are needed
because
 validation is performed versus predetermined specifications. If
specifications do not exist, they should be written before continuing
with the validation.

The need for validation is indicated in situations where the

desired
characteristics of the finished device cannot be readily measured.
Where
in-process and finished device testing is not adequate or practical,
a
manufacturer can assure, through careful design of the device and
packaging, and careful design and validation of both the process and
process controls, that there is a very high probability that all
manufactured units from successive lots will be acceptable.

Validating a process also reduces the dependence upon intensive

in-process and finished device testing and is particularly indicated
when such testing is destructive or is done on a sampling basis for
an
important parameter such as the package integrity of a sterile device.
Thus, for some devices and processes as listed below, validation may
be
the only practical means for assuring that these processes will
consistently produce devices that meet their predetermined
specifications.
 o The finished device tests have insufficient sensitivity to
determine the desired safety and efficacy information.

o Clinical or destructive testing would be required to show

that
the manufacturing process is adequate to produce the
desired
device.

o The finished device testing does not reveal all safety and
effectiveness related variations that may occur in the
device.

o For practical reasons, the finished device or package needs

to
be tested on a sampling basis. (Sampling is valid only when
a
process is operating in a state-of-control, which in the
cases
listed here means that the process has been validated.)

o The process uses software which contains so many

interactive
elements that the system behavior under all reasonable
circumstances might not be known.

o The process capability is unknown, or it is suspected that

the
process is barely capable of meeting the device
specifications.

o For some devices, such as those that use certain biological

raw materials, finished device testing is sufficient to
show
effectiveness, but the variability of the biological raw
materials renders adequate testing impossible or the
testing
of incoming biological materials is not technically
feasible.
(Thus, some batches of finished devices will fail and must
be
discarded. In this situation, it is important that
appropriate
processes be validated so that failures will be due to only
the one known but nonmeasurable cause -- the raw material -
-
and not due to unknown causes.)
General programs for validating these processes include planning,
written protocols, equipment qualification, process performance
qualification, revalidation considerations, and documentation of the
results of the validation program. In some cases, such as for
sterilization processes, process-compatible devices and packaging
must
be available for use during the validation program.
 Validation Planning and Protocol

A manufacturer should evaluate and document all factors that

affect
device quality when designing and performing a validation study.
These
factors may vary considerably among different devices and
manufacturing
technologies and could include, for example, component specifications,
air and water handling systems, environmental controls, process
equipment functions, and process control operations.

Validation documentation should include evidence of the

suitability

of materials, the performance and reliability of process equipment

and
control systems, the suitability of buildings, and the competence of
personnel.

Prospective validation includes those considerations that should

be
made before an entirely new device is manufactured or when there is a
significant change in the manufacturing process, which may affect the
device's attributes, such as uniformity and identity. It is usually
not
 sufficient to process a device using procedures that were either
established for another device or that are preconceived, without
actually qualifying the specific device. There is an inherent danger
in
relying on perceived similarities between devices, processes, and
equipment without appropriate analysis and/or challenges. Some key
elements to consider are the validation protocol, device
specifications,
equipment and processes qualification, challenges, performance
qualification, documentation, and revalidation.

It is important that the manufacturer prepare a written

validation
protocol, which specifies the procedures to follow, the tests to be
conducted, and the data to be collected. The purpose for which data
are
collected must be clear, the data must reflect facts, and data must
be
carefully and accurately collected. A protocol should specify a
sufficient number of replicate process runs to demonstrate
reproducibility. The number of runs should be selected to yield a
valid
measure of variability among successive runs and include a full
challenge of the process.

The challenge of the process should encompass those operational

limits of actual production allowed in the firm's written standard
operating procedures. These constitute conditions most likely to
result
in a few devices that do not conform to specifications.

Process variables should be monitored during the validation runs.

Analysis of the data
collected from monitoring will establish the variability of process
parameters for individual runs and will help establish if the
equipment
and process controls are adequate to assure that device
specifications
are met.

Equipment and Process Qualification

The process(es) and equipment should be designed and/or selected

so
that in-process and finished device specifications are consistently
achieved (Also see chapter 4.) This selection should be done with the
participation of all appropriate groups that are concerned with
assuring
a quality device, e.g., engineering design, production operations,
and
quality assurance. The next step is to obtain, install and qualify
the
 equipment. Then the performance of the overall process including the
qualified equipment is qualified.
Equipment: installation qualification

Installation qualification studies establish confidence that the

process equipment and ancillary systems are capable of consistently
operating within established limits and tolerances. After process
equipment is designed or selected, it should be reviewed, calibrated,
evaluated, and tested to verify that it is capable of operating
satisfactorily within the operating limits required by the process
specifications.

The installation qualification phase of process validation

includes:

o examination of equipment design;

o determination of calibration, maintenance, and adjustment
requirements; and,
o identification of important elements that could affect the
 device.

Information obtained from the installation qualification studies

of
process equipment and ancillary systems should be documented and used
to:

o establish written equipment calibration and maintenance

procedures;

o establish manufacturing procedures for the monitoring,

operation, and control of the equipment including the minimum number
of
operators;

o establish any needed environmental controls and procedures;

and,

o assure that the work area has sufficient space to perform

the
processing and associated activities.

Equipment fabricators perform qualification runs at their

facilities
and analyze the results to determine that the process equipment is
ready
for delivery. Device manufacturers should obtain copies of the
suppliers' qualification studies to use as a guide, to obtain basic
data, and to reduce their own qualification studies. However, it is
usually insufficient to rely solely upon the representations and
studies
of the equipment supplier, or upon limited experience in producing
another device. The ultimate decision regarding equipment suitability
should be based on collection of data from appropriate evaluation,
challenge, and testing of the equipment as applied to the specific
device in question, before the equipment is used for routine
production.

Tests and challenges of equipment operation should include the

operational range in the written standard operating procedures. It is
important that test conditions simulate actual production conditions
within and at the established operating limits of the equipment for
the
device and process involved. In most cases, it is important that
tests
be performed at the upper and lower limits of the operational range
because the intent is to include those allowed conditions that pose
the
greatest chance of the process or device not meeting specifications.
When establishing challenges, events such as loss of electricity, air
pressure, vacuum, steam, water, etc.; and failure of valves, sensors,
etc., may need to be considered.
 In evaluating an entire processing system for a device, it may be
necessary to study the interaction of several process elements to
determine the cumulative effect on the attributes of the finished
devices.

When necessary, the tests and challenges should be repeated a

sufficient number of times to assure reliable and meaningful results.
If
the equipment is shown not to perform within its specifications, then
the equipment and related systems must be evaluated to identify the
cause. Corrections should be made and additional test runs performed
to
verify that the equipment performs within specifications.

All acceptance criteria must be met during the final acceptance

tests or challenges. The observed variability of the equipment
between
 and within runs can be used as a basis for the total number of trials
selected for the subsequent performance qualification studies of the
process.

After the equipment configuration and performance characteristics

are established and qualified, they should be documented.

During the qualification phase, planning for eventual maintenance

can reduce or prevent confusion during emergency repairs, which could
lead to improper repairs, such as use of a wrong replacement part.
Therefore, the installation qualification should include a review of
pertinent maintenance procedures, repair parts lists, and calibration
methods for each piece of equipment. If necessary to prevent
inadvertent
manufacture of nonconforming devices, post-repair cleaning and
calibration requirements should be developed. The objective is to
assure
that all repairs can be performed in a way that will not affect the
characteristics of material processed or devices manufactured after
repairs.

Process: performance qualification

The purpose of performance qualification is to rigorously test

the
process to demonstrate effectiveness and repeatability in producing
in-process or finished devices. Each step where variability can
affect
device specifications should be challenged. In entering the
performance
qualification phase of validation, it is understood that the:

o device, packaging, and process specifications have been

established, documented, and essentially proven acceptable through
laboratory or other trial methods; and,

o process and ancillary equipment has been judged acceptable

on
the basis of suitable installation qualification studies.

Challenges must simulate those conditions that will be

encountered
during actual production. A range of conditions at and within
established process specification limits for a given process should
be
used. The challenges must include the range of conditions allowed in
written standard operating procedures and should be repeated enough
times to assure that the results are meaningful and consistent.

At this step of validation, some function tests may be needed to

establish that finished devices meet the device specifications. As
 stated earlier, routine function testing for desired attributes of
some
types of finished devices is generally not practical. Therefore,
during
validation some finished devices may need to be evaluated by special
test methods and test equipment, which are not practical for use on a
routine basis. For example, the tests may be destructive.

Validation Documentation

It is essential that the validation program results be documented

and that the documentation be properly maintained. Each process must
be
defined and described in sufficient detail so that employees
understand
what is required for control, routine production, and maintenance
(Also
see chapter 6, Device Master Records.) Approval and release of the
process for use in routine manufacturing should be based upon a
review
 of:

o all the validation documentation,

o data from the equipment qualification,
o process performance qualification data, and
o finished device and/or package function testing.

After the process is validated, routine production may start. The

process must be operated according to the device master record
specifications. These, of course, contain the setpoints, parameters,
and
procedures determined and documented during the validation program.

For routine production, it is important to record process details

such as time, temperature, and equipment used, and to record any
changes
that have occurred. Also a maintenance log can be useful in failure
investigations of a specific manufacturing lot if the need arises.

Revalidation

As long as the process routinely operates in a state-of-control,

it
does not have to be revalidated. Whether the process is routinely
operating in a state-of-control is determined by comparing the
day-to-day process control data and any feasible finished
device/package
evaluation data (i.e. device history record data) with the master
record
specifications. If control problems develop, or if the device,
packaging, or processing are modified, information regarding the
device,
package, production control, and original validation program and
results
must be carefully analyzed. If indicated by the analysis, all or
parts
of the process must be revalidated. Processes may also be validated
on a
periodic basis but, as noted, if problems develop or changes are made,
the need for immediate revalidation must be considered.

Revalidation is performed using applicable portions or all of the

same program as described for the original validation.

PERSONNEL TRAINING

The firm must assure that there are properly trained personnel or
programs to train personnel as needed to produce the new or modified
device. In one very valuable training technique, manufacturing
personnel
 assist research and development personnel in assembling and
evaluating
engineering prototype devices. This technique:

o achieves advance training for manufacturing personnel;

o reduces production problems by improving the producibility

of
the device based on the expertise and input of the
manufacturing personnel; and,

o improves communications and technology transfer between the

various departments -- important and valuable side benefits.

DEVICE EVALUATION AND HISTORY RECORD

The research and development programs for the device and
manufacturing processes, and pilot production, if needed, must result
in
the development of verified procedures for in-process and finished
 device inspection and test. These inspection and/or test procedures
must
not be deliberately allowed to evolve during full-scale production --
to
do so is a violation of the GMP regulation, particularly Subpart F,
Production and Process Controls, and Subpart I, Device Evaluation.
All
devices placed into commercial distribution must be manufactured
under a
quality assurance system that meets the requirements of the
GMP regulation -- not just the devices that are produced several
months
after the first lot or batch is produced. The GMP regulation, of
course,
allows devices, processes and master records to be changed after
initial
production; however, a manufacturer is not allowed to deliberately
produce and commercially distribute devices without an adequate
device
master record.

During pilot production it is very important that device

evaluation
and other device history record information be collected and analyzed
to
make certain that the specifications of the device intended to be
produced, the device master record, and the actual finished devices
agree with one another. This conformance is a fundamental objective
of
the GMP regulation and additional information on this topic is
presented
in chapter 9, Production Applications, and chapter 10, Device
Evaluation.

FINISHED DEVICE RELEASE

An adequate quality assurance program for new or modified devices

requires that final prototypes or pilot-production models be formally
evaluated by the product development group to determine that the
devices
conform to specifications. Then the evaluation data and associated
records should be reviewed by the design review group. Any
discrepancies
in the finished devices versus the specification and other elements
of
the master record must be resolved before the device is released for
full-scale production. If pilot models are to be commercially
distributed, the firm must ensure that pilot units meet master record
requirements and are approved for release. Most firms, however, use
the
pilot models in training programs for technical writers, production
and
 service personnel, etc. Pilot models are also used in early marketing
displays.

EXHIBITS

Design Transfer Checklists

The use of a product assurance audit checklist or transfer

checklist
such as one of the following examples is highly recommended in order
to
make certain that all necessary activities have been performed before
the device design is transferred into full-scale production. Note
that
these checklists cover an extensive number of activities or documents
that need to be audited or reviewed. Variations of the first sample
checklist for electromechanical devices has been used for more than
15
years in the medical device industry and has proven to be effective.
This checklist may be used for almost any type of hardware device if
the
user of the list adds appropriate performance factors for the
specific
device being reviewed, evaluated, or audited. The second checklist
may
be used as a guide in developing a checklist suitable for a specific
in
vitro diagnostic product.

The sample checklists are in trigger-word form; therefore, they

 should be used only by appropriately trained personnel. Persons
completing these checklists should refer to national and
international
general safety standards and specific device standards for consensus
requirements for grounding, leakage current, fire barriers,
mechanical
and chemical safety, and other safety factors.

Some of the items in the checklist such as human factors were not
discussed in detail in this manual because the intent here is to
describe a quality assurance system for controlling the listed items
or
activities rather than a text on how to design a product.

gmp1-5: 3/1/91
Sheet 1 of 3

TRANSFER CHECKLIST FOR ELECTROMECHANICAL DEVICES

Device Name: _______________________________

Model: __________________________
Company: ___________________________________
Serial No.: _____________________
Vendor: ____________________________________
Add: ____________________________
Auditor's Signature _____________________________________
Date: _______________

ITEM COMMENTS*
(INSIDE THE DEVICE)

1. Primary Grounding Connect. -

2. Dead Metal Grounding -
3. Overcurrent Protection -
4. Fuseholder Polarity -
5. 2-Wire On-Off Switch -
6. Abrasion, Strain Protect. -
7. Circuit Spacing -
8. Wiring Dress -
9. Assembly, General -
10. Hardware Tight -
11. Cleanliness -
12. Control Labels -
13. Caution Labels -
14. Interlocks; Labels -
15. Barriers, Insulation -
16. Moving Part Clearance -
17. Fire Protection -

HARDWARE
1. Device Specification -
2. Connectors & Cables -
3. Connector Propriety -
4. Power Plug & Cord -
5. Cord Strain Relief -
6. General Construction -
7. Physical Stability -
8. Sharp; Hot; Moving;
Pinching Parts -
 9. Liquid & Dirt Protect. -
10. Corrosion Resistance -
11. Maintainability -

* The following abbreviations may be used in the comment column to

save time.
U = Unsatisfactory NA = Not Applicable
GS = Generally Satisfactory NI = Needs Improvements
S = Satisfactory

Form ____________ Revised _________ Approved _____________ Date

__________

Sheet 2 of 3
COMMENTS

12. Grounding Resistance Test -

13. Grounding Leakage Current -
14. Patient Circuit Leakage
Current -
15. Power Dielectric Test -
16. Patient Circuit
Dielectric Test -
17. Transients Produced -
18. Transient Immunity -
Line, Signal, Static
19. Bat. Charge & Life Test -
20. Line Volt. Tolerance -
21. Temperature Tol. Test -
22. Humidity Tol. Test -
23. Shock Tolerance Test -
24. Vibration, Ship. Test -
25. Failure Modes &
Effects Analysis -
26. Performance Factors (add list for item being evaluated)
-
-
-
-
27. Normal Inputs -
28. Abnormal Inputs -
29. Sensor Failures -
30. Output Device Fail. -
31. Power Loss & Restart -

LABELING

1. Fuse & Circuit

Breaker Labels -
2. Control Labels -
3. Warning Labels -
4. Instruction Manual -
5. Maintenance Manual -
SOFTWARE

1. Specifications -
2. Annotated Code -
3. Flow Diagrams -
4. Displays -
5. Printouts -
7. Code Review -
8. Changeable -
9. Error Handling -
10. Operator Prompts -
11. Op. Error Prevent. -
Sheet 3 of 3
COMMENTS

12. Performance Tests (add list for item being evaluated)

13. Normal Inputs -
14. Abnormal Inputs -
15. Sensor Failures -
16. Output Device Fail. -
17. Power Loss & Restart -

HUMAN FACTORS

1. Hardware -
2. Software -

DOCUMENTATION

1. Master Record Index -

2. Verified Device Specs. -
3. Verified Test and
Inspect. Procedures -
4. Burn-in Procedures -
5. Validation Documentation -
6. Packaging & Box Labels -
7. Labels, Artwork -
8. Device Master Record -
(overall review)
9. SOP & QA Man. Ref. List -
10. Purchase Specifications -
11. Vendor Evaluation -
12. 510(k) or IDE/PMA Submission -

MANUFACTURING

1. Equipment Qualification -
2. Process Validation -
4. Pilot Production -
5. Pilot Release -
Sheet 1 of 1
TRANSFER CHECKLIST FOR IVDP
(For Non-Electromechanical IVDP)
Device Name: Catalog No.:

Company: Batch No:

Vendor: Add:

Auditor's Signature Date:

ITEM COMMENTS*

1. Product Specification -
2. Verify Prod. Spec. -
3. Performance Factors -
-
4. Accuracy -
5. Precision -
6. Specificity -
7. Sensitivity -
8. Range -
9. Linearity -
10. Shelf-life Studies -
11. Preservative Performance -
12. Lyophilization Studies -
13. Reconstitution Studies -
14. Temp. Tolerance Test -
15. Humidity Tol. Test -
16. Shipping Test -
17. Verified Standards/Controls
Re Low, Normal & High Values -
18. Inner Containers -
19. Outer Packaging -
20. Packaging Labels -
21. Package Insert -
22. Aseptic Fill Validation -
23. Process Validation -
24. Environmental Controls -
25. Personnel Practices & Gowning -
26. Review Master Record & Index -
27. Processing Procedures -
28. Verified Test and Inspect. Proced. -
29. Data Forms -
30. Finished Dev. Storage -
31. Purchase Specifications -
32. Vendor Evaluation -
33. 510(k) or IDE/PMA Submission -
 * The following abbreviations may be used in the comment column to
save
time.
U = Unsatisfactory NA = Not Applicable
GS = Generally Satisfactory NI = Needs Improvements
S = Satisfactory
Form ___________ Revised __________ Approved _________ Date ________

gmp 1-5: 3/18/91

 GMP - CHAPTER 4 - BUILDINGS AND ENVIRONMENT

CHAPTER 4 BUILDINGS AND ENVIRONMENT

INTRODUCTION
BUILDINGS
Repackers and Rebuilders
Contamination Control
Orderly Operations
ENVIRONMENTAL CONTROL
General Controls
Analyze Operation
Specifications
Monitoring
CLEANING AND SANITATION
Personnel Sanitation Practices
Prevent Contamination by Hazardous Substances
Personnel Practices
EXHIBITS
Cleanroom and Station Procedure
Cleaning Procedure for the Aseptic Filling Room

INTRODUCTION

The buildings and environment in which components, devices, and

records are processed, rebuilt or stored, and the personnel that
perform these operations must be controlled so that finished devices
will consistently meet the specifications established by the
manufacturer. The degree of control must allow for changes in such
elements as weather, flora, personnel, components, devices, and
records.

BUILDINGS

Facilities of medical device manufacturers and their contractors

in
which components, in-process devices, accessories, and finished
devices
are handled, processed, and stored must have sufficient space and be
designed to allow proper cleaning, maintenance, and other necessary
operations in order to meet the requirements of section 820.40 of the
Good Manufacturing Practices (GMP) regulation. Buildings should be
suitably designed so that there is adequate space for manufacturing,
receiving, packaging/labeling, storage, etc., to: minimize
contaminates; assure orderly handling procedures; and prevent mixups.
As
the company grows or the product line is changed, existing
facilities
 may become inadequate. Thus, as part of the quality assurance
program
audit, existing buildings must be reviewed to determine if these are
adversely impacting quality assurance requirements.

Repackers and Rebuilders

 The GMP requirements for buildings extend to firms that repackage
and/or relabel un-packaged bulk devices or change the condition of
devices. The number of operations needed to repackage or relabel a
product may be less than for actual manufacturing of a product;
nevertheless, there is a need to design and arrange facilities so
that
repackaging and/or relabeling operations, particularly for sterile
devices, can be performed in a controlled manner. Because modifying,
updating, and rebuilding of devices is manufacturing, the GMP
requirements for buildings and facilities extend to areas where
modifications are per-formed. In some firms these modifications have
been done in cluttered repair shops. Under these conditions, there
is
an increased probability for contamination or mixup, hence such
firms
must take appropriate precautions as required by the GMP regulation.

Contamination Control

Typical problems in manufacturing and storage facilities include

environmental contamination and insufficient space for receiving and
holding incoming components and materials before test and inspection.
For each area in the building where components or devices are
processed, any elements such as particulates (cardboard dust, slitter
by-products, etc.), microorganisms, humidity, temperature, static
electricity, etc., which a manufacturer has determined might cause
contamination must be controlled. Buildings should be appropriately
constructed to prevent, reduce, and control these parameters and
support
the firm's environmental control program as discussed later. For
example, the control of dust may require that driveways and parking
lots be paved. Crowding causes mixups and can result in contamination
or
in the use of unapproved components, materials or rejected in-process
assemblies. Designated areas should be assigned for various
production
activities such as receiving, inspection/testing, manufacturing,
labeling, packaging, recordkeeping, etc. Traffic by personnel who do
not
work in or manage the designated areas should be held to a minimum.

Orderly Operations

In addition to having sufficient space, the facility must be

designed and arranged so that all operations can be performed in an
orderly manner. This will facilitate the satisfactory performance of
all
operations and, in manufacturing areas, prevent confusion that can
lead
to unsatisfactory job performance and mixups.

To preclude mixups, distinct operations or processes should be

 separated either physically, for example, by walls or partitions; or
spatially, by providing enough room between operations to indicate
that
separate activities are being performed. An appropriate degree of
separation, or walls, curtains, etc., must exist so that no activity
will spray, dust, or otherwise have an adverse effect on other
adjacent
activities. For example, there must be a handling and storage system
to
preclude the mixup of labeled "sterile" but not-yet- sterilized
devices
from the same type of devices that have been sterilized. Likewise,
samples of labeled "sterile" devices to be given away must be sterile
because they may be used. Firms that have more than one labeling
operation must maintain adequate separation of these to prevent any
mixups occurring between various products and their specified
labeling.
Labeling mixups are a major cause of product recalls and a number of
these mix-ups can be traced to inadequate separation of operations
during the labeling of devices.
 ENVIRONMENTAL CONTROL

One of the variables that can significantly impact affect product

quality and employee performance is the environment. A controlled
environment is, to various degrees, an integral part of most
production
facilities. Some environmental factors to be considered are lighting,
ventilation, temperature, humidity, pressure, particulates, and
static
electricity. Section 820.46, Environmental Control, of the GMP
regulation, is considered by FDA to be a "discretionary" requirement;
that is, the degree of environmental control to be maintained must be
consistent with the intended use of the device and details of how to
achieve this control is left to the manufacturer to decide.
"Discretionary GMP requirements" are those which may or may not apply
to
the manufacturer of a specific device. In
these cases the manufacturer must make a prudent decision as to
whether
such requirements are necessary to assure the quality of the
finished
device made by a particular manufacturing operation. These
requirements
are modified in the GMP regulation by phrases such as "where----
could
have an adverse affect" or "where----necessary."

General Controls

General air conditioning is normally not regarded as an

environmental control; how-ever, changes in temperature and lighting
can
have an adverse effect on employee performance and, in turn, on
assuring
that the device is properly assembled, inspected and test-ed. Air
conditioning can control humidity which, in turn, can reduce static
charges. Static charges on the hands of employees can damage some
electronic components and, in such situations, need to be controlled.
Production workers are a major source of particulate contamination
and
standard operating procedures for personnel are often necessary in
order
that employees not adversely affect the environment.

Analyze Operation

If the environment in which components or devices are

manufactured
or held can have an adverse effect on the devices' fitness for use,
that environment must be controlled. For each operation, the
manufacturer should analyze the manufacturing operations in order for
the finished device to meet the device specifications; be fit for the
 intended use; and to control costs. For example, in the manufacture
of
sterile devices such as implants, or diagnostic media that requires
aseptic filling, the environment must be controlled to reduce viable
microorganisms and particulate matter. The packaging for these must
be
stored in a clean, dry, insect-free area. Components that support
bacterial growth must be stored in a controlled environment which,
in
some cases, will include refrigeration. Because particles can bridge
across submicron circuits and static electricity can rupture
semiconductor junctions, microcircuits for use in devices should be
manufactured in a clean-room environment where particulates and
humidity are controlled.

When analyzing the production of a device to determine the degree

of
control needed, the manufacturer should identify exactly what needs
to
be controlled: the device itself; area for one task; or large
production area. For example, if the device can be cleaned after
production, there usually is no need for extensive environmental
control
 during production. The cleaned devices are stored in clean
containers
or are immediately packaged. The environment usually must be
controlled
where the device is being packaged. If the work area needs to be
controlled, how much must be controlled -- a work bench, room, or
factory? For example, a HEPA filtered laminar-flow bench maintains a
low-particulate environment that is large enough for many small tasks
or
operations. If a larger area is needed, then it may be possible to
set
a broad environmental specification for most of the room area and
use a
local laminar- flow unit and curtains to create a small very clean
area. Considerations such as these can reduce environmental facility
and
equipment costs and reduce the activities required to maintain and
monitor the controlled area and operations.

Specifications

When it is necessary to control the environment, specifications

for
parameters such as temperature, humidity, colony forming units
(CFU's),
and particulates per cubic foot, etc., must be established. No FDA
guidelines for these parameters presently exist for environmentally
controlled areas such as cleanrooms. Federal Standard 209b with its
appendices is suggested as a guideline for developing cleanroom
controls
such as particle counts per cubic foot. Federal standard 209d
defines
various levels of environmental control such as Class 1000. A Class
1000 room contains no more than 1000 particles 0.5 micron diameter
or
larger per cubic foot of air. Information may also be obtained from
manufacturers of
cleanroom equipment. Aseptic manufacturing and filling are usually
done
in a Class 100 or better cleanroom or bench. The Class 100 status is
maintained during routine operations -- during idle periods the
particle count will generally be much lower than 100. Some
manufacturers
use a Class 10,000 clean room for the assembly and packaging of
devices
that will be terminally sterilized and where a low particulate count
on
the devices is desired. The specifications for such a room could be:

Particulates: Maximum of 10,000 of 0.5 micron diameter or

larger
per cubit foot
Humidity: 45 +/- 5 percent
 Temperature: 72 +/- 2.5 degrees F
Air Velocity: 90 feet/minute +/- 2 percent
Air Pressure: 0.05 inches water between the clean room and
other
areas

For assembly of many types of convenience kits and assembly of

medical devices that need to be free of visible particles, many
manufacturers use an "industrially clean area or controlled
environment
area." Such rooms are air conditioned and use furnace filters and,
in
some cases, prefilters (much better than furnace filters) are also
used.
The temperature is controlled by a normal room thermostat. Humidity
variations are limited by the normal air conditioning (cooling below
the dewpoint and reheat are not necessarily used). Air velocity is
as
established for the air conditioning; and the room is known to have
positive pressure with respect to other areas by a flow or pressure
indicator. A particle class is not specified; however, these
manufacturers have established a con-trolled environment and
appropriate
specifications for temperature, cleaning, and people control must be
met. For example, filters must be replaced per schedule or as needed
based on scheduled inspections. Any practices or factors from the
following list that the manufacturer has deemed appropriate and
elected
to use must be specified and routinely per-formed or followed. Some
 additional factors that must be considered when planning and using a
controlled environment include:

o proper attire and dressing anteroom;

o controlled use of and entry into controlled areas;
o prohibiting eating, drinking, smoking, or gum chewing;
o preventing use of lead pencils;
o regulating the storage of glassware and containers;
o preventing or controlling the cutting, tearing or storage of
cardboard, debris, etc.;
o cleaning the room and production equipment per written
procedure;
o the original design and cleaning of work surfaces and chairs;

o selecting correct furniture and eliminating use of extra

furniture;
o controlling room air quality, pressure, velocity, and
exchange
rate;
o eliminating electrostatic charges by controlling work
surface
composition or grounding;
o ensuring cleanliness of raw materials, components and tools;

o controlling the purity, sterility, and non-pyrogenicity of

process water; and
o maintaining prefilters, HEPA filters, and electrostatic
precipitators.

Also see at the end of this chapter the procedure, "Cleanroom and
Work Station", which covers work practices, dress codes, and hygiene
for employees working in cleanrooms or at laminar-flow benches.

Monitoring

An appropriate system for regular monitoring must be established

and
maintained for each of these factors to be controlled for a given
operation. This will ensure that equipment is performing properly and
that the quality of the environment is within specifications. When a
particle count Class is specified, monitoring of airborne
particulates is
usually done with an air sampler. Monitoring of work surfaces for
microbes [colony forming units] may be done with surface contact
plates
or settling plates. However, settling plates should not be used for
monitoring when horizontal laminar air flow is used. All sampling
should be done per written procedure and the data recorded. Further,
periodic inspections of environmental controls and documentation of
the
 inspections are required by the GMP regulation. The inspection
checkoff
form or other record should be kept simple. Appropriate action
limits
for particle counts and CFU's should be established. Action limits
for
surface CFU's should take into account that large counts from
handprints
occasionally will be encountered unless gloves are worn.

CLEANING AND SANITATION

The GMP regulation requires in 820.56 that every manufacturer

have
adequate cleaning procedures and schedules to meet manufacturing
process specifications and prevent contamination. These process
specifications are established by the manufacturer to ensure that
finished devices will meet the company's quality claims. Typical
device
 examples are: in vitro devices that are not contaminated with
microbes,
detergents or rodenticides; circuits that are not contaminated with
flux; and implants that are not contaminated with body oils and
pyrogens. If necessary for the device to meet company product
specifications or labeling claims, cleaning procedures and schedules
to
meet the requirements of section 820.56 must be written. Each
operation
should be analyzed in order to write an appropriate procedure or
determine that one is not needed. For example, written procedures are
usually not required for cleaning floors and work benches in areas
where non-sterile and non- growth promoting components or devices
are
processed and packaged.

An example of a procedure and schedule for cleaning an aseptic

filling room is exhibited at the end of this chapter. Records related
to
facilities, the environment and personnel practices need to be kept
simple as shown by this example. Note that the schedule and record
of
cleaning are both on page 4 of the procedure. The record of cleaning
may
be a checkmark, initial, or signature. Where a checkmark is used for
repetitive work, companies commonly require that the person's name be
on
the record at least once. The schedule for cleaning may be posted or
filed as long as it is in a convenient location. As appropriate,
manufacturers may use this procedure as is, modify it, or use it as a
guide to develop a procedure to meet specific needs.

Personnel Sanitation Practices

Adequate bathroom, dressing, storage and waste facilities must be

provided, as appropriate, for personnel to maintain cleanliness. Such
facilities must be maintained on a regularly scheduled basis. Where
necessary, such as in a cleanroom, special clothing and an area to
don
and store the garments must be provided. Cleanroom clothing must not
be
worn into uncontrolled rooms or outside the facility.

Prevent Contamination by Hazardous Substances

If rodenticides, insecticides or other hazardous substances are

used, written procedures to limit their use or for their removal from
work surfaces and devices must be established to prevent any adverse
affect on the manufacturing process or the device.

Personnel Practices
 If eating, drinking, or smoking could have an adverse affect on
the
devices' fitness for use, manufacturing procedures must include
instructions on how to avoid such adverse effects. For example,
these
activities could be confined to specially designated areas.
Directions
and containers or equipment must be provided for timely and safe
disposal of trash, by-products, effluents and other refuse.

EXHIBITS

Reprinted on the following pages are two examples of procedures

that
may be used to comply with the cleaning requirements of the GMP
regulation. Both of these procedures deal with sensitive areas of
the
plant: cleanroom and aseptic filling rooms. Therefore these are more
comprehensive than is normally needed for general plant cleaning.

Note that these procedures follow good labeling practices in that

 the tasks or rules are broken into numbered steps; and only one or
two
activities or rules are included in each step. Thus, the directions
or
rules are easy to read, remember, and execute or obey.

Cleanroom and Station Procedure

This procedure is divided into general requirements, nonlaminar

airflow cleanrooms and workstations, laminar airflow cleanrooms and
workstations, and cleanroom personnel rules. The first part of this
procedure contains useful information for any area of a plant were
moderate control is needed to reduce particulate contamination. The
level of control needed increases as the procedure goes from
nonlaminar
airflow to laminar airflow. The final section contains additional
requirements for personnel working in a cleanroom.

Cleaning Procedure for the Aseptic Filling Room

This is a standard operating procedure used by personnel that are

charged with cleaning an aseptic filling area and not for personnel
that generally work in this area. This cleaning procedure is divided
into two sections, daily and weekly tasks, thus giving personnel
guidance on when as well as how to perform these tasks. There are two
items of interest in this procedure that should help keep to a
minimum
any entering and exiting of this area: the equipment list at the
beginning, and the maintenance information at the end. The equipment
list is important because it alerts personnel as to the proper
equipment
that has to be obtained before beginning work. The maintenance
procedures allows the personnel to perform maintenance tasks without
calling in a special crew or having to exit and reenter the room
more
than is necessary.

gmp1-18: 3/12/91

Sheet 1 of 2

PROCEDURE TITLE: Cleanroom and Station Procedure No.

Rev.

Prepared by App. by Date

A. General Requirements

1. No eating, drinking, smoking, or chewing gum.

2. Specified garments must be worn when entering and in the clean

area. These shall be stored in the anteroom and not worn in non-
clean areas.

3. Only approved cleanroom paper shall be allowed in the area.

4. Use only ballpoint pens (fine point preferred).

5. Rouge, lipstick, eye shadow, eyebrow pencil, mascara and false

 eyelashes shall not be worn by any worker while in any clean
area.

6. No cosmetics of any kind are to be applied or removed in the

clean
area.

7. Skin lotions or lanolin-base soaps are in the restrooms for

employees to use to tighten the skin and guard against
epidermal
scaling.

8. Solvent contact with the bare skin should be avoided, as most

solvents will remove the natural skin oils and cause excessive
skin
flaking.

9. The use of paper or fabric towels is not recommended --

washrooms
should have electrically powered, warm-air dryers.

10 Approved pliers, tweezers or lint-free gloves must be used to

handle manufacturing materials, components or finished devices.

11. Do not touch with gloves or finger cots any covered or uncovered
part of the body, or any item or surface that has not been
thoroughly cleaned.

12 All containers, racks, jigs, fixtures, and tools should be

cleaned
to the same level of cleanliness specified for the device being
processed.

B. Nonlaminar Airflow Cleanrooms and Work Stations

1. Garments shall be pocketless, lint-free coveralls, with snug

fitting fasteners at the neck, wrist, and ankles.

2. Lint-free caps must be worn and must completely cover the head
and
hair except for the eyes, nose, mouth, and chin.

3. Shoes shall be cleaned and covered with a non-shedding boot-type

cover, or changed to approved cleanroom footwear. If special
footwear is provided, it shall not be worn outside the cleanroom
and dressing room.

Sheet 2 of 2

4. Janitorial services shall be performed only by adequately

trained
 and supervised personnel, each of whom must be properly garbed.

5. All equipment to be brought into the cleanroom shall first be

thoroughly cleaned. Use only equipment that will not generate
contaminants.

6. Traffic into and within the cleanroom shall be restricted to

authorized and properly garbed personnel and unnecessary
movements
by these personnel shall be minimized.

C. Laminar Airflow Cleanrooms and Work Stations

1. Garments may vary with the operation being performed, but the
minimum garment shall be a pocketless, lint-free smock which
 extends to within 15 inches below the work surface. The collar
and
cuffs shall have fasteners.

2. Head covering shall be worn, and shall completely cover the hair.
If the operation requires the wearer to lean over the work, or
move into the airstream between the filter bank and the work
piece, the front, sides, and rear neck areas of the head shall
also be covered.

3. Shoe covers are not necessary for vertical or horizontal laminar

airflow facilities except when the work is being performed less
than 24 inches from the floor.

4. A face mask may be needed if an operator has a cold, or if the

nose
and mouth must be brought very close to the work piece for work
on
miniature components or devices. Check with your supervisor for
instructions.

D. Cleanroom Personnel Rules

Personnel will be asked to cooperate in maintaining a low

contaminant emission rate by observing the following rules.

1. Bathe at night, instead of in the morning, due to the removal of

normal body oils which cause increased shedding. Also, use skin
lotions.

2. Wear clean, unstarched, low-shedding garments.

3. Shave daily and be clean shaven (male employees).

4. Avoid touching, rubbing, and scratching exposed areas of the

body.

5. Exercise extra care to rid the hands of normal residue from home
duties such as starching, baking, plastering, wallpapering,
painting, concrete work, carpentering or other particulate
generating activity.

Page 1 of 4

STANDARD OPERATING PROCEDURE: Number G021 Revision A

TITLE: Cleaning Procedure for the Aseptic Filling Room

APPROVED BY: Date:

PURPOSE: Control of surface contamination within the Aseptic Filling

Room.

EQUIPMENT NEEDED:

1. Cleaning solution: See SOP G044

2. Non-linting wiping cloths
3. Stainless-steel basins and pails
4. Dry-wet vacuum cleaner for floors
5. Sponge mops with replaceable sterile heads
6. Mop buckets
 7. Stainless-steel sponges
8. Latex surgical gloves, sterile
9. Head and shoe covers, sterile
10. Face masks and gowns, sterile
11. Stainless-steel cart
12. Sprayer
13. Trash can plastic liners
14. Stepladder

DAILY CLEANING REQUIREMENTS:

CAUTION: Be careful when using stepladder and when walking in wet

areas.
USE EXTREME CARE WHEN CLEANING ELECTRICAL FIXTURES AND OUTLETS. USE
DAMP (NOT WET) CLOTH TO WIPE ELECTRICAL ITEMS.

A. Gowning Room:

Shoe and head covers are required in this area. Begin all
cleaning
at the top and finish at the bottom of any equipment or surface
to
be cleaned.

1. Empty trash containers and replace plastic liners.

2. Replenish stock of shoe covers, masks, head covers, gowns,
gloves
and put into proper areas.
3. Fill dispenser with 0.45 u filtered 70% Isopropyl alcohol.
4. Mix cleaning solution of XXXXXXXX using process water (SOP
G044).
5. Fill a stainless-steel basin with cleaning solution and
begin
wiping in this order: the boot box; stool; wash station; top and
outsides of all cabinets; counter tops; and the tops of the trash
containers.
6. Remove excess debris and wet mop the floor with cleaning
solution. 7. Fill sprayer with cleaning solution and wet the
floor;
allow it to air dry.
8. Gown according to gowning procedures and go into the filling
area
(SOP G014).

Page 2 of 4

B. Filling Room:
 1. Move any remaining products (devices) to appropriate areas as
directed by your supervisor.
2. Empty all trash containers and replace liners.
3. Remove particulate matter from ledges, cabinets and external
surfaces of laminar-flow benches with a wiping cloth and
cleaning
solution.
4. Perform general straightening of shelves.
5. Remove debris and wet mop the floor with cleaning solution.
6. Spray the entire floor in the filling room with cleaning
solution,
using the provided sprayer. Allow the floor to air dry.

WEEKLY CLEANING REQUIREMENTS:

 All daily cleaning requirements are included in the weekly
cleaning
requirements. The additions to the weekly cleaning are ceilings,
walls, and
THE INTERNAL WORK SURFACES OF THE LAMINAR-FLOW WORK BENCHES.
RODAC
(TM) PLATes measurements are taken after cleaning and before the next
production shift.

A. Gowning Room:

1. Use only one entrance and one exit when cleaning. The cleaning
direction will flow from entrance to exit.
2. Remove all non-essential equipment from the room and clean it.
Return he equipment after the entire area is cleaned.
3. Begin cleaning the room by wiping the entire ceiling area with
the
cleaning solution.

Frequent changes of the cleaning solution and the wiping cloths are
needed for effective cleaning of large areas such as the ceilings
and
walls. Make new solution and change wiping cloths when dirty.

4. Clean air vents, lighting fixtures, and sprinkler heads.

5. Clean the walls next, starting at the top and cleaning toward
the
floor.
6. When the ceilings and walls are cleaned, follow steps 1, 2, 3
and 5
of the Daily Cleaning Requirements for the gowning room.

7. Remove debris and wet mop the floor with cleaning solution.
8. Fill the sprayer with cleaning solution and wet the floor. Allow
to
air dry.
9. Gown according to procedure and go into the Filling room (SOP
G014).

B. Filling Room:

1. Follow steps 1, 2, 3 and 4 of Daily Cleaning Requirements for

Filling Room.
2. Begin cleaning operation by wiping the entire ceiling area with
cleaning solution. Make new cleaning solution and change wiping
cloth
when dirty.
3. Clean air vents, ultraviolet and fluorescent lighting fixtures
and
sprinkler heads.

Page 3 of 4
 4. Clean the walls next, starting at the top and cleaning toward
the
floor. Make new cleaning solution, and change wiping cloth when
dirty. 5. Empty all shelves and wipe with the cleaning solution.
Wipe
the
removed materials and put them back onto the cleaned shelf.
6. Wipe all cabinets and equipment with the cleaning solution from
top
to bottom.
7. Wipe all ledges and surfaces with the cleaning solution.
8. Pay particular attention to the laminar-flow workbenches because
the cleaning operation must end in the internal work surface of
the
hood.

Use a fresh wiping cloth and cleaning solution for the internal work
 surfaces. Do not use the same cloth or solution which was used for
the
external cleaning. Discard solution and wiping cloths after cleaning
each hood.

8.1 First, switch off the laminar-flow hood, then clean all outside
surfaces from top of hood to bottom stand.
8.2 Second, clean all internal work surfaces such as:

a. Light covers
b. Air diffuser screen
c. Plexiglas sides
d. Workbench top.

9. Clean the floors. Scrub stains or spills first, with stainless-

steel sponges, to loosen debris. Use the sponge mop to clean the
loosened
debris. Fill the sprayer with cleaning solution and wet the entire
floor
area. Allow to air dry. Rodacs (TM) plate measurements are made
after
cleaning and before the next production shift.

10. Complete the documentation ledger and sign it. See Attachment A.

C. Maintenance of Cleaning Equipment After Daily and Weekly Cleaning:

1. Use the same solution as used for general cleaning.

2. Wipe stepladder from top to bottom, in that order, and put it
into
storage cabinet.

3. Wipe stainless-steel basins and pails with cleaning solution,

allow to air dry, and put into storage cabinet.
4. Rinse mops and buckets with cleaning solution. Do not leave
dirty
solution in buckets or vacuum cleaner.
5. Rinse sponge mops with warm water. If mop head needs replacing,
replace it and put mop into storage cabinet.
6. Wipe stainless-steel cart with cleaning solution and put into
storage cabinet.
7. Rinse sprayer with cleaning solution and put into storage
cabinet.

8. Rinse vacuum cleaner with cleaning solution. Remove filters and

clean with cleaning storage cabinet.
9. Autoclave mop heads and buckets per procedure GAC 09.

<ASEPTIC FILL DEPARTMENT CLEANING RECORD>

 GMP - CHAPTER 5 - EQUIPMENT AND CALIBRATION

CHAPTER 5 EQUIPMENT AND CALIBRATION

INTRODUCTION
MAINTENANCE
Records
Equipment Selection
MANUFACTURING MATERIALS
Analyze Use
Control Use
AUTOMATED PRODUCTION AND QA SYSTEMS
Software Validation Guidelines
Employee Responsibility and Training
Formal Development of Software
Commercial Software and Equipment
Validation of Equipment and Processes
Automated Data Collection and Processing
Equipment Controls and Audits
EQUIPMENT CALIBRATION
CALIBRATION REQUIREMENTS
Procedures
Personnel
Records
Schedules
Standards
EQUIPMENT ENVIRONMENT
AUDIT OF CALIBRATION SYSTEM
INTEGRATING MEASUREMENTS INTO THE QA SYSTEM
EXHIBITS
P.C. Board Cleaning
Calibration Procedures for Mechanical Measuring Tools

INTRODUCTION

The Good Manufacturing Practices (GMP) regulation requires that

all
equipment used to manufacture a device be designed and installed so
that it can be adequately cleaned, serviced, and adjusted as
necessary
to maintain the equipment's accuracy, performance, and reliability
(820.60). The degree of maintenance of all equipment and frequency of
calibration of measuring equipment will depend on the type of
equipment,
frequency of use, and importance in the manufacturing process. The
GMP
regulation also implies that manufacturing materials such as mold
release compounds, cleaning agents, lubricating oils, and other
 substances used to facilitate manufacturing, be procured and received
as
components. If any of these materials has an adverse effect on the
finished device, then it must be removed to a safe level.

MAINTENANCE

Device manufacturers must maintain, clean, and adjust equipment

used
 in the manufacture of medical devices where failure to do so could
have
an adverse effect on the equipment's operation and hence the device.
For example, failure to maintain, clean, and adjust a sealing and/or
packaging machine used for primary packaging of sterile devices will
eventually result in defective packages and thus nonsterile products.

A manufacturer must determine if the equipment requires

maintenance
and apply the appropriate parts of the GMP requirements for equipment.
The user usually can determine if specific equipment requires
maintenance by reviewing the equipment operations and maintenance
manuals usually supplied by the equipment manufacturer. If failure to
maintain equipment does not appear to adversely affect the device,
FDA
will not insist that the manufacturer meet the maintenance
requirement.
Typically, a manufacturer will maintain equipment simply because it
prolongs equipment life and minimizes the need for major service. If
it
is necessary to maintain, clean, or adjust equipment, the
manufacturer
must:

o have a written schedule for performing these activities;

o post the schedule or make it readily available;

o document the activities;

o where adjustment is necessary to maintain proper operation,

post the inherent limitations and allowable tolerances of
the
equipment or make these readily available to personnel
responsible for making the adjustments; and

o audit the activities and document the audit.

Records

As appropriate, maintenance records should be maintained for each

piece of equipment. Maintenance records and schedules are not needed
for equipment such as lathes, presses, grinders, etc., that are used
in
a machine shop and maintained by skilled employees on a daily basis.
Automated machining equipment will require maintenance schedules.

There is no GMP requirement for a written maintenance procedure,

although one is recommended to assure that all aspects of
maintenance
are covered. An example of an operation and maintenance procedure,
"P.C. Board Cleaning," is exhibited at the end of this chapter.
 Equipment Selection

The purchase of stable and accurate measuring equipment can

reduce
the frequency of calibration and increase confidence in the
company's
metrology program. Where economically feasible, equipment with more
accuracy than needed for various measurements can be used longer
without recalibration than equipment that marginally meets the
desired
accuracy requirements. Delicate instruments, however, that are
"pushing
the state-of-the-art" should not be used for routine measurements
unless no other approach is feasible.
MANUFACTURING MATERIALS

The proper or optimum operation of manufacturing equipment often

requires the use of manufacturing materials. The GMP regulation
defines
 "manufacturing material" as any material, such as a cleaning agent,
mold-release compound, lubricating oil, or other substance, used to
facilitate a manufacturing process and which is not intended by the
manufacturer to be included in the finished device [820.3(l)].
Manufacturing materials are specified, procured, inspected/tested,
etc., the same as components. For details see Components, chapter 8
of
this manual.

Analyze Use

The use of manufacturing materials that may adversely affect the

finished device should be carefully analyzed. Each process should be
designed to use a minimum amount of adverse materials so as to
reduce
costs, reduce removal efforts, and increase the intrinsic safety of
the
device. The fact that a manufacturing material has been removed or
limited below the adverse level may be determined by either of the
two
general approaches below.

o The adverse material may be measured directly and compared

to
the process specification.

o If feasible, the component, in-process device or finished

device may be tested against its specification. If the item
passes, it follows that the residue is not affecting the
performance. The test specification must be appropriate for
this method of evaluating residues and may need to include
tests for toxicity, pyrogens, etc.

Control Use

Section 820.60(d) requires a written procedure for the use and

removal of manufacturing materials that can have an adverse effect on
devices. Usually, the procedure used for routine cleaning of the
device
and its assemblies can be used for this purpose. If so, a special
procedure is not necessary; however, when residues from such agents
as
ethylene oxide must be removed, special instructions usually are
necessary.

When manufacturing materials such as oils, mold-release compounds,

gases, cleaning agents, etc., are used on or in equipment,
manufacturers must:
o remove the material or limit it to a safe amount;
o provide written procedures for the use and removal of
materials;
and o document the removal.
 A sample procedure "P.C. Board Cleaning" for removing an adverse
manufacturing material is exhibited at the end of this chapter. This
procedure covers the removal of flux (not mentioned in the
procedure),
finger oils, etc., from printed circuit (PC) boards. In most cases,
flux is an adverse manufacturing material.

AUTOMATED PRODUCTION AND QA SYSTEMS

The hardware system, software program and general quality

assurance
system controls discussed below are essential in the automated
manufacture of medical devices. The systematic validation of software
and associated equipment will assure compliance with the GMP
 regulation; and reduce confusion, increase employee morale, reduce
costs, and improve quality. Further, proper validation will smooth
the
integration of automated production and quality assurance equipment
into manufacturing operations.

Medical devices and the manufacturing processes used to produce

them
vary from the simple to the very complex, thus, the GMP regulation
needs to be and is a flexible quality assurance system. This
flexibility is valuable as more device manufacturers move to auto-
mated
production, test/inspection, and record keeping systems.

One of the basic requirements of the GMP regulation is that

formal
processing procedures be established, implemented, and controlled as
necessary to assure that device design specifications are met
[820.100]. Thus, among many other quality assurance elements,
processing
methods and equipment [820.20(a), 820.60] must be selected, and
specific
operating parameters established and evaluated, in order to establish
valid and reliable manufacturing processes. The activities conducted
to
verify process and equipment specifications are collectively referred
to
as process validation.

In addition to this general requirement for all significant

processes, the GMP regulation has specific requirements in sections
820.61 and 820.195 for validating and controlling automated
equipment
used in the manufacture of medical devices.

Software Validation Guidelines

The GMP regulation requires [820.61] that software programs be

validated by adequate and documented testing when computers are used
as
part of an automated production or quality assurance system.
Software
used in automated production and quality assurance systems consists
of
programs or codes that cause computerized equipment to perform
desired
tasks, plus operator manuals and instructions. FDA has drafted an
information document "Application of the Medical Device GMPs to
Computerized Devices and Manufacturing Processes" reprinted in the
Appendix. Also, FDA has drafted general guidelines, "Principles of
Process Validation" reprinted in the Appendix. Both of these
documents
can be used with the GMP regulation to establish a software QA and
 validation program.

There are also standards, books, and articles that can be used
for
guidance. Military Specification MIL-S-52779A and the Institute of
Electrical and Electronic Engineers (IEEE) "Standard for Software
Quality Assurance Plan" (IEEE Std 730-1984) are examples.
Manufacturers,
however, should not rely completely on such documents, but must
examine
their software needs and develop whatever controls are necessary to
assure software is adequate for its intended use [820.20(a)(4)].

Employee Responsibility and Training

The device manufacturer should identify individuals or

departments
responsible for software quality and clearly specify their
responsibilities. These individuals and/or department personnel
should
have sufficient training, authority, responsibility, and freedom of
action to specify and evaluate the design and use of software and
associated equipment.

A manufacturer probably will experience problems if employees

 operating the automated system or inputting data do not have
adequate
background and/or training. Employees must have adequate knowledge
of
the system through both on-the-job experience and formal training.
Those
responsible for data input should be able to recognize data errors
[820.25]. The GMP regulation requires that adequate checks be
designed
and implemented to help pre-vent inaccurate data input [820.20(a)(4),
820.195]. This requirement can be accomplished by the aforementioned
training and by software controls. Where practical, software pro-
grams
should have built-in error controls such as prompts, alpha-only
fields,
numeric- only fields, length limits, range limits, and sign (+)
control to help eliminate mistakes during data entry. These error-
control or human-factors requirements, as appropriate, should be
part
of the specifications for software being developed or purchased.

Formal Development of Software

Manufacturers that develop their own software should follow a

prescribed quality assurance plan and document each step of the
development. The software should be appropriately structured and
documented so that any future changes can be accomplished, even by a
different programmer, with a minimum of difficulty and maximum
reliability.

To validate software, it must be:

o structured, documented and evaluated as it is developed;

o checked to make sure that it meets specifications;

o adequately tested with the assigned hardware systems; and

o operated under varied conditions by the intended operators

or
persons of like training to assure that it will perform
consistently and correctly.

Each module or routine of the program should be evaluated to make

sure it performs the specified function. The main core of the
program
should be checked to make certain that all parameters are correctly
initialized and that data is correctly transferred between the
routines. The input-output routines should be checked for proper
operation with the intended peripherals to the extent feasible at
this
stage of the development. The testing is performed with real or
simulated input data. The input data should accurately represent the
 real data that will occur in the next phase of testing and should
also
represent data at the boundaries of acceptability. The test protocol,
data and results should be documented. The documentation should be
made
available to the party who will evaluate the soft-ware with the
automated production or quality assurance equipment to be used in
routine manufacturing.

The testing of the software with the actual medical device

production or testing equipment should exercise all program
functions
under all expected production conditions. The testing should include
the input of normal and abnormal data to test program performance and
error handling. The validation must assure to a high degree that the
software and associated equipment meet the company specifications.
Testing and results should be documented. Any serious deficiencies
must
be corrected.
 Commercial Software and Equipment

When an outside contractor is engaged to develop software, the

device manufacturer must make sure that the contractor clearly
understands the software requirements and translates them into
documented specifications with sufficient objectivity that compliance
can be measured. FDA recognizes that most of the validation may be
done
by the contractor; however, the device manufacturer is still
responsible for the adequacy and the validation of the software.
Therefore, the contract should require the contractor to develop the
software according to a quality assurance plan that includes
validation.

When possible, the purchaser also should conduct pre-award audits

to
verify adequacy of the contractor's quality assurance program. Two
key
elements that should be checked are the contractor's test plans and
system for controlling changes to documentation. Subsequent audits
should be conducted as needed to verify that the contractor is
complying
with the quality assurance plan. The manufacturer who has custom
software prepared and validated by a contractor must ensure the
software
program is running properly and producing correct results before
using
the program to produce medical devices for distribution.
Manufacturers who purchase commercial equipment with incorporated
software must still validate the software and associated equipment
for
the intended applications. If, however, the software has been
validated
by the developer and proven through use, the purchaser need not test
it
as comprehensively as new software. For example, automated production
and test equipment that is controlled by software can usually be
validated through use of a "dummy" device. This "dummy" device
should
exercise all functions and decisions in normal and worst-case
situations that may reasonably be expected during production. In some
cases, vendors provide test programs that may be used to assure that
the
equipment will appropriately and accurately perform all intended
functions before it is used for routine production.

Validation of Equipment and Processes

Automated machine tools such as lathes, printed-circuit drills

and
 component inserters usually can be validated by conducting a first-
and
last- piece inspection of representative product lots. The record of
this activity may be noted on the routine quality control or
production
records for the machine. Validation of complex microprocessor-
controlled
equipment, such as sterilizers, to verify satisfactory operation is
generally a more ext
extensive activity than the validation of machine tools. Typically,
verification must be done by using calibrated measurement
instruments
to check the actual parameters achieved during trial runs, and
comparing these measurements with the setpoints and data outputs of
the
automated system. In all cases, under the GMP regulation the user is
responsible for:

o assuring the adequacy of automated equipment and software;

o verifying that all intended functions will be correctly and
reliably performed; and
maintaining appropriate records.

Validation records [820.61] for software and automated equipment

 must be maintained by the user and, upon request, made available to
FDA
investigators for review and copying during their audit [820.180] of
the manufacturer's GMP system. Likewise, specifications for the
hardware and software including directions for their use, if any,
must
be included or referenced in the device master record [820.181].

The master record [820.3(i)], as explained in chapter 6, is a

compilation of records containing the design, formulation,
specifications, complete manufacturing procedures, quality assurance
requirements, and labeling for a finished device.

All changes to specifications, software programs, and other

master
record documents must be formally reviewed and approved before
implementation [820.100(a) and (b)]. Because changes in one part of
software can affect other parts of software, adequate consideration
must be given to side-effects of these changes. Such changes are much
easier to make and evaluate when the original software is
appropriately
structured and thoroughly documented.

Automated Data Collection and Processing

In addition to aiding the production of devices, computers may be

used to collect and maintain quality control and production records.
These records are called the device his-tory record in the GMP
regulation. A device history [820.3(h)] is a compilation of records
containing the production history of a finished device. When device
history records or master records are maintained by computer,
appropriate controls must be used to assure that data is entered
accurately, changes are instituted only by authorized personnel, and
records are secure. Hard copy or alternative systems such as
duplicates,
tapes, or micro-film should also be used to avoid losing records as a
result of inadvertent erasure or other catastrophe. As appropriate,
access to records and data bases should be restricted to designated
individuals.

The GMP regulation requires [820.181] that device master records

be
signed by designated individuals, and that changes to master records
be
signed by individuals designated to authorize such changes. In
addition, signatures are required when certain data [820. 185(a)(2),
820.185(c)] are recorded in critical device history records. The GMP
regulation also requires [820.101] that only designated employees
operate equipment used to perform critical operations on critical
devices and that the history record contain [820.185(b)] the names
of
these individuals.
 The GMP regulation was promulgated when most records were hard
copy
for which written signatures were appropriate; however, the
increased
use of computers and related input/ output peripherals has affected
FDA
policy regarding GMP signature requirements. In response to the use
of
new electronic technology, FDA has issued an advisory opinion stating
that magnetically coded badges or other computer-compatible
identifiers
may be used in lieu of signatures as long as there are adequate
controls to prevent inaccurate data input. If coded badges and the
like
are not controlled (i.e., not restricted to designated employees),
they
will not meet the applicable GMP requirements.

Manufacturers may wish to keep appropriate records such as master

records and com-plaint files at central or corporate offices. If the
 overall data handling system is con-trolled as stated above, firms
may
maintain appropriate GMP records at central locations if they can
transmit these records to the manufacturing establishment by
electronic
mail (computer plus modem) or other highspeed data transfer system.

Equipment Controls and Audits

Automated equipment and any peripheral equipment requiring
maintenance and/or calibration must be included in a formal
calibration
and maintenance program [820.60, 820.61]. Also, environmental
factors
such as temperature, humidity, cleanliness, static electricity,
magnetic
fields, and power-supply fluctuations can adversely affect automated
equipment and data storage mechanisms such as magnetic discs and
tapes.
Consequently, necessary precautions, environmental controls, and
maintenance programs [820.46, 820.60 and 820.61] must be implemented
to
prevent adverse effects on the equipment and stored data.

During their quality assurance system audit [820.20(b)],

manufacturers should audit the use and control of their automated
production and quality assurance systems. The audit should include
software and equipment maintenance procedures and records, and should
evaluate the adequacy of security measures, change controls, and
other
controls necessary to maintain software quality and proper
performance
of associated equipment. The audit must be documented, important
results reviewed with management, and corrective action taken as
appropriate.

EQUIPMENT CALIBRATION

The GMP regulation is intended to help assure that devices will

be
safe, effective and in compliance with the FD& C Act. To support
this
goal, each medical device manufacturer must develop and implement a
quality assurance (QA) program that assures with a high degree of
confidence that all finished devices meet the company's device master
record specifications. These specifications should, in turn, reflect
the company quality claims (see section 501(c), FD& C Act). Such
assurance is obtained by many activities including the measurement
of
component and device parameters. These measurements must be made with
appropriate and calibrated equipment.
 Each manufacturer must assure that production equipment and
quality
assurance measurement equipment (mechanical, electronic, automated,
etc.) are:

o suitable for the intended use in manufacture and testing of

in-process and finished devices;

o operated by trained employees;

o capable of producing valid results; and

o properly calibrated versus a suitable standard.

To succeed, the QA system must include a calibration program that

is
at least as stringent as that required by the GMP regulation
(820.61).
The intent of the GMP calibration requirements is to assure adequate
and
continuous performance of measurement equipment with respect to
accuracy, precision, etc. The calibration program implemented by a
company can be as simple or as sophisticated as required for the
 measurements to be made. Some instruments need only be checked to
see
that their performance is within specified limits, while others may
require extensive calibration to a specification.

In establishing a quality assurance system, manufacturers should

determine which measurements are necessary to assure that finished
devices meet approved master record specifications, and that the
instruments used to make these measurements are included in a
calibration program. When measurement equipment that is part of the
calibration system is located in the same areas as instruments that
are
not part of the system, the system equipment should be identified by
label, tag, color code, etc., to assure it is the only equipment
used
in determining compliance of a component, in-process devices, or
finished device with specifications.

Equipment used only for monitoring a parameter need not be

calibrated but should be identified (e.g., for monitoring). A
monitoring function might be to indicate if a voltage or other
parameter exists, but the exact value is not important.

CALIBRATION REQUIREMENTS

The GMP regulation requires in section 820.61(a) that equipment

be
calibrated ac-cording to written procedures that include specific
directions and limits for accuracy and precision. Figure 5.1
illustrates bias, precision and accuracy.

Figure 5.1 <Bias, Precision and Accuracy>

Precision has no unit of measure and only indicates a relative

degree of repeat-ability, i.e., how closely the values within a
series
of replicate measurements agree with each other. Repeatability is
the
result of resolution and stability.

Bias is a measure of how closely the mean value in a series of

replicate measurements approaches the true value. The mean value is
that number attained by dividing the sum of the individual values in
a
series by the total number of individual values.

Accuracy is the measure of an instrument's capability to approach

a
true or absolute value. Accuracy is a function of precision and bias.
Because different manufacturers have different accuracy requirements,
each manufacturer must decide the level of accuracy required for each
measurement and provide equipment to achieve that accuracy.
 Proper and periodic calibration will assure that the selected
equipment continues to have the desired accuracy. GMP calibration
requirements are:
o routine calibration according to written procedures;

o documentation of the calibration of each piece of equipment

requiring calibration;

o documented validation of the software programs used in

automated production or quality assurance equipment;

o specification of accuracy and precision limits;

 o training of calibration personnel;

o use of standards traceable to the National Bureau of

Standards
(NBS), or other recognizable standards; and

o provisions for remedial action to in-process or finished

devices.

Remedial action includes recalibration and evaluation of the

impact
of out-of- tolerance measurements on the quality of existing in-
process
or finished devices, and appropriate corrective action.

Procedures

There are a number of sources of information from which

calibration
procedures can be developed. Instrumentation manufacturers often
include calibration instructions with their instruction manuals.
Although these instructions alone are not adequate to meet the GMP
requirements for a calibration procedure, they usually can be used
for
the actual calibration process. In some cases, voluntary standards
exist
such as those by American Society for Testing and Materials (ASTM),
American National Standards Institute (ANSI), and Institute of
Electrical and Electronic Engineers (IEEE).

Information contained in calibration procedures should be

adequate
to enable qualified personnel to properly perform the calibrations.
An
example of a calibration procedure for mechanical measuring tools
appears at the end of this chapter.

A typical equipment calibration procedure includes:

o purpose and scope;

o frequency of calibration;
o equipment and standards required;
o limits for accuracy and precision;
o preliminary examinations and operations;
o calibration process description;
o remedial action for product; and
o documentation requirements.

Personnel
Managers and administrators must understand the scope,
significance
and complication of a metrology program in order to effectively
 administer it.

The selection and training of competent calibration personnel is

an
important consideration in establishing an effective metrology
program.
The GMP regulation requires that, "calibration shall be performed by
personnel having the necessary education, training, and experience."
Personnel involved in calibration should ideally possess the
following
qualities:

o technical education and experience in the area of job

assignment;

o basic knowledge of metrology and calibration concepts;

 o an understanding of basic principles of measurement
disciplines, data processing steps, and acceptance
requirements;

o ability to follow instructions regarding the maintenance

and
use of measurement equipment and standards;

o knowledge of the overall calibration program; and

o mental attitude which results in safe, careful, and

exacting
execution of his or her duties.

Records

Calibration of each piece of equipment must be documented to

include
the calibration date, the calibrator, and the date the next
calibration
is due. Many manufacturers use a system where each device has a
decal
or tag which contains the date of calibration, by whom calibrated,
and
date the next calibration is due. Examples of such decals are shown
on
the next page.

These decals are examples of the types commonly used to identify

the
status of measuring instruments and tools. They are available as
catalog items or a firm may use its own artwork to purchase decals
with
specialized wording.

<Example Decals>

Calibration information is entered onto cards or forms, one for

each piece of equipment, or entered into a computerized data system.
Most data systems include the calibration date, by whom calibrated,
date
recalibration is due, the reason for the calibration, comments,
address
of the manufacturer and calibration laboratory, equipment
specifications, serial number, use, etc. An example of a typical card
used to record calibration information follows.

<Example Calibration Card>

Schedules

Measuring instruments should be calibrated at periodic intervals

 established on the basis of stability, purpose, and degree of usage
of
the equipment. Intervals should be shortened as required to assure
prescribed accuracy as evidenced by the results of preceding
calibrations. Intervals should be lengthened only when the results of
previous calibrations indicate that such action will not adversely
affect the accuracy of the system, i.e., the quality of the finished
product.

A firm should use a suitable method to remind employees that

recalibration is due. For small firms, calibration decals on the
measuring equipment may be sufficient because recalibration can be
tracked by scanning the decals for the recalibration date. For other
firms, a computerized system, calibration cycle cards, tickler file,
or
the like may be used. Calibration cycle cards are maintained in a
12-
month (12-section) tickler file. There is one card per item of
measuring equipment. The cards in the section of the file for the
current month are pulled and all of the equipment listed is
calibrated.
 For example, in a 6-month calibration cycle, when an instrument is
calibrated in May, the card is moved from the May section to the
October section of the file. When the file is checked in October,
the
cycle card will be there to remind the firm that calibration is due.
The
process is repeated until an event such as instrument wear-out occurs
and the respective cycle card is removed from the file.

Cycle cards are used where a firm has many instruments to be

calibrated. It would be rather difficult to keep track of the
calibration of a large number of instruments by re-viewing
calibration
record cards or scanning the decal on each instrument. It is easier
to
use a cycle card file. A cycle card file or equivalent also must be
used
if the calibration records are filed by type of instrument or
manufacturer rather than due date. A typical cycle card follows. The
"calibration card number" blank refers to the calibration record
card
for the same item of equipment.

<Example Calibration Cycle Card>

Standards

Where practical, the GMP regulation requires that standards used

to
calibrate equipment be traceable to the National Bureau of Standards
(NBS), or other recognized standards. Traceability also can be
achieved
through a contract calibration laboratory which in turn uses NBS
services.

The meaning of traceability to NBS is not always self-evident.

Two
general methods commonly used to establish and maintain traceability
to
NBS are:

o NBS calibration of standards or instruments: When this

method
is used, private standards are physically sent to NBS for
calibration and return.

o Standard Reference Materials (SRM's): NBS provides

reference
materials to be used in a user's calibration program. These
SRM's are widely used in the chemical, biological, medical
and
environmental fields.
 Information can be obtained from the "Catalog of NBS Standard
Reference Materials", NBS Publication 260, 1984-1985 Edition,
available
free from the National Bureau of Standards, Office of Standard
Reference Materials, Chemistry Building, Room B311, Washington, D.C.
20234.

The GMP regulation states: "If national standards are not

practical
for the parameter being measured, an independent standard shall be
used. If no applicable standard exists, an in-house standard shall
be
developed and used." In-house standards should be fully described in
the device master record. Independent or in-house standards must be
given appropriate care and maintenance and must be used according to
a
written procedure as is required for other calibration activities.

EQUIPMENT ENVIRONMENT

As appropriate, environmental controls must be established and

 monitored to assure that measuring instruments and standards are
calibrated and used in an environment that will not adversely effect
the accuracy required. Consideration should be given to the effects
of
temperature, humidity, vibration, and cleanliness when purchasing,
using, calibrating, and storing instruments.

AUDIT OF CALIBRATION SYSTEM

The calibration program must be included in the quality assurance

system audits required by the GMP regulation. These audits should
determine the continuing adequacy of the calibration program and
assess
compliance with the program.

Many manufacturers utilize contract calibration laboratories to

calibrate their measurement and test equipment. If this is the case,
the
FDA views the contract laboratory as an extension of the
manufacturer's
GMP program or quality assurance program. Normally, FDA does not
inspect contract laboratory facilities, but it would expect the
manufacturer to audit the contract lab, if feasible, to verify that
proper procedures are being used. If problems occurred due to
inadequate calibration, and FDA needed to determine where the
problems
existed, FDA could visit the contract laboratory. Either the contract
laboratory
or the manufacturer might be held responsible for inadequate
procedures
leading to a defective, unsafe device or false data. Generally, the
manufacturer of the finished device is responsible for assuring the
device is manufactured under an acceptable GMP program.

When a medical device manufacturer utilizes a contract

calibration
laboratory, FDA expects the manufacturer to have evidence that the
equipment was calibrated according to the GMP requirements. The
manufacturer can do this by:
o requiring and receiving certification that the equipment
was
calibrated under controlled conditions using traceable
standards;

o maintaining an adequate calibration schedule;

o maintaining records of calibration; or

o periodically auditing the contractor to assure appropriate

and
adequate GMP procedures are being followed.

Certification notes and data should include accuracy of equipment

 when received by the lab to facilitate remedial action by the
finished
device manufacturer, if necessary. Certification should also include
accuracy after calibration, standards used, and environmental
conditions
under which the equipment was calibrated. The certification should be
signed and dated by a responsible employee of the contract lab.

The contractor should have in place the applicable controls

called
for in the GMP regulation. For example, the contractor should have:

o written calibration procedures;

o records of calibration;
o trained calibration personnel; and
o standards traceable to NBS or other independent
reproducible
standards.

If in-house standards are used by a contractor to calibrate

device-
 related measuring equipment, these standards must be documented,
used,
and maintained the same as other standards.

INTEGRATING MEASUREMENTS INTO THE QA SYSTEM

Proper and controlled calibration can contribute to overall

quality
by assuring that unacceptable items are not accepted, and acceptable
items are not rejected. If the appropriate product-quality
parameters
are not checked, however, calibrated equipment will have little
impact
on assuring quality.

A good quality assurance program must include calibration

activities. However, proper calibration will be of little use unless
the applications of the measurement equipment are properly developed
and qualified during the preproduction development of inspection test
methods and procedures. As stated, effectiveness depends on the
participation and influence of QA at the preproduction stage.
Calibration of equipment cannot correct poor design of products nor
can
it compensate for poor applications of equipment and techniques. It
is
the continued use of a complete, integrated quality assurance system
that assures that safe and effective devices are produced.

gmp1-14: 3/7/91

EXHIBITS

Examples of calibration cards, decals, and cycle cards were

presented above in the text. Examples of a device cleaning procedure
and a calibration procedure follow. Manufacturers may use these as
presented if they match the firms operations; or may modify them to
meet specific requirements.

P.C. Board Cleaning

This procedure covers the cleaning of printed circuit boards by

using an automatic washer. The procedure covers operation, shut down,
cleaning, and routine maintenance.

Calibration Procedures for Mechanical Measuring Tools

This is a calibration procedure for mechanical measuring tools.

In
actual use, the initial accuracy of each tool is checked using the
procedure and is recorded. Thereafter, each tool is recalibrated
(checked) versus the initial accuracy. Of course, the initial
accuracy
 must meet or exceed the requirements of the measurements to be made
with
the tool. Precision is checked by making several measurements at
various points on the tool's measuring face (surface).

TITLE: P.C. Board Cleaning

NO: REV: Sheet: 1 of 2

DRAFT: ___________________________
APP: ____________
Date: __
[database1.0 PURPOSE: The purpose of this procedure is to document
production
operations performed on the XXXXXX printed circuit board washer.
 2.0 This procedure sequentially identifies all operations necessary
to
properly operate and maintain this equipment.

3.0 OPERATING PROCEDURES:

3.0.1 Switch the Exhaust Systems fan on.

3.0.2 Assure that the sump pump is on at the circuit breaker panel.

3.1 Turn the power switch to the "ON" position.

3.2 Push the main power "START" button (#21 on Control Panel
Diagram).

3.3 Visually inspect all pump compartment and screen filters for
debris
- make sure they are clean before continuing.

3.4 Push the fill buttons on the rear control panel to fill the wash
and rinse sections with water. Make sure all drain lines are closed.
The
incoming water will stop automatically when the tanks are filled to
the
correct levels.

3.4.1 Add 4 gallons XXXXXX detergent to the wash tank.

3.5 Depress the center knob on the temperature controllers (#30 on

control panel diagram) and turn clockwise until the red pointer
indicates 60 C (140oF) for the wash tank and 60 C (140oF) for
the
rinse tank.

3.6 Wait about 10 min. for water temperature to rise in the wash and
rinse tanks. Wait until the red lights on the temperature
controllers go off and the black needle aligns with the red
pointer.

3.7 Push the START-STOP button (#25 on diagram) on for the conveyer.

3.7.1 Adjust the "SPEED CONTROL" (#27 on diagram) to the correct

setting for the boards to be run. See the cleaning
specifications for each family of boards for the
setpoints.

3.8 Push the "START" button (#28 on diagram) on for the Dryer cycle.
NOTE: conveyer belt MUST be moving when dryer section is on or the
equipment will be damaged.

3.9 Turn Photocell Switch (on Rear Panel) to the "Automatic"

position.
 Sheet 2 of 2

4.0 SHUT DOWN PROCEDURES:

4.1 Push the dryer cycle "STOP" button for the Wash and Rinse
sections
(#29 on control panel).

4.2 Turn Photocell Switch (on Rear Panel) to the "OFF" position.

4.3 Push the conveyer "START - STOP" button (#25 on diagram) to stop
the conveyer.)
 4.4 Pull the DRAIN buttons on the control panel for the wash and
rinse
sections. Using litmus paper, take a reading on the wash tank
before
draining it. IF the wash water has a reading of "10" or less
drain
it; otherwise, do not drain the wash tank. Always drain the
rinse
tank.

4.5 Pull the FILL buttons on the control panel for the wash and
rinse
sections to let water flush the equipment for 5 minutes. Using a soft
cloth, wipe off any residue remaining on the equipment.

4.6 Pull the drain buttons on the control panel for the wash and
rinse
sections to let the water drain.

4.7 Remove the screen filter in the washer and remove any debris.

4.8 Wipe the exterior front section of the machine with a soft cloth.

4.9 Push the main power "STOP" button, (#33) to shut off the
equipment.

5.0 MAINTENANCE:

5.1 Monthly

5.1.1 Lubricate the conveyer drive chain with high temperature

grease.

5.1.2 Check the wear strips on the conveyer belt frame and replace
if
required. These are 2 white plastic strips located at the front of
the equipment.

5.1.3 Check conveyer belt tightness - using a wire cutter and needle
nose pliers, remove links to tighten if required.

5.2 Quarterly

5.2.1 Shut off power in main panel at rear of equipment.

5.2.2 Lubricate pump motor ball bearing using standard bearing

grease.

5.2.3 Lubricate flange bearings on conveyer shafts with bearing

grease.

5.2.4 Check all wiring for loose connections and tighten if

necessary.
 5.2.5 Check all heater contacts - replace worn contacts.

Sheet 1 of 1

TITLE: Calibration Procedures for Mechanical Measuring Tools

No. Rev. ECN Notes

______________________________________________

________________________________________________________________________
______ Drafted by App. Date

PURPOSE: This procedure establishes a standard method for the

calibration and maintenance of mechanical measuring tools such as
 micrometers, calipers, etc.

SCOPE: All measuring tools being used to set specifications or

measure
conformance to specifications, such as micrometers, calipers, etc.,
will be included in the calibration program. Each tool will be
assigned a number and checked every six months for accuracy. If you
suspect a tool is damaged or out of calibration, it should be removed
from service and brought to the Quality Control Lab (QC) for checking.
To enter a tool in the program, take it to QC where a number will be
assigned and initial accuracy checked and recorded.

PROCEDURE:

1. Each measuring tool shall be kept clean and maintained in a

protective container. As needed, all threads and slides shall be
lubricated with a fine tool oil to assure free movement.

2. The calibration shall be done by a comparison to standard gage

blocks traceable to the National Bureau of Standards with an
accuracy 3
to 10 times greater than that of the measuring tool.

3. The comparisons shall be made at different points along the

measuring range of the tool. The gage blocks used shall be picked at
random to assure that the measuring tool is not checked at the same
points on each calibration cycle. When a measurement is made, move
the
gage blocks from one side of the tool's measuring face to the other
on
an X/Y axis to assure no wear or taper exists on the measuring faces.

4. Measurement tools not intended for testing or manufacturing do

not
require calibration in accordance with the GMP regulation. These
tools
should be kept out of manufacturing or labeled to avoid inadvertent
use.
Otherwise, they should be entered in this calibration program.

5. After calibration, the date of calibration and the next due date
of
calibration shall be recorded on the Calibration Form No. .
Any
adjustments and/or repairs to the tool should be recorded. The form
is
placed in the tickler file according to the next calibration date.

6. If a tool is found to be out of calibration, the QC lab will

immediately pass the out-of-calibration information to the
appropriate
supervisor in the department where the tool is used. The Department
and
QC management will take appropriate remedial action for affected in-
process or finished devices.

gmp1-14: 3/8/91

gmp 1.18 3/12/91

 GMP - CHAPTER 6 - DEVICE MASTER RECORDS

CHAPTER 6 DEVICE MASTER RECORDS

INTRODUCTION
Document For Intended Employees
Adequate Information
Preparation and Signatures
Location of Records
Record Retention
DMR CONTENTS
DMR Index
General Documents
Specific Documents
Records for In Vitro Diagnostic Products
Device Specification
WRITTEN PROCEDURES
Developing Procedures
Content of Procedures
CHANGE CONTROL
EXHIBITS
Documents That May Appear in a Device Master Record
Device Master Record Index
Product Specification Portable Defibrillators
Zener Diode Specification
Label Example
Handle Assembly and Parts List
Cable Assembly and Parts List
Device Master Record Index for Amylase
Product Description
Amylase Diluent Solution
Filling Record Liquid, Non Freeze Dried
Finished Product Release Form
Production Sample Card
Shop Order Traveler

INTRODUCTION

A device master record (DMR) is a term used in the Good

Manufacturing Practices (GMP) regulation for all of the routine
documentation required to manufacture devices that will consistently
meet company requirements. Section 820.3(i) of the GMP regulation
defines "device master record" as a compilation of records
containing
the design, formulation, specifications, complete manufacturing
procedures, quality assurance requirements and labeling of a
finished
 device. The detailed requirements for master records are contained
in
section 820.100, 820.181, 820.182, etc.; however, almost all sections
of
the GMP regulation have requirements related to the DMR. The DMR
contains specifications for, or a full description of, the device,
and
a full description of how to manufacture the device
 including facilities, environment, and production equipment. In
addition
to the device specifications, a DMR contains documents that cover
typical manufacturing activities such as:

o procurement,
o assembly,
o labeling,
o test and inspection, and
o packaging.

Note that the listed activities and records or documents are

required to produce any product -- medical, industrial or consumer.
There is nothing special about device master records except the name!
Also, note that in common usage, the term "device master record" is
used for the total record or any of its individual records. Therefore,
the term is singular for the total record, singular for a single
document, and plural for a group of single documents. The term also
may
refer to an original record or copy of a record.

Master records must be technically correct, contain and/or

reflect
the approved device and process designs, be change controlled,
contain
the release or other control date, contain an approval signature, and
be
directed toward the intended user. These requirements are in the GMP
regulation because the DMR is the "beginning and end" of a product --
errors in the DMR will have a serious impact on the state-of-control
of
the manufacturing operation and may have a serious impact on the
safety
and performance of the device. The DMR must be accurate and complete
because the essence of the GMP regulation is a quality assurance
program based on producing a finished device that meets the device
master record requirements. In turn, the device master record must
accurately reflect the device intended to be produced by a firm.

Document For Intended Employees

The content, style, language, GRAPHICs, etc., of master records

must
be directed toward the needs of the intended employees and, if the
record is for labeling, it must be directed toward users. A failure
to
consider the intended user leads to confusion and means that the
company has not achieved the state-of-control intended by the GMP
regulation. Therefore, applicable records must be directed toward the
needs of procurement, processing, and test/inspection personnel,
rather
than the needs of drafting, technical services, or product
development
 departments. Likewise, installation instructions must be directed to
installers. Labeling is often prepared by the same employees that
draft
master records; and, these employees should also be aware that
labeling
must meet the needs of the user as directed by 21 CFR 809.10 and
801.6.

In any manufacturing activity such as assembly, labeling,

processing, testing, etc., achieving and maintaining a state-of-
control
is enhanced by appropriate personnel knowing:

o what task is to be done,

o how to do the task,
o who is to do the task,
o what task is being done, and
o what task was done and/or the results of the activity.

In order for employees to perform a job correctly, they must

know
 exactly what is to be done and exactly how to do the work. GMP
sections
820.181, 820.182 require that what is to be done be documented in
the
device master record. The DMR also contains test and inspection
procedures and data forms that are used to help determine and record
what was done.

Documents that instruct people how to fabricate, assemble, mix,

label, test, inspect, etc., or how to operate equipment should:

o be directed toward the needs of the employees who will be

using them and not directed toward the draftsperson or
researcher;

o match the tools and equipment to be used;

o be correct, complete and current;

o depend on part numbers and basic drawings to transfer

information rather than almost photoGRAPHIC quality
drawings.
If a component is changed, the pictorial representations on
the drawings are no longer correct and may be very
confusing
to employees, particularly new employees.

The how-to-manufacture instructions must be adequate for use by

the
intended employees and correct for the intended operation. In the
medium-to-large company, the instructions tend to be extensive
technical (engineering) drawings and written procedures. In any
company,
particularly small firms, the work instructions may take several
forms
as discussed below.

o Engineering drawings may be used if employees are trained

to
read and use them. Some of the how-to information comes
from
employee training rather than from drawings.

o Assembly drawings may contain parts list and quality

control
criteria. A separate quality control test and/or inspection
procedure is not always necessary. An example of an
engineering drawing for assembling a handle is exhibited at
the end of this chapter. This drawing also includes some of
the quality control criteria for evaluating the handle in
Notes 1 and 2. The parts list for the handle is on the page
after the assembly drawing. Some firms use larger sheets of
 paper for assembly drawings and include the parts list on
it.
The combination drawing results in instant availability of
the
parts list and reduces the number of drawings to be
controlled. An example of an engineering drawing for
assembling a cable and the associated parts list follows
the
handle assembly drawings.

o Exploded-view drawings are used when employees cannot read

plan-view engineering drawings. Exploded-view drawings tend
to
be more "how to" than plan-view drawings. Exploded-view
drawings are expensive to draft -- in some cases it may
cost
less to teach employees how to read and use ordinary plan-
view
drawings.

o Step-by-step written procedures may be used to detail how

to
perform specific tasks with check-off blanks to show that
each
specific task was performed. This type of procedure is
 commonly used for critical operations and where there is
little or no visual indication of what has been done,
such
as for mixing chemicals. 6

Documentation may be supported by production aids such as labeled

photographs, video tapes, slide shows, assemblies, or sample
finished
devices. All of these perform master-record functions and must be
current, correct, and approved for the intended operation.

The most commonly used aids are models or samples. There are two
conditions that should be satisfied in order to use these aids.
First,
a written specification for the sample must be contained in the
device
master record. This specification, of course, may be the same as the
specification for the assembly or finished device to be manufactured.
This specification must be subject to a formal change-control
procedure.
Even though a model is available, the specification is needed for
present and future product development, and for production control
purposes. Second, the sample must:

o adequately reflect the device master record specification;

o be identified as an approved acceptable sample, which means

it
should meet the company required workmanship standards; and

o when appropriate, contain a drawing number, revision level,

and control number (lot, serial, batch).

A card/tag as shown in the exhibits or an equivalent card may be

used to identify and help control the use of samples of assemblies
or
finished devices. Such tags are usually covered by a clear plastic
pouch and attached to the model or sample.

Samples and other aids such as photographs are subject to normal

wear and tear in a production environment. Therefore, such aids
should
be adequately protected by a suitable means such as being located in
a
protected area, or covered by a protective pouch or container.
Production aids must be periodically audited to make sure they
continue
to be suitable for the intended use (see sections 820.20, 820.100,
and
820.181).

Adequate Information
 Although a firm tries to document for the intended employees,
there
is a need to audit periodically to see how well the goal is being
met.
There are various means of determining if information in the device
master record, production tools, and other production elements are
adequate for a given operation and associated employees. These
include
analyzing the amount of:

o assistance required by new employees;

o assistance required when a new device is manufactured;
o confusion and hesitation;
o exchanging of information among employees;
o drafting of "homemade" documentation by the line employees;
o rework;
o products produced (productivity);
o complaints from departments that subsequently process the
device;
 o customer complaints.

If any of these factors persist and if they are out of line with
industry norms or with the production of old designs, then the firm
should take corrective action. The corrective action may include
changes in supervision, documentation, adding new documentation,
modifying the design, using different tools, modifying the
environment,
etc. Corrective action, other than necessary "fire fighting" to
prevent
shipment of defective devices, should not be taken, however, until
the
real problem is identified.

Preparation and Signatures

A separate device master record is required for each type or

family
of devices. Also, a separate device master record is required for
accessories to devices when these are distributed separately for
healthcare purposes. Such accessories are considered to be finished
devices. In practice, if the device and accessories are made by the
same
firm, the master record for the accessory may be incorporated into
the
master record for the primary device.

Section 820.181 of the GMP regulation requires that an

individual(s)
be designated to: prepare, date, and approve the DMR; and authorize
changes. An individual(s) with the necessary technical training and
experience must be designated to prepare and control master records.
In
addition to requiring approval signatures on device master records,
the
GMP regulation requires individual identification for a few other
activities. For convenience, these activities along with the section
numbers that require them are listed in Table 6.1.

Table 6.1 GMP ACTIVITIES REQUIRING INDIVIDUAL IDENTIFICATION

820.20(b) Audit Certification

820.121 Proofreading Critical Device Labeling
820.161 Release of Finished Critical Devices
820.181 Device Master Record
820.181 Changes in Master Record
820.185(a) Acceptance Record for Critical Components
820.185(c) Inspect/Test Records for Critical Devices
 The list is self-explanatory except for audit certification. When
a
firm certifies in writing to FDA that GMP system audits have been
performed, the certification letter is signed by a company official
according to standard commercial practice.

If a record that requires a signature is maintained on a computer,

it is best if the designated individual(s) maintains an up-to-date
signed printout of the record. Where it is impracticable to maintain
current printouts, computer-compatible identifiers may be used in
lieu
of signatures as long as there are adequate controls to prevent
improper
use, lack of employee identification, inaccurate data input, or
other
 inappropriate activity. If identifiers such as coded badges and
equipment keys are not controlled (i.e., not restricted to
designated
employees), then these will not meet applicable GMP requirements.

Location of Records

Device master records must be stored at the manufacturing

establishment or at other locations (820.180) that are reasonably
accessible to company employees responsible for the manufacturing
activities and accessible to FDA investigators. Appropriate records
may
be maintained in computer data banks if the records are protected,
change controlled, and readily accessible for use by responsible
employees at all relevant facilities. It is acceptable for a
manufacturer to maintain records on microfilm and discard the
original
hard copies. Microfiche and/or microfilm reductions may be used in
lieu
of original record retention if the following conditions are met.

o All reductions must be readily available for review and

copying by FDA investigators and designated company
personnel
at any reasonable time.

o All necessary equipment must be provided for viewing and

copying the records.

o Reproductions must be true and accurate copies of the

original
record.

If the reproduction process results in a copy that does not

reveal
changes or additions to the original record, the original must be
retained. In this situation, the reproduced copy and any image shown
on
a viewing screen must note any alteration from the original and
indicate that the original record is available.

By maintaining master, complaint, and other records required by

the
GMP regulation at the manufacturing establishment or other
reasonably
accessible location, responsible officials of a company can exercise
control and accountability over the entire manufacturing process and,
thereby, maximize the probability that the finished device conforms
to
its design specifications. This GMP requirement helps assure that
responsible officials at the manufacturing establishment have ready
access to those documents essential for producing devices and for
 conducting self-inspections, complaint investigations, failure
analyses, and audits. The device master record must be a single
source
document or file, as stated in the preamble to the GMP regulation.
Portions of this file may be kept in various locations. A device
master
record may exist as:

o one or more files or volumes of the actual records

containing
the information required by the GMP regulation;

o a reference list of such documents and their location; or

o any combination of actual documents or reference lists.

These documents must contain the latest revisions, be signed, and

be
dated to show they have been checked for accuracy and approved for
use.
 The GMP regulation allows use of reference lists as a means to
reduce the duplication of records, particularly duplication of
general
documents such as standard operating procedures (SOP's). Use of a
reference list also allows filing of master record documents at
several
convenient locations. If the master record contains a list of
documentation, the actual documents must be available for employee
use
and FDA inspection at the manufacturing site or other reasonably
accessible locations. As noted above, this is a key and important GMP
requirement. Typical locations of various master records are shown in
Table 6.2.

Although the GMP regulation allows use of reference lists, FDA

investigators performing an inspection of a company must have access
to
actual records for review and copying during reasonable business
hours.
FDA investigators review these records to determine if a firm is
complying with the GMP regulation and with the Food, Drug, and
Cosmetic
Act. Records deemed confidential by a manufacturer should be marked
to
aid FDA in determining whether or not specific information may be
disclosed under the Freedom of Information Act.

Record Retention

The GMP regulation in section 820.180(b) requires that all

records
pertaining to a device shall be retained for a period of time
equivalent to the design and expected life of the device, but in no
case less than two years from the date of release for commercial
distribution by the manufacturer. For very short life devices, such
as
RIA products, manufacturers may obtain a variance from FDA to reduce
the
two-year requirement to one year. In some cases, where maintaining
records for the life of the device may be overly burdensome or
impractical, manufacturers may decide the appropriate time to retain
records beyond the two-year minimum. Thus, manufacturers of long-life
products should make prudent decisions as to how long to keep
records
beyond two years. For example, there is no value in keeping records
for
long-life devices such as stretchers, surgical tools, containers,
etc.,
beyond two years as the probability is low that any post-distribution
remedial activity will occur. For devices that must be repaired or
capital equipment devices that probably will be updated, records
must
 be retained, as appropriate, to support these repairs or
modifications.
Master record requirements apply to devices modified in the field by
the manufacturer's representatives after the devices are commercially
distributed. Modification of a device is manufacturing and the GMP
regulation covers all manufacturing of devices where the result is
placed into commercial distribution. In any case,
a firm must be prepared to provide a rationale for its decision to
discontinue record-keeping. For example, the decision could be based
on
the length of time beyond two years that records have been
maintained
and on the fact that there has been no adverse feedback from
customers
during that period on the device's "fitness for use."

Table 6.2 LOCATION OF DEVICE MASTER RECORDS

Typical Locations of Documents

 TYPE OF DMR ELEMENT ORIGINALS
WORKING
COPIES

Reference list(s) Engr. master file

Component drawings Engr. or Manuf. Engr. Manuf. or

Procurement
master file

Component acceptance SOP master file Receiving

department
procedures

Device specifications Engr. master file Marketing or

Engineering

Manufacturing procedures Engr. or Manuf. Engr. Manufacturing

master

file

Test specifications Engr. master file Engr. or Manuf.

Engr.

Test procedures Engr. or Manuf. Engr. Manuf., QA, or

QC
master file

General inspection Manuf., QC, or SOP Manufacturing

or QC
procedures

ma

st

er

fi

le

Label drawings Engr. master file Engr., QA, or

Manuf.

Label artwork Artwork master file Engr.,

Procurement

Label control procedures Manuf., QC, or SOP Manufacturing

master file

Cleaning procedures SOP master file

 System audit procedures SOP or QA master file Quality
Assurance

SOP = Standard Operating Procedure

QA = Quality Assurance
QC = Quality Control

DMR CONTENTS

As discussed above, the DMR shows and/or tells employees how to

perform specific and general functions related to the production of
a
device. The GMP regulation does not dictate how this information is
to
be arranged or filed except that it must be readily accessible. In
most
firms, this information is contained in records that are specific for
the device being produced and in general records that are applicable
to
all devices being produced. Because a DMR may contain many documents,
an index is usually needed.
 DMR Index
A master record for a complex device or a device manufactured by
complex processes may contain many documents. For convenience, many
firms generate an index, which lists all of the documents in a
master
record. An index, of course, is an overall reference list. It may
eliminate the need for other lists, incorporate other lists, or refer
to
other lists. An index may be arranged: according to the standard
flow
of manufacturing operations; by major subassemblies in the device;
or
by specific operational area in a factory. A sample index and
associated procedure are presented later in this chapter. Using an
index, employees can find related drawings and information even if
they
only know the correct name of the device. An index is a valuable
communication tool which increases the state-of-control of a firm and
reduces costs by reducing the effort, time, and frustration required
to
locate a document or related documents. Thus, an index helps
manufacturers meet the accessibility requirement for records.

General Documents

General documents are used for many activities that are essential
to
operating a manufacturing establishment -- these are not specific to
any
given product even if the company produces only one product. Thus,
the
DMR includes general documents such as standard operating procedures
(SOP's) and standard quality assurance procedures (QAP's). If the
company added another product line, the basic content of these
documents would undergo none or only minor changes.

In a typical manufacturing operation, general SOP and QAP

documents
include the following:

Cleaning procedures Product development protocol

Insecticide use-removal procedures Component inspection
procedures

Air conditioning/heating procedures Workmanship standards

Tool kit policy Design review
policy/procedure
Safety procedures Label review policy/procedure

Procurement procedures Sterile water system

maintenance
Returned goods policies
Ca

li

br

at

io

po

li

cy

Drawing numbering system Complaint procedure

Change control procedure Recall procedure
Service policy Materials review
policy/procedure
This list is not all inclusive. Medium-to-large companies tend to
have many of these general documents to guide management in
maintaining
consistent operations. A very small company would have only the most
essential and appropriate of these documents, such as procedures for
numbering drawings, change control, and use of hazardous materials.
 The original master copy of each general procedure is filed in
the
department specified by management as having responsibility for
maintaining each of them. The working copies of the above procedures
are usually located in SOP manuals and QA manuals. The procedures
are
usually numbered and arranged in a logical order by topic. The GMP
regulation does not require firms to have SOP or QA manuals; however,
the experience of many industries has demonstrated that such manuals
are worthwhile if they are kept current, contain real working
procedures, and do not contain useless puffery.

Specific Documents

Specific documents are drawings, procedures, labels, data forms,

etc., for a specific product or family of products. The originals of
specific documents are usually located in files in engineering or
technical service departments. In most firms, specific documents
contain no general information; however, they often refer to general
documents. (A list of specific and general documents is exhibited
later
in this chapter.) The number of specific documents for a given
product
line may range from about 10 to several hundred. If large numbers of
documents are needed, an index is usually needed to help locate them.

Records for In Vitro Diagnostic Products

The main differences between master records for chemical-based in

vitro products and for electromechanical products, such as
instruments
and artificial kidneys, is terminology and relatively extensive use
of
written processing procedures and status reports rather than a few
assembly drawings and test/inspection reports. For example, master
records for chemical-based devices would contain a manufacturing
section dealing with areas such as solution preparation and filling,
whereas manufacturing sections for electromechanical products would
cover operations such as assembly. Status records for weighing,
mixing,
filling, etc., are used for general control of in vitro products.
They
are also used because it is often difficult to determine the status
of
in-process in vitro products by looking at them -- the opposite is
true
for most hardware devices. Records for in vitro devices also must
contain data that allows major components and assemblies to be traced
(809.10).

Device Specification

A device or product specification is a specific document in the

 device master record that briefly describes and gives all important
details of the external characteristics of a device. The
specifications
may also contain some internal characteristics of the device that
are
important to the manufacturer and/or the users. For some devices,
many
of the external characteristics such as temperature tolerance are
related to the environment in which the devices will function
properly.
For some in vitro products, the package insert is used as the device
specification.

Generally a product specification will contain the device's:

o product trade and common name(s);

o intended use(s);
o performance characteristics and theory of operation;
 o regulatory classification;
o physical characteristics;
o environmental limitations and product stability;
o important components and formula (if applicable);
o manufacturing cautions; and
o user safety characteristics.

Manufacturers should have device specifications for all devices

being manufactured to help assure that manufacturing specifications
are
adequate to produce devices that conform to the approved design of
the
device. A preliminary device specification should be written at the
beginning of a project and updated as the device is developed or
modified. Specifications are usually developed by the marketing and
product development departments with review and consultation by
quality
assurance, manufacturing, and other departments. The contents of the
final specification must agree with the other elements of the device
master record and with actual devices when they are manufactured.
Before
the start of full-scale production and commercial distribution, the
device specification must be dated, approved, and placed under
change
control.

Table 6.3 contains a list of characteristics that often appear on

device specifications; however, note that not all of the listed items
will appear in the specifications for a given device.

In addition to defining and describing a device, a specification

is
a communication tool which, if used in a timely manner, can help
achieve some important results. First, it helps assure that everyone
is
talking about the same device and working toward the same objectives
with respect to safety, effectiveness, human factors, configuration,
etc. Also, it is used as a guideline for developing test and
inspection
procedures for the finished device.

Ultimately, the device specification or a condensed version of it

should be used in catalogs, or other product documentation to aid
communications between salespersons and customers.

The use of device specifications will result in:

o improved communications between employees on a departmental

and interdepartmental basis;

o less confusion and increased morale;

o an improved state-of-control; and

 o a higher probability of meeting cost, time, safety,
effectiveness, and regulatory compliance objectives.

Also, if the marketing department uses the specifications when

preparing advertisements and catalog sheets, public relations with
users
will be enhanced because the marketing documents are based on proven
scientific safety and performance claims for the actual device. That
is, the user has an opportunity to read the technical specifications
of
the item actually being offered for sale.

A sample product specification for a portable defibrillator is in

the exhibits at the end of this chapter. This specification is long
and
detailed because it is a combined product and test specification, and
because it is for a complex critical device.

Table 6.3 ITEMS THAT MAY APPEAR IN A DEVICE SPECIFICATION

1. Name of Product

a. Tradename d. Chemical name

b. Trademark e. Official name
c. Generic name f. Common name

2. Performance Characteristics

a. Description/Intended use e. Contraindications

b. Accessories f. Input/Output requirements
c. Functional parameters g. Human interface
d. Limitations h. Other

3. Classification

a. Regulatory c. Functional
b. Commercial d. Other

4. Physical Characteristics

a. Weight e. Consistency
b. Size f. Packaging
c. Color g. Power requirements
d. Form/Shape h. Other

5. Environmental Limitations

a. Operating temperature f. Moisture protection

b. Storage temperature g. Pressure, altitude
c. Vibration and shock h. Electromagnetic interference
d. Voltage limits i. Electrical transients
e. Humidity j. Other

6. Important Components

a. Active ingredients f. Service labeling

b. Major subsystems g. Components supplied by user
c. Diagnostic kit materials h. Software
d. Accessories i. Other
e. Labeling

7. User Safety and Performance Considerations

a. Chemical e. Personnel training

b. Electrical f. Periodic testing
c. Heat g. Maintenance
 d. Sharp, moving parts h. Other

WRITTEN PROCEDURES
 Many sections of the GMP regulation require written procedures
for
guidance in performing various QA and manufacturing tasks. Certain
devices, such as in vitro products, because of the nature of the
manufacturing operations tend to have a relatively large number of
written procedures.

Written procedures are used for product development,

manufacturing,
and post-marketing activities to:

o improve communications and guidance;

o assure consistent and complete performance of assigned
tasks;
and
o promote management of operations.

In large manufacturing facilities involving many operations and

people of various skill levels, written procedures are usually
necessary. In a small firm, communication lines are usually short,
few
people are involved, and management is readily available to provide
guidance, so that the need for written procedures is usually
considerably less than for a larger firm.

A firm, particularly a small firm, may conclude that GMP

requirements for written procedures are not applicable for a
particular
operation. Such a decision, however, must be supported by management
observations that sufficient control is present to meet the intent
of
the written procedure, for example, on the basis of the limited
number
of rejects, lack of complaints, complaints, etc. If rework,
confusion,
or complaints are excessive such that unsafe or ineffective devices
are
likely to be or are being distributed, then written procedures
and/or
other corrective actions are needed.

Often training and work experience alone or combined with

drawings,
photographs, and models are valid substitutes for written procedures.
For example, machinists are typically skilled personnel who
fabricate
components and finished devices using dimensioned drawings for
guidance
instead of written procedures. The company and FDA investigator must
evaluate each situation and determine the need for written
procedures
based on the training and knowledge of the operators and the control
 needed to meet device specifications. Typically, a written procedure
is
not necessary when:

o the activity is very simple;

o the activity is relatively simple and models are used as

aids;

o straightforward quantitative rather than qualitative

standards
determine acceptility; and

o the operation is performed by personnel highly skilled

relative to the task being performed.

Written procedures and associated history or status records,

however, are often needed for filling, mixing, or other activities
where there is no change, such as color, texture, or form, to
indicate
that the activity has been performed. Such procedures and records are
needed for critical manufacturing operations.

When the GMP regulation requires a procedure, but does not

specify a
 "written" procedure as in section 820.115, manufacturers must
evaluate
their existing controls to determine if these are adequate without
written procedures. Some firms, however, have found that they must
use
written procedures even if not required by the GMP regulation in a
specific area in order to comply with the overall GMP regulation. For
example, some firms have found that they cannot comply with 820.115,
Reprocessing of Devices, unless they use a written procedure because
reprocessing is not frequently done for some types of products. Thus
employees tend to forget how to perform the reprocessing. Firms
should
determine that they meet all GMP requirements and, if necessary,
exceed
them in order to produce finished devices that meet DMR
specifications
because FDA insists that firms meet their quality claims [FD& C Act,
section 501(c), and GMP 820.100 and 820.160]. To achieve this
required
state-of-control may require fewer or more written procedures than
specifically required by the GMP regulation. FDA does not insist that
a
firm meet GMP requirements or generate records that do not
contribute
to assuring conformance to specifications simply because they are
part
of the GMP regulation. Also, section 519(a)(1) of the FD& C Act
prohibits recordkeeping requirements that are unduly burdensome to a
device manufacturer.

Developing Procedures

Developing written procedures is relatively labor intensive and

time
consuming which may lead to use of "back-of-the-envelope" notes
instead
of formal procedures. Likewise, changing these procedures is time
consuming which may lead to delays or forgetting to make the changes.
Drafting or changing written procedures is also prone to errors.
Therefore, manufacturers are encouraged to consider the use of
microcomputers and low-cost printers as word processors to aid in
writing and changing procedures. With the use of micro-computers,
these
tasks become easier thereby increasing the probability that they will
be
performed correctly and when needed. Microcomputers can also be used
for
generating and maintaining master record indices, complaint files,
and
performing a host other GMP-related activities.

There is a method for developing procedures that will result in

short, clear procedures that help solve real problems. The first two
 steps are:

o identify the problem to be solved; and

o decide if new or modified procedures are needed to help
solve
or reduce the problems.

Events that point to a problem are excessive rework, employee

confusion, and customer complaints. These "pointers," however, may
not
be the real problem -- the real problem may be inadequate design,
components, equipment, maintenance, operational techniques,
documentation, environment, etc. The real problem must be identified
before it can be solved -- a written procedure may or may not be
needed
to help solve it.

The real problem can be identified by careful analysis of:

o the "pointers" noted above,

o device design,
o process design,
o process flow and employee work habits (operational
analysis),
o test and inspection data, and
 o any other activity related to the quality of the device.

Operational analysis is aided by flowcharting which is a step-by-

step chart of the minute details of the operation. Thus, a flow
chart
is much more detailed than a QA audit report and is very helpful in
determining what is actually happening in a particular manufacturing
operation. This knowledge may lead to a solution of manufacturing and
quality problems. An example of a flow chart appears in the exhibit
section of chapter 8.

From a company personnel management viewpoint, the problem, the

reason for flow-charting the given activity, etc., should be
discussed
with affected personnel. Their input should be requested with
respect
to identifying and solving the real problem. By using the
information
presented by the flowchart and the experience gained while producing
the chart, the auditor is better able to:

o analyze the particular operation with respect to process

requirements;

o determine what needs to be added, modified, or deleted to

solve any problems or improve performance; and

o if needed, write or modify a procedure to cover the new way

of
performing the activity.

Content of Procedures

Written procedures are widely used and industry experience has

shown
that these should contain the following items:

o company identification and a procedure title;

o an identification or control number with a revision level

code;

o an approval signature, and date the procedure becomes

effective;

o the number of pages (e.g., sheet 1 of 4) in the procedure

or
another means to indicate that the employee has the
complete
document.

o a body that describes the activities to be performed.

 The effective date may be the same as the approval date. Also,
the
effective date may appear on a separate document such as an
engineering
change order (ECO) form. The main body of the procedure should cover,
as appropriate:

o subject, scope, and objectives;

o who is assigned to perform the task;
o what activity or task is to be performed;
o when and where the task is to be performed; and,
o how to perform the task including what tools, materials,
etc.,
to use.

Particularly for the new employee, it is important for the

procedure
to state the reason for performing a function and the reason it must
be
 performed in a certain way. Background information such as this
helps
the employee to understand an assignment and remember how to perform
it. For example, when working on CMOS integrated circuits that are
easily damaged by electrostatic potentials, unskilled employees need
to
understand why they have to be grounded, work on grounded mats and,
especially, why they are not allowed to wear certain clothing while
at
work. Likewise, employees working in environmentally controlled,
clean
manufacturing areas need to be told about invisible microbes and
particulates, and that humans are the major source of these unwelcome
contaminates. If so informed, employees are more likely to follow
the
operational procedures for working in controlled areas.

The task description in each procedure should cover appropriate

details such as:

o the expected and actual results from performing the tasks,

such as what data to collect and how to analyze, file, and
report it;

o what to do with the component, in-process device, or

finished
device if such is involved; and

o any related activities that need to be performed in order

for
the overall operation to remain in a state-of-control or
for
the device to meet all of the device master record
specifications.

If the procedure being developed, for example, covers change

control, the procedure must also cover related activities such as
changes to labeling. Consider a change to a device where an analog
meter is replaced with a digital meter -- obviously the instruction
manual (labeling) and service manual also need to be modified.
Otherwise
the finished device: may not meet company labeling policies; is
misbranded because it does not meet the labeling requirements of the
FD& C Act; and, is adulterated because the change does not meet the
change control requirements of the GMP regulation.

After the procedure is drafted, if appropriate, it should be

reviewed with the affected personnel before it is approved and
implemented. During the initial implementation, the use of the
procedure should be monitored. Then, based on actual experience in
using
the procedure, if necessary, it should be modified to more exactly
meet
 the need of the operation or process.

CHANGE CONTROL

The GMP regulation requires in section 820.181 that any changes

to
the device master record be authorized by the signature of a
designated
individual(s). Change control requirements also appear throughout the
GMP regulation. The control of changes to devices, processes and the
associated master records is one of the most important elements of a
quality assurance system. The requirements for a successful change
control system are so extensive that the entire next chapter of this
manual is devoted to changes and associated procedures.

EXHIBITS

Reprinted on the next pages are typical documents (records) that

 appear in DMR's. Firms may use these as guides in developing their
device master records.

Documents That May Appear in a Device Master Record

First is a list which contains documents that might appear in

device
master records. Each DMR would contain only those documents that are
applicable for a specific device. Some of the listed documents are
general rather than product specific. General documents are usually
called standard operating procedures (SOP's) and are normally
referenced
in the DMR rather than actually being included.

Device Master Record Index

This exhibit is a policy/procedure for drafting a DMR index. An

index is also known as a document plan, table of contents, etc. An
example of a DMR index follows immediately after the policy/procedure.
Note that this particular policy/procedure contains definitions. In a
case like a DMR index where employees may not be familiar with the
terminology, it is important that procedures contain definitions.

Product Specification for a Portable Defibrillator

Specifications are the backbone of any device master record. The

one
illustrated as the third exhibit is for a complicated piece of
equipment and is therefore extensive. For long documents it is
recommended that a table of contents be incorporated as was done in
this specification. Appendix A and B of this specification are not
exhibited.

Zener Diode Specification

This specification is for a non-complicated part. This

specification, although short, contains the necessary information to
describe the item in sufficient detail for the correct part to be
procured.

Label Example

An example of a label is exhibited. Labels and labeling are

components and their master records are part of the device master
record. As for any component, labeling must be specified
(documented).
The resulting master record must be reviewed, approved, change
controlled, and stored such that it may be readily accessed.

Handle Assembly and Parts List

This exhibit is an engineering drawing and parts list for a

handle
 assembly. Engineering drawings, parts lists, or formulations are a
vital
part of many device master records. In this case, the engineering
drawing not only details how this assembly is to be made, but there
is
also important information in the notes on the drawing. If properly
trained and with sufficient experience, employees are able to use
this
drawing as the instructions for assembly of this handle. A written
procedure is not necessary.

Cable Assembly and Parts List

This exhibit is similar to the handle assembly mentioned above.

The
 type of drawing used and information on a drawing can aid a firm in
reducing paperwork needed to manufacture a specific product.

Device Master Record Index for Amylase

This document is a device master record index for an in-vitro

diagnostic product. Proprietary information in this index is
replaced
by X's. The company that prepared this index uses purchase
specifications and raw material specifications. Some firms,
particularly
small companies, specify and purchase standard items such as bottles
and
caps by using catalog numbers -- specification drawings usually are
not
used.

Product Description

This exhibit is a product description for an in vitro diagnostic

product. The standard operating procedures, quality control
procedures,
manufacturing flow sheets, and notes mentioned in this product
description are not reprinted herein.

Amylase Diluent Solution

This exhibit is the procedure for making a batch of amylase

solution. In this procedure, note that for each step the company
requires the initials or signature of the person actually performing
the operation and of the individual who checked that persons
performance of the operation.

Filling Record - Liquid, Non Freeze Dried

This is an exhibit of a filling record used for liquid products

to
document the steps in a filling operation. The completed filling
record
becomes a part of the device history record for the batch being
filled.

Finished Product Release Form

This form is used to record that the history record is complete

for
a lot of product, the product meets specifications, and may be
approved
for release.

Production Sample Card

 This exhibit shows both sides of a card or tag used to identify
and
help control the use of manufacturing aids such as samples of
assemblies or finished devices. The use of a sample identification
card
is described in the main text.

Shop Order Traveler

The last exhibit is two job travelers or job followers. These

cards,
forms, tags, etc., are used to identify a batch or sub-batch of in-
process assemblies as they are passed from one department to another.
Where needed, travelers are used to reduce mixups and confusion and,
in
general increase the state-of-control of an overall manufacturing
operation.

DOCUMENTS THAT MAY APPEAR IN A DEVICE MASTER RECORD

1.0 Device Master Record Index

 The DMR Index is a table of contents which is used for
convenience. It may be known as a:

Documentation or Master Record Unit;

Documentation Plan;
Product Tree;
Documentation Index;
Product Structure; or
Bill of Materials (if it lists DMR documents).

2.0 Device Specifications

(Device specifications are described in the chapter text.)

3.0 Manufacturing Information

3.1 Index
(Optional. See 1.0 above for total table of contents.)

3.2 Formulation or top assembly

3.3 List of components

1. List of ingredients (including grade or type)
2. Bill of materials (i.e., component list usually arranged
by subassembly or other sub-product level or by process
steps)
3. Formula

3.4 Procurement documentation

1. Specifications
2. Drawings
3. Certificate of compliance requirements
4. Vendor evaluation procedures

3.5 Device documentation

1. Fabrication drawings
2. Surface finish procedures
3. Subassembly drawings
4. Wiring and piping diagrams
5. Assembly procedures
6. Assembly drawings
7. Reference documentation
1. Wiring and piping schematics
2. Test specifications
8. Sub-batch procedures
9. Blending or mixing procedures
10. Solution procedures
11. Final formulation procedures
12. Software packages

3.6 Precautions and special notations

1. Apparel
2. Cleaning
 3. Storage conditions
4. Filling, mixing conditions
5. Hazards and safety precautions

3.7 Equipment, lines, and procedures

 1. Process lines
2. Assembly lines
3. Vessels
4. Mixers, tools
5. Molds
6. Machine maintenance procedures
7. Calibration procedures
8. Setup procedures
9. Operating procedures
10. Process flow charts

3.8 Sterilization procedures

1. For ethylene oxide, radiation, filtration, steam, etc.
2. Handling and flow procedures
3. Cycle parameter specifications
4. Loading diagrams

3.9 Production control documentation

1. Inspection procedures
2. Test procedures
3. Blank job travelers
4. Blank inspection/test forms
5. Instruments charts
6. Reporting forms
7. Approved deviations

4.0 Labeling and Packaging

4.1 Index (Optional. see 1.0 above.)

4.2 Labeling
1. Label drawings
2. Labeling drawings
3. Label/labeling review procedures and forms
4. Production control procedures and history record forms
5. Instruction manuals
6. Service manuals
7. Customer software
8. Customer feedback forms

4.3 Packaging
1. Package drawings
2. Closure drawings
3. Filling and/or packaging procedures
4. Packing procedures
5. Special shipment procedures

4.4 Storage requirements

1. Temperature
2. Humidity
3. Shelf-life

5.0 Control Procedures and Activities

5.1 Index (Optional. see 1.0 above.)

5.2 Inspection procedures

1. Incoming
2. In-process
3. Finished devices
 4. Process control charts
5. Blank data reporting forms

5.3 Test procedures

1. Incoming
2. In-process
3. Pretest conditioning
4. Finished device
5. Process control charts
6. Blank device history record forms
7. Automated test programs and/or software

6.0 Final Release

6.1 Release document review list

6.2 Distribution procedures

6.3 Blank device history record forms

Title: DEVICE MASTER RECORD INDEX

Policy No. _______ Rev. _____ Approval __________ Date _______

1.0 Purpose and Scope: To prescribe the responsibilities for

preparing device master record (DMR) Indices and content of DMR
Indices (lists).

2.0 Policy: A DMR Index shall be prepared and maintained for all
devices being developed or manufactured.

3.0 Definition: A DMR Index is a table of contents for the master

record of a device. It also contains information on the
breakdown
of the device into assemblies and/or manufacturing steps. It is
called a document plan during planning and early development of
a
new product. A DMR is:

3.1 An aid in proposing, planning, tasking, and reviewing

projects;

3.2 A framework for preparing drawings, parts lists, and test

equipment lists;

3.3 A means of familiarizing personnel with the device

configuration;

3.4 A current record and status of the physical configuration

of
the device and a list of all reference documentation
required; and
 3.5 An index to the product-specific documentation required for
procurement of components, manufacture, and evaluation of a
device.

4.0 Procedure:

4.1 Preliminary document plans may be generated for the

convenience of Engineering. Upon completion of the design
when formal records are needed, a formal document plan will
 be initiated.

4.2 The configuration and structure of the document plan is set

by the Engineering, Manufacturing Engineering, and Drafting
Supervisors.

4.3 After agreements, the plan will be drawn, document numbers

assigned, status of drawings indicated, and the plan
approved by Engineering and Manufacturing. All non-product
specific documents such as standard operating procedures
that are used during production of the device will be
listed
on the plan. (Because the plan is now complete, it is a DMR
Index.)

5.0 Example: Part of an index in "tree" form is on the following

pages. A "tree" form allows a large amount of information to be
displayed in a small area. Each column covers a major section of
the documentation such as the battery charger. The index
contains
codes to convey additional information such as a rectangle with
a
dark triangle in a top corner or a mark such as "#" to indicate
a
parts list is included with a particular drawing.

<INDEX IN TREE FORM (2 pages)>

PRODUCT SPECIFICATION PORTABLE DEFIBRILLATORS

Title: PRODUCT SPECIFICATION PORTABLE DEFIBRILLATORS

DR BY: A J Lucas DATE: 4/15/75

APP'D: ______________ DATE: ________

DWG NO: 04300538 Sheet 1 of 14

REVISON: A Date: 3/10/77

CONTENTS

PRODUCT SPECIFICATION

1.0 Reference Documents

2.0 Overall Description

3.0 Configurations
4.0 Functional Characteristics

5.0 Performance Characteristics

APPENDIX A (not reprinted in this manual)

TEST RECOMMENDATIONS

APPENDIX B (not reprinted in this manual)

 TEST POINT AND BOARD INTERCONNECT SIGNAL

DEFINITIONS

Throughout Product Specification * indicates need for test.

NOTE: Values not in parentheses refer to models D320 and D320W.

Values in parentheses refer to Models D400 and D400W.

|LTR | DESCRIPTION | DATE | APPROVED

|
| 1 | Pilot released per ER - 3556 | 4/23/75 |
|
| 2 | Revised and Retyped per ECO - 3968 | 1/27/76 |
|
| 3 | Revised and Retyped per ECO - 4225 | 5/28/76 |
|
| 4 | Revised per ECO - 4636 | 12/28/76 |
|
| A | Released to Production per ERN 4645 | 3/10/77 |
|

PRODUCT SPECIFICATICN PORTABLE DEFIBRILLATORS - D320, D320W, D400, &

D400W

1.0 REFERENCE DOCUMENTS

1.1 Portable Defibrillators D320/400 and D320W/400W 23990081-XX

1.2 Adult Anterior Paddles 24990082-01 450 AA

1.3 Adult Anterior-Posterior Paddles 24990113-01 450 APA

1.4 Adult Anterior Paddles 24990114-03 450 AI

1.5 Pediatric Anterior Paddles 24990082-02 450 PA

1.6 Pediatric Internal Paddles 24990114-02 450 PI

1.7 Infant Internal Paddles 24990114-01 450 II

1.8 Adult Anterior Paddles with Remote Charge 24990082-03 450 AAR

1.9 Patient Cable Assy. 3 Electrode -21 D24990118-01

1.10 Tube XXXXXX (712) 1042507001

1.11 D320/400 Shipping List

1.12 D320/400 Operators Manual

1.13 D320/400 Maintenance Manual

 2.0 OVERALL DESCRIPTION

The D320/400 (Ref. 1.1) is a portable defibrillator with integral

isolated input, solid trace, ECG monitor scope. The D320/400W
contains
in addition a 40m strip chart recorder. They may be used for
non-synchronous ventricular defibrillation or synchronous conversion
of arrhythmias. Power is derived from internal rechargeable batteries
or from the AC power line whenever the unit is connected to the AC
power line via the internal charger.

Standard accessories included in the D320 Shipping List (Ref. 1.11)

 are:

1 - Adult Anterior Paddle Set (Ref. 1.2)

1 - Patient Cable -21 (Ref. 1.8)
1 - Tube XXXXXX Electrode Paste (Ref. 1.9)
1 - Operator's Manual (Ref. 1.11)
1 - Shipping Carton

Optional Accessories are alternate paddles described in section 4.

3.0 CONFIGURATIONS

23990081-01 Battery Operated Defibrillator - D320 (120V)

23990081-02 Battery Operated Defibrillator - D320 (220V)
23990081-03 Battery Operated Defibrillator with Writer - D320W (120V)
23990081-04 Battery Operated Defibrillator with writer - D320W (220V)
2399 Battery Operated Defibrillator - D400 (120V)
2399 Battery Operated Defibrillator - D400 (220V)
2399 Battery Operated Defibrillator with Writer - D400 (120V)
2399 Battery Operated Defibrillator with Writer - D400W (220V)

4.0 FUNCTIONAL CHARACTERISTICS

4.1 DEFIBRILLATOR FUNCTIONAL CHARACTERISTICS

The defibrillator becomes operational in the non-synchronous mode

when
the power switch is turned ON and the paddle connector is attached. A
charge cycle is initiated by depressing and holding the MANUAL CHARGE
button until the desired charge is reached. Automatic charge to 160
(200) or 320 (400) joules is accomplished by depressing the AUTO
CHARGE 160 (200) or AUTO CHARGE 320 (400) buttons respectively. An
audible tone and a DELIVERED ENERGY bar display on the scope indicate
when a charge is in process. When the charge cycle is complete, the
audible tone stops and the DELIVERED ENERGY meter indicates the
amount
of energy to be delivered. The stored energy is delivered in the form
of an Edmark waveform by pressing the buttons located on the anterior
paddles or, if interior paddles are used, pressing the INTERNAL
PADDLE
switch located on the control panel.

For safety and equipment protection, a charge cycle is followed by an

automatic time out that dumps the stored energy (disarms) after 45
seconds if energy is not delivered or the charge button pressed again
within the time out period. The stored energy is also automatically
dumped when the power switch is turned OFF. The operator may disarm
the unit by depressing the DISARM button.

4.1.1 Delivered Energy Indicator

The DELIVERED ENERGY INDICATOR displays the energy to be delivered

into a 50 ohm load as a horizontal line at the top of the CRT screen.
When a charge is initiated, the end of a solid bar will follow the
 amount of energy to be delivered.

4.1.2 Paddle and Accessory Storage

A molded paddle holder is in the defibrillator front panel cover for

one set of anterior-anterior adult defibrillator paddles. One
(D320W/400W) or two (D320/400) accessory holders are located below
the
front panel to hold cables, electrodes, and paste. Under normal usage,
the defibrillator is stored or transported with defibrillator cables
 connected. This approach minimizes the number of steps needed to
bring
the defibrillator from an idle state to the emergency non-synchronous
mode.

4.1.3 Anterior-Anterior paddles

Anterior-anterior paddle assemblies are available with two electrode

sizes: adult 8.5 cm (Ref. 1.2) and pediatric 5.0 cm (Ref. 1.7). Each
assembly consists of a connector, two paddles with discharge buttons,
and a dual coiled cord extendable to 10 feet. Ethylene oxide
sterilization is the only permissible sterilization technique for all
of these paddles.

4.1.4 Anterior-Anterior Paddles with Remote Charge (Optional)

Same as 4.1.3 except one paddle will have a charge button that
functions identically to MANUAL CHARGE button on the front panel (Ref.
1.8).

4.1.5 Anterior-Posterior Paddles

An anterior-posterior paddle assembly (Ref. 1.4) is available for use

only on adults. It consists of an anterior paddle identical to the
8.5
cm paddle in a 4.1.3, a posterior 12 cm paddle, a dual 10 ft. coiled
cord, and connector.

4.1.6 Internal Paddles

Internal paddle assemblies are available with three electrode sizes:

adult 8.5 cm (Ref. 1.4), pediatric 5.0 cm (Ref. 1.5), and infant 2.5
cm (Ref. 1.6). Each assembly consists of a connector, two paddles,
and
a dual coiled cord extendable to 10 ft.

4.2 ECG AMPLIFIER AND SOLID TRACE SCOPE FUNCTIONAL CHARACTERISTICS

4.2.1 ECG Amplifier

The ECG amplifier is an isolated, variable gain amplifier which feeds

the display, QRS detector, and output jack. Input to the amplifier is
through the defibrillator paddle connector or through the patient
cable. A lead selector switch selects the paddles, or leads I, II, or
III for input. The amplifier incorporates the following features:

1. Slew Rate Limit - Limits the slew rate and, therefore, the
amplitude of the pacer pulses so that they can be seen on the display
and will not trigger the QRS detector in most lead configurations.

2. Fast Recovery Circuit - Returns the signal to on screen limits

within .5 seconds after defibrillation or other overload.

4.2.2 Solid Trace Display

 The solid trace display shows the last 4 seconds of ECG waveform on
the screen. The waveform appears as if a strip chart recorder were
writing the ECG at the right hand edge of the screen and the paper
was
being pulled from right to left. Current information is displayed at
the right of the screen with information becoming increasingly older
towards the left. When operating the defibrillator in the synchronous
mode, sync pulses appear showing where the energy would have been
delivered had the discharge buttons been pushed. The waveform may be
 stopped or "frozen" for review by pushing the latching FREEZE button.

4.3 HEART RATE METER FUNCTIONAL CHARACTERISTICS

The heart rate meter displays heart rate as a bar at the screen
bottom. The heart rate is also compared to alarm limits that are
displayed on the same bar. When a limit is exceeded for longer than
three seconds, the red alarm led blinks, an audible alarm sounds, and
the writer runs (D320W/400W only). Alarms are disabled or reset by
putting the LOW LIMIT knob fully counter-clockwise and the HIGH LIMIT
fully clockwise. In this position the limit indications are not
displayed on the screen.

The threshold for QRS detection is automatically adjusted depending

on
the amplitude of the QRS complex. The minimum threshold is equivalent
to 0.6 cm on the scope display. At maximum gain, a .3 mv QRS complex
will be detected. Detection of a complex will cause an audible beep
if
the BEEP pushbutton is depressed. Proper adjustment of the gain
control will result in an R-wave amplitude on the screen of one to
two
cm.

*4.4 SYNCHRONIZED CARDIOVERTER FUNCTIONAL CHARACTERISTICS

The synchronizer detects the peak of the R wave and, after the
discharge buttons on both defibrillator paddles have been pushed,
delivers the stored energy. The QRS amplitude must be set to at least
0.6 cm on the scope display using the SIZE control. QRS detection is
verified by an audible QRS beep and by a SYNC pulse displayed on the
scope at the time relative to each QRS complex that the energy would
have been delivered.

4.5 WRITER FUNCTIONAL CHARACTERISTICS (D320W/400W only)

The D320/40OW is equipped with a 40 mm direct writer. The writer is

started manually by the RECORD pushbutton on the front panel or
automatically on alarm. No other controls are provided. Gain of the
writer is equal to the gain of the scope. Therefore, setting the QRS
size control to a convenient point for the scope will produce a
reasonable gain for the writer. Centering of the writer is automatic
to within approximately .25 cm. An internal stylus heat adjustment is
provided. An external control is not needed due to the regulation of
the stylus power supply.

4.6 MODES OF OPERATION

The defibrillator has two modes of operation: non-synchronous

defibrillation and synchronous defibrillation. The defibrillator is
always in the non-synchronous defibrillation mode when power is
turned
on. It can be switched from the non-synchronous mode to the
synchronous mode by pressing the SYNC ON pushbutton. It can be
 returned to the non-synchronous mode by pressing the SYNC OFF
pushbutton. Synchronous mode is indicated by a SYNC light on the
front
panel and by sync pulses appearing on the scope coincident with QRS
detection.

*4.7 OPERATOR CONTROLS

4.7.1 ON/OFF

A two pushbutton switch turns on the ECG amplifier and Solid Trace
 Scope and puts the unit in the non-synchronous mode when ON is
depressed.

When OFF is depressed it dumps (disarms) the defibrillator capacitor

and switches off all power to the unit. Closing the front cover
automatically depresses OFF.

4.7.2 MANUAL CHARGE

A momentary pushbutton that causes the capacitor to be charged while

depressed.

4.7.3 AUTO CHARGE 160 (AUTO CHARGE 200)

A momentary pushbutton which initiates an automatic charge to 160

joules delivered.

4.7.4 AUTO CHARGE 320 (AUTO CHARGE 400)

A momentary pushbutton which initiates an automatic charge to 320

joules delivered.

4.7.5 PADDLE CHARGE (Optional)

A momentary pushbutton located on the right paddle which functions

identically to the MANUAL CHARGE pushbutton.

4.7.6 SYNC ON/SYNC OFF (Labeled SYNC/DEFIB ON D400/400W)

Two momentary pushbuttons used to select synchronous or

non-synchronous mode of operation. Pressing SYNC ON after the power
is
turned on puts the unit in the synchronous mode and illuminates the
SYNC light. The unit is put in the non-synchronous mode when power is
turned on or by pressing SYNC OFF when operating in the synchronous
mode.

4.7.7 DISARM

A momentary pushbutton that is used to dump the internal stored

charge. It is used if a lower energy than the one already selected is
desired, or if no more countershocks are to be delivered.

4.7.8 QRS SIZE

A potentiometer used for setting the gain of the ECG amplifier. Gain
may be varied from X300 at fully CCW to X3000 at fully CW. At center
position, the gain is X1000.

4.7.9 FREEZE

A latching pushbutton that causes the scope to cease updating.

4.7.10 1MV
A momentary pushbutton that injects a 1 mv +/- 2.5% signal

4.7.11 BEEP

A latching pushbutton that activates the QRS beep when depressed.

 4.7.12 HIGH LIMIT

A potentiometer used for setting the alarm high rate limit over a
range of at least 100 to 250 BPM. It is set to 120 BPM with knob
pointer is straight up.

4.7.13 LOW LIMIT

A potentiometer used for setting the alarm low rate limit over a
range
of at least 0 to 150 BPM. It is set to 60 BPM with knob pointer is
straight up.

4.7.14 RECORD

A latching pushputton that starts the writer when depressed. The

writer is always started on alarm.

4.7.15 LEAD SELECT

Four interlocking pushbuttons labeled PADDLES, I, II, III that select

paddles or standard leads I, II, III respectively as input to the ECG
amplifier. A three-lead cable with RA, LA, and LL (which may be
labeled R) can be used.

*4.8 INDICATORS

4.8.1 BATTERY LOW

A red lamp that begins flashing when the battery has a minimum of 1/2
hour of continuous monitoring capacity left or 2 charges to 320
joules
(1 charge to 400 joules). The lamp flashes to indicate circuit
operation when power is turned on.

4.8.2 SYNC

An amber LED that illuminates when unit is operating in the

synchronous mode.

4.8.3 DELIVERED ENERGY, JOULES

An illuminated bar that indicates the energy in joules to be

delivered
into a 50 ohm load.

4.8.4 TEST

A light located on the defibrillator paddle holder that illuminates

when a counter shock of at least 300 joules is discharged into the
paddle holders.

4.8.5 ALARM
A red light that flashed during an alarm.

4.8.6 LINE

Two red lights that illuminate when AC power is being received by the
unit.

4.8.7 QRS Beep

An audible tone that is produced every time a QRS complex is detected
when the BEEP pushbutton is depressed.

4.8.8 Charging

A audible tone that increases in pitch as the capacitor charges.

4.8.9 Sync Pulse

A negative pulse displayed on the ECG trace with its center within 20
ms of where the energy should have been delivered if the DISCHARGE
BUTTON(S) had been pushed.

4.8.10 Heart Rate Bar

An illuminated bar graph showing Heart Rate and alarm limit settings.

*4.9 CONNECTORS

4.9.1 Defibrillator Paddle Connector

G pin High Voltage Connector

Pin D -High Voltage Paddle Lead

Pin A +High Voltage Paddle Lead
Pin F Ground
Pin C INTPDL - (Internal Paddle Jumper)
Pin B FDLSW - (Paddle Switch)
Pin E RMTCHG - (Remote Charge Switch)

4.9.2 Isolated Input Connector

5 pins MS series Connector - Located on front panel.

Pin A Right Arm

Pin B Left Arm
Pin C Left Leg
Pin D Left Leg
Pin E Left Leg

4.9.3 ECG/Output Connector

3-wire phone jack on front panel

Tip - ECG Output

Ring - Signal Ground
Sleeve - Chassis Ground

5.0 PERFORMANCE CHARACTERISTICS

5.1 DEFIBRILLATOR OUTPUT

5.1.1 Waveform: Monophasic pulse (Edmark Waveform)

*5.1.2 Energy Range: 10-320 joules delivered into a 50 ohm
D320/320W load.

Energy Range: 10-400 joules delivered into a 50 ohm

D400/400W load.
 *5.1.3 Energy Accuracy: Error less than 10% or 4 joules,
DELIVERED ENERGY whichever is greater, into 50 ohms
INDICATOR OR AUTO 320 and 25% or 4 joules, whichever is
(400) and AUTO 160 greater, into a 25 to 100 ohm load
when
(200) pushbuttons measured in accordance with XXX
recommendations.

5.1.4 Pulse Width: 95% of the energy delivered in <5 ms

into 50 ohm load.

*5.1.5 Charge Time: Charges to 320 joules in 10 sec. max.

D320/320W) 8.5 sec. typical.
Charge Time: Charge to 400 joules in 12 sec. max.
D400/400W) 10.5 sec. typical.

5.1.6 Pulse Rate: Deliver 15 400-joule counter shocks in

<5 minutes.

5.1.7 Energy Loss Rate: <15% in 30 seconds.

5.1.8 Charge Dump Time <25 volts left in 4 seconds and <2
joules in 3 minutes after activation
of
capacitor dump circuit.

*5.1.9 Isolation Withstands 8 KV DC from either paddle

to chassis with relay in fire position.

5.2 ECG AMPLIFIER

*Frequency Response: .5 to 40 Hz. +0, -3 db max. from

isolated input connector to ECG output
on front connector or scope display at
1cm scope deflection.

*Risk Current: <10 ua at 120 v 60 Hz without patient

cable.
<20 ua with 120 VAC applied to
electrode end of ECG patient cable.

*Gain: adjustable x300 to x3000. x1000 at

nominal gain position.

Input Impedance: >1 megohm differential, DC to 60 Hz

through patient cable.

Input Offset Tolerance: >1 volt

Input Dynamic Range: +/- 3.5 mv at nominal gain setting.

*Isolation Voltage: 2500 volts RMS at 60 Hz from any

patient lead or combination of patient
leads to AC line for one minute.
 Defibrillator Protection: Will withstand 5 pulses at 20 second
intervals from defibrillator set to
400
ws delivered energy and delivered
across a 100 ohm load in parallel with
any two patient cable leads.

*Reset Recovery Automatic return to on screen

within .5
 seconds after an electrosurgical or
defibrillator overload.

Slew Rate: Internally limited at .2 to .25 mv/ms

referred to input at nominal gain.

*Calibration Signal: 1 mv +/-2.5% referred to input.

Output: High-level single-ended output on

front
panel. Output level dependent on gain
setting.

Output Impedance: <100 ohms

Output Dynamic Range: 3.5 volts +/-10%

*Output Offset <50 mv for DC input @ 25C

<200 mv @ nom gain over full temp
range

Output Current >+/-5 ma

*Noise: <5 uv RMS referred to input at ECG

output with RA and LA connected to RL
by shielded 25 Kohm resistors.

<50 uv RMS referred to input at scope

display at nominal Gain setting.

Common Mode Input >12 megohms from patient leads to

Impedance: chassis ground, from DC to 50 Hz.

5.3 SOLID TRACE SCOPE

Viewing Area: 3.94" wide x 3.15 high (8x10 cm)

*Gain .33 mv/cm to 3.3 mv/cm from patient

leads to scope display depending on
ECG
amplifier gain setting.

Brightness: Internal adjustment.

Sweep Speed: 25 mm/sec. +/-5%

Warm-up: Visible in 15 seconds.

Memory Time: 4 seconds visible

Sample Rate: 240/sec.

Resolution: 8 bits
 Phosphor: P31

Refresh Rate: 60 Hz

*Transient Response: <5 percent overshoot to step input of

any magnitude up to full scale.

*Frequency Response: .5 to 40Hz +0-3db max. from isolated

input to scope display @ 1cm
deflection.
 Horizontal Sweep Linearity: Better than 5% over full viewing area.

Vertical Linearity: Better than 5% over 6 cm central

viewing area from isolated input to
scope display.

Drift: Baseline will not drift more than .5

cm
with 5 minutes after power turn on.

Sampling Noise: <.3 mm at any gain setting.

5.4 SYNCHRONIZED CARDIOVERTER

QRS Detector: Automatic threshold greater than .6 cm

either polarity QRS complex.

*Sensitivity: <.3 mv at maximum gain setting

Range: 0-250 beats per minute.

QRS Tone: 1 KHz tone

Marker Pulse: Shown on scope +/-20 ms from beginning

of counter shock.

*Discharge Delay: Energy is delivered within 40 ms of

the
R wave peak with proper gain setting.

5.5 HEART RATE METER

*Range 0-250 BPM

*Accuracy 3 BPM or 5% of reading whichever is

greater.

Response Time: <5 seconds for rates greater than 50

and an input step change of 70 BPM

Alarm Setting Accuracy: Better than +/-5 BPM

Alarm Delay: 3 Seconds +/-1 second

*Pacer Artifact Rejection: Will not respond to pacer spikes <= 4

ms with proper lead placement.

5.6 WRITER (D320W/400W only)

Linearity: 1% of full scale

*Frequency Response: .5 to 40 Hz +O, -3db maximum from

isolated input connector at 1 cm
deflection.
Chart Width: 40 mm

Chart Speed: 25 mm/sec +/-3%

5.7 DEFIBRILLATOR BATTERY SUPPLY

 *Battery Life: Minimum of 5 hours of monitoring, 1.7
(D320/320W) hr of monitoring with writer running,
or 50 defibrillator charges at 320
joules, or any proportional
combination
at 25C. 6 hours of monitoring or 60
shots typical.
*Battery Life Minimum of 5 hours of monitoring, 1.7
(D400/400W) hrs of monitoring with writer running,
or 40 defibrillator charges at 400
joules or any proportional combination
at 25C. 6 hours of monitoring or 50
shots typical.

Battery Type: NiCad 12 volt battery

pack
located inside unit.

*Battery Charge Time: 14 hours to full charge

*Low Battery Indicator: Comes on when minimum of 1/2 hour of

monitoring or 2 charges to 320 joules
of battery capacity left.

5.8 AC LINE REQUIREMENTS

Input Requirements 97/127 VAC 48-65 Hz. -01,-03,-05, -07

194/254 VAC 48-65 Hz. -02, -04,-06,-08

Power Requirements: 55 watts max, with fully discharged

battery in charge mode.

*Green Wire Leakage: <50 ua RMS at 120 VAC 60 Hz measured

with AAMI load.

*Hipot: 2500 VAC RMS 60 Hz between AC hot and

neutral and green wire ground.

5.9 PADDLES

Electrode Finish: <250 micro inches RMS surface

roughness.

Electrode Material 400 series stainless steel.

Handle Material: Flame resistant plastic

5.10 PHYSICAL CHARACTERISTICS

5.10.1 Size: 17.81" x 15.10" x 8.94"

45.24 cm x 38.35 cm x 22.54 cm

Weight: 33 lbs. (-Ol,-03,-05,-07)

37 lbs. (-02,-04,-06,-08)
5.11 ENVIRONMENTAL CHARACTERISTICS

5.11.1 Temperature

Operating: -10C to 55C (14F to 131F)

Storage: -25C to 55C (-13F to 158F)

 Notes: Continuous battery charge over 40C ambient
reduces battery life. Long term storage over 50C
reduces battery life.

5.11.2 Humidity

Operating: 5% to 96% relative humidity

Storage: 5% to 80% relative humidity

5.11.3 Atmospheric Pressure

70 kPA to 103 kPA

5.11.4 Shock and Vibration

Shall comply with the shock and vibration requirements of

section 3.2.3 of the XXX Cardiac Defibrillator Standard,
document number XXX-XXX-021-0001.

TITLE: IN4278 ZENER DIODE SPECIFICATICN

SPECIFICATION NUMBER _______

Drafted by __________ App. __________ Date _______

REV. ECN History Date

________ _______________________________________________ _________

1. SCOPE: This specification describes a one-watt zener diode used

for voltage reference in the XYZ Stimulator.

2. ELECTRONIC CHARACTERIISTICS

2.1 Zener Voltage: 3.1 vdc @ 76 madc

2.2 Maximum Zener Impedance: 10 ohms @ 76 madc

2.3 Reverse Leakage Current: (25%) 100 microamps (max) @ 1 vdc

3. TESTING: All diodes shall meet the requirements of JANTX IN4278

as specified in MIL-S-19500/127G.

4. PHYSICAL CHARACTERISTICS

4.1 Diodes shall be packaged in a void-free silicone case.

4.2 Leads shall be readily solderable.

5. MARKING

5.1 The cathode shall be identified by a color band.

 5.2 An identification number and lot number or date code shall
represent a specific manufacturing period.

5.3 All markings shall be permanent such that cleaning solutions

will
not remove the markings.
6. CERTIFICATION

6.1 A certification of compliance with this specification and a test

data sheet must accompany each lot shipped.

6.2 Certification must include a statement that no changes have been

made in materials or physical or electrical characteristics.

7. APPROVED VENDORS

7.1 XXXXXXXXXXXXXXXXXX
XXXXXXXXXXXXXXXXXX
Phoenix, MD 21131

<Label Example>

<Handle Assembly Drawing>

<Handle Assembly Parts List>

<Cable Assembly Drawing>

<Cable Assembly Parts List>

Title: DEVICE MASTER RECORD INDEX FOR AMYLASE

DR BY:__________ DATE: _______ DWG NO: XXXXXXX Sheet 1 of 2

REVISON: A Date:
APP'D:__________ DATE: _______

1.0 PRODUCT DESCRIPTION

1.0 Number XXXXXXX, Product specification

2.0 PREPARATION MANUFACTURING

2.1 Purchase specifications

2.101 PS 01-0003 XXXXXXX Starch

2.102 PS 01-0008 Sodium Hydroxide
2.103 PS 01-0017 Hydrochloric XXXXXXXXXXX
2.104 PS 01-0002 XXXXXXXXXXXXXXXXXXXXXXXX
2.105 PS 01-0005 XXXXXXXXXXXXXXXXXXXXXXXX
2.106 PS 01-0012 XXXXXXXXXXXXXXXXXXXXXXXX
2.107 PS 01-0004 Sodium Chloride
2.108 PS 01-0007 XXXXXXXXXXXXXXXXXXXXXXXX
2.109 PS 01-0001 XXXXXXXXXXXXXXXXXXXXXXXX

2.2 Preparation

2.201 #1076 Starch pretreatment

2.202 #1079,1080 XXXXXX Diluent solution
 2.203 #1078 XXXXXX Iodine solution
2.204 #1082 XXXXXX Substrate

3.0 FILLING, LABELING AND PACKAGING

3.1 Purchase specifications

 3.101 PS 02-0201 Tube
3.102 PS 02-0103 Cap

Cat. XXXXXXX

3.103 PS 02-0001 Bottle

3.104 PS 02-0101 Cap
3.105 PS 05-0006 Teflon liner
3.106 PS 02-0701A Label
3.107 PS 03-0701 Instruction sheet
3.108 PS 03-0320 Platforms
3.109 PS 03-0001 Boxes

Cat. XXXXXXX

3.110 PS 02-0002 Bottle

3.111 PS 02-0102 Cap
3.112 PS 05-0007 Teflon liner
3.113 PS 02-0701B Label
3.114 PS 03-0707 Instruction sheet
3.115 PS 03-0301 Boxes
3.116 PS 03-0002 Platforms

3.2 XXXXXXX Production

3.201 SOP-XXXXXXX Filling, labeling and packaging

4. Quality control specifications

4.1 Raw material specification (RM)

4.101 RM 01-0002 XXXXXXXXXXXXXXXXXXXXXXX

4.102 RM 01-0003 XXXXXXXXXXXXXXXXXXXXXXX
4.103 RM 01-0005 XXXXXXXXXXXXXXXXXXXXXXX
4.104 RM 01-0007 XXXXXXXXXXXXXXXXXXXXXXX
4.105 RM 01-0008 Sodium Hydroxide
4.106 RM 01-0012 XXXXXXXXXXXXXXXXXXXXXXX
4.107 RM 01-0017 Hydrochloric XXXXXXXXXX
4.108 RM 01-0004 Sodium Chloride
4.109 RM 01-0001 Bottle (3200-01)
4.110 RM 01-0002 Bottle (3200-10)
4.111 RM 01-0101 Cap (3200-01)
4.112 RM 01-0102 Cap (3200-10)
4.113 RM 02-0701A Label (3200-01)
4.114 RM 02-0701B Label (3200-10)
4.115 RM 03-0001 Boxes (3200-01)
4.116 RM 03-0002 Platform (3200-10)
4.117 RM 03-0301 Boxes (3200-01)
4.118 RM 03-0320 Boxes (3200-10)
4.119 RM 03-0701 Instruction sheet (3200-01)
4.120 RM 03-0707 Instruction sheet (3200-10)
4.121 RM 05-0006 Teflon liner (3200-01)
4.122 RM 05-0007 Teflon liner (3200-10)
4.123 RM 01-0001 XXXXXXXXXXXXXXXXXXXXXXX
4.2 In-process specifications

4.201 SOP-58200B-0 Optical Density of XXXXXXX substrate

 4.3 Final specifications

4.301 QC-PB-007 Finished goods quality control-XXXXXXX set

5. Final release

5.1 Final release specification

5.101 #1087 Final product release form

Title: AMYLASE DESCRIPTION

DR BY:__________ DATE: _______ DWG NO: XX-3200 Sheet 1 of 3

REVISON: A Date:
APP'D:__________ DATE: _______

1. PRODUCT SPECIFICATION FOR CATALOG NO. 3200

1.1 Product name: Amylase Set

1.2 Description of product

This Amylase Set is used for the quantitative determination of

amylase
in biological fluids.

The principle of the procedure is as follows:

Starch + H 2O (amylase) > colorless starch fragments

Unhydrolyzed Starch + I 2 ---> colored starch-iodine complex

The color produced by the starch-iodine complex after 7.5 minutes

incubation of substrate with specimen and 15 minutes color
development
is compared with a reagent blank. The decrease in absorbance optical
density (OD) at 660 nm is proportional to amylase activity in the
specimen because the enzyme hydrolyzes starch to fragments that do
not
react with the iodine reagent.

1.3 Product availability

Catalog No.: 3200-01

Catalog No.: 3200-10

1.4 Components of product

Catalog No. 3200-01

15 Tubes of lyophilized substrate
1 Bottle (10 ml) Iodine (.OIN)
1 Instruction sheet
 Catalog No. 3200-10
100 tubes lyophilized substrate
2 Bottles (30 ml ea.) Iodine (.OIN)
1 Instruction sheet

1.5 Storage of reagent

Store at room temperature. Do not refrigerate.

Minimum shelf life is one year.
 Do not use any substrate tube in which moisture is observed.

1.6 Stability of specimen

Amylase activity in serum is stable up to one week at room

temperature
and for one to two months if refrigerated at 2 to 8 C.

1.7 Procedure for urine amylase

Collect a timed (minimum of 2 hours) sample of urine and measure the

volume. Follow the same procedure as used for serum amylase.
Calculate
the amylase activity excreted in the urine per hour as follows:

Urine amylase (unit/hour) =

OD Reagent blank - OD Specimen IOV

= ------------------------------ x --- x Tf
OD Reagent blank H

V = total volume of timed urine specimen in milliliters;

H = total collection time in hours;
Tf = temperature correction factor.

Example:

2 hour volume of urine = 130 ml;

OD blank = 0.57;
OD Specimen = 0.48;
Temperature = 37C;

Urine amylase (unit/hour) =

0.57 - 0.48 10 x 130

= ----------- x -------- x 1 = 103
0.57 2

Caution: Some urine specimens may contain reducing substances which

could exhaust the iodine reagent.

1.8 Units

One amylase unit is defined as that amount of enzyme activity which,

under the conditions of this procedure, will hydrolyze 10 mg of
starch
in 30 minutes to a stage at which no color is generated with iodine.

1.9 Normal Range

Normal range for serum is 50 to 200 units at 37C. Infants below two
months have no measurable serum amylase. Adult level is reached by
the
age of one year. The above normal range includes an average serum
 blank of 25 amylase units. Normal values for urine is less than 375
units per hour at 37C.

1.10 Precision

Coefficient of variation of 5 to 6 percent at a level of 120 units

and
3 to 5 percent at a level of 250 units are obtained with good
laboratory technique.

1.11 Performance characteristics

 This assay measures amylase levels up to 500 units per 100ml specimen
in a linear mamer. Specimens with higher activity must be diluted by
the procedure given in Note 2 [not reprinted in this manual]. The
calculated value includes a serum blank, which averages about 25
units
in human sera. Control sera may have larger serum blanks, often up to
100 units. Values obtained on patient sera when corrected for the
serum blank activity of approximately 25 units are very close to the
values obtained by the Somogyi saccharogenic method.

1.12 Cautions

This product must be protected from contamination by amylase. Saliva

is a very potent source of amylase. Perspiration contains some
amylase
as do other body fluids. Insensible droplets of saliva are projected
during speech, sneezing, etc.

Face masks and hair covering must be worn during solution and diluent
preparation, solution filling, tube racking and capping, and when
handling any raw material defined for use with this diagnostic test.

Equipment used in the procedure should be designed "For Amylase only".

Glassware and other equipment suspected of amylase contamination must
be rinsed with XXXXXXX. Avoid contamination with detergents or soap.
(See SOP #G021). Observe safety precautions when handling acids (SOP
#G022).

1.13 Manufacturing Flow Sheet. See Form No. 9926. [Not reprinted in
this Manual].

Procedure Amylase Diluent Solution No. _____ Rev. ________

Completed by ________________ Date __________ Date Eff. __________

Checked by __________________ Date __________ Approved ___________

FOR USE IN CATALOG Numbers: XXXX-01 15 tests and XXXX-10 100 tests

Batch No. ______________ Code No. _______________ Date ___________

Prepared by _____________________ Checked by _____________________

MASKS MUST BE WORN THROUGHOUT THIS PROCEDURE TO PREVENT SALIVA

CONTAMINATION.

FOR 50 LITERS OF AMYLASE DILUENT SOLUTION:

1. Weigh the following chemicals and place them in 43 liters of

deionized water in a calibrated clean container.

DEIONIZED WATER: Source _________ Vol. _____ ml Done By _________

 Conductivity Light: On _____ Off _____ Checked By _________

VENDOR LOT AMOUNT WEIGHED

CHECKED
RM NO. CHEMI[CAL CODE NO. REQ'D WEIGHT BY BY
 01-0004 Sodium Chloride ______ ___ 425.0 g G_____ _______
_______
0.1 T_____
N_____

01-000X XXXXXX_________ ______ ___ 523.25 G_____ _______

_______
Basic 0.1 T_____
N_____

01-000X XXXXXX_________ ______ ___ 1275.0 g G_____ _______

_______
Basic 0.1 T_____
N_____

Note: Slowly add the sodium XXXXXXXX to prevent caking.

2. Stir the diluent until all of the salts go into solution.

Done by __________________

3. Check the pH of the solution against 7.00 pH reference buffer.

Initial pH _______________ Checked by _______________

4. Adjust the solution to a pH of 7.00 0.05 @ 25C using 2N NaOH

____ mls of _____ used. Lot No. _____ pH ____ @ 25C.

Checked by _________________

5. Add 125 mls of 1% _XXXXXX_ solution & mix well. Done by ______

No. of mls added _______. Vendor ____________ Lot No. _______

6. Bring the volume to 50 liters with deionized water and mix well.
Re-check the pH. It should still be 7.00 0.05 @ 25C. Adjust, if
necessary, with 2N NaOH or 6N HCl.

DEIONIZED WATER:

Source ____________ Final Vol. _____ mls. Done by ____________

Conductivity Light: On _____ Off _____ Checked by ____________

___ ml of ________ used to adjust. Lot No. ____ Done by _______

Final pH @ 25C __________ Checked by _______

7. Solution must be approved by the Solutions Supervisor(s) or their

designee before it can be used.
Approved by: __________________ Date _______
8. The Solution is now ready to be used in the preparation of Amylase.
It will be filtered as used during that preparation.

9. Label the Diluent Solution with the Name, Batch Number, and Date of
manufacturing.

Form No. 1084

FILLING RECORD - Liquid, Non Freeze Dried
Product Name _____________________________ Kit Cat. # ___________
Distributor _____________________________ Kit Lot # ___________
Theoretical Tube & Vial Yield ____________ Kit Exp. Date ________

SPECIAL INFORMATION _____________________________________________

_________________________________________________________________

IODINE
Batch # __________________ Date Manuf. _________________
Date Received ____________ Time Received _______________

TUBE AND VIAL Code # _______________ # Racked ______________

INFORMATION # Lost _______________ Total # Used __________

FILLING DATA
Machine(s) Before Filling - Signed _________________ Date _______
Cleaned:
After Filling - Signed _________________ Date _______
Fill Vol. _______ ml Limits ______ ml Filling
Batch Vol. ______ ml Leftover _______ml Method ________________
# Tubes or Vials Filled ______ #Bad Fills ______ [ ] Refilled
[ ] Not Refilled
APU ___________ ml TPU ___________ ml TPR ___________ ml

Filling Operators 1) ________ 2) ________ 3) ________ 4) ________

Volumetric Fill Checks: 1) __________ 2) __________ 3) __________

4) _________ 5) __________ 6) _________ 7) _________ 8) _________

Checks done by _________________________ Date _______________

CAP AND LABEL INFORMATION

1. Cap Code # __________ # Used __________ # Lost __________

2. Cap Code # __________ # Used __________ # Lost __________
Label Code # __________ # Used __________ # Lost __________

Signed _______________________________ Date _______________

Checked by ___________________________ Date _______________

ATTACH SAMPLES OF LABELS

Form No. _______

FINISHED PRODUCT RELEASE FORM

AMYLASE SET Catalog No.

Packaging LOT # _______ XXXX-01
XXXX-10
(Circle One)
=====================================================================
The following device history documents were reviewed.
 MFG QC

1. Form No. 9926 Product Flow Sheet [ ] [ ]

2. Form No. 1077 or 1078 Iodine Solution [ ] [ ]
(circle one)

3. Form No. 1082 Substrate Solution [ ] [ ]

4. Form No. 1083 Substrate Tube Filling Sheet [ ] [ ]

5. Form No. 1084 or 1085 Iodine Filling Sheet [ ] [ ]

(circle one)

6. Form No. 1086 Packaging Record [ ] [ ]

7. Form No. QC-PB-007 Finished Goods Specification [ ] [ ]

QC-CO-001
(circle one)

Dissapproved [ ] Approved [ ]

Comments: ___________________________________________________________

_____________________________________________________________________

_______________________________
Designee for Manufacturing

Dissapproved [ ] Approved [ ] for Release

Comments: ___________________________________________________________

_____________________________________________________________________

_______________________________
Designee for Quality Control

<Production Sample Card>

<Shop Order Traveler>

 GMP - CHAPTER 7 - CHANGE CONTROL

CHAPTER 7 CHANGE CONTROL

INTRODUCTION
CHANGE CONTROL PROCEDURE
Identification
Effective Date
Responsibility
Revision Level
Evaluation
Communication
Updating Documentation
Documentation Distribution
Disposition of In-Process Items
Remedial Actions
Regulatory Submissions
Business Factors
QUALITY ASSURANCE REVIEW
CHANGES UNDER PREMARKET NOTIFICATION
Regulatory Background
Premarket Notification Decisions
GMP Control Always Required
EXHIBITS
Engineering Change Policy/Procedure
Change Control Forms

INTRODUCTION

We may as well face reality -- there is no easy way to control

changes to devices, processes, master records, etc. -- change
control
is a complex process. On the other hand, failure to have an adequate
change control system can have equally "complex" results. In-adequate
change control exposes a company to product liability actions,
results
in product recalls, causes internal confusion, and is a serious
violation of the Good Manufacturing Practices (GMP) regulation. The
GMP
regulation "recognizes" the importance of change control -- seven
sections of the GMP regulation cover change control and/or have an
impact on change control requirements.

Change control applies to: components, including software;

labeling
and packaging; devices; processes; production equipment;
manufacturing
materials; and all associated documentation such as standard
operating
 procedures, quality assurance procedures and data forms, and
product-
specific documentation. These documents constitute the device master
record (DMR). The DMR is defined in 21 CFR 820.3(i) as "a compilation
of
records containing the design, formulation, specifications, complete
manufacturing procedures, quality assurance requirements, and
labeling
of a finished device." In addition to the master record, FDA allows
manufacturers to use production aids such as labeled photographs and
models or samples of assemblies and finished devices. Because these
are
 used to support, or in lieu of more extensive master records, these
production aids must also be under change control.

A given device design and associated manufacturing process must

be
documented in the device master record. It follows that changes in
components, design, labeling, etc., of a device; or changes to
processes, equipment, etc., used to produce a device for commercial
distribution, must result in a changed device master record.
Therefore,
most of the discussion herein is centered around the master record.

CHANGE CONTROL PROCEDURE

The device master record should be managed and controlled

according
to documented procedures. For the medium to large company, a change
control procedure is one of a family of standard operating
procedures
(SOP's) used to produce, number, size, change, and control
documentation or control activities that result in documentation. The
sample engineering change policy/procedure exhibited at the end of
this
chapter lists a group of six such procedures. However, this chapter
concentrates on only one of these -- change control procedures --
because of the specific requirements for change control in the GMP
regulation.

The written change control procedure should describe the company-

approved procedures to be followed from the time the master record
is
first released for production of a device, or a change is requested
for
an in-process device or the associated manufacturing processes,
through
examination of the change in relation to other appropriate documents,
activities, and implementation.

The company procedure should have an appropriate degree of

flexibility integrated into it. That is, all changes do not need the
same degree of evaluation and approval. Consider firms such as
repackers/relabelers that may have to make simple changes such as the
size of a container or arrangement of the items in a kit. Also,
production runs for some kits may last only a few hours. Obviously,
these firms should develop and use a change control procedure that
allows rapid changes, approvals, and implementation. The GMP rule is
a
flexible regulation which allows firms to develop and use procedures
that meet their specific needs.

All changes must be made according to the approved company policy

and procedure. A trap that is easy to wander into is the situation
 where a company, knowingly or unknowingly, allows research and
development personnel or other appropriate personnel to make changes
to
a device that is already in production or make changes to an ongoing
process without following the approved procedure. Such changes
generally do not receive the necessary evaluation and review and,
therefore, they may and have resulted in hazardous or ineffective
devices. Making such uncontrolled changes is a violation of several
sections of the GMP regulation, particularly sections 820.20,
820.100
and 820.181. Such a company is not operating in a state-of-control.
It
bears repeating: all changes MUST be made according to approved
company
policy and procedure.

A change control procedure may be long because of the large

number
of activities that must be covered as discussed in detail later.
This
fact may also be seen by reviewing the example policy and procedure
 exhibited at the end of this chapter. All firms should analyze their
operations and determine whether or not a written procedure for
change
control is needed. For example, if a small firm has only a few
manufacturing procedures, the person(s) designated to change and
approve
master records may use the following procedure.

o Draw a black line through but do not black out the old
information.

o Ink in the new information.

o Date and sign at the change or place a mark at the change

which refers the user to the date and signature.

o See that the modified documents are placed into use and the
old documents are removed from production.

o See that in-process and old finished devices are

reprocessed
or discarded.

The above procedure obviously depends on the devoted attention

and
knowledge of the designee. It is easy to see that for a larger firm,
or
for complex operations, the designee would not or could not "pass the
word" to everyone that has a need to know. Hence, the need for
written
procedures. Small firms, with short communication lines, usually need
a
less extensive procedure than a large firm; however, the use of a
change
control form, as described below, by small firms is highly
recommended.
As the firm grows, all procedures, particularly the change control
procedure, should be analyzed and modified to meet current needs.
Such
a review should be part of the quality assurance systems audit.

A typical change control procedure for a device, manufacturing

processes, equipment and associated DMR should cover: identification
of
what is being changed; effective date; responsibility; revision
levels;
evaluation of the change and affected documentation; communication;
updating documentation, document distribution and disposition; in-
process control; finished-device remedial action; regulatory
submissions; coherence of the DMR with device and processes; and
business factors. These elements of a typical change control system
are
 explained below.

Identification
The written procedure must cover the identification of the
changed
device, assembly, component, labeling, software, process or
procedure,
and other related details. The change control form should have
blanks
for recording this data and other data discussed below.

Effective Date

The procedure must cover the effective date of the change which
is
usually a completion date, or action to be performed when a specific
event occurs, such as "implement the change when the new mixer is
installed and operational." The blank on the change control form for
recording the effective date should not be left empty.

Responsibility
 The change control procedure should state which department or
designee is responsible for each function to be performed. One of
these
is the issuance, use, and control of blank and completed change
control
forms.

Revision Level

The way the revision level is to be incremented and which code

should be used need to be covered by the change procedure for:
components including software, assemblies, and devices; and
associated
documentation such as labeling, process procedures, and assembly
drawings.

Evaluation

Each changed device or process must be thoroughly tested and

evaluated by the appropriate department. Then the test results and
all
information related to the change should be reviewed by the change-
control board or other designated review group. This procedure is
the
same as needed for introducing a new product or process into
production.
See chapter 3, Preproduction Planning, for more details. The change
control procedure must state the details of the evaluation and
review
process. It must define the responsibilities of the various
departments
and members of the review board.

Communication

The change procedure must cover the communication of changes to

all
affected parties such as reproduction, purchasing, contractors,
vendors, etc. As appropriate, activities that apply to internal
operations are also applicable to vendors. Examples are disposition
of
in-process assemblies, use of revised drawings and/or procedures, and
disposition of old documents.

Updating Documentation

The procedure must cover updating of primary and secondary

documentation such as instruction manuals. Usually there are no
problems
with updating (revising) primary documentation -- in fact, that is
the
major reason the given change order is being processed. In contrast,
it
 is rather easy to forget that related secondary documents such as
compo-
nent drawings and instruction manuals must be revised if affected by
a
given change. The use of a good change control form can alleviate
this
problem.

Documentation Distribution

Revised documentation must be distributed to persons responsible

for
the operations affected by the change and old documents removed and
filed or discarded, as appropriate. Documentation must be accessible
to
company employees, as stressed in the preamble to the GMP and
required
by section 820.180. The revised documentation must be used and
controlled as required by 820.180. Distribution of new documents and
disposition of old documents must be covered by the change procedure.
Supervisors must be vigilant in overseeing the flow and use of
documentation, especially if a change is being phased in, because
both
the old and revised documentation will exist in a given department
during the transition period.
 Disposition of In-Process Items

The procedure must list by name or job title the individuals

designated as responsible for, and also cover the procedure to
follow
for the disposition of in-process devices, components, assemblies,
and
labeling. The written procedure and implementation of it must be
adequate to prevent mixups of old and revised items.

Remedial Actions

Certain changes will require remedial action in the field or

rework
of warehouse stock. Changes of this nature must be addressed in the
change control procedure. It must outline the documentation and
activities required for field remedial actions or rework of
warehouse
stock. (Note that field remedial actions may be classified as recalls
depending on the nature of the change. Generally, rework of
warehouse
stock which is under a firm's control does not involve a recall.)

Regulatory Submissions

Premarket notification [21 CFR Part 807.81(g)] or premarket

approval
(PMA) supplement (21 CFR Part 814) decisions for modifications to
devices or manufacturing processes must be made and should be
covered
under the change control procedure or a regulatory submissions policy
and procedure. The change order form is a convenient document for
reminding employees that regulatory submissions must be considered.
Premarket notification submissions for significant changes are
briefly
discussed later in this chapter.
Business Factors

In order for the change procedure to be complete, it should cover

other factors such as financial impact, update of products in
commercial distribution, etc.

QUALITY ASSURANCE REVIEW

After the change is implemented, resulting devices and components

must be as specified in the revised DMR and Device History Record.
This
agreement, of course, is assured by the change control procedure and
the remainder of a firm's quality assurance system. Quality
assurance
or other designated personnel must make certain that the agreement
exists during routine production as required by 820.20(a), 820.160
and
 820.184. These GMP sections cover:

o review of production records;

o approval of components, labels, materials, etc.;

o assuring that quality assurance checks are appropriate and

adequate for their purpose and are performed correctly;

o finished device evaluation; and

o collection of history record data to demonstrate that the

device is manufactured in accordance with the updated
device
master record.

The change procedure must cover these activities and must specify
that they be accomplished before the first lot of the changed devices
 are released for distribution.

CHANGES UNDER PREMARKET NOTIFICATION

When making changes to devices and associated manufacturing

processes for substantially equivalent devices, firms must consider
both
Subpart E of Part 807, and Part 820 of Title 21, Code of Federal
Regulations, which address Premarket Notification Procedures and
Good
Manufacturing Practice for Medical Devices, respectively. By
considering
these simultaneously, labor costs can be reduced and compliance
enhanced.

Regulatory Background

Section 807.81 requires that a Premarket Notification submission

[i.e., 510(k)] be made to FDA if a device or one of its components,
or
the intended use of either, is to be significantly changed or
modified.
Examples of significant changes or modifications cited are those
that
could affect safety or effectiveness of the device, such as those
involving design, material, chemical composition, energy source, or
manufacturing process.

It is stated in comment 18 of the Preamble which precedes Part

807
in the Federal Register, 8/23/77, that "under the Act, the burden is
on
the manufacturer to determine whether a premarket notification should
be
submitted for a change or modification in a device. The Commissioner
believes that the manufacturer is the person best qualified to make
this
determination." From the same source, "The Commissioner did not
intend
that the owner or operator should submit a premarket notification
for
every change in design, material, chemical composition, energy
source,
or manufacturing process." Thus, it is clearly the manufacturer's
responsibility to determine if a proposed change could significantly
affect safety or effectiveness.

Changes in manufacturing, labels, packaging, master record, etc.,

of
a device are also subject to GMP requirements in sections 820.61,
820.100, 820.101, 820.115, 820.116, and 820.181. Compliance of most
firms with these change-control requirements is checked during
 comprehensive inspections by FDA investigators, who also challenge
other
quality assurance elements required by the GMP regulation. Firms may
consider their degree of compliance with the GMP regulation as one
factor, but not the sole factor, when making decisions about
premarket
notification submissions for modified devices or processes.

Premarket Notification Decisions

Premarket notification submissions are required for new or

modified
intended uses. Submissions are not required for marketing or
convenience changes where safety or effectiveness could not be
significantly affected. Establishment management must decide whether
or
not to submit a premarket notification for other changes as briefly
described herein and detailed in the Federal Register, 8/23/77.
While
waiting for an FDA review of the submission, a firm may continue to
distribute the unchanged device for its original intended use.

Some manufacturers with highly qualified personnel and

substantial
experience may feel confident in performing various technical
operations and analyzing results to determine that a particular
change
 in a device, component, or manufacturing process will not
significantly
affect safety or effectiveness of the device. After technical
activities
are completed and documented, the results should be reviewed by a
design-review panel, change control board, or equivalent group.
After
reviewing changes, if you are confident -- because of your design
evaluation, change-control procedures, equipment qualification,
equipment calibration, process validation, personnel training, and
routine manufacturing procedures -- that the change(s) could not
significantly affect safety or effectiveness of the device, then the
intent of the regulation has been addressed and there is no need to
submit a premarket notification.

After a thorough review of proposed changes, if a manufacturer is

uncertain whether a change may significantly affect safety or
effectiveness, or believes that a change will significantly affect
safety and effectiveness, then a premarket notification must be
submitted.

GMP Controls Always Required

Section 807.87(g) requires that a premarket notification

submission
"include appropriate supporting data to show that the manufacturer
has
considered what consequences and effects the change or modification
or
new use might have on the safety and effectiveness of the device."
Regardless of whether or not a change is submitted under the 510(k)
process, the change must be evaluated and the associated data must
be
filed for an appropriate period (820.180) because demonstration of
process effectiveness and use of adequate quality-assurance checks
for
finished device release are GMP requirements. Change control is also
necessary to assure that a modified device or process results in a
device that meets company quality claims. Otherwise, the device is
adulterated according to Section 501(c) of the FD& C Act.

The above information applies to changes contemplated for devices

and associated processes that are subject to premarket notification
requirements. If proposed device and process changes are for devices
subject to Investigational Device Exemption (IDE) or Premarket
Approval
(PMA) requirements, then FDA approval must be obtained, in advance,
by
submitting a supplemental IDE or PMA.

gmp2-7:8/11/87

EXHIBITS
 An example of a detailed change control procedure and several
change
control forms are described below and exhibited.

Engineering Change Policy/Procedure

This example of a change control procedure is typical of those

used
by many manufacturers of electromechanical products. It includes all
of
the elements described in this chapter and may be used as a guide in
developing a change control procedure for medical devices.

Change Control Forms

To aid in the day-to-day use of a change control system,

manufacturers often use two forms in conjunction with the change
control procedure. Examples of these forms are printed after the
sample
 change control policy/procedures. The first form is called a request
for engineering action (REA) or a similar title -- it is a "technical
suggestion box." The use of this form encourages all personnel to be
involved in product and process improve-ment, allows management to
assign priorities to various tasks, and tends to prevent lack of
action.
The second form is called an engineering change order (ECO),
engineering
change notice (ECN), or a similar title. For many firms, the use of
ECO
forms is essential for the implementation and control of all the
many
elements in a DMR change control system. A log of changes is usually
maintained for fast reference to old ECO's and for controlling the
issuance of sequential numbers for new ECO's. Also, the completed REA
and ECO forms need to be filed as required by the GMP regulation in
820.180.

One of the example forms, Engineering Change Package (ECP), is

simply an ECO cover sheet for a group of ECO's. An example of a
filled-
in group change is included. It includes the completed ECP cover
sheet
and two completed ECO forms. The other three completed ECO forms
noted
on the example ECP are not reprinted.

The contents of any forms selected for use by a firm and how to
use
them should be discussed with all affected departments. Firms may
use
as is the example forms exhibited or modify them to meet their
specific
needs. In either case, after using an ECO procedure and forms for a
few
changes to products, processes, and associated documentation, needed
improvements to the form or procedure will become obvious.

gmp2-7:8/11/87

COMPANY LOGO

No: _____________
Rev: ____________
DATE: ___________
Sheet 1 of 7
---------------------------------------------------------------------
---
---SUBJECT: ENGINEERING CHANGE POLICY/PROCEDURE APPROVED:
President
 1.0 PURPOSE: The intent of this policy is to assure that our
products
are safe, efficacious and reliable; meet the needs of the marketplace;
and are cost effective to manufacture and test on a continuing basis.

2.0 SCOPE: This policy establishes the procedures to be followed

for
engineering changes to devices or manufacturing processes.

3.0 APPLICABILITY: The responsibilities and procedures established

by
this policy shall apply to all released documents. The policy becomes
effective immediately upon approval by the President.

4.0 APPLICABLE DOCUMENTS: The latest revision of the following

documents form a part of this policy to the extent specified
herein:

No. Document Control Policy/Procedure

 No. Document Part Number Policy/Procedure
No. Interchangeability Policy/Procedure
No. Obsolescence Policy/Procedure
No. Change Request Policy/Procedure
No. Design Review Policy/Procedure

(Copies of these procedures and the ECO form discussed below

are
not included in this Manual. The REA form is reprinted at the end of
this procedure.)

5.0 DEFINITIONS

5.1 Engineering Change Board: Each Engineering Change Board Member

will represent a major area of activity. The Board will be under the
direction of a chairperson appointed by the President. The Change
Board
will meet to review the technical content of all proposed changes to
released documentation for accuracy and impact on safety, efficacy,
reliability, product cost, parts and finished goods inventory, work-
in-
process, instruc- tion and service manuals, data sheets, test
procedures, product specifiations, compatibility with existing
products,
and other factors listed in section of Design Review Procedure No.

5.2 Change Request: A engineering change request (ECR) is a

completed
engineering change form filled out as described in this policy but
unsigned by the Change Board (i.e., is, it is an unsigned ECO form -
-
there is no ECR form). To merit consideration by the Board, the
change request must be complete. Unless the change is so simple
that
it can be readily under stood from the Engineering Change "Request"
form, the form must be accompanied by a reproducible copy of the last
released revision of each sheet of documentation that will be
affected by the ECR if it is accepted. The reproducible copy must be
marked with all proposed changes.

5.3 Engineering Change Order (ECO): An ECO is an ECR (that is, the
completed ECO form and associated documents) which has been approved
by
the Engineering Change Board. An ECO must present a statement of the
problem, a solution, updated documentation, an effective date, and a
statement that the device and proposed changes meet regulatory
requirements.
 5.4 Regulatory Compliance: The review by the Change Board includes
an
analysis of the change with respect to regulatory requirements. For
example, the following questions should be answered.

1. Is the change significant enough to require a 510(k)

submission?
2. Is there a major change in the intended use? [Requires a
510(k).]

3. Does the change affect our GMP system? (A new use such as
infusion pumping by an existing precision metering pump means that a
switch to critical device GMP's is required.)

4. Do we need to change the labeling in order not to be

 misbranded?

5.5 Disposition: This action statement defines the updating or

disposition of nonconforming materials, components, labeling,
software,
in-process assemblies, and finished devices at all applicable
locations
such as vendors, stockroom, production lines, final test area,
finished
goods storage, and in the field.

5.6 Effective Date: The effective date will be expressed in terms

of
shipment date. That is, every change shall be applicable to all units
shipped after a specific date. If shipment does not occur by the date
specified, an amendment must be issued. The amendment will be
presented
to the Change Board and upon approval, the ECO cover sheet will be
reissued. Quality Assurance has responsibility for verifying that the
effective date is met as specified and for maintaining records
showing
the actual effective date of each change. If a change is not
effective
by the date specified, Quality Assurance shall be responsible for
requesting an amendment to change the effective date.

5.7 Cost: At the Change Board meeting, each department shall be

prepared to give the cost impact on its area for implementing each
change order. Finance shall assure that all financial implications
are
considered because the cost analysis must include engineering time,
manufacturing time and material, and field service material and labor.
The following cost data is to be available at the meeting.

1. Amount of increase or decrease in per unit unburdened

material
and labor cost. This cost change is not to include
extraordinary costs of rework and scrap which are
incurred
only when the change is first phased in.

2. Total unburdened cost of material to be scrapped in each

location indicated on the ECO form.

3. Total unburdened rework cost for all items requiring rework.

Sheet 2 of 7

4. Total unburdened engineering manpower and material required

 to design, test and document the change.

5. Where rework or replacement of units in the field is

involved,
Field Service must indicate the proportion of costs to be charged to
warranty expense.

5.8 Amendment: An amendment may be issued only to change the

effective date or correct drafting errors in implementing the change
order. Any Board Member may request that an amendment be issued.

5.9 Board Member: An Engineering Change Board Member shall be a

person appointed to represent a particular functional area by the
area
manager. A Board Member may represent more than one functional area.

5.10 Alternate: Each functional area shall also designate an

Alternate
 who shall be available to attend Change Board meetings in the event
that
the Board Member is not available. Each functional area is to notify
the
Change Board Chairperson of the names of its Board Member and
Alternate.

6.0 RESPONSIBILITIES

6.1 Engineering Change Board Chairperson: The Engineering Change

Board will meet at the discretion of the Chairperson. The Engineering
Change Board Chairperson is responsible for the conduct of the Change
Board meetings. This person is appointed by the President for an
indefinite term. At least one full working day before each meeting of
the Change Board, the Board Chairperson shall distribute to all Board
Members a copy of all ECR's to be discussed at the next meeting of
the
Board.

6.2 Engineering Change Board Members: Engineering Change Board

Members shall be responsible for the functional areas they represent
in
all matters relating to engineering changes and shall be empowered to
act on behalf of their areas in Board actions. The Board Members or
Alternates shall come to each meeting thoroughly prepared to discuss
each Engineering Change Request (ECR) to be discussed. Specific Board
Member responsibilities are listed below.

Product Management - Product Management shall determine the

effect
of changes on marketability, field information, catalogs, price lists,
data sheets, and gross profit margin. Product Management must verify
the
suitability of each change in the international as well as the
domestic
marketplace.

Field Service - Field Service has responsibility for

determining
the: time required to implement the change in the field; availability
of
components and assemblies for retrofit; impact of the change on
service
manuals; and adjustments to service stock. Field Service will make
the
changes in the areas under their jurisdiction and pass other defined
tasks to appropriate departments.

Quality Assurance - Quality Assurance shall determine the

effect
of all changes on test requirements and on overall quality of our
products plus compliance with customer, corporate and regulatory
agency
 requirements.

Sheet 3 of 7

Manufacturing - Manufacturing shall determine component and raw

material availability, break-in point, effect on material-on-order,
material-inprocess and material-in-stock. Manufacturing shall
determine
total cost to the Manufacturing Department of implementing each
change.

Engineering - Engineering is responsible for making certain

that
the change is technically feasible and complies with appropriate
company
and customer specifications and with accepted standards. Every major
change must be fully tested and the results documented by Engineering
before it becomes a change order. Any Change Board Member may request
that Engineering furnish evidence of technical viability of a change.
If
the Board so decides, a change may be tried in Manufacturing on a
limited pilot production basis before final approval and
implementation
in fullscale production. None of the trial units may be shipped until
the change has received final approval. If, as the result of such
trial
 production, the change is altered or modified before final approval,
all
of the trial units must be changed to the final form before shipment.

Finance - Finance shall make certain that all financial aspects

have been considered.

6.3 Engineering Documentation Section (Engineering Services):

Engineering Documentation Section shall have overall responsibility
for
coordinating, scheduling and executing documentation changes.

7.0 PROCEDURE: The procedure followed for a given change depends

upon
whether the change is only to documentation or is a change that
affects
design and/or the manufacturing process.

7.1 Procedure for Design and Process Changes

1. A request for engineering action (REA) is completed and

forwarded to the Manager of Engineering Services. (The REA form is
reprinted at the end of this procedure.)

2. A number is assigned and appropriate audit controls are

established. Engineering Services then sends a copy of the REA to the
cognizant device or process design section for recommended solutions,
evaluation of impact on specifications, and a recommended effective
date. The REA is then forwarded to the Engineering Documentation
Section.

3. Upon evaluation for adequacy of data, where-used

considerations for the items being changed are made. Engineering
Services makes certain that the latest revision of all affected
documentation is included. If not already done, an "ECR" (unsigned
ECO)
form is completed at this stage.

4. Sepias are made of all affected documents. The ECR number

and
proposed changes are marked on the sepias. These sepias are included
as
part of the ECR. The only exception from this procedure is where the
change is basically self-explanatory, i.e., where all necessary
information can be discerned from the section on the ECR form
indicating
"change from" and "change to."

Sheet 4 of 7

5. The Engineering Documentation Section will then duplicate

and
 distribute copies of the ECR to each Change Board Member. Upon
receipt
of the ECR, each Member shall review the proposed change and
determine
the impact on their area.

6. The Change Board Chairperson then calls a Change Board

Meeting.

7. All aspects of the change request are reviewed at the

meeting
including the following: Is the ECR presented so that anyone may
understand the problem and the solution? Has all documentation
including
manuals and data sheets been updated?

The Board will then establish a reasonable effective date. Finance

will make certain that all costs of this change have been considered.
After agreeing upon an effective date, each Board Member signs the
 change request. Each signature implies concurrence with the
effective
date, method of solution, and costs. If the Board Members are unable
to
reach a unanimous decision, the issue is submitted to the President
for
resolution.

After all Board Members in attendance have signed, the ECR becomes
an
engineering change order (ECO). Copies of the cover sheet may be
issued
by Technical Services upon request of the Board Members if the
effective
date is very near and the Change Board has not modified the ECR
before
approval. This action permits Manufacturing to use the previously
distributed marked-up sepias or "from-to" information on the ECR as
operating documentation until copies of the updated original
documents
are available for distribution.

It is the responsibility of Manufacturing to indicate the earliest

permissible effective date in all areas, i.e., vendor, stockroom, raw
material, and work-in-process. It is the responsibility of Field
Service
to indicate an effective date for the field activities.

8. The change order is then sent back to Technical Services

where
copies are made for the Board Members who requested them. Upon
completion of this task, the master documentation is withdrawn from
the
print file, updated to the new revision, and copies are distributed
and
obsolete documents are collected. During the updating process, a copy
of
the marked-up sepia (if any) replaces the master in the print file.
After all documents are updated, the change order is filed
permanently
in the print room.

7.2 Procedure for Minor Changes and Changes in Documentation Only.

This procedure is the same as that for design changes except

that
the second and third steps read as follows.

2. A number is assigned and appropriate audit controls are

established. Upon evaluation for adequacy of data, where-used
considerations are made. Technical Services assures that all affected
documentation is included and that it is the latest revision.
 Sheet 5 of 7

3. Technical Services then sends a copy of the ECR to the

Design
Section for evaluation of the effect of the changes on the design and
for recommendations on the effective date to be suggested to the
Change
Board. The ECR is then returned to Technical Services.

8.0 ENGINEERING CHANGE ORDER FORM (ECO): A definition of the

various
items on the form and instructions on completing each item follows.

1. Status: At the top of the form are the words "Engineering

Change" followed by two words, REQUEST and ORDER. When the mark
appears
in the request area or the form is not signed by the Board
Chairperson,
it shall be considered a request or preliminary copy -- not an action
copy. The change order is an action copy which must bear the
signature
of all Board Members or their Alternates. (The Chairperson is
empowered
to sign for any function not represented at a meeting.)

2. Amendments: Amendments shall be designated by an alpha

suffix, e.g., A, B, C, etc.
 3. Originator: The individual who initiated the REA that
resulted in the ECR or ECO.

4. Interchangeability: This area is made up of two blocks.

First
block is "Yes", second block is "No". Interchangeability is expected
to
be checked off as "Yes" when it affects form, fit, or function of any
numbered part.

5. Change Complete Block: The drafting supervisor shall sign

this block when the documentation is updated.

6. Prerequisite: Is there another ECO or new Product Release

Notice which must be effective before this change can be implemented?
If so, what are the numbers?

7. Reference: In this block will be listed any references

such
as REA's, etc.

8. Device Affected: This block is used to indicate which

device(s) or device line is affected by this particular change notice.

9. Description of the Problem: The description must be

presented
so it can be fully understood by the technical personnel involved.

10. Solution: The solution is what has to be done to correct

the
problem. It must be explained in terms that can be fully understood
by
our technicians.

11. Item Number: A sequential number beginning with 1.

12. Size: The size of the sheets of the drawing or procedure.

13. Revision: From what revision level the document is leaving

and to what revision level it will go.

Sheet 6 of 7

14. Description: This section must contain a general

description
of the drawing, not necessarily its title.

15. Where Used: To which device(s) or processes do the changes

apply? This information is especially important if a component is
used
on several devices.

16. Disposition
 1. Engineering Cost: List engineering cost of design and
documentation change.

2. Vendor: What needs to be done to update in-process assemblies

at
a vendor, i.e., rework, use as is, or scrap?

3. Stock Room: What should be done with non-conforming purchased

components in our stock room? By what date should the above action be
complete?

4. Work-in-Process: What do we wish to do with the material on

the
floor?
 5. Finished Goods: What do we do with the material in finished
goods?

6. Field: What should be done to devices in the field?

7. Cost: Each department is responsible for reporting the cost of

the change with respect to its area.

17. Effective Date: Each change shall be applicable to all units

shipped after a particular date where the date is relatively
unimportant
because the change is a minor documentation change. In all other
changes, an effective date must be assigned by the Board. If it is
important to a particular functional area that a change be
implemented
by a date or not sooner than a date, it is the responsibility of the
appropriate Board Member to assure that an acceptable effective date
is
designated.

The change notice is broken into Parts 1 and 2. Part 1 shows how
to
update the documentation. Part 2 is the special rework instructions
required by Manufacturing or Field Operations on how to update a
component or assembly that does not conform to the new revision.

(Note: The specific ECO form for this procedure is not included
in
this manual. However, several ECO forms follow. One of the example
forms, Engineering Change Package (ECP), is simply an ECO cover sheet
for a group of ECO's. An example of a filled-in group change is
included. It includes the completed ECP cover sheet and two
completed
ECO forms. The other three completed ECO forms noted on the example
ECP
are not reprinted.)

<REQUEST FOR ENGINEERING ACTION>

<ENGINEERING CHANGE ORDER No. 1>

<ENGINERRING CHANGE ORDER No. 2>

<Engineering Change Package (1 of 2)>

<Example Engineering Change Package (1 of 3)>

 GMP - CHAPTER 8 - COMPONENTS AND MATERIALS

CHAPTER 8 COMPONENTS AND MATERIALS

INTRODUCTION
COMPONENT QUALIFICATION
GMP CONTROLS
Specifications
Vendor Qualification
Acceptance Procedures
Acceptance Criteria
Testing and Inspection of Components
Acceptance and Rejection Records
Obsolete, Deteriorated, and Rejected Components
Component Storage
Critical Components
Supplier agreements
Rejected lots
Written test procedure
Sampling plans
Control numbers
EXHIBITS
Acceptance of Components
Material Receiving and Inspection Procedure
Identification Decals
Receiving Rejection Notice

INTRODUCTION

Manufacturers of medical devices must maintain a consistent,

systematic quality assur-ance program which, along with other quality
assurance activities, must assure that all components and materials
are
acceptable for their intended use, that their quality is suf-ficient,
and that adequate steps are taken to prevent mixups. This component
control is a combination of: component qualifications; data
collection,
analysis and corrective action; component specifications; vendor
qualification; identification and status labeling and/or quarantine;
and operational procedures.

"Component" is defined in paragraph 820.3(c) of the Good

Manufacturing Practices (GMP) regulation as "any material, substance,
piece, part, or assembly used during device manu-facture which is
intended to be included in the finished device." For example, blood
tub-
ing assemblies and labels are components. This definition excludes
"manufacturing materi-als," which by definition, are not intended to
be
included in the finished device. Accord-ing to section 820.3(l),
 "manufacturing material" is any material such as cleaning agent,
mold-
release agent, lubricating oil, or other substance used to facilitate
a
manufacturing process, which is not intended by the manufacturer to
be
included in the finished device. The GMP regulation, however,
requires
in 820.20(a) that both manufacturing materials and components be
addressed by the quality assurance program and that each be approved
or
re-jected. Thus, both must be controlled upon receipt using the
 requirements in Subpart E, Control of Components.

If a component is manufactured in the same or proximal facility,

and
produced exclu-sively for use in finished medical devices, then the
component is considered part of the production of the finished
devices
and is subject to the applicable requirements of the GMP regulation.
If
the component is manufactured in a separate plant owned by the
finished
device manufacturer, then the manufacturer has flexibility in
handling
the quality assurance activities related to the control of
components.
One satisfactory approach is to have the plant that builds the
components operate in full GMP compliance. Under this arrangement,
the
plant which does the final device assembly would still be responsible
for ascertaining that the quality and integrity of incoming
components
have not been damaged during shipment. Alternately, the component
manufacturing plant may not fully comply with GMP regulation. Then
the
plant that does final assembly must handle the acceptance of
components
with the same degree of control as if the components were purchased
from
an outside vendor.

The GMP regulation applies to component manufacturers who produce

components or acces-sories ready to be used for health-related
purposes.
An accessory is viewed as any finish-ed unit distributed separately
but
intended to be attached to or used in conjunction with another
finished
device. Components, software, tubing sets, and other accessories
ready
to be used for health-related purposes and packaged or labeled for
commercial distribution for such health-related purposes are
considered
finished devices. Therefore, any manu-facturer of these must meet all
FDA regulations for a finished device. These regulations include 21
CFR
Part 807 Subpart E, Premarket Notification; 21 CFR Part 807 Subparts
B,C, and D, Registration and Listing; 21 CFR Part 820, Good
Manufacturing Practices (GMP); 21 CFR Parts 801 and 809, Labeling,
etc.

Manufacturers of components sold only for further manufacturing

are
not required to comply with any of the requirements for finished
 devices. Many components of devices, such as transistors, containers,
hardware, etc., are readily available in the marketplace and are not
manufactured exclusively for use in devices. Many of these
manufacturers
supply only a fraction of their production to finished device
manufacturers. However, section 820.1 of the GMP regulation
encourages
component manufacturers to use the GMP elements as guidelines where
appropriate.

A repackager/relabeler receives only finished devices; therefore,

the GMP sections pertaining to component receiving, acceptance and
rejection do not directly apply except to identify the devices
received
as being the items ordered. However, a repacker/relabeler is subject
to
the process controls in section 820.100 of the GMP regulation. In
addition, a requirement that all manufacturers assure that
manufacturing materials, packaging, la-beling, and finished devices
are
acceptable for use is contained in section 820.20(a)(2). To meet
these
requirements, incoming finished devices may be treated as components,
and controlled per applicable portions of 820 Subpart E, Control of
Components.

For components such as labels, packaging, inserts, etc., there is

additional information in chapter 11, Labeling; and chapter 12,
Packaging.
 COMPONENT QUALIFICATION

Qualification of components is a very important step towards

designing and producing a high quality product. Qualification of
components consists of verifying through documented testing that a
component will perform its function reliably in the intended
application
and under the most adverse environmental conditions in which the
device
is expected to be used. These conditions should consider the user's
expectations and must encompass the manufacturer's labeling claims
for
the device. (Also see the Appendix and paragraph 501c of the Food,
Drug
and Cosmetic Act.)

Components have to be carefully selected, using the requirements

of
the product as a guide. Components should be chosen so that they
will
not be over-stressed and will be compatible with the internal device
environment as well as the external environment that the device is
expected to encounter during manufacture, distribution, and use. The
comp-onents should then be appropriately tested, alone and as part of
the device, versus the specifications established for the component
and
the device. This testing should include parameter and life testing
as
well as compatibility testing for both the internal and ex-ternal
environment. Well known, industry standard components that are used
in
their normal application and that are not overstressed will need
only
minor testing. A record of the qualification testing must be
maintained. This record should include the component iden-tity, the
testing methods that were used as well as the actual test data and
results.

GMP CONTROLS

After the device has been properly qualified, component quality

is
maintained through correct specifications, procurement, incoming
acceptance, storage, handling, installation, and change control.
Feedback from the quality assurance system is needed to monitor the
adequacy of these activities and procedures, and make corrections if
necessary.

Specifications

Component specifications are required to be part of the device

master record. The specifications must be well designed, achievable,
and acceptable to vendors. They must adequately describe the quality
 characteristics, dimensions, design, materials, perform-ance, and any
other feature necessary to assure receipt of the item desired. For
unusual, vital, new or key components the specification data is
derived
primarily from the qualifi-cation data with minor details from
catalogue
data. For routine components, such as those that have been used for
a
long time or have a known performance history, a catalog desig-nation
may be adequate to describe a component and assure purchase of the
desired compo-nent. For some components such as transistors, the
catalog
number also may be used to ob-tain complete specifications from a
reference manual. Specifications should reflect both design
requirements and quality/reliability needs. The quality level for
each
component must be specified. Components usually are available in
several quality levels such as reagent grade, military grade, etc.
In
some cases, a significant increase in component quality can be
obtained
for a modest increase in cost by specifying a higher grade, thus
reducing the probability of future quality problems and possible
significant costs associ-ated with these quality problems.
 Vendor Qualification

A major factor in obtaining high quality components is the

selection
of vendors. Al-though a manufacturer's knowledge of vendor operations
may be limited and information about the operations difficult to
obtain, the GMP requirement that a manufacturer is re-sponsible for
quality remains undiminished. To the maximum extent feasible,
selection
and qualification of vendors by audits, performance analysis, etc.,
should be part of a qual-ity assurance program. If the manufacturer
does
not have the capability to test components for conformance to
specifications, then vendor test data or outside lab results are ac-
ceptable provided that components are tested and inspected in a
statistically valid manner to show their acceptability for use in
the
finished device. Any outside test results should be accompanied by
relevant raw data used for the test so that judgments of authen-
ticity
may be made by the finished device manufacturer. Excluding a vendor
whose compo-nents are unreliable from supplying components for a new
design may help prevent problems with the final device and is
certainly
worthwhile as a cost reduction effort.

It is important to remember that raw components acquire

cumulative
value as they are processed through receiving, assembly, test,
inspection and as they ultimately become part of the finished device.
If a component fails during assembly, or as part of the device,
additional costs will be incurred for fault isolation, removal,
replacement, inspection, testing, etc. When field failures occur,
the
ultimate cost of the component becomes even higher because its
replacement requires travel, trouble-shooting, and retrofit. In
addit-
ion, customer dissatisfaction, user injury, product liability action,
medical device re-porting, or regulatory action may result. Usually,
the
initial cost of a component is rel-atively insignificant compared to
the
later cost should the component prove to be defec-tive or improper
for
the selected use. Many recalls occur because manufacturers fail to
qualify components properly or to assure that a vendor's
manufacturing
methods and QA system are adequate.

Acceptance Procedures
 In medium to large manufacturing operations, written instructions
are usually neces-sary to assure that components and manufacturing
materials are properly identified, pro-cessed and stored when
received.
Written inspection and test procedures are necessary to prescribe
the:
inspections and tests to be conducted; equipment to be used; test and
in-spection methods to be implemented; and data to be recorded. Prior
to
acceptance, all components must be either physically separated
(quarantined) or clearly identified as not yet accepted. The
decision
to separate or tag not-yet-accepted components should be made based
on
the characteristics of the device, the potential for mixups, plant
conditions, and manufacturing practices.

Although section 820.80 requires a written procedure for

accepting
components, the GMP regulation in 820.5 allows discretion in the QA
program. Thus a very small firm, usually 10 or fewer employees, may
not
need written acceptance procedures other than purchase orders and
receiving tickets as noted above. As the size of the operation, the
numbers of activities, and people involved increase, the need for
 comprehensive written instructions generally increases.

Acceptance Criteria

Manufacturers must have specific acceptance criteria for

components.
Acceptance cri-teria are the attributes of a component that determine
its acceptability, such as appear-ance, dimension, purity,
performance
characteristics, etc. Typically, acceptance criteria are made a part
of
the inspection/test procedure or may take other forms. For example,
if
component specifications or a drawing adequately describe the
attributes
needed in order for the component to perform in its intended manner,
these may serve as the acceptance criteria. If noncritical
components
or the suppliers of the components have a history of good
performance,
the components may be accepted for use after a visual check to assure
they are the items intended and that they are not damaged or
contaminated. Components which need only a visual inspection,
particularly for a very small firm, may be accepted using the
purchase
order data as acceptance criteria. The purchase order and/or
receiving
ticket must at a minimum contain the following information for a
noncritical device: name of vendor; description of component; and
quantity shipped. For a standard component, the catalog number might
serve as a description. QA personnel should determine whether use of
any "abbreviated" criteria are adequate during their audit of
production
rework, history records, complaint files, and service records.

Testing and Inspection of Components

The GMP regulation requires that all incoming components receive

at
least a visual in-spection for contamination and/or damage and be
identified as the component specified on the purchase order. A
manufacturer of a noncritical component has the discretion to deter-
mine
when and where components should be inspected, sampled, and tested
for
conformance to
specifications. As appropriate, components may be tested and/or
inspected at the vendor, as they are received, during manufacture of
the device, or as part of the finished device. If components are
tested
as part of the finished device, the testing must be able to re-veal
 failed and "out-of-spec" components. However, the GMP regulation
requires a manu-facturer to sample and test a component if deviations
from component specifications could result in a noncritical device
being unfit for its intended use.

Manufacturers who decide not to sample or test components must be

able to justify that decision based on such factors as knowledge of
the
supplier's previous performance in pro-viding high quality components,
the component performance history, and application of the components.
Manufacturers may rely on component suppliers to conduct testing if:
the
manu-facturer specifies or is knowledgeable about the supplier's
quality
assurance program, particularly the inspection and test programs;
and
the supplier has specifications that properly define the
manufacturer's
acceptable limits for the component or material param-eters. These
specifications may meet the master record requirements for component
specifi-cations, if these accurately reflect the parameters,
composition
and configuration requir-ed for the component to perform the function
for which it was selected. Supplier specifi-cations are usually
adequate
for standard components. However, a manufacturer who relies on
supplier
specifications usually has no control over changes in these and,
 therefore, must assure at an appropriate point in the manufacturing
process that the components re-ceived meet the desired specifications.
If components are tested by the vendor, acceptance of components can
be
based on certification and review of test data submitted by the ven-
dor
for the specific components supplied. Certification must accompany
each
lot of compo-nents. When certification is used, the manufacturer
should
periodically verify the val-idity of the certification through an
audit
of the vendor.

Where historical data shows that certain noncritical components

have
been substandard and resulted in a device failing to meet
specifications, or where performance history has not been
established,
specific steps must be taken to assure components meet specifi-
cations.
Typically, this task is accomplished by sampling and testing each lot
of
com-ponents to assure that the components meet specifications. Where
appropriate, all complex components should be sampled and tested.

Another testing scheme allowed under 820.3(c) permits

manufacturers
to test entire as-semblies of components rather than individual
components. If, however, testing an assembly cannot assure fitness-
for-
use of components, components must be tested on an individual or lot
basis, whichever is appropriate. For example, assemblies with an
internal feedback circuit could have a very marginal component.
Because
of the circuit design, the condition of the marginal component might
not be detected by testing the entire assembly. Therefore, the
feedback
loop in the assembly must be opened during one of the tests, or the
individu-al components must be tested.

When using a contract laboratory to test production components

(not
a design evalua-tion), the laboratory becomes an extension of the
device
manufacturer's quality assurance program. The device manufacturer is
responsible for assuring that the contractor's test and inspection
procedures are acceptable. Typically, this assurance is obtained by
audits of the laboratory by the lab staff and by the finished device
manufacturer.

Inspection and testing will not improve the quality of components;

however, if the in-spection and testing is appropriate and performed
 adequately, these activities can be used to prevent or significantly
reduce the use of low-quality or defective components. Through
feedback
into the overall QA program, data on components will help identify
basic
causes of problems and lead to solutions. If problems are found,
actions such as design changes, tighter acceptance criteria, vendor
audits, or change of vendors may be appropriate.
Acceptance and Rejection Records

Adequate records must be maintained to provide objective evidence

that components were inspected and accepted, or rejected. These
records
are a part of the device history record and should be maintained in
a
format that facilitates review. The records, however, are not
required
to be maintained in a single file with other production history
records,
and are typically filed in the receiving or quality control area
according to part number or component nomenclature. Small
manufacturers
can use purchase orders or packing slips to record acceptance and
rejection if they contain adequate information.

The GMP regulation specifies that a record of component

acceptance
and rejection be maintained. Typically, acceptance/rejection records
 should indicate: the nature and number of observations; number and
type
of deficiencies; quantities approved and rejected; and nature of
corrective action taken. As a minimum, the manufacturer must record
the
number of components accepted and rejected. In all situations a
qualified individual(s) must be designated as having the
responsibility
for accepting components.

Obsolete, Deteriorated, and Rejected Components

Obsolete, deteriorated and rejected components must be identified

as
such and be placed in a separate quarantine area or specially
identified area to prevent mixups. If practical, components should
be
individually identified as rejects. Where it is not feasible to tag
each rejected component, as in the case of transistors, bolts, etc.,
the
container or packages of rejected lots should be clearly marked and
otherwise appropri-ately segregated from accepted components. There
is
no specific GMP requirement for a written procedure for handling
obsolete, deteriorated or rejected components. Firms should
determine
the need for a written procedure for handling these components based
on
the size of the firm, and complexity of their devices and operations.

To assure that unacceptable components are not used, the GMP

regulation requires re-cords be maintained of their disposition.
These
should state whether the components were returned, scraped, reworked,
etc. If it is unlikely that such components could be used because
they
would not fit, are obviously a reject, etc., records may not be
necessary. Particularly in very small firms, disposition can be
recorded directly onto the purchase order and/or receiving tickets.
Small-to-medium sized firms generally record disposition on the form
used to receive components. Most large manufacturers record
disposition
of rejected components on standard forms such as a Nonconforming
Material Report (NMR).

When components and materials become obsolete, many manufacturers

assign new identifi-cation numbers to the replacement components and
materials. The obsolete items are retain-ed for other uses, such as
repair parts, engineering projects, etc. In these cases, the old and
new items must be adequately segregated and/or identified to prevent
inadvertent use of obsolete components in production.
 Component Storage

Although not a direct GMP requirement, all raw materials and

components used in the finished device should be received through a
central control point. Centralized receiving leads to orderly
storage,
limits access to stored material, and aids a firm in meeting other
GMP
requirements. When components are not immediately processed, the GMP
regulation requires that components be held in a quarantine area or
identified upon receipt as not yet accepted. Components and raw
materials must be identified or stored so that at all times it is
obvious that a component or material has been: accepted, rejected, or
awaiting a disposition decision. A quarantine area can be either a
physically secure area or simply limited access area identified as a
quarantine area. If special environmental storage conditions are
required, such as for many biologically derived components, these
condi-
tions must be controlled and monitored, and the associated
specifications included in the device master record.
 When the device is to be sterilized, consideration should be
given
to storage conditions to prevent contamination of components and
packaging by bacteria or filth. Also, temperatures must be
controlled
as necessary to prevent growth of bacteria. The higher bioburden
(bacteria, etc.) levels may challenge the sterilization cycle to an
extent greater than the capability established during validation and,
thereby, result in a sterility assurance level that may not meet the
finished device specification. Aside from the hazard of increased
bioburden levels, there is the danger that some of the viable
bacteria
may produce pyrogens. These fever-producing substances will not be
destroyed by subsequent sterilization. Some components, particularly
those used in the manufacture of in vitro diagnostic devices, if not
stored properly, may support growth of bacteria.

Critical Components

The GMP regulation contains additional requirements for critical

components used in critical devices. A "critical device" is a device
intended for surgical implant into the body or to support or sustain
life and whose failure to perform when properly used in accordance
with
instructions for use provided in the labeling can be reasonably
expected
to result in a significant injury to the user. As a guideline,
"significant injury" may be understood to include death, mutilation,
amputation, dismemberment, loss of body function, disfigurement,
long-
term debilitation, or injury that requires extended hospitalization.
A
critical component is defined as "any component of a critical device
whose failure to perform can be reasonably expected to cause the
failure of a critical device or to affect its safety or
effectiveness."
"Failure to perform" can be defined as complete failure or variation
from performance specifications to a degree that the component does
not
perform its intended function.

The intent of the GMP requirements is to prevent the production

of
nonconforming prod-uct. Therefore, quality requirements cannot be
relaxed on the basis that distributed de-vices are amenable to
inspection, testing, and modification or that there will be back-up
devices or trained personnel available to relieve the result of a
failure. Although alarms and indicators may sometimes alert a user
that
a device is about to, or has malfunctioned or failed, these features
will not prevent a device from malfunctioning or failing. There-fore,
repairs, back-up devices, alarms, and indicators are not considered
when
identifying critical components.
 The criteria for identifying a critical device should be
restricted
to the effect of its failure. Therefore, user error and the
environment
are not presently considered by FDA when identifying critical
devices.
Identification of critical devices should be based on the health
hazard
presented should the device fail to meet its performance
specifications
when operated as intended. User error is not a performance failure,
although it could be considered a result of inadequate directions
for
use, other inadequate labeling, or poor human factors design. The
environment could result in failure of a device but it should not
effect the result of the failure of the device.

FDA is concerned about the failure of components that would

result
in sudden or cata-strophic device failure, such as no output from an
implantable cardiac pacemaker; fracture of on implanted orthopedic
 implant; run-away in an implanted cardiac pacemaker; misfiring of a
synchronized defibrillator; etc., which can reasonably be expected to
result in significant injury to the user.

To identify a critical component, a manufacturer must know in

detail
how the device functions and the purpose of each component in the
finished device. The effect that each component will have on
finished
device performance, should the component fail to perform as intended,
must be determined. Thus, manufacturers must carefully study the
possible failure modes of their devices and decide which components
are
truly critical under the various modes. This determination may be
time-
consuming with respect to some devices, but it is necessary. It will,
in the long run, save manufacturers liability, repair, and re-
placement
costs. To make such a determination, manufacturers should conduct
reliability tests and failure effects analyses, preferably during
the
design phase, in order to accurately identify critical components.
If
as a result of a failure, the performance, lack of performance, or
effect on safety or effectiveness of the finished device could
result
in significant injury to the user when the device is properly used in
accordance with instructions in the labeling, the component under
study
can be considered a "critical component."

The number of components that need to be considered as potential

critical components can be reduced by considering the reliability of
components and whether they "reasonably" can be expected to fail.
For
example, power cords, clamps, plugs, etc. seldom fail. There-fore,
manufacturers may not need to consider these types of components when
critical com-ponents are being identified. Also, manufacturers can
consider a subassembly as a com-ponent and thereby reduce
recordkeeping.

If a finished device in commercial distribution is converted from

a
non-critical device to a critical device by adding a module or
software, then the module or software is a critical component for
the
purpose of applying GMP requirements. In subsequent produc-tion, the
added critical module or software and associated components, etc.,
must
be ana-lyzed to determined if other parts of the system must be
treated
 as critical components.

If failsafe circuits can be designed into a device so that a

component failure would not result in significant injury, then some
components could be removed from consideration as critical
components.
However, the components that comprise the failsafe circuit then
become
critical components and could, depending on the design efficiency,
actually in-crease rather than reduce the number of critical
components.

Supplier agreements

Manufacturers of critical devices are required to obtain from

critical component sup-pliers an agreement in which the supplier
agrees
to notify the manufacturer of any changes in the critical component
or
its manufacture. A manufacturer may not always find a suppli-er
agreeable to such an arrangement. If unable to obtain an agreement,
documentation of a goodfaith attempt is sufficient in lieu of the
written agreement. Copies of pertinent cor-respondence between the
manufacturer and the supplier would be considered acceptable evi-
dence
 by FDA of an attempt to secure a supplier agreement. If unable to
obtain
an agree-ment, the manufacturer must be vigilant in looking for gross
and subtle changes in mate-rials, components and their performance.

Rejected lots

Records of critical component receipt must be indexed by supplier

name, and the per-centage of lots that are rejected must be recorded.
This data can be used by the finished device manufacturer to
determine
supplier performance. If the raw acceptance data can be readily
reviewed for this purpose, the GMP requirement to calculate and
record
percentages may be unnecessary.

Written test procedures

A critical device manufacturer must assure that all lots of

critical
components are accepted, sampled, tested and/or inspected using
written
procedures. The inspection/test procedure for each component must be
dated and approved. The procedure also should specify the items to
which it applies, the component characteristics to be
inspected/tested,
ac-ceptance/ rejection criteria, data forms, sampling plans, and
necessary test inspection equipment and tools.

The GMP regulation does not require mandatory reserve sampling.

Although 820.81(a) in-cludes a provision for maintaining reserve
samples
of critical components, this require-ment is discretionary per GMP
regulation preamble comment 76 in the Federal Register, July 21,
1978.

Sampling plans

When seeking to assure that critical components meet acceptance

criteria, manufac-turers may test either all critical components or
may
test a portion of the components using a sampling plan based upon an
acceptable statistical rationale. A manufacturer must be prepared to
demonstrate the statistical rationale for any sampling plan used.
Plans
should be developed by qualified mathematicians or statisticians, or
be
taken from estab-lished standards such as MIL-STD-105D or MIL-STD-414.
All sampling plans have a built-in risk of accepting a bad lot.
 This sampling risk is typically determined in quantitative terms
by
deriving the "operating characteristic curve" for the selected plan.
Each sampling plan has a charac-teristic curve. Both MIL-STD-105D and
MIL-STD-414 contain operating characteristic curves for sampling
plans
presented in the standards, and they can be used to determine the
risk
a sampling plan presents. A manufacturer should be aware of the risks
the chosen plan pre-sents. Operating characteristic curves are a
means
of GRAPHICally showing the relationship between the:

o quality of lots submitted for sampling inspection, usually

expressed in percent defective, but may be expressed in
defect
per hundred units; and

o the probability that the sampling plan will yield a decision

to
accept the lot, de- scribed as the "probability of acceptance".

Control numbers
 Control numbers for component traceability are mandatory for
critical components and "components" of in vitro diagnostic kits (21
CFR 809.10). Control numbers must be assigned to each lot or batch
of
critical components that were manufactured under similar condi-tions
over the same time period so that defects can be traced to the
component
manufactur-er and the cause of the defects determined and corrected.
If
a subassembly is regarded as a critical component by the
manufacturer,
a control number for that critical subassembly must be shown in the
device history record.

gmp .6

EXHIBITS

Examples of forms that may be used for accepting, receiving, and

inspecting components are exhibited below. These examples show the
types of information required by the GMP regulation. Procedures and
forms for a particular situation may be more or less compre-hensive
than
these, and may assume other formats or arrangements according to
needs.

Acceptance of Components

The first example is intended as an acceptance procedure that may

be
followed by a small to medium size firm. The procedure has space for
the number, revision level, and a blank for "ECN History". The
history
blank is for adding brief notes about changes that have been made to
this procedure. Included as part of this procedure is a "Receiving
History Log" which immediately follows the procedure. The other forms
mentioned in the procedure are not reprinted; however, similar forms
are included with the "Procedure for Receiving and Inspection of
Material" described below with the example located immediately
following the "Receiving History Log".

Material Receiving and Inspection Procedure

This document is a more extensive receiving procedure than the

one
discussed above and it can be used by a medium to large firm. As
part
of this procedure you will note an ex-tensive revision record section.
Also, part of the procedure is a flow chart which out-lines the steps
in
the procedure and the branches for each step. Next is a "Daily Report
of Goods Received" which includes the vendor name, quantity received,
 lot number or item number, P.O. or REO number, and information on
where
the item was sent. The next item in the procedure is a "Receiving
and
Inspection Report" which contains information about the item and the
sampling and testing performed on the item. The report includes an
acceptance or rejection slot along with a space for the cause for
rejection. The procedure continues with a "Daily Inspection Log"
which
is a summary of the items received and their disposi-tion, either
accepted or rejected. Finally, as part of the procedure, we find
examples of the stickers to be used to accept, reject, or quarantine
the incoming items.

Identification Decals and Forms

Examples of decals and travelers used to identify materials,

components and in-process assemblies are exhibited. Two of the
decals
deal with critical components and can be used as a means of assuring
proper disposition of these items. A "Material Lot Identification"
is
 exhibited which is used to identify components in a container. This
form
has space for, among other information, lot number, expiration date,
quantity in the subject container, date it was issued to stock, and
the
person who received the container. The final example in this group
is a
"Stock Requisition" form, used whenever items are being released from
stock to production. This form contains information such as, part
number, quantity ordered and issued, and lot number. Note that part
of
this form is used to indicate if the issued item is to replace a
defective item.

Receiving Rejection Notice

This form is used when incoming components and materials are

rejected and includes sections for the inspectors report listing the
sampling plan, specification tested for, number of defects, and a
description of the defects. There is a section for a preliminary
review, if necessary, and finally a section for the Material Review
Board (MRB) decision on the disposition of the rejected lot. A MRB
may
accept temporary deviations or changes that do not affect safety and
effectiveness. These deviations or changes must be approved by the
MRB
or other designee. MRB activities must be performed per a written
procedure and otherwise meet GMP requirements. The MRB must not
change
a device master record (DMR) or be used as a substitute for the
primary
change control system of a manufacturer.

Pages 8-12 and 8-13 follow.

TITLE: ACCEPTANCE OF COMPONENTS Sheet 1 of 3

No. Rev. ECN History

________________________________________________________________________
___
Drafted by App. by Date

1.0 SCOPE

These procedures are to be followed in the receipt, inspection, and

storage of materials, components, parts, raw materials, etc., used
in
the manufacture of the XYZ Stimulator, a noncritical device.
 2.0 RECEIVING

2.1 All incoming shipments must be examined for external signs of

damage. If the shipment to the unloading Hold area until disposition
is
decided by shipment is damaged, immediately notify Purchasing and
move
the Purchasing.

2.2 Upon receipt, check each shipment against the appropriate

purchase order and verify identity and quantity.

2.3 Enter the appropriate data into the Received Goods Log for
each
shipment received.

2.4 After completing the data entry, attach a yellow "HOLD" tag to
 the
components, etc., and move the components, etc., immediately to the
receiving quarantine area. The pink copy of the purchase order must
accompany the material.

2.5 Notify Quality Control when materials requiring inspection are

received in the quarantine area. This information is obtained from
the
specification for the item ordered.

2.6 Quality control shall, after examining for damage and identity,
move the components, etc., to be inspected to the components, etc.,
to
the Receiving Inspection area.

3.0 INSPECTION

3.1 Pull the inspection history file for the components, etc., to
be
inspected. This file contains the Receiving History form and
inspection
procedure. Enter the appropriate data from the purchase order onto
the
Receiving History form and perform the inspection per the procedure.
Sheet 2 of 3

3.2 The QC manager shall assign a five digit lot number to each
vendor
lot received and enter the number on the Receiving History form.

3.3 After the inspection is completed, enter on the Receiving

History
form:
a. the quantity accepted and sent to stock;
b. the quantity rejected; and
c. your signature and the date.

4.0 DISPOSITION

4.1 Receiving and test data for each shipment are sent to the
designated individual for review and the decision regarding the
acceptability of the lot.

4.2 For accepted components, etc., enter the quantity accepted,

date
accepted, and lot number on a green "ACCEPTED" tag, attach the tag to
the components, etc., and move them to the stockroom.

4.3 For rejected components, etc., attach a red "REJECTED" tag to

the
rejected components, etc., and complete a Rejected Material form.
Place
all rejected components, etc., in the rejected quarantine area and
 forward the Rejected Material form to Quality Engineering for
disposition.

5.0 STOCKROOM

5.1 All items entering the stockroom must be accompanied by a

green
"ACCEPTED" tag.

5.2 Components and other materials shall be stored and issued per
SOP
17320.

5.3 Components and other materials will be issued from the

stockroom
on
a first-in, first-out basis. All materials with a limited shelf life
or
requiring controlled storage conditions will be stored appropriately
per
 SOP 17321.

Note: Sheet 3 is the Receiving History log for this procedure. The
other
forms mentioned in this procedure are not reprinted. However,
similar
forms are in-cluded with another procedure located later in this
chapter.

<Receiving History Log>

<Material Receiving and Inspection Procedure SHEET 1 OF 9>

1.0 PROCEDURES FOR RECEIVING AND INSPECTION

1.1 Responsibilities of Receiving Clerk.

1.1.1 Sign for items received.

1.1.2 Verify numbers of packages, check for obvious shipping

damage and verify indentification of packages to bill
of lading.

1.1.3 Record infomation in receiving log and assign

sequential receiving number.

1.1.4 Obtain packing slip from container of items.

A. Attach to bill of lading, if available.

B. Stamp receiving date on packing slip.

C. Obtain receiving copy of purchase order from file.

D. Verify count, hidden damage and identification of

items to packing slip.

If there is a problem refer information to

supervisor for resolution.

E. Circle quantity on packing slip.

F. Record receiving number on packing slip.

1.1.5 Production items.

A. Prepare part 1 of the receiving and inspection

report (RIR). Use receiving number as RIR number.

B. Record receiving number on yellow quarantined tag

and attach to item.

C. Move parts to quarantine area.

 D. Send RIR to inspection.

E. Send packing slip to purchasing.

1.1.6 Non production items.

A. Send packing slip to purchasing.

 B. Move material as per purchase order.

1.2 RESPONSIBILITIES OF RECEIVING INSPECTION

1.2.1 Receive RIR.

1.2.2 Obtain parts from quarantine area.

1.2.3 Obtain necessary instruction documents, such as

specification sheets and purchase orders from Q.C.
files and uncontrolled drawings from engineering files.

1.2.4 Perform inspection in accordance with instructions.

1.2.5 Record results of inspection on part II of RIR and

sign
and date.

1.2.6 Fill out inspection log.

1.2.7 File original of RIR by receiving number.

1.2.8 If incoming materials are accepted:

A. Prepare green aprroved tag and attach tag to

container, or item as appropriate.

B. Destroy yellow quarantine tag.

C. Return parts to quarantine area.

D. Discard pink copy of RIR.

E. Send yellow copy of RIR to material handler.

1.2.9 If incoming materils are non-conforming:

A. Prepare red rejection tag and attach to container,

or item, as appropriate.

B. Destroy yellow quarantine tag.

C. Return parts to quarantine area.

D. Send pink and yellow copies of RIR to purchasing.

<Procedure Flow Chart (Sheet 4 of 9) (1 of 2)>

<DAILY REPORT OF GOODS RECEIVED (Sheet 6 of 9)>

<RECEIVING & INSPECTION REPORT (Sheet 7 of 9)>

<DAILY INSPECTION LOG (8 of 9 sheets)>

<Examples of Stickers (Sheet 9 of 9)>

<Examples of Decals and Travelers>

<RECEIVING REJECTION NOTICE>

 GMP - CHAPTER 9 - PRODUCTION APPLICATIONS

CHAPTER 9 PRODUCTION APPLICATIONS

INTRODUCTION
Is Master Record Adequate
Responsibility
What is Being Done
What Was Done
PRODUCTION AND PROCESS CONTROL
Specifications
Specification Changes
Processing Controls
Critical Devices
REPROCESSING
Retesting
Returned Devices
Critical Device Reprocessing
REPACKER/RELABELER PRODUCTION AND PROCESS CONTROLS
Operation Control
Reprocessing
CONTRACT STERILIZATION
Labeling Requirements
GMP Requirements for Contract Sterilization

INTRODUCTION

In production, appropriate components, manufacturing materials,

equipment, documentation and trained personnel are brought together
in a
facility with a controlled environment. The Good Manufacturing
Practices
(GMP) requirements for each of these are discussed in previous
chapters.
In this chapter, the integration of these elements for general
production applications and some specific applications is discussed.

In any manufacturing activity such as procurement, storage,

assembly, labeling, processing, testing, etc., achieving a state-of-
control is enhanced by appropriate personnel knowing:

o what task is to be done;

o how to do the task;
o who is to do the task;
o what task is being done; and
o what task was done.

In order for employees to perform a job correctly, they must know

 exactly what is to be done and exactly how to do the work. The GMP
regulation requires in sections 820.100, 820.115, 820.181, etc., that
what task is to be done and how to do it be documented in the device
master record. (See chapter 6 for details on master records). In case
something goes wrong or a change is made in the device or
manufacturing
 processes, the device master record also must contain a change
control
procedure. By following this procedure, changes can be correctly made
and the various manufacturing operations remain in a state-of-control.

In some companies, the documentation produced by the product

development group or technical services group is not intended to meet
the complete needs of manufacturing. Therefore, manufacturing
engineering or technical services must expand the documentation in
order
to meet the needs of production. All such documentation is part of
the
device master record and must meet the GMP requirements as described
in
chapters 6 and 7.

Also, production documentation may be supported by aids such as

labeled photographs, video tapes, slide shows, sample assemblies, or
sample finished devices. These aids perform master record functions
and
must be current, correct, and approved for the intended operation.

The most commonly used production aids are models or samples.

There
are two conditions that should be satisfied in order to use these
aids.
First, a written specification for the sample must be contained in
the
device master record. This specification, of course, may be the same
as
the specification for the assembly or finished device to be
manufactured. This specification must be subject to a formal change-
control procedure. Even though a model is available, the
specification
is needed for present and future product development, and for
production
control purposes. Second, the sample must:

o adequately reflect the device master record specification;

o be identified with a tag or card as an approved acceptable

sample which means it should meet the company required
workmanship standards; and

o contain a drawing number, revision level, and control code

such as a lot, serial, or batch number, as appropriate.

Samples and other aids such as photographs are subject to normal

wear and tear in a production environment. Therefore, they should be
adequately protected by a suitable means such as being located in a
protected area, or covered by a protective pouch or container. These
aids must be periodically audited to make sure they continue to be
 suitable for the intended use (See sections 820.20, 820.100, and
820.181
of the GMP regulation).

Is Master Record Adequate

There are various means of determining if the how-to information

in
the device master record and also tools or other items supplied to
production are adequate for a given operation and associated
employees.
These include analyzing the amount of:

o assistance required by new employees;

o assistance required when a new device is manufactured;
o employee confusion and hesitation;
o exchanging of information among employees;
o drafting of "homemade" documentation by the line employees;
o rework;
 o products produced (productivity);
o complaints from departments that subsequently process the
device; and
o customer complaints.

Of these items, the existence of "homemade" documentation is a

very
visible indicator that some of the device master records are
inadequate.
If any of these factors persists and if they are out-of-line with
industry norms or with the production of old designs, the firm should
take corrective action. The corrective action may include changes in
supervision, documentation, adding new documentation, modifying the
design, using different tools, modifying the environment, etc.
Corrective action, other than necessary "fire fighting" to prevent
shipment of defective devices, should not be taken, however, until
the
real problem is identified.

Responsibility

Who is to perform a given function is specified by management.

The
GMP regulation, however, requires in section 820.25, Personnel, that
employees have the necessary education, background, training and
experience to correctly perform all assigned operations. In some
cases,
the GMP regulation specifies that an individual(s) be designated to
perform certain activities such as performing critical operations
(820.101) and checking associated acceptance records (820.161). Where
training programs are necessary to assure that personnel have a
thorough
understanding of their jobs, such programs must be conducted and
documented. This documentation may be any appropriate record that
states
the facts about the training.

All employees must be made aware of device defects that may occur
from the improper performance of their specific jobs. Quality
assurance
personnel must be made aware of defects and errors likely to be
encountered as part of their quality assurance functions.

The need for active and responsible supervision is obvious from

the
above GMP requirements and from the activities needed to achieve
production control. Supervisors and designated individuals should be
aware of what is being done by actively monitoring the operations and
appropriately reviewing the data generated during the operations.
What is Being Done

Active and responsible supervision is an important source of

 information in determining what is being done. It is usually
information
about the exceptional aspects of what is being or not being done that
is
desired. If supervisors, quality assurance personnel, auditors, and
managers determine whether or not information supplied to employees
is
adequate and is being used, then many aspects of what is being done
will
be known. In addition, objective evidence of what is being done is
obtained by collecting and analyzing production and quality
information
using predetermined and approved procedures. For the average
operation,
this information is a significant part of the device history record
as
mentioned below and detailed later in chapter 10.

Collecting data and analyzing it will reveal problems and

sometimes
reveal the cause of the problem; however, such activities may never
reveal the cause of some problems, and thus never lead to a cure. For
example, a firm knew for two years that they had a specific problem
 because the problem was manifested by final inspection data and
customer
complaints. The firm responded by "fire fighting" while it tried to
determine the real problem. The "fire fighting" consisted of pep
talks
and better training, better tools, and more inspection -- the "fire
fighting" activities increased production but did not solve the real
problem. The real problem was caused by the operational technique
used
by a few employees to assemble the device. The root cause of the
problem
was ultimately identified by operational analysis by management and
not
by collection and review of data. The point is all are needed to
maintain a state-of-control: management, trained line employees,
device
master record, data collection, data analysis, and operational
analysis.

What Was Done

The device master record provides information on what is to be

done,
but how does a firm determine that these instructions have been
correctly executed? The GMP regulation requires that production
information on what was done be recorded in the device history record.
As defined in section 820.3, a device history record "means a
compilation of records containing the complete production record of a
finished device." The term "complete" must be interpreted with
respect
to the complexity of the device and the associated manufacturing
process. This record should contain sufficient information to confirm
that device master record procedures were executed during production
and
device specifications have been met. The device history record serves
several useful functions.

o It contains the information required by auditors to confirm

that device master record procedures and specifications are
in
place and operating properly.

o The device history record contains information that is

needed
to perform trend analysis. By reviewing what was done, a
firm
can see if there are any persistent production problems
which
require correction.

o The history record is the basis for taking corrective

action
 resulting from trends noted in the production process, or
for
corrective action stemming from defective products caused
by
design, component, or manufacturing problems.

When investigating causes for defects, it is important to have

records of what was done. By comparing this data with previous
acceptable production or with the requirements of the device master
record, problems can be isolated and solutions formulated. The device
history record is "proof of the pudding", so to speak, that
established
controls are being used and that they work.

Finally, a broad view of what was done, what is being done, and
what
is likely to happen in the future is determined from a quality
assurance
systems audit. Audits are covered in chapter 15 of this manual. This
objective review of all quality assurance elements by individuals who
are not directly responsible for the operation being audited may
reveal
elements that need improvement. Management review and corrective
action
can change what is likely to happen to yield better quality products
and
higher profits.

PRODUCTION AND PROCESS CONTROL

 The objective of production and process control is to assure that
the device design is accurately transferred into written
specifications
for the device and manufacturing processes. Also, production
processes
must be adequate and controlled to the extent necessary to assure the
finished device is manufactured according to these specifications.
Specifications describe the intention of the design, and processes
are
planned so that devices produced by them meet specifications. For a
given design, note that these specifications are the device-specific
documents in the device master record. Of course, general documents
in
the master record are also used to manufacture a given device.

Specifications

Section 820.100(a)(1) requires manufacturers to establish

procedures
to insure that the approved design is accurately transferred into
written specifications; and that there are sufficient specifications
which accurately describe the device, its components, and packaging.
Typically, control of design transfer is accomplished through a
formal
review process to verify that the design is adequately translated
into
specifications as is discussed in chapter 3. These specifications
must
be adequate to assure that design configuration and performance
requirements can be met if the device is manufactured and assembled
according to these specifications. If the design basis is not
adequately
translated into specifications, as needed to procure components and
materials, and manufacture finished devices, the resulting product
may
be ineffective and unsafe. The need for a written procedure for this
documentation and transfer activity should be determined on the basis
of
need for communication, the complexity of the activity, etc. The GMP
regulation does not mandate a written procedure; however, many firms
simply use their change control procedure to introduce a new product
into production.

Specification Changes

Specification changes must be technically sound, acceptable, and

authorized before they are implemented. Specification changes may be
made using standard forms, such as Engineering Change Notices, or
other
method that will assure the history of the documentation is
maintained
and that changes are properly reviewed, approved, and dated before
implementation as described in chapter 7. Change authorization must
 include the approval date and date the change becomes effective.
Documentation of specification changes for the device, its labeling
and
packaging is necessary to control the device configuration and to
determine configuration at any point in time. Such knowledge is
essential if it becomes necessary to investigate a product defect or
determine which devices must be recalled.

Some firms use Material Review Boards (MRB) to accept temporary

changes or deviations that do not affect safety and effectiveness.
The
MRB determines the acceptance of components, in-process items,
finished
devices, services, etc., that deviate slightly from device master
record
(DMR) specifications. MRB activities are performed per a written
procedure and changes must be documented and approved by the MRB or
other designee. The MRB must not change the DMR or be used as a
substitute for the primary change control system of a firm.
 Processing Controls

Manufacturers must establish process controls to insure that the

device(s) is not adversely affected by the process and that the
process
will achieve its intended purpose. Process controls include standards,
blueprints, first-piece evaluation, written instructions, operation
certification, engineering drawings, inspection, test, etc., as well
as
process validation. The FDA "Guideline on General Principles of
Process
Validation" is reprinted in the Appendix. Firms must assure that all
processes are conducted properly. Assurance is obtained through
training, supervision, audits, inspection, testing, documentation,
etc.
The need for written procedures to assure process control depends on
the
complexity of the process and the training of the operator(s). In
some
cases the success of the process depends on the skill of the employee.
In such cases, written instructions may not be needed. For example,
written procedures are usually not needed in a routine soldering
operation. Sometimes workmanship standards are made available to the
employee and inspection is conducted to assure the soldering is done
correctly. For other processes, specifications or drawings may be
used
in lieu of written procedures. For example, machinists usually use
engineering drawings as guidance rather than written procedures.

All changes to processes must be properly reviewed, validated,

documented, and communicated in a timely manner. The methods
described
in Chapter 7 are used to obtain approval of and to control
specification
changes and to control and document process changes. Process
validation
is covered in chapter 3 and in the "Guideline on General Principles
of
Process Validation" in the Appendix.

Critical Devices

In addition to the requirements in section 820.100, a

manufacturer
of critical devices must identify critical operations and establish
additional controls for these operations.

A "critical operation" is an operation in the manufacture of a

critical device which, if improperly performed, can reasonably be
expected to cause the failure of a critical device or to affect its
safety or effectiveness. Almost all manufacturing operations can have
an
impact on safety and effectiveness of the finished device and
therefore
 a reasonable approach should be taken when evaluating a critical
device
manufacturing process to identify critical operations. Answering the
following "decision-tree" questions will help assist in establishing
which manufacturing operations should be classified as critical.

1. Is this operation being performed on a critical component,

assembly,
or critical device?

If NO, this operation is not critical.

If YES, go to question 2.

2. Will improper performance of this manufacturing operation result

in
a serious hazard such as could be caused by the following events?

o Toxic materials contacting the patient or operator

o Unusual loss of blood
o Air entering the blood steam
o Hemolysis
 o Asphyxiation
o Infection in the patient or operator
o Immediate and dangerous chemical imbalance in the patient
o Electric shock (fibrillation or dangerous involuntary
reaction)
o Significant electrolysis (i.e., apply direct current)
o Undermedication or over-medication
o Mechanical, chemical or thermal damage, or ionizing
radiation
o Operator or user confusion
o Discontinued or inadequate treatment that is not detected
o Nonfunctioning machine parameter that is not detected
o (Other hazardous situations or events)

If NO, this operation is not critical.

If YES, the operation is critical.

In accordance with section 820.101, when a critical manufacturing

operation is identified or designated by company management, it must
be:

o performed by a suitable (i.e., adequately trained)

individual(s);
o conducted using suitable (i.e., adequately qualified)
equipment;
o verified; and,
o recorded in the device history record.

In the list immediately above, the main added requirement for

critical devices is verification. The other elements are also
required
for noncritical devices. A critical operation may be verified by one
or
more methods such as:

o inspection or test of the characteristics added, removed,

or
modified by the operation;

o the production process or assembly operation itself, that

is,
further assembly operations which will reveal improperly
formed parts or assemblies; or

o controlling and monitoring production equipment or

processes
used in manufacturing.

If physical examination, measurement, or test of in-process,

processed, or finished product is impossible or impractical, indirect
control by monitoring the processing method, equipment, and personnel
may be used. Such processes must be validated.
 The sterilization process used to sterilize a critical device is
a
critical operation. The same process, however, is not, by definition,
a
"critical" operation when the process is used to sterilize a
noncritical
device because critical operations apply only to critical devices. In
actuality, however, the process controls for sterilizing a
noncritical
device are the same as for a critical device.

REPROCESSING

If components, subassemblies, assemblies, in-process devices, or

finished devices fail to meet specifications, they are often
reprocessed, repaired, reworked, etc., to meet specification. The GMP
 regulation reprocessing requirements apply to any activity that
involves
recycling of the device or its components through any part of the
manufacturing process including sterilization.
Section 820.115(a) states that "procedures" shall be established,
implemented, and controlled to assure a reprocessed device meets
specifications. In this requirement, "procedures" refers to actions
or
activities taken to assure the reprocessed device meets
specifications.
It does not necessarily mean a written procedure. When the GMP
specifies
that procedures shall be used, but does not specify "written
procedures," the manufacturer must evaluate the controls in place and
determine if they are adequate without written procedures. If so,
written procedures are not required. Regardless of the decisions made,
each manufacturer should be prepared to provide rationale for each
decision. Medium-to- large firms will tend to need written procedures
for reprocessing, particularly when the status of the in-process
device
cannot be determined by a casual observation.

It is not always possible to predict in advance all types of

reprocessing that might occur and, therefore, it is not feasible to
write a procedure which covers all occasions. For example, a
manufacturer often finds it necessary to replace components. Although
this is technically reprocessing, it would be impractical to write a
procedure that would fit all situations where components are replaced.
If the manufacturer determines through observation of errors, defects,
etc., that written procedures are necessary to assure all parts of an
activity are performed, they should be written and implemented. In
many
cases, the reprocessing procedure can be written into the original
manufacturing procedure -- separate reprocessing instructions
generally
do not need to be written if they simply duplicate another existing
procedure.

Specifications for reprocessing should document the specific

tests
and processes to be repeated for each assembly or device and the
limits
on the amount of reprocessing permitted for a unit. These
specifications
should be based on studies to measure the effects of reprocessing
operations. For example, if an electronic component is repeatedly
replaced, the effect of repeated application of heat during soldering
must be determined. If there is an effect such as separation of pad
and
conductors or degradation of insulation, limits should be set on the
number of times a component may be replaced. On the other hand,
replacing a defective printed circuit board (PCB) with a good one may
only require marking the defective board, segregating it, and, after
 replacement with a good PCB, retesting the finished device.
Procedures
used in controlling such reprocessing need only be as detailed as
deemed
necessary to assure the finished device or component meets the
approved
specifications.

For process type industries, firms must evaluate the reprocessing

to
assure that devices will not be adversely affected. For example,
following resterilization, devices must be inspected for
characteristics
which may have been altered. The following are examples of effects
that
might need consideration:

o temperature and moisture effects on steam-sterilized

devices
and packages;

o vacuum and pressure effects and gas byproduct residue

levels
for gas-sterilized devices; and
 o package and device material degradation for radiation-
sterilized devices.

Devices and components to be reprocessed must be identified to

distinguish them from acceptable devices and components. Depending
upon
the degree of control needed, identification may be accomplished by
tagging the individual devices or components, marking their
containers,
or marking the area in which they are held.

Retesting

Manufacturers must implement appropriate QA checks to assure

reprocessed devices meet specifications. When a finished device is
reprocessed, the finished device must be subjected to reinspection,
and/or testing, to the extent necessary to assure the reprocessing
was
adequate and did not have an adverse effect on the performance of the
device. In most cases the procedure used to inspect/test the original
device is adequate for this purpose.

Returned Devices

Once a device is finished and distributed, the GMP reprocessing

requirements do not apply. Therefore, when devices are returned for
repair or reconditioning due to failure or wear, the GMP reprocessing
requirements do not apply. If a product is returned due to a
malfunction
or defect, however, section 820.162, Failure Investigation, applies.
If
the returned device is modified (updated), the GMP requirements also
change because modifying a device is manufacturing and all the
applicable requirements of the GMP regulation must be met. These
usually
include revised: processing or assembly documentation; test/
inspection
procedures; labeling; etc.

Critical Device Reprocessing

The GMP requires written procedures for reprocessing critical

devices and components. Reprocessing instructions may be included in
the
original process instructions or separate procedures may be used.
However, there is some leeway and the actual need for written
procedures
should be determined beforehand based on the degree of reprocessing
that
may be required. When procedures are deemed necessary, they should
prescribe the following elements.
 o The equipment to be used need only be prescribed if it is
different from that used during routine production.

o Any special QA methods or tests needed should be listed. If

routine methods are used, these need only be referenced.

In addition, the activities listed below must be performed when

critical devices are expected to be or are reprocessed.

o The manufacturer must determine the effect of reprocessing

on
the finished device to make certain it will not be
adulterated
or adversely affected. For example, when devices intended
to
be sterile are resterilized by heat, radiation, or ETO, the
possibility of damage or residual contaminants must be
considered.
 o The manufacturer must clearly identify those devices to be
reprocessed and separate them from those not requiring
reprocessing. When a device is reprocessed, this fact
should be reflected in the history record of the
reprocessed
device.

o The individuals designated to approve changes must formally

review and approve new reprocessing procedures or changes
to
these procedures. The change control procedures implemented
by
a manufacturer to meet the requirements of 820.100(a)(2),
Specification Changes, can be used to meet this requirement.

o The firm must generate written testing and sampling

procedures
to assure reprocessed devices and components conform to
approved specifications. The procedures used for routine
inspection and test of the finished device may be used to
meet
this requirement, if appropriate.

REPACKER/RELABELER PRODUCTION AND PROCESS CONTROLS

Repackaging and relabeling are manufacturing operations and thus

must be performed in accordance with applicable requirements of the
GMP
regulation as noted in chapter 1 of this manual. It is important to
consider the flexibility allowed by Section 820.5 of the GMP
regulation
when developing a quality assurance system for repacking and
relabeling.
Note the flexibility written into or implied by the following typical
repacking process. For example, assembly drawings are usually not
needed
and the quantity manufactured is not recorded -- recording the
quantity
released for distribution is adequate to meet the flexible
requirements.

Operation Control

Typically, a repacking and/or relabeling process involves kit

assembly or reducing bulk amounts of finished material into smaller
amounts. Written procedures have limited application but may contain
such information as the packing order for complex kits which is
usually
last-in, first-out (LIFO) in order of use. Other master record
documents
such as labels, package inserts, component lists, environmental
control
procedures, etc., are needed, as appropriate.
 Incoming finished goods must be examined to see if these are the
items ordered -- usually the examination consist of a labeling check
and visual examination for damage and identity versus the purchase
specifications. Incoming components such as cartons, packaging,
adhesives, components of devices, and manufacturing materials are
received as described in Chapter 8, Components and Materials.
Incoming
finished devices and components must be properly indentified and
stored.

A typical kit assembly operation contains the following steps.

These
steps however, are not mandatory. The applicable GMP controls are
indicated for each step.

1. Using a workorder or other manufacturing document, remove kit(s)

items, labeling, packaging from stock following a first-in first-out
(FIFO) system as applicable.

Examine labeling for identity and record [820.120(e)]. This

record
is a part of the history record and may be made on the workorder, or
other appropriate document.
 2. Clear the assembly area of prior kit items, labeling, etc.,
[820.120(c)].

Separate operations adequately to prevent mixups [820.120(b)].

3. Transfer kit items to the assembly area.

Set up operations in a manner designed to assure conformance with

kit specifications.

4. Verify that the kit items are the desired items by checking
against
workorder, specifications, etc.

Examine labeling for identity and record if not done as part of

step
number 1.

Record lot number of kit items where required. Lot numbers are
required for critical devices or when specified by the kit
manufacturer.
Lot numbers should be recorded in a manner that will facilitate ready
identification of all kits containing items with the same lot number.

5. Assemble the kit(s).

The workorder, itemized list, pictorial or actual model can be

used
as guidance in assembling the kit in lieu of a written process
procedure. Models, pictures, etc., used in lieu of master record
documents must be approved for use and kept current.

6. Visually inspect kit(s) to assure conformance to specifications

including labeling requirements. The workorder, itemized lists,
pictorial or model may be used as acceptance criteria.
If required, label the kit with the expiration date. Where
applicable, the expiration date of the overall kit should be the same
as
the kit item with the shortest expiration date.

7. If specified, seal the finished kits and place them in cartons.

Label cartons if not preprinted. Inspect carton contents and

labeling to verify correct contents and labeling.

8. Record the dates of manufacture, quantity released for

distribution
and any control number used.

This data can be recorded on the workorder or any other document

that will be retained. This record becomes part of the device history
record.
 Reprocessing

Reprocessing at a repacker/relabeler typically would involve only

packaging or labeling. However, in some cases a repacker/relabeler
may
reprocess a device that is damaged or contaminated. When a
repacker/relabeler elects to reprocess a device, the applicable GMP
reprocessing requirements apply. When reprocessing is necessary, the
reprocessed device must meet the same quality standards or
specifications as the original device. The same controls used to
determine the quality conformance of the original devices can usually
be
used to determine the quality of reprocessed devices, and the
additional
 GMP reprocessing requirements would not be necessary. If processes
other
than simple packaging are used, such as aseptic filling,
sterilization,
etc., additional GMP manufacturing and reprocessing controls may be
necessary as discussed under "Reprocessing," in this chapter. In any
case the effect of the reprocessing on the device must be determined
by
the repacker or relabeler.

CONTRACT STERILIZATION

Production and contract sterilization of medical devices must be

performed such that the device manufacturer and the contract
sterilizer
meet the applicable parts of the Good Manufacturing Practices (GMP)
regulation and the labeling requirements of 21 CFR 801.

Labeling Requirements

Manufacturers of sterile devices commonly label devices as

sterile
at one establishment and ship them to another facility or a contract
sterilizer for sterilization. Shipments of nonsterile devices labeled
as
sterile are clearly misbranded and adulterated, and they may be
diverted
into consumer channels, thus creating a potential health hazard. FDA
recognizes that this longstanding practice is an economic necessity
for
many manufacturers. Therefore, to meet the needs of these
manufacturers
in a way that will also assure the protection of the public health,
FDA
added Part 801.150(e) to the Code of Federal Regulations (CFR). It is
reprinted below.

(e) As it is a common industry practice to manufacture and/or

assemble, package, and fully label a device as sterile at one
establishment and then ship such device in interstate commerce to
another establishment or to a contract sterilizer for sterilization,
the
Food and Drug Administration will initiate no regulatory action
against
the device as misbranded or adulterated when the nonsterile device is
labeled sterile, provided all the following conditions are met:

(1) There is in effect a written agreement which:

(i) Contains the names and post office addresses of the firms
involved
and is signed by the person authorizing such shipment and the
operator
 or person in charge of the establishment receiving the devices for
sterilization.

(ii) Provides instructions for maintaining proper records or

otherwise
accounting for the number of units in each shipment to insure that
the
number of units shipped is the same as the number received and
sterilized.

(iii) Acknowledges that the device is nonsterile and is being shipped

for further processing, and

(iv) States in detail the sterilization process, the gaseous mixture

or
other media, the equipment, and the testing method or quality
controls
to be used by the contract sterilizer to assure that the device will
be
brought into full compliance with the Federal Food, Drug and Cosmetic
Act.

(2) Each pallet, carton, or other designated unit is conspicuously

marked to show its nonsterile nature when it is introduced into and
is
 moving in interstate commerce, and while it is being held prior to
sterilization. Following sterilization, and until such time as it is
established that the device is sterile and can be released from
quarantine, each pallet, carton, or other designated unit is
conspicuously marked to show that it has not been released from
quarantine, e.g., "sterilized -- awaiting test results" or an
equivalent
designation.

GMP Requirements for Contract Sterilization

The sterilization process must be performed in compliance with

applicable parts of the GMP regulation for medical devices because
sterilization is a manufacturing process. Thus the contract
sterilizer
is a manufacturer [(820.3(k)] and the device master record (DMR) must
contain, or refer to, the location of sterilization process
specifications. Process specifications may be generated by either the
manufacturer, contract sterilizer, or by both parties, although
overall
responsibility rests with the finished device manufacturer.

The GMP arrangements between the manufacturer and the contract

sterilizer may be in the same written agreement used to cover the
801.150(e) labeling requirements. It is the manufacturer's and
contractor's responsibility to assure the agreement is a workable,
practical document and is followed by both parties. FDA inspects
finished device manufacturers and contract sterilizers to determine
compliance. The following is GMP-related information that should be
in
the written agreement for contract sterilization and implemented
during
production, sterilization and release.

Information transfer

The manufacturer and contract sterilizer must designate the

individual(s) at each facility responsible for coordinating the flow
of
information between establishments and for approving changes in
procedures. All technical, procedural, and other information that
pertains to the sterilization process and associated activities must
pass through these designees. The manufacturer and the contractor
should
agree to inform one another of any process changes, especially those
that may require cycle requalification.

Recordkeeping

Documentation such as procedures, records, etc., to be used and

maintained should be specified. If changes are made to the
documentation, both parties should agree on the manner in which the
 changes are to be made. These documentation changes must comply with
GMP
requirements in section 820.100a(2) and b(3) for manufacturing and
process specification changes, and with 820.181 for changes in device
master records.

Process qualification (validation)

The manufacturer has primary responsibility for assuring the

sterility of the device and, therefore, must work with the contract
sterilizer to assure the facilities, equipment, instrumentation,
sterilization process, and other related activities (e.g., aeration,
preconditioning) are qualified. The agreement should specify all
parameters to be qualified by the contractor and the criteria for
requalification. Cycle parameters should be qualified and documented
for
 each specific device or family of devices. The agreement should list
the
measurements to be taken and the records to be kept for each lot of
devices sterilized during the qualification process.

Firms that manufacture customer-specified kits need to establish

a
"worst-case" cycle because the contents of the kits vary from
customer
to customer. One acceptable approach is to fabricate challenge
assurance
test (CAT) kits composed of the most- difficult-to- sterilize items
for
the process to be used. The CAT kits must have the same or greater
impediments to sterilization as the actual device kit for appropriate
parameters such as permeability, density, moisture absorption, heat
absorption, etc.

Fabricate one kit for each spore strip (biological indicator)

required by the protocol being followed. Place the spore strip inside
the package of an item or on an item in the CAT kit. Distribute the
CAT
kits throughout a chamber filled with routine device kits. Develop
the
cycle by following your normal protocol for cycle development. Most
protocols call for three runs. For repeat use of a CAT kit: dismantle;
if appropriate, aerate; inspect for any unit package or product
degradation; and reassemble the CAT kits. If feasible, place the
spore
strip in a different item in the kit for each run. CAT kits should be
double CSR wrapped and, along with other intended items, should
contain:

o towels and other water absorbers if steam will be used to

sterilize;

o high density items such as containers of water if radiation

will be used to sterilize; or

o water absorbers and mated surfaces such as syringes,

covered
scapels, stopcocks, etc., if ETO will be used as the
sterilizing agent.

The completed kit must be placed in typical primary package and

then
placed in a carton of regular kits or in a secondary container that
simulates a typical filled secondary carton.

Bioindicators and dosimeters

The agreement should state who is responsible for, and it must

 define, placement, recovery, handling, and processing of product
samples
and any biological, chemical, or physical indicators. The agreement
should include instructions for packaging and shipment of indicators
and
samples to test laboratories for analysis.

Loading configuration

The loading parameters for each lot of device(s) or device family

should be specified. Precautions should be taken when different
devices, particularly those with different packaging, occluded
surfaces,
and densities are sterilized as mixed loads.

When loads are mixed, a "worst-case" load can be established by

scientifically reviewing the impediment characteristics of all
devices,
all product packaging types, and loading configurations that are
allowed
to occur. After this "worst-case" load is validated, any mixed load
that
does not exceed the "worst-case" conditions with respect to
impediments
 to sterilization can be assumed to be validated. A contract
sterilizer
offers a process that is intended to sterilize, whether promoted as
such
or not. As such, the contractor must share responsibility with the
finished-device manufacturer in assuring the process will sterilize
the
product accepted for processing in mixed or single loads.

Preconditioning

The agreement should address preconditioning requirements for

external preconditioning and/or in-chamber conditioning.

Cycle parameters and process control

Contract sterilizers are responsible for meeting those GMP

requirements that apply to their manufacturing operations, e.g.,
equipment maintenance and calibration, recordkeeping, in-process
controls, etc. After the process is qualified, the contract
sterilizer
must maintain control over the process to make certain that process
specifications are routinely achieved. Cycle parameters must be
clearly
defined in written specifications, accurately monitored, and the
actual
parameter values achieved during each run must be recorded.

The primary manufacturer must produce the product under a GMP

system
which includes appropriate environmental control procedures such as
bioburden control when bioburden is a concern. Thus, the product is
the
"same" product as that for which the original process was developed
or
specified.

Post-sterilization handling and aeration

The agreement should address procedures for post-sterilization

quarantine of the product before release for distribution. While
waiting
for release, the pallets, cartons, or designated unit must be marked
to
indicate the status of the product; for example, "sterilized:
awaiting
test results," or an equivalent statement. If an aeration period is
required, it should be specified. Both parties should acknowledge
that
the product is not to be shipped for commercial distribution until it
is
properly approved for distribution in accordance with procedures in
the
 agreement.

If correctly labeled, a device that has been sterilized may be

shipped to a controlled distribution point before final release by
the
manufacturer. Routine distributors are not considered to be
"controlled
distribution points." Shipments to a company warehouse or to another
finished-device manufacturer may be acceptable as long as the
manufacturers are able to show that they have control of the product
until final release and could recall it if necessary. See CFR 801
Subparts A & E and 820.150, 820.160, and 820.161.

History records and review

Both parties should agree on the procedures and responsibility

for
reviewing and approving the device history records.
Finished device release

The agreement should include device release procedures.

Individuals
responsible for approving device release for distribution should be
identified. A contract sterilizer may handle the final release of a
 batch of sterilized devices. The manufacturer should make sure,
however,
that this agreement is part of a written contract. In addition, the
manufacturer must audit or have a consultant audit the contract
sterilizer; review the contractor's own QA audit report; or obtain
written certification of compliance to assure that personnel and
procedures are adequate to meet the requirements of 820.160 and other
applicable GMP requirements.

Audits of both facilities

The device manufacturer should audit his quality assurance

program
and assure by audits or other means such as a review of the
contractor's
own QA audit that the contractor has adequate control over the
sterilization process. The agreement should cover the extent and
frequency of the audit, corrective actions, records, confidentiality,
and the auditor(s).

Training

The manufacturer should assure that the entire sterilization

process
is performed and controlled by properly trained operators. The
agreement
should provide the manufacturer access to applicable training records
during agreed-upon audits.

Nonconformance

Both parties should mutually agree to inform one another if the

device or process deviates from the agreed-upon specifications. As
appropriate, the nonconformance should be investigated, evaluated,
and,
if necessary, corrective actions should be instituted. The parties
should consider and agree on conditions for, and document all
reprocessing.

(It is highly recommended that manufacturers of sterile medical

devices obtain and read: Sterile Medical Devices - A GMP Workshop
Manual. Contact the FDA Division of Small Manufacturers Assistance
for
ordering information.)

gmp2-8:8/3/87
 GMP - CHAPTER 10 - DEVICE EVALUATION

Chapter 10 DEVICE EVALUATION

INTRODUCTION
Evaluation Specifications
FINISHED DEVICE EVALUATION
Simulated-use testing
Sampling Plans
Labeling and Packaging Inspection
Records
Product Release
Additional Requirements for Critical Devices
FAILURE INVESTIGATION
REPACKER/RELABELER DEVICE EVALUATION
EXHIBITS
Portable Defibrillator Test Procedure
Test DHR of a Printed Circuit Board Assembly
Device History Record (urine plate)
Batch Production Record (XLD)
Batch Production Record (Thayer Martin)
Batch Production Record (Blank form)

INTRODUCTION

The GMP requirements for finished device evaluation are covered

in
section 820.160 which requires written procedures for finished device
inspection to assure that device specifications are met. Before
releasing devices for commercial distribution, manufacturers must
assure
that finished devices perform intended functions by checking or
testing
those characteristics that must meet device master record safety and
performance specifications in order for the device to be fit for the
intended use.

If a firm has adequate test and inspection procedures and these

are
used correctly by appropriately trained personnel, then there is a
high
probability that all devices released for distribution will meet the
company device specification. Further, the data collected during
inprocess or finished device evaluation are appropriate, complete,
correct, and may be fed back into the quality assurance system to
identify and solve real problems, and to help maintain and improve
the
quality assurance system.
 Evaluation Specifications

A firm must decide which characteristics of a device to test

and/or
inspect and to what detail or extent to test and/or inspect versus
the
device specifications in order to be assured that a device is fit for
 the intended use. For example, this decision is typically based on
the:
o intended use;
o intended user;
o nature of the device and its components;
o intrinsic safety of the device;
o reliability of the device;
o overall process capability of the manufacturing operation;
o characteristics of test and inspection equipment and
procedures;
o performance margin of the device versus the device
specification.

These evaluation decisions are made during the product and

process
development phase; and final debugging is usually performed during
pilot
production as discussed in chapter 3. At the start of full scale
production, the test and inspections decisions must be completed,
documented as test/inspection procedures, and be approved for use. It
is
a violation of the GMP regulation to place inadequately evaluated
devices into commercial distribution. It is also a violation of the
GMP
regulation to deliberately allow test and inspection procedures to
evolve during production, except during a highly controlled pilot-
production phase. Further, devices that are not adequately evaluated
may
not meet company written or unwritten quality claims -- firms cannot
bypass their responsibility by simply not writing quality claims.
Under
Section 501(c) of the Food, Drug, and Cosmetic Act, a device is
adulterated if its purity or quality falls below that which it
purports
or is represented to possess.
Device test and/or inspection specifications, and test and/or
inspection procedures, must be carefully written and must cover all
appropriate points in the device specification, in order to improve
communications and reduce errors. Completeness is assured if each
appropriate and numbered paragraph in the device specification has a
corresponding numbered paragraph in the test and inspection procedure
and numbered blank on the data form. Generally, each numbered
paragraph
in the test and inspection procedure describes the detailed process
for
evaluating a specific aspect of the device. The data sheet or history
record form has a blank with the same unique paragraph number for
recording the data obtained when evaluating each characteristic of
the
device. This correlation can be seen at the end of this chapter in
the
sample procedure for the defibrillator by comparing paragraph 5.4.2
with
blank 5.4.2 on the data form.
 Thus, at the production phase, the device specifications are
supported by one or more test and inspection documents which form
part
of the device master record. To reduce drafting, filing, retrieval
and
copying costs, test and inspection specifications may appear on
process
and assembly documents. Combination documents are commonly used for
the
fabrication and inspection/testing of subassemblies. There may be
several test and inspection documents because evaluation may be
performed at several in-process stages and at the finished device
stage.

There are situations where a simple data sheet or blueprint that

lists the acceptance criteria can be used in lieu of a written
procedure. For example, the acceptance of a simple molded or machined
device may be determined by using a checklist, blueprint, or
specification which specifies finished dimensions, flash removal, etc.
In machine-shop operations, a blueprint or engineering drawing may be
used as acceptance criteria and used to meet the GMP written
procedure
requirements.
 Whether simple or complex, all manufacturing documentation,
including data sheets, must be under formal change control. Likewise,
the test equipment must be suitable, calibrated, and under a formal
recalibration control program.

FINISHED DEVICE EVALUATION

Finished device inspection is typically a final test and review

of
safety, performance and configuration characteristics to assure these
meet the specifications in the device master record. For many medical
devices this assurance requires an analysis, electrical test, or
mechanical test. For some simple devices, however, such as eyeglass
frames, a visual or dimensional check may be sufficient to prove
acceptability.

Manufacturers must have specifications or criteria for

determining
acceptability of the finished device as discussed above and in
chapters
3 and 6. It is important that the device characteristics to be
evaluated
are defined and also, where applicable, the equipment, environment,
and
handling procedure be defined and established. These are specified in
a
written procedure as required by Section 820.160 which typically
includes tests to be conducted, test equipment configuration, and any
standards or reference materials to be used.

Simulated-Use Testing

Where practical, a finished device must be selected periodically

and
tested under conditions which simulate those under which the device
is
expected to operate reliably. These factors may include a specific
environment, load, external interference; use with other devices; etc.
Simulated use of implantable pacemakers would consist of submerging
the
pacemakers for a specified time in a 38oC saline solution with an
electrical load applied to simulate the fluids, temperature, and
electrical load presented by the body.

Many recalls could have been prevented if the manufacturer had

adequately tested the device under simulated conditions before
distribution. For example, blood tubing was recalled because it would
not properly occlude when used in a blood pump. Testing under actual
operating conditions would have detected this problem.

When a simulated test is used, the test specifications must be

included in the device master record. These and all other test
 specifications must be designed for the intended use and the adequacy
of
the resulting tests must be verified [FD& C Act, Section 501(c)] as
discussed in chapter 3 of this manual in order to help assure that
finished devices meet quality claims.

Sampling Plans

Manufacturers may test all devices to assure they meet acceptance

criteria; or, if the manufacturing process is operating in a state-
of-
control, they may test a portion by using a sampling plan based upon
an
acceptable statistical rationale. A manufacturer must be prepared to
demonstrate the statistical rationale for any sampling plan used.
Plans
should be developed by qualified mathematicians or be selected from
 established standards such as MIL-STD-105d or MIL-STD-414. Copies of
these standards may be obtained by writing to: Naval Publications and
Forms Center, 5801 Tabor Avenue, Philadelphia, Pa. 19120-5099.

All sampling plans have a built-in sampling risk. A sampling risk

is
the probability of shipping (or receiving, from the customers
viewpoint)
a "bad" lot and is typically determined in quantitative terms by
deriving the "operating characteristic curve" for the selected plan.
Each sampling plan has an operating characteristic curve which is a
means of GRAPHICally showing the relationship between: quality of
lots
submitted for sampling inspection, (usually expressed in percent
defective, but may also be expressed in defect per hundred units);
and
the probability that the sampling plan will yield a decision to ship
the
lot. MIL-STD-105d and MIL-STD-414 contain operating characteristic
curves for sampling plans presented in them; and, these curves can be
used to determine the risk each sampling plan presents.

When sampling plans are used, a few defective devices will be

shipped to the user. Thus, manufacturers should be aware of the risks
a
particular plan presents to the firm and to the user. Questions such
as
those listed below should be considered before selecting a sampling
plan.

o Will the defect be obvious to the user? If not, what are

the
consequences of using the defective device?

o What is the state-of-the-art technology for testing this

device?

o Does the competition use sampling?

o What is the probability of a product liability suit?

o What are the regulatory consequences?

o Does the marketplace expect or accept devices that have

been
sample tested or inspected?

Acceptance of sample-tested devices is usually set by the price

the
user is willing to pay -- 100 percent testing usually costs more than
sampling. Whether sample testing and inspection of a particular
family
of devices is acceptable to the user also changes with technology.
 Manufacturers should also recognize that straightforward logical
answers
to the listed questions are not always suitable -- political,
litigious,
and emotional climates should also be considered when deciding which
sampling plans to use or what risks to take.

Labeling and Packaging Inspection

Before release, the finished device, its containers, and

packaging
must be examined as applicable to assure they are not damaged or
misbranded. That is, these must contain correct labels, package
inserts,
or manuals. The packaging of sterile devices must be examined after
sterilization to make sure integrity, sealing, and labeling
requirements
are met.

Records
 Section 820.160 is not specific regarding finished device test
and
inspection records for noncritical devices; however, these records
must
be generated as they must be included as part of the device history
record (820.184). A device history record is a compilation of records
containing the complete production history of a finished device
[820.3(h)]. The term "complete" is interpreted for each family of
devices as allowed by 820.5. For many devices and manufacturing
operations, the major documents in the device history record are the
finished device inspection and test records. The history record must
be
reviewed because these records are used to show that finished devices
are manufactured in accordance with the device master record.

Product Release

Finished device manufacturers must have sufficient controls to

assure that only devices that have passed test and inspection are
released as discussed in chapter 13, Distribution. To prevent mixups,
devices that have been through final evaluation and accepted for
release
must be segregated from not-yet-accepted or rejected devices; or,
otherwise controlled such as by location, boxing, or manifest tagging.

Production and inspection/test records should be reviewed before

releasing each lot of finished devices. Section 820.20(a) makes the
QA
organization responsible for reviewing production records. This
requirement does not specify when to review records. To meet GMP
requirements, however, they must be reviewed often enough to assure
operations are in a state-of-control.

Additional Requirements for Critical Devices

If a critical device or critical component does not pass the

final
inspection and/or testing, the cause of the failure must be
determined
and corrections must be made to prevent similar failures (820.161).
The
investigation, conclusions, and followup must be documented. When a
critical or noncritical device fails testing, it should not be
repeatedly retested until it passes without first determining the
cause
for failure. If a manufacturer's acceptance procedures allow
acceptance
after repeated testing and rework, there must be a valid basis for
such
an acceptance procedure. Failed devices must be identified and
segregated from acceptable devices and from the flow of the
production
process.
 Before critical devices are released for distribution, or
released
from control of the manufacturer, history records for the devices
must
be reviewed. The history record files should be in a minimum of
locations in order to expedite reviews and increase the probability
of
maintaining a state-of-control. Reviews must be conducted to assure
that
all records and documentation required by the device master record
are
present, and that all operations required by the master record have
been
correctly completed. The responsibility for this function must be
assigned to one or more designated individuals. The GMP regulation
does
not mandate that all records be reviewed by a single individual at
one
time, although this is the preferred approach. The history records
may
be signed in stages by designated individuals. These individuals must
authorize, by signature, the release of the device.

FAILURE INVESTIGATION
 GMP sections 820.162 and 820.198 require investigations after a
critical or non-critical finished device is released for distribution
and fails or allegedly fails to meet performance specifications.
Section
820.162 refers to analysis of actual failed devices, i.e., the
determination of the failure mechanism, and whether it is design or
manufacturing related. Section 820.198 is intended to apply to the
investigation of complaints involving possible failure of a device,
i.e., an investigation to determine if there actually is a failure.

After devices are distributed, if they fail to meet specifications,

the failed devices must be investigated if the manufacturer has them
or
can obtain them. Failure to meet specifications also includes
packaging
and labeling integrity failures. Technically, all devices returned
for
repair or service due to failure to meet specifications are subject
to
820.162. FDA, however, will accept routine service and repair records
in
lieu of the written record of investigation required by 820.162 as
long
as manufacturers have a system for identifying failure trends
[820.20(a)(3)] and investigating the cause of the trends.

The significance of the device and any hazard the defective

device
presents should be taken into consideration when determining
compliance
with failure investigation requirements. Analysis must be taken to
the
level necessary to determine the actual failure mechanism, e.g.,
defective component, incorrect raw material, erosion, composition,
etc.
The cause of failure is obvious in some cases and a formal
investigation
may not be needed. A record of the investigation, followup, and
conclusions must be made in accordance with GMP sections 820.162 and
820.20(a)(3).

Failure analysis should be conducted by experienced personnel

using
a written protocol to assure that handling and testing do not
compromise
determining the cause of failure. A written protocol, however, is not
a
GMP requirement. The cause of a failure is identified to the point of
objective reality such that appropriate corrective action can be
taken.

When a systematic failure has been diagnosed, manufacturers need

not
 analyze every device with the same diagnosed symptoms. However,
enough
devices must be analyzed to clearly establish symptoms before any
assumptions are made about the cause of failure or about corrective
actions. When an investigation verifies that a particular device
characteristic such as component, design, etc., is deficient, and
that
this deficiency may exist in other product lines, the investigation
must
extend to determining the effect on other product lines.

When a failure is determined to be related to documentation,

assembly, processing, labeling, testing, packaging or other
manufacturing operations, the manufacturing deficiency must be
determined, corrected, and documented. If the failure is design
related,
the design must be corrected in order for the devices to meet company
quality claims and be in compliance with FD& C Act section 501(c).

REPACKER/RELABELER DEVICE EVALUATION

Finished devices received by a repacker/relabeler typically have

been inspected and conformance to specifications determined by the
original manufacturer except for packaging and/or labeling. In most
cases a repacker/relabeler would not have to assure the finished
device
as received meets performance and configuration specifications,
except
 for finished bulk materials, such as dental resins, in vitro
diagnostics, etc. These may be accepted on the basis of a
certificate
of analysis for each batch.

Before releasing devices for distribution, repackers/relabelers

must
assure that packaged and labeled devices are properly labeled (see
chapter 11) and packaged (integrity, contents, etc., also see chapter
12). Often this can be accomplished using a list, illustration, or a
model. When the packaged product is sterilized or aseptically filled,
written instructions and inspection/test are usually necessary. Final
acceptance of repacked/ relabeled devices should be recorded. For
additional information, please see "Repacker/ Relabeler Production
and
Process Controls" in chapter 9.

EXHIBITS

Several forms for recording device production and evaluation data

are briefly described below and then exhibited. For one of these, the
defibrillator test procedures, part of the test procedure is also
exhibited.

Portable Defibrillator Test Procedure

Ten pages extracted from a 31-page test specification for a

family
of portable defibrillators are reprinted below. This test procedure
is
long and detailed because a defibrillator is a complex critical
device
with a benefit to risk ratio that approaches infinity. This sample
evaluation procedure covers final manufacturing, testing, and data
collection performed by the production department to make absolutely
certain that finished defibrillators comply with device master record
specifications. This test procedure was developed based on the
company
approved device specifications. The complete device specification is
exhibited at the end of chapter 6. Note that the device
specifications
and other drawings are referenced on page 2 of this sample test
procedure.

To reduce errors and increase clarity, the test number column on

the
data sheet contains the paragraph number of the detailed requirements
in
the specifications section of the procedure. The test equipment and
schematics are not reprinted here.

Test DHR of a Printed Circuit Board Assembly

 A data or "device history record" card for a printed circuit
board
is exhibited. The test procedure for the board is not reprinted. This
data card is not the device history record for the finished device.
When
the finished device is tested, this board is tested again as an
integral
part of it.

Device History Record (urine plate)

A record sheet of the filling, labeling sample, inspection, and

sample testing of a five-media urine plate is exhibited. Each
activity
is performed per procedure -- these procedures are not exhibited. The
label record is an actual label as printed on the urine plates -- the
record sheet is passed through the printing machine. This technique
reduces costs and eliminates human copying errors.
 Batch Production Record (XLD)

This exhibit is the batch production record of the XLD component

used to fill one section of the five-part urine plate discussed
above.

Batch Production Record (Thayer Martin)

This exhibit is a blank copy of the form used to record the batch
production record for the Thayer Martin component used in the urine
plate.

Batch Production Record (Blank form)

This exhibit is a form used to record the batch production record

of
various growth media. It could be used to record the production of
XLD
as mentioned above.

gmp2-2:8/3/87

<Portable Defibrillator Test Procedure (10 pages)>

<Test DHR of a Printed Circuit Board Assembly>

<Device History Record (urine plate)>

<Batch Production Record (XLD)>

<Batch Production Record (Thayer Martin)>

<Batch Production Record (Blank Form)>

 GMP - CHAPTER 11 - LABELING

CHAPTER 11 LABELING

LABELING REGULATIONS
Misbranding
False or Misleading Labeling
Adequate Directions for Use
Prescription Devices
Sterile Devices
CONTENT DEVELOPMENT AND APPROVAL
Write to Reader
Refer to Actual Device
Obvious Identification of Controls
Don't Distract Reader
Short and to the Point
Gobbledygook
Introduce Each Item
Accentuate Key Terms
Select Words Wisely
Try Labeling
Approval Policy and Procedure
GMP CONTROL OF LABELING
Label Integrity
Receipt and Inspection
Area Separation and Inspection
Storage
Label Check and Record
Critical Device Labeling
CHANGES
SHIPPING FOR PROCESSING
RELABELING AND OVER-LABELING
EXHIBITS
Drafting and Approval of Labeling
Approval Form for Labeling, Advertising, Literature, etc.
Administration Set Label
Labeling Control Record (1 Blank and 1 Completed)
Device History Record: OB/GYN (Plate)
User/Reader Comments

LABELING REGULATIONS

Medical devices in commercial distribution in the U.S. must be

properly labeled according to laws and regulations enforced by the
Food
and Drug Administration (FDA). Specific labeling requirements for
medical devices are contained in:

o The Federal Food, Drug, and Cosmetic (FD& C) Act;

o The Fair Packaging and Labeling Act;
 o The Radiation Control for Health and Safety Act;

o Title 21 of the U.S. Code of Federal Regulations, Part 801

for
 general devices, and Part 809 for in vitro diagnostic
products;

o Title 21 of the U.S. Code of Federal Regulations, Part 820

for
manufacturing controls for labeling; and

o Title 21 of the U.S. Code of Federal Regulations, Part 1010

-
Performance standards for Electronic Products. Also see
Parts
1020 and 1040.

Section 201(k) of the FD& C Act defines the term "label" as "a
display of written, printed, or GRAPHIC matter upon the immediate
container of any article . . . ." The term "immediate container" does
not include a package liner. Any word, statement, or other
information
appearing on the immediate container must also appear on the outside
container or wrapper, if any, of the retail package or be easily
legible
through the outside container or wrapper. This labeling is not
required
on the shipping carton.

Section 201(m) of the FD& C Act defines the term "labeling" as

all
labels and other written, printed, or GRAPHIC matter: (1) on the
device
or any of its containers or wrappers, or (2) accompanying the device.
The term applies any time while the article is in interstate commerce,
or being held for sale after shipment or delivery in interstate
commerce. The term "accompanied" is interpreted liberally. It extends
to
posters, tags, pamphlets, circulars, booklets, direction sheets,
fillers, etc., that may be displayed in proximity to the article or
shipped to the user before or after shipment of the device.

The distinction between labeling and advertising, while both draw

attention to the article to be sold, is often nebulous or superficial.
Both are forms of publicity and are used for an identical purpose.
According to an appellate court decision: "Most, if not all, labeling
is
advertising. The term 'labeling' is defined in the Act [Section
201(k)]
as including all printed matter accompanying any article. Congress
did
not, and we cannot, exclude from this definition printed matter which
constitutes advertising."

Section 502(f)(1) and (2) of the FD& C Act requires that device
labeling bear adequate directions for use, operating and servicing
 instructions, and either adequate warnings against uses dangerous to
health, or information necessary for the protection of users. All
devices require directions for use unless specifically exempted by
regulation. Conditions for exemption from this requirement are in 21
CFR
801, Subpart D.

Misbranding

Section 502 of the FD& C Act contains the misbranding provisions

for
drugs and devices. It states a device is misbranded if:

o its labeling is false or misleading;

o its packaging does not bear a label containing the name and
place of business of the manufacturer, packer, or
distributor,
and an accurate statement of the quantity of contents;
 o words, statements, or other required information are not
prominent on the labeling or are not stated clearly;

o it is intended for human use, and the label fails to bear

the
name and quantity or proportion of any narcotic or
habit-forming substance contained in the product, and fails
to
display the statement, "Warning: may be habit forming";

o its label does not contain adequate directions for use.

These
include warnings against use in certain pathological
conditions; by children where its use may be dangerous to
health; against unsafe dosage, methods, duration of
administration or application unless exempt as unnecessary
to
protect the public health;

o it is dangerous to health when used in the dosage or manner,

or with the frequency or duration prescribed, recommended
or
suggested in the labeling;

o it does not comply with the color additive provisions

listed
under Section 706 of the FD& C Act.

The Medical Device Amendments expanded the authority of the FD& C

Act
over misbranded medical devices. These amendments contain further
circumstances under which a device is misbranded:

o the device's established name, if it has one, name in an

official compendium, or common or usual name, is not
printed
prominently in type at least half as large as used for any
proprietary name;

o the device is subject to a performance standard and it does

not bear the labeling requirements prescribed in that
standard;

o there is a failure or refusal to comply with any

requirement
prescribed under Section 518 on notification and other
remedies; failure to furnish material or information
requested
by or under Section 518; or failure to furnish any
materials
or information requested by or under Section 519 on records
and reports; and
 o the device is commercially distributed without FDA
concurrence
on a 510(k) premarket notification submission.

False or Misleading Labeling

Section 502(a) states that a drug or device is misbranded if its

labeling proves false or misleading in any particular. It is not a
necessary condition that the labeling should be flatly and baldly
false
for the FDA to take action. The word "misleading" in the FD& C Act
means
that labeling is deceptive if it creates or leads to a false
impression
in the mind of a reader. A "false impression" may result not only
from a
false or deceptive statement, but may be instilled in the mind of the
purchaser by ambiguity and indirection. It might be caused by failure
to
inform the consumer of facts that are relevant to those statements
actually made. In other words, the label that remains silent as to
certain consequences may be as deceptive as the label that contains
extravagant claims. Examples of misleading labeling include ambiguity;
 half truths and trade puffery; expressions of opinion or subjective
statements; and failure to reveal material facts, consequences that
may
result from use, or the existence of difference of opinion.

Objectionable labeling includes such practices as deceptive

pictorial matter, misleading testimonials, misleading lists of parts
or
components, and brand or trade names instead of "established names"
(see
Sections 201(h), 502(e)(2), and 508 of the FD& C Act). Examples of
false
representations are:

o incorrect, inadequate or incomplete identification;

o unsubstantiated claims of therapeutic value;

o inaccuracies concerning condition, state, treatment, size,

shape, or style;

o substitution of parts or material;

o subjective or unsubstantiated quality or performance claims;

and,

o use of the prefix U.S. or other similar indication

suggesting
government or agency approval or endorsement of the
product.

Adequate Directions for Use

Title 21, CFR Part 801.5, defines "adequate directions for use"
as
"directions under which the layman can use a device safely and for
the
purpose for which it is intended." See Part 801.4 for a definition of
"intended use."

Among other reasons, directions for use may be inadequate because

there is partial or total omission or incorrect specification of one
or
more of the following items.

o Statement of all conditions, purposes, or uses for which

the
device is intended. This includes conditions, purposes, or
uses for which it is prescribed, recommended, or suggested
in
its oral, written, printed, or GRAPHIC advertising. Also
conditions, purposes, or uses for which the drug or device
is
 commonly used; except that these statements shall not refer
to
conditions, uses, or purposes for which the drug or device
can
be used safely only under the supervision of a practitioner
licensed by law and for which it is advertised solely to
such
practitioner.

o Quantity of dose including usual quantities for each

intended
use and usual quantities for persons of different ages and
physical conditions.

o Frequency of administration or application.

o Duration of administration or application.

o Time of administration or application in relation to meals,

onset of symptoms, or other time factors.

o Preparation for use, adjustment of temperature, or other

 manipulation or process.

Prescription Devices

Labeling exemptions for prescription devices are in 21 CFR Part

801.109. These are devices which because of a potential for harmful
effect, method of use, or the collateral measures necessary to use,
are
not safe except under the supervision of a practitioner licensed by
law.
Hence "adequate directions for use" cannot be prepared for these
devices. They are exempt from Section 502(f)(1) of the FD& C Act
provided
that all conditions specified in the labeling regulation are met.

These conditions state that the device must be in the possession

of
a person, or his or her agents, or employees regularly and lawfully
engaged in the manufacture, transportation, storage, or wholesale
distribution of prescription devices; or in the possession of a
practitioner such as physician, dentist, or veterinarian licensed by
law
to use or order the use of these devices. These devices can be sold
only
to, on the prescrition of, or order of such practitioner for use in
the
course of their professional practice.

The label of the prescription device other than instruments is

required to bear:

o the statement "Caution: Federal law restricts this device

to
sale by or on the order of a _____", the blank to be filled
with the word "physician", "dentist", "veterinarian", or
with
the descriptive designation of any other practitioner
licensed
by the law of the State in which he or she practices to use
or
order the use of the device; and

o the method for its application or use.

Labeling on or within the package from which the device is to be

dispensed must also bear information for use under which
practitioners
licensed by law to administer the device can use the device safely
and
for the purposes for which it is advertised or represented. Labeling
information on administration includes indications, effects, dosages,
routes, methods, frequency, and duration. Safety labeling includes
 relevant information on hazards, contraindications, side effects, and
precautions.

When a device is capable of producing serious injury, even when

used
by a person thoroughly familiar with its operation, the directions
for
use must provide detailed information. For example, the Food and Drug
Administration has specific regulations on the labeling of
intrauterine
contraceptive devices, 21 CFR 801.427, and for diagnostic x-ray
devices,
21 CFR 1020.30(h). In addition, FDA has issued general guidelines for
labeling certain devices, i.e., transcutaneous electrical nerve
stimulators and electronic muscle stimulators.

Where appropriate, directions for use must be supplemented with

adequate warnings against the use of the drug or device under certain
conditions. Any caution statement, similar to the directions
statement,
may appear in the labeling of the product; it is not necessary that
it
be printed on the label. In each instance, the responsibility for the
adequacy of the warning statement appearing on the labeling rests
with
 the manufacturer or distributor. For some devices, there are national
consensus standards that specify that certain caution statements be
on
the device.

Sterile Devices

Special attention should be given to the labeling of sterile

devices. Devices that are not sterile in their entirety (for example,
sterility may be needed only for the lumen of certain devices) must
be
labeled to properly inform users what is actually intended to be
"sterile" in the package. For example, a possible limiting statement
might be:

"Caution: Only the fluid path of the set is sterile and nonpyrogenic.
Do not use in a sterile or aseptic area without proper precautions."

Some devices are intended to be sterilized by the user before use.

In this situation, the labeling should provide adequate information
as
to the method of sterilization and any precautions or safeguards to
be
followed. For example, the labeling should describe any:
o special cleaning methods required;

o changes in the physical characteristics of the device that

may
result from reprocessing which affect its safety,
effectiveness, or performance; and,

o limit on the number of times resterilization and reuse can

be
done without affecting the safety or effectiveness of the
device.

In the case of single-use sterile devices, many manufacturers

include labeling to advise against resterilization and reuse. Some
devices are simply not designed or constructed to be recleaned, and
may
not be capable of withstanding the necessary recleaning and
resterilization procedures. Where reuse is common practice,
manufacturers are encouraged to provide the information described in
the
above list.

The label of multi-device kits or packages containing a

combination
of sterile and nonsterile products must not state or imply that all
contents are sterile.

The need for users to have instructions on how to open a sterile

device package to avoid contamination of the device also needs to be
 evaluated, and when necessary, such instructions should be included
in
the labeling.

When a manufacturer modifies a device, the manufacturer must also

review the labeling to ensure that it reflects current revisions and
specifications. Some manufacturers identify labeling with a drawing
number plus a revision code or date as an aid in identifying current
labeling. The package insert or other labeling for in vitro
diagnostic
products is required to contain the revision date [21 CFR
809.10(b)(15)].

Shelf-life dating solely for package integrity and sterility is

not
usually required for general medical devices. There may be a need for
expiration dating when a particular component of a device, such as a
 battery or diagnostic reagent, has a finite useful life. Labeling for
in
vitro diagnostic devices [809.10 (a) and (b)] requires an expiration
date or some other means by which users may be assured of quality at
the
time of use. This requirement applies to both sterile and nonsterile
in
vitro diagnostic devices.

Although not required by regulation, most manufacturers of

complex
devices and sterile devices voluntarily use lot or serial numbers for
production control and, if the need arises, to expedite failure
investigations, repairs, modifications, or recalls. Lot, batch, or
other
control numbers are required for:

o critical devices (820.121);

o some products subject to radiological health standards; and
o in vitro diagnostic devices [809.10(a)(9)].

Adequate labeling for a medical device requires proper design and

procurement of the labels and labeling. Design includes labeling
content
that meets the requirement of the GMP regulation as well as the needs
of
the customer. To achieve these goals a number of concepts must be
kept
in mind such as: writing to the reader, referring to the actual
device
in labeling, obvious identification of the controls used, etc. These
concerns as well as others are discussed on the following pages.

CONTENT DEVELOPMENT AND APPROVAL

There are some basic guidelines, rules, and practices that can be
used to immediately improve such writing. The following paragraphs
will
discuss them, with emphasis on how they can be used to make labeling
clear and comprehensible. Writers are also encouraged to obtain and
use
a standard college-level text on technical writing.

As an essential aid, writers are encourage to obtain a copy of

40,000 Words or a similarly titled book by any of the reference-book
publishing companies. Most of these reference books have about four
pages of punctuation rules. Using the four small pages of rules can
immediately improve your writing. For example, you can avoid the
common
punctuation error of not using semi-colons to replace commas when
needed.

Write to Reader
 The most serious problem is that writers tend to write to
themselves. Their material is clear to them -- and they mistakenly
think
it is as clear to others. For example, the sensitivity control on an
instrument is called: "gain" control on page one of the instruction
manual, "amplitude" control on page two, and "level" control in the
next
section. Further, the photograph in the Introduction shows the same
control with a call-out labeled "Signal Adjust". No wonder readers
are
confused! Yet the author of the example knew what he was trying to
write
about and, most certainly, he was writing to himself. When writing
labeling, especially for an OTC device, the author must know the
reading
level of the target audience. If data on reading levels is not
available, this may nessitate reader interviews to establish a
reading
level for the target audience.

Refer to Actual Device

One simple way to reduce control identity confusion as described

 above, reduce other types of labeling errors, and increase clarity is
for authors to keep a labeled instrument, kit, or photograph(s)
nearby
and refer to it as they write. It is easier to write the truth when
you
know the truth. Make sure the terminology and descriptions in the
labeling matches that on the device. Always use the same title for
each
given item or control throughout the manual, insert, label, or
advertisement. Likewise, the same title should be used in charts,
figures, or screen displays such as cathode-ray tubes, LCD panels,
etc.
Remember to write to your intended readers, write with a labeled
device
or photographs in sight, and use consistent titles.

Obvious Identification of Controls

Because the title of controls or other items in screen displays

and
other labeling should be exactly the same as in the labels on
equipment,
reagents, accessories, etc., authors may need to develop and use an
appropriate correlation technique for corresponding titles in
instruction manuals, package inserts, etc. One common technique is to
use all capitals for the titles of controls in labeling. For example:

Flip the POWER switch to ON.

In about three seconds, the READY lamp will illuminate.
Now press the HEAT button to switch the heater on.

With this correlation technique, the words "on" and "off" are
capitalized in the labeling only when they actually appear on the
instrument control panel. Note that "ON" is capitalized in "POWER
switch
to ON" as the actual switch has "POWER", "ON", and "OFF" printed by
it.
In contrast, note that "on" is not capitalized in the example "to
switch
the heater on" as it is not a label of a control on the device. Also,
be
careful to use a simple correlation system that is readily apparent
to
the intended audience.

Don't Distract Reader

Readers are very busy trying to learn how to use a new device.
They
should not be annoyed by any unnecessary distractions such as:

o changes in format,
o unusual typeface,
 o incorrect page numbers, and
o incorrect figure numbers.

For a person trying to read in a hurry, a font such as script,

can
be a major distraction; therefore, don't use script, italics, or any
other unusual or hard-to-read type-faces. Remember, you have decided
to
write for the benefit of the intended audience. Forget about your
personal preferences and use only the most common fonts. Also, select
a
type size that is readable at the intended distance. For example,
labeling displayed on the screen of a wall-mounted heart monitor must
be
readable fro several feet away. Also, use a consistent format
throughout
the document. Also, check the format and section titles against
information on the contents page. In some cases, such as for in vitro
diagnostic products, the arrangement of information in the labeling
may
be dictated by a regulation. Page numbers should not be referenced in
instruction or service manuals. It is too easy for the actual page
numbers to be changed during the original writing or when the manual
is
updated. It is much better to refer to paragraph titles or numbers as
 these are less likely to change; and, if changed, titles are more
noticeable by writers and typists than are page numbers. The use of
correct figure numbers is easy -- just check them.

Short and to the Point

It is important to use sentence structure that will convey the

intended message with a minimum of misinterpretation or need to
reread.
Tests have been conducted to determine the ability of readers to
follow
instructions in a sentence based on the number of activities to be
performed. The average person's ability to follow instructions
decreases
rapidly when a sentence contains more than two facts. (Keep in mind
your
own experiences in reading instructions.) Therefore, sentences in
labeling need to be short and to the point. Avoid long strings of
adjectives and be specific. Try to be as specific as possible with
your
instructions. For example, "ambient" or "room temperature" generally
should not be used. Instead specify the desired or necessary range of
operating conditions. In many cases a list of activities to be
performed
is better than burying the facts in long sentences. If it takes lots
of
words to get to the point, the reader will probably miss the point!
Short, choppy sentences are acceptable in instruction manuals and
other
labeling. You are not trying to entertain readers with beautiful,
flowing prose -- rather, you want to "shock" them into remembering
key
facts until they correctly perform the specified instructions. Thus,
use
short sentences, get to the point, be specific, and keep pictures
near
the corresponding text.

Gobbledygook

Another way to be more specific and shorten sentences is to avoid

"gobbledygook". The following terms were collected from actual
instruction manuals:

ORIGINAL EQUIVALENT

Makes provisions for *

Serves to *
At the time of When
In conjunction with And
Carried out in Perform
Comes up to Reaches
 Will also serve as a chance to May
Will be sure that will Ensure
Available through the use of *
Care should be used so as not to Be careful
Be provided for positive determination *
Causes power to be applied to Switches power to
Due to the fact that Because
Take the form of Be

In most cases, the equivalent term in the list can replace the
original term. For the asterished items, the equivalent is simply a
direct statement of what is intended. Of the terms listed, the
combination most often used is "makes provision for". Simply
eliminating
"makes provision for" and "be provided for" from labeling will result
in
an immediate improvement for readers.
 Introduce Each Item

Always introduce each control, indicator, device or subject

before
they are discussed in the text. The introductions should be brief and
may be very brief. Keep in mind the items will be described in more
detail later. Abbreviations and new or uncommon terms must be defined.
The introductions and definitions prevent the reader from going into
mental shock, breaking their train of thought, and asking: What is
this?
By then the reader has probably forgotten the last two or three facts
read. Also, the reader may wonder about any "cliff-hanging" item when
they resume reading. This disturbance may detract the person from
fully
assimilating the next instructions being read. To avoid distractions
and
confusion, a writer of labeling should always:

o introduce each item, and

o define new or uncommon terms.

With respect to definitions, a writer should never give a new

meaning to an existing term. For example, quality assurance personnel
of
medical device firms can no longer use the word "critical" in their
routine technical conversations because "critical" was given a
specialized definition in the GMP regulation. To avoid this
disservice,
coin a special term or code number such as Class C, Code 1, or Level
2.

Accentuate Key Terms

Whenever it is stated in instructions that something must be done,

then "must" should be underlined, set in bold type, or otherwise
delineated. Likewise, caution and warning statements should be
delineated by underlining, boxing, bold type, etc. Refer to any
regu-lations or standards for a specific product and use the
recommended
or required caution statements. When standard terminology exists,
creating new caution statements is not the best way for a writer to
be
creative.

Select Words Wisely

When large print is needed for reading at a distance or to

attract
attention, signs, caution labels, screen prompts, and control labels
generally must be short in order to fit the available space. This
situation places a burden on the writer to select terms that convey
the
 desired message. Consider the following wording from two actual
highway
signs:

PLANT TRAFFIC NO FISHING

ENTERING HIGHWAY OFF BRIDGE

Have you ever been run over by a pachysandra? If you can't fish
off
the bridge, does that mean you are allowed to fish only on or from
the
bridge? Better choices for the intended messages are: "Traffic
entering highway" or "No fishing from bridge".

Try Labeling
 Finally, always have someone not familiar with the product
operate
it exactly according to the draft instructions and screen displays,
if
any. No coaching -- this is the "acid" test -- good luck! During the
trials, note any significant problems and make appropriate
corrections
to the instructions, prompts, or other labeling.

Approval Policy and Procedure

Before release for use, labeling should be reviewed and approved

by
product development, service, marketing, quality assurance, and other
appropriate managers. Medium-to-large firms need to have a
policy/procedure which covers the drafting, review, and approval of
labeling. Approval forms are generally used in conjunction with such
a
policy/procedure. A sample approval form and procedure are presented
at
the end of this chapter. Other procedures and forms such as "Change
Control" are referenced in this procedure. Note that this procedure
also
covers some GMP elements such as a correct master record, correct
transfer of labels into production, lot control, change control, etc.
Samples of various procedures appear at the end of chapters
throughout
this manual.

GMP CONTROL Of LABELING

Medical device manufacturers must incorporate in their QA program

several elements that relate to labeling in order to meet the
requirements of the GMP regulation. The QA program must be adequate
to
assure that labeling meets the device master record requirements with
respect to legibility, adhesion, etc., and assure that labeling
operations are controlled so that the correct labeling is always
issued
and used.

Because several activities must be performed and controlled

during
the development and use of labeling, Table 11.1 is presented as a
guideline or checklist. It contains a typical sequence of events
required to develop and control labeling. Labeling content is
mentioned
in the table, and details are given earlier in this chapter. GMP
controls are discussed below.

Labeling includes equipment labels, control labels, package

labels,
directions for use, maintenance manuals, etc. The displays on CRT's
and
 other electronic message panels are considered labeling if
instructions
and parameter identification information are given.

Various sections of the GMP regulation have an impact on labeling:

Section 820.20(a)(2) requires approval or rejection of packaging
materials and labeling; and Section 820.40 requires buildings to be
of
suitable design and have sufficient space for packaging and labeling
operations. Section 820.120 deals with specific requirements for the
design and control of labeling. It applies to the physical design
application of labeling to assure legibility under normal conditions
of
use over the expected life of the device; and also to inspection,
handling, storage, and distribution of labeling. FDA considers a
device
to be adulterated if these requirements are not met. These
requirements
do not apply to the adequacy of labeling content, except to ensure
the
content meets the labeling specifications contained in the device
master
record. However, failure to comply with GMP requirements such as
proofreading and change control could result in content errors. In
such
cases, the device is misbranded and adulterated.
 Specifications are required in the device master record for the
content and physical design parameters of labels. (see chapter 6).
Labeling specifications are the engineering drawing and/or artwork
for
each label, appropriate inspection or control procedures, and
appropriate procedures for attaching the labels. All procedures,
drawings and artwork must have the name of the preparer, an approval
signature, and a date. The approval signature,

Table 11.1 TYPICAL SEQUENCE OF THE GMP CONTROL OF LABELS

GMP
PHASE DEVICE TYPE SECTION CONTROL ACTIVITY

1. Development NC* C* 120 & Text review Quality

of
.100 mounting (rivets,
adhesives, etc.).
Quality
of ink,
anodize, etc.
Content per
21 CFR 801, 807,
809,
company claims
and
standards.

2. Evaluation NC C. 120 Simulated or actual

processing (e.g.,
sterilization),
shipping
tests, etc.

3. Documentation NC C. 181 Approve, date and

change

control label drawings.

C .121a A key label must
contain
control number of
finished device.

4. File Sample C .182b Copy of actual

label or
artwork in the
master
record. See .181.

5. Procurement NC C .120a Proofread before

release
 to inventory
stock.

C .121b Record signature of

proofreader and
date.

6. Storage NC C .121d Store labels so as

to
prevent mixups.

C .121c Restrict access to

labels
to authorized
persons.

7. Separate
Operations NC C .120b Separate multiple
operations to
prevent
mixups.

8. Area
Inspection NC C .120c Before beginning
labeling
 operations,
designee to
inspect area
and
remove
extraneous devices
and
labels.

9. Issuance NC C .120e Examine for

identity and,
where appropriate,
expiration date
and
control

number. Record date

and
person examining
labels.

10. Inspection NC C .160 Inspect finished

device
per written
procedure.

C .161 Designee must check

all
acceptance
records and
test results and
see
that records are
present
and complete.

* NC = Noncritical; C = Critical The numbers refer to Part 820,

e.g.,
120 is 820.120
date, etc., may be on the backside of artwork or on a label approval
form. Further, artwork may contain only an identification code or
title
if the "content" of the artwork is duplicated on approved engineering
drawings or adequately identified (cross-referenced) with respect to
the
label approval form.

Hardcopy labels, package inserts, and similar labeling are

specified
and purchased as components (see chapter 8). For correct purchase and
use of labeling, specifications are usually stated on engineering
 drawings and/or purchase specifications. Thus, artwork or "copy"
alone
will not fulfill the device master record requirements for labeling
except for the most simplistic labeling such as brief errata sheets.

The engineering drawings or purchase specifications must specify,

as
appropriate, the label substrate, dimensions, ink, finish, mounting
method, etc., so that the purchased label will remain attached and
legible during the customary conditions of processing, storage,
handling, distribution, and use.

Front panels, other instrument panels, meters, fuses, pushbuttons,

and the like often either are labels or contain labels and thus must,
as
appropriate, meet GMP master record and control requirements.
Component
specifications, assembly drawings and test/inspection procedures are
appropriate GMP controls to prevent mixup of meters, pushbuttons and
other labeled instrument controls. Controls to prevent mixups are
generally not needed for front and other panels.

Whether a firm considers a software driven display to be labeling

or
data makes little difference under the GMP regulation, because,
either
way, the finished device labeling or data must meet the device master
record specifications. When firms develop and validate software, they
 should also review these electronic displays to see that the
"labeling"
meets all applicable requirements, such as adherence to
specifications
in the master record, correct parameter identification, agreement
with
the instruction manual, and, of course, correct display of
performance
data.

When reviewing or auditing labeling operations, it is wise to

keep
in mind that the GMP regulation is a flexible quality assurance
program.
The degree of labeling control needed to satisfy the GMP regulation
varies considerably for different devices and operations. In order to
avoid wasting money and increasing the cost of health care,
manufacturers need to give considerable and prudent thought to the
appropriate level of control needed for their operations as allowed
by
820.5. Information and guidelines presented in this manual should aid
manufacturers in making these decisions. The level of control needed
should be reconsidered when products are changed. Likewise, the
controls
needed and success of the existing control program must be reviewed
during QA system audits (see chapter 15).

Label Integrity

All labels must be designed and applied to devices and containers

so
that the labels will remain in place and legible during the customary
conditions of distribution, storage, and use. Likewise, other
labeling
such as user instructions should remain legible during customary
storage
and use. Note that 820.120(a) which states, "Labels shall be designed,
printed, and applied so as to remain legible ___ ", refers to the
actual
design of the label and mounting method -- not just testing or
inspection of these to show that design requirements have been met.
[Inspection is covered by the second sentence of 820.120(a), and by
820.120(e), 820.20(a), 820.80 and 820.160.] For example, labeling
printed by machines onto plastic in vitro diagnostic media plates is
often smeared and thus is inadequate [FD& C 502(f)]. The
manufacturers of
such devices must assure that the print is legible and will remain
legible until used.

Many magazines use "wet" ink which smears when touched by sweaty
or
oily fingers. Obviously, this type ink will not meet the GMP design
requirements for package inserts, instruction manuals, and the like.
 Labels may be mounted by adhesives, screws, rivets, drive screws,
etc., or printed or etched onto panels and/or onto controls. The
labels
should be located so that they will be seen but not be abraded during
use. (All of us have seen the unbelievable cases where safety labels
on
ladders and riding lawnmowers were placed in the foot rest areas. Of
course, they were scrubbed off after a few uses!)

Receipt and Inspection

Upon receipt, all packaging and labeling materials, including

preprinted containers, inserts, and preprinted packaging materials,
must
be examined and, if deemed necessary by the company, tested to assure
conformance with specifications as discussed in chapter 8, Components
and Materials. Also, samples of labels must be proofread by a
designated
individual(s). After being accepted by a responsible individual,
these
components may be placed into inventory or into production. These
inspections must be recorded in the device history record as required
by
820.80(a) and 820.120 to show that inspection and proofreading were
performed. The inspection record for device labeling should be kept
 simple.

Area Separation and Inspection

All labeling and packaging operations should be separated to the

degree necessary (820.5 and 820.40) to assure there are no mixups
between similar products or labels. Separation may be either a
physical
or spatial separation or by performing the labeling and packaging at
different times for different devices. Separation is not required
when
mixups are impossible such as the case of labeled front panels that
only
fit the intended family of instruments (devices).
The likelihood of a labeling mixup determines how stringent
production area controls should be. For example, label control need
not
be stringent if only dissimilar products and labeling are processed.
Before beginning any packaging and labeling operation in which mixup
could occur, the production area and equipment for the operation must
be
thoroughly examined to ensure that any devices and labeling materials
remaining from previous operations have been removed. It is important
to
make certain that the surrounding area, tables, packaging lines,
printing machines, and other equipment are cleared of labels and
other
materials used in the previous operation.

Unused labeling that contains pre-coded serial numbers,

manufacturing date, expiration date, control number, etc., should be
destroyed and not returned to the label storage area. The GMP
regulation does not require reconciliation of the number of labels
used
versus the number issued, although, this control is recommended for
some
devices, such as when different sizes of the same product are being
packaged or otherwise labeled.

Storage

All printed packaging and labeling materials, including

preprinted
containers, inserts and preprinted packaging materials, must be
stored
in an area and manner suitable to prevent mixups (820.40, 820.120).
Labeling should be identified and segregated to the degree necessary
to
prevent mixing of similar labeling. Access to labeling should be
limited
to authorized personnel.

Storage control should be appropriate for the number and kind of

 devices. For example, a firm that manufactures only one product with
one
label does not need an elaborately controlled storage area. Similarly,
a
firm with only a few types of devices having dissimilar labeling
would
not normally require stringent control.

One case that requires dedicated attention to storage and control

is
prelabeled "sterile" but not-yet-sterilized devices. Firms must make
absolutely certain that mixups cannot occur. Also make certain that
all
such samples, if used for market promotion, are sterile or stamped
with
a manifest caution statement because a packaged and labeled
market-promotion sample might be used by the recipient. Quality
awareness training is required by section 820.25 and marketing
personnel
must be informed of labeling control requirements and the
consequences
of a violation.

Label Check and Record

When issued for use, labeling must be carefully examined to

assure
 the contents of the labeling comply with the labeling specifications
in
the device master record. This examination must include any control
numbers or expiration dates used on the labels. A record of this
issuance check, including the date and name of the person performing
the
examination must be made in the device history record.

If used, expiration dates must reflect the time after final

packaging during which the device is fit for its intended use when
stored and use per its labeling. The manufacturer should have
stability
test data which establishes the interval that the device remains fit
for
use.

If label mixups cannot occur -- for example, a firm makes only

one
device or uses only one label -- and there are no control numbers or
expiration dates, the original inspection when the labeling was
placed
into inventory is an adequate check for compliance with the master
record specifications. A second check need not be performed because
it
serves no purpose (820.5). If, however, there is any possibility that
incorrect labeling can be used, a second check must be made when the
labeling is issued for application, packaging or shipping.

Critical Device Labeling

Labeling for critical devices must meet the noncritical device

labeling requirements and meet the three additional requirements in
section 820.121 as covered below.

Control number

Critical device labeling must contain a control number, serial

number, letters, etc., for traceability. This means a control number
for
the finished device, and not the label itself. Most labeling, however,
also contains another number, such as a drawing number, for control
of
labeling configuration and procurement.

The control number for traceability need not be on every label on

the device; however, the control number must appear on the unit label
that goes to the ultimate user. The label on a shipping carton does
not
meet this requirement because bulk items may go to a central
distribution point in the user-facility and the shipping carton would
most likely be disregarded. In order to meet this traceability
requirement, a label that would most likely reach the nurse or other
user station must have the control number.
 Proofreader's signature

Before releasing labeling for critical devices to inventory,

samples
of labeling must be proofread as required for noncritical devices. In
addition, the signature of the proofreader and the date of the
proofreading must be recorded in the device history record.

Access restriction

Access to labeling must be restricted to authorized personnel.

Labeling also should be stored in an adequately segregated area to
minimize the chance of mixups. Although the access requirement
applies
to labeling for critical devices, it is also recommended for labeling
for noncritical devices because it increases the control over the
label
storage area with no significant increase in cost.
 CHANGES

Labeling is part of the device master record; therefore, all

changes
to labeling must be made under a formal change control system similar
to
that required for specifications [820.100(a)(2)]. Any changes to
labeling must be formally reviewed and authorized before
implementation
as discussed in chapter 7.

When making changes to primary aspects of a device and to primary

documentation, the review group must determine if any secondary items
such as labels or instructions are affected and also need changing.
There should be a check-off block on change-order forms for recording
that the effect of the primary change on labeling was considered and
appropriate action was taken.

SHIPPING FOR PROCESSING

Devices that have been sterilized and shipped to the

manufacturer's
warehouse or other controlled distribution point before final release
must be properly labeled. The pallets, or designated unit, must be
marked to indicate the status of the device, such as "non-sterile",
"sterilized: awaiting test results", or an equivalent statement. The
company must be able to show that it has control of the devices until
final release and, if necessary, could have them destroyed or
returned
for reprocessing. For this reason, a distributor's warehouse or
facility
is not considered a controlled distribution point. For regulations on
distribution, see 21 CFR 801, Subparts A and E; and Sections 820.150,
820.160 and 820.161.

RELABELING AND OVER-LABELING

Over-labeling by placing a new label over an old label is

discouraged by FDA but is acceptable as long as the new label and its
use meet GMP requirements (820.120, 820.115) for attachment,
legibility,
reprocessing, and change control. (Over-labeling is also discouraged
in
some foreign countries.)

EXHIBITS

Exhibits that cover labeling design and labeling control are

presented on the following pages. These exhibits show how some GMP
requirements for label control may be met. These procedures and forms
may need to be modified to meet the needs of a specific operation.

Drafting and Approval of Labeling

 This drafting and approval procedure is used to establish a
uniform
system for controlling the content of labeling and for approving
labeling. This procedure is adaptable
to use by any size firm. The following approval from may be used with
this procedure.

Approval Form for Labeling, Advertising, Literature, etc.

This form is intended for use by a medium to large firm, however,

the checklist style can be adapted even to a small firm. The areas of
concern are listed under the group that is responsible for that
concern.
Thus, every department in the firm has input into the acceptability
of
 the labeling.

Administration Set Label

This example of a label for an administration set begins with a

complete description of the device inside the package. The directions
for use section is arranged so that each point in the directions for
use
is numbered and only one point is made for each step. The various
points
in the directions are short and to the point. Where emphasis is
needed
as in the case of air bubbles, the information is stated twice and
bolded for further emphasis.

Labeling Control Record (1 Blank and 1 Completed)

Two copies of the same form are reproduced, one blank and the
other
showing what the form looks like when filled in. At the bottom of the
form, there is space to attach the actual labeling used so that a
comparison of the actual labeling used versus that required can be
made
during product release review.

Device History Record: OB/GYN (Plate)

The history record exhibited here is limited to the filling

operation for a media product. The form has space to print the same
label as printed on the plates during the filling operation for label
control and release review. This technique eliminates human copying
errors.

User/Reader Comments

Feedback is an important element in any QA system. Whenever

manuals
or instructions form part of the labeling for a product, it is wise
to
solicit review from persons not familiar with the use of the product.
These people can be employees of the firm or, as in this exhibit,
actual
users of the product. The information received will reflect the
problems
encountered by persons trying to follow the instructions without any
preconceived knowledge of the actual operation of the product.

gmp3-9:8/7/87
 Sheet 1
of 2
POLICY/PROCEDURE TITLE: Drafting and Approval of Labeling

Procedure Number _________ Revision Level ________

Prepared By App. By Date

ECN History
 1.0 PURPOSE

To establish a uniform procedure for controlling the content of

labels
and
obtaining label approval.

To assure compliance with GMP requirements and with company

policy
directives.

2.0 SCOPE

Applies to all devices including those used for market research

or clin-
ical investigations.

Promotional material is excluded from this SOP. It is covered by

SOP
#____, "Promotional Material Control and Approval."

3.0 REFERENCE DOCUMENTS

3.1 Food and Drug Administration GMP requirements

3.2 SOP #_____, "Promotional Material Control and Approval"
3.3 SOP #_____, "Change Control System"

4.0 FORMS

4.1 Form SOP #_____, Labeling Approval Form

4.2 Form SOP #_____, Engineering Change Order Form

5.0 DEFINITIONS

5.1 Labeling is all labels and other written, printed or

GRAPHIC matter

accompanying or attached to the device or its container.

6.0 PROCEDURE

6.1 Preparation and Approval

6.1.1 The need for a label or labeling is determined by an

operating
de-
partment such as Engineering, Marketing, Manufacturing,
or
Quality
Assurance.

6.1.2 The Engineering Department prepares a manuscript complete

with
 illustrations or prepares a drawing(s) of the label
showing the
wording, label use, and/or location.

6.1.3 The Engineering Services Department then prepares form

SOP
#_____,
"Labeling Approval Form", and circulates it to the
originating
department, Training and Education, Marketing, and
Quality
Assurance for approval. (See the following approval form
in this
manual.)

6.1.4 Engineering Services will coordinate and keep track of

all label
approvals and approval forms.
 6.1.5 When approval is received, the label or manuscript is
assigned a
drawing number and is released and added to the product
structure

(DMR Index) following the Engineering Change Control

System (SOP
#_____).

6.2 Implementation and Control

6.2.1 When the labels or labeling (printed material) are

produced,
Quality Control must proofread the material and verify
that it is

correct and so indicate by signing an appropriate

document (first

article inspection.)

6.2.2 All labels and labeling will be reviewed for criticality

and lot
control requirements. Each document will be marked to
indicate the
level of control required. At least one label on each
critical
device must have a lot, serial, or other control number.

7.0 EXPERIMENTAL DEVICES

7.1 Labels and labeling for experimental devices is required.

7.2 The documentation need not be as complete as for production

labels
and labeling; but, it must be adequate to allow procurement
of the
labels or labeling and adequate for the intended use.

8.0 CHANGES

8.1 Any changes to labels or labeling are accomplished by SOP

#_____,
"Change Control System".

9.0 SCHEDULES

9.1 Drafts must be generated according to a schedule that

allows a nor-
mal approval procedure. While urgent copy approval is
occasionally
necessary, it should not become standard operating
procedure.
 gmp3-7:8/3/87

<APPROVAL FORM FOR LABELING, ADVERTISING, LITERATURE, Etc.>

<ADMINISTRATION SET LABEL>

LABELING CONTROL RECORD

1. Labeling area was inspected and no labels from previous

operations were
present. Initials

2. Just before starting labeling operation, labels were examined for

correct:
[ ] identity [ ] expiration date on label [ ] control
number.

Name ___________________________________ Date

 3. REAGENT INFORMATION CONTAINER INFORMATION

Description ____________________________ Size

Catalog Number _________________________ Type

Stability ______________________________ Quantity

Lot Number _____________________________

Exp. Date of Reagent ___________________

Initials _______________________________ Date Recorded

3. Labels were correctly applied. [ ]

4. Unused labels with filled-in expiration date were destroyed. [ ]

5. Completion date Inspector

Comments, if any:

6. Place sample(s) of labels here:

When completed, place this inspection form in the device history

record.

Form No. Rev. Approved Date

<EXAMPLE LABELING CONTROL RECORD>

<DEVICE HISTORY RECORD: OB/GYN (PLATE)>

<Example User/Reader Comments Form>

 GMP - CHAPTER 12 - PACKAGING

CHAPTER 12 PACKAGING

INTRODUCTION
PACKAGING DESIGN AND MATERIALS
User Preference
PROCUREMENT, ACCEPTANCE AND STORAGE
PACKAGING PROCESS
EXHIBITS
Product Specification: Pouch
Header Bag (Specification Form)

INTRODUCTION

Manufacturers of medical devices should integrate the design of

the
device, packaging and manufacturing processes; and they should
consider
the needs of the user. They must document these designs in the device
master record; then, procure, handle, store, and use the specified
materials according to the master record.

Packaging and sealing machines must be set up according to a

written
procedure based on the known process capability of the packaging and
sealing system. Process capability must be determined by validation.
The
results must be documented.

Finally, manufacturers must perform quality assurance tests on

the
finished packages and, if sterilized, repeat the tests after
sterilization. The results of testing and/or inspection must be
recorded
in the device history records. Correctly performing these activities
can
prevent product liability actions and recalls.

PACKAGING DESIGN AND MATERIALS

An effective primary package for a medical device should be

designed
and developed along with the product as discussed in chapter 3. In
fact,
 the total device and package system should be considered with respect
to: device characteristics, sterilization process, bonding, labeling,
secondary packaging, shipping, environment, end use, and Federal
regulations. Defective packaging and seals have been a major cause of
medical device recalls -- recalls that can be eliminated by correct
design of the device and package system, correct design and
validation
of packaging and sealing processes, and subsequent production,
packaging
and sealing of the device under an adequate quality assurance system.

During development, if design tests and analysis point toward

limited reliability, changes in the device, packaging, sealing method,
and manufacturing processes should be made before production starts
in
 order to minimize costs and liability. Package redesign, change of
sterilization process, even device redesign during the development
stages, might prevent needless patient risk and save dollars that
might
be spent later in replacing damaged or contaminated goods and, of
course, the belated redesign will cost the same or more than if it
had
been performed before production started.

The package and device should be designed together so that all

factors in the product and package system can be considered, such as
device sharp edges and severe vacuum stresses. Some factors to
consider
are:

End use Sterilization process

Temperature Adhesives
Moisture resistance Package porosity
Thermal capacity Cling resistance
Device composition Pressure
Device size, and shape Vacuum

It is important to be aware of the state-of-the-art in sealing

methods and packaging materials, including their physical, chemical,
biological, and compatibility characteristics and, of course, cost.
If
necessary, o
obtain guidance from suppliers, technical literature, and consultants.

FDA regulations are compatible with this total systems approach

to
device, package and process design. To assure the integrity and
appropriate sterility assurance level of sterile medical devices, FDA
regulates devices, their processing and packaging. FDA assures that
adequate device packaging is used mainly by implementing the Good
Manufacturing Practice (GMP) regulation, Title 21 Code of Federal
Regulations (CFR), Part 820. Also, the quality of packaging must be
appropriately considered in relation to the 21 CFR Part 812,
Investigational Device Exemptions (IDE's) for clinical evaluations;
Part
814, Premarket Approval (PMA) applications; Part 807, Premarket
Notification [510(k)] submissions and, of course, customer
requirements.

Requirements for components, device master records, environmental

control, etc. that affect the selection and use of packaging appear
throughout the GMP regulation. The specific requirements for
packaging
are in section 820.130; and the closely related label integrity
requirements are in section 820.120. The packaging requirement in the
GMP regulation is not lengthy; however, it is far reaching. For
example,
 packaging is one of the few areas in the GMP regulation where design
is
directly addressed. Section 820.130 states that: "The device
package
and any shipping container for a device shall be designed and
constructed to protect the device from alteration or damage during
the
customary conditions of processing, storage, handling, and
distribution."

As can be seen from the regulation, the primary package and the
secondary package or shipping container must adequately protect the
device under all reasonable conditions from packaging to ultimate use.
Failure to meet this requirement renders a device adulterated and has
resulted in recalls of sterile devices.

Sterile devices and their packages must be designed to meet the

requirements of the sterilization process, package sealing method,
and
intended use. For example, radiation sterilization may discolor
 packaging and sealing materials, or modify their functional
capabilities. All plastics are somewhat affected by radiation
sterilization, and consideration should be given to the effect
produced
and the radiation dose needed to produce an effect. In some materials,
parameters are improved and, in others, they are degraded by
radiation.
Complete storage and stability data should be compiled for
sterilization
packaging or obtained from the vendor.

Ethylene oxide (EtO) sterilization requires packaging material of

sufficient porosity to allow air to leave the package and the gas to
rapidly permeate the package, sterilize the product, and then leave
the
package. Adverse levels of EtO residues must not be left on the
device
to harm the patient. Air washing at the end of the cycle reduces
residues. Evacuation of the sterilization chamber for air removal,
gas
fill, and air washing can induce package stress, particularly when
the
cycle calls for high temperature, pressure, and rapid pressure
changes
before and after the gas exposure (dwell) period.

"Wet" devices require high-barrier package materials and sealants

with impermeability; resistance to solvents, grease, chemicals, and
heat; and the ability to contain wetting agents, reagents, oils, or
fragrances. The ability to seal through liquid components, if
spillage
occurs in the seal area, is important. Some peelable adhesives are
highly solvent-resistant and also remain intact during radiation
sterilization.

In addition to the GMP requirements, manufacturers should always

study current packaging practices for products similar to theirs to
determine current favorable practices and to prevent packaging
problems.
For example, customary use may dictate the use of double primary
packaging for some sterile devices.

The design and processing factors noted above must be considered

when selecting packaging, adhesives, and sealing method. Finally, any
packaging used for medical devices must satisfy the end user as well
as
GMP requirements -- a key point to be considered during the design
phrase.

User Preference

In the March 1982 issue of Medical Device and Diagnostic Industry

magazine, the article, "Hospital-User Preference in Sterile Device
 Packaging", reports the results of a survey of nurses from operating
room and central services areas of hospitals. Several conclusions
from
the test results are listed below that should be of interest to
sterile
device manufacturers.

o 96 percent of the nurses had become "increasingly aware of

the
importance of quality packaging to infection control."

o 90 percent said that packaging quality could influence

their
selection of a sterile medical device.

o 87 percent wanted at least one package side to be

transparent.

o 95 percent preferred the adhesive to transfer from the lid

to
the lip of a tray when opened to indicate a broken seal.
 o 89 percent wanted sterilization process indicators printed
on
packages for sterile devices.

o 99 percent felt fiber-free opening of a sterile device

package
to be important or very important.

o 55 percent believed larger, high-profile devices would be

best
packaged in a tray with a peelable lid.

o 55 percent preferred black printing on the package for easy

reading.

Package features that might favorably influence practitioners in the

selection of a sterile medical device include:

o clean, fiber-free opening,

o double packaging,
o printed process indicator,
o easy-open notches on chevron peel pouches, and
o lids with adhesive transfer.

The nurses believe that being able to see and clearly identify a
device is a "very important criterion of user preference". Also, as
stated above, double primary packaging is preferred for some sterile
devices.

PROCUREMENT, ACCEPTANCE AND STORAGE

The device master record (820.181) must contain appropriate

specifications such that the desired packaging components may be
purchased, properly stored, and properly used. A manufacturer must
have
adequate procedures for approval or rejection of all incoming
packaging
components such as adhesives, pouches and cartons (see 820.80 and
chapter 8). The supplier might test these components and provide the
manufacturer with a protocol for testing and the test results for
each
batch (i.e., certificate of conformance to purchase specifications).
The
manufacturer could accept this specific data as sufficient
certification
or order his own testing.

At a minimum, incoming components must be visually examined for

damage and identity before being used. Thereafter, primary packaging
must be handled and stored in such a way that it is kept clean and
safe
from damage. Primary packaging and devices to be sterilized must be
kept
 especially clean before sterilization. For implant, indwelling, and
infusion devices, the firm must carefully and appropriately control
the
environment to which the associated packaging materials are exposed
in
order to control bioburden and bacteria cellular debris. Pyrogens
primarily arise from cellular debris of gram-negative bacteria. (See
chapter 4).

PACKAGING PROCESS

The packaging operation is a manufacturing process, and GMP

sections
820.80, Components; 820.100(b), Processing Controls; and 820.160,
Finished Device Inspection; apply to packaging. These sections
require
adequate controls for components, processing, and test/inspection.
The
controls necessary for all devices must assure that:
 o labeling (separate label or printed on the package)
properly
reflects the package contents; and,

o only devices approved for release are packaged and released.

The controls required will vary with the type of device packaged.
For example, when a sterile device is packaged, a manufacturer's
considerations must include:

o environmental and personnel hygiene control;

o validated operating procedures for sealing equipment;
o inspection to assure package integrity and sanitation; and,
o control of devices marked "sterile" but not yet sterilized.

For a product to be sterilized in-house, either a physical

quarantine area or label control must be used to prevent shipment of
devices marked sterile, but not yet sterilized. The required level of
control is relatively high. The control extends to give-away samples
--
samples must be sterile if so labeled because they might be used.

If the labeled product is to be shipped to a contract sterilizer,

the shipping, handling, and processing must be controlled as required
by
the GMP regulation and section 801.150(e) of the labeling regulation.
For all cases, FDA recommends a contract as required by 801.150(e)
for
interstate shipping.

Section 820.181(d) requires that the device master record include

packaging methods and processes. Written instructions should be
provided
to assure that the necessary controls are understood and consistently
implemented. The need for and extent of written instructions should
be
determined based on the complexity of the operation and the nature of
the product. Some products such as radioimmunoassay test kits can
deteriorate during packaging if the process is not timed properly. In
such cases, written instructions should describe how the device(s)
should be handled and expedited during packaging in order to prevent
delays, and thus deterioration.

The process capability of packaging and sealing equipment should

be
determined by process validation and documented. Process validation
must
be performed for sealing systems for sterile devices. Then a sealing
cycle is selected, verified, and written into a setup and operations
procedure to be used for routine packaging and sealing of the device
with the selected packaging materials.
 The procedure for test and/or inspection of finished packages
must
be written (820.160). To the extent feasible, the testing of finished
packages should be quantitative. The packaging of sterile devices
should
be tested and/or inspected before and after sterilization and is
usually
done on a sampling basis.

The results of test and/or inspection must be appropriately

recorded
in the device history record along with control (lot) numbers, if any.
The use of lot numbers for sterile products is common practice.
Control
numbers are required for critical devices (820.121) and in vitro
diagnostic products (820.10).

The test and/or inspection procedures must include any sampling

plan(s) to be used when large quantities of devices are being
produced
or when the testing is destructive. Sampling plans are valid only
when a
 process is in a state-of-control; therefore, the device must be
manufactured and packaged using a quality assurance system as
described
in this manual.

gmp3-6:8/3/87

EXHIBITS

The examples that follow will aid a company in preparing product

packaging specifications and/or in purchasing standard packaging.

Product Specification: Pouch

This form is used to purchase specific pouches from a standard

family
of pouches. The finished device manufacturer completes the form with
the
desired size, material, style, etc. The form refers to other
documents
which define the technical characteristics of the pouches.

Header Bag (Specification Form)

This specification for a header bag is set up as a checklist with

the specifications on the righthand side and a drawing of the bag on
the
left. The finished device manufacturer completes the form with the
desired technical characteristics, assigns it a part number, and
approves the finished document. An interesting idea reflected in this
form is the important information block at the bottom of the form.
This
is a good way to remind personnel of pertinent information that is
not
strictly a part of the specification yet is vital to the control of
this
particular item.

<Product Specification: Pouch>

<Header Bag (Specification Form)>

 GMP - CHAPTER 13 - DISTRIBUTION

CHAPTER 13
DISTRIBUTION

INTRODUCTION
Holding and Distribution Procedures
Warehouse Storage
Distribution Records
DEVICE INSTALLATION
EXHIBITS
Finished Product Release Form
Release To Finished Goods/Shipping
Product Shipping Hold
Release From Product Shipping Hold

INTRODUCTION

The Device Good Manufacturing Practices (GMP) regulation covers

the
manufacture, distribution (820.150) and installation (820.152) of
finished devices. For a manufacturer, from a survival standpoint,
distribution is one of the most important steps in the process.
Distribution also is important from a quality assurance standpoint.
After a product is distributed, a firm no longer has direct control
over
the product or how it is used. It is important that controls be in
place
to assure that only correctly labeled and approved finished devices
are
distributed.

Holding and Distribution Procedures

The GMP regulation requires that written procedures be provided

for
warehouse control and distribution of finished devices. The purpose
of
this requirement is to assure that only approved devices are
distributed. Each manufacturer should determine whether written
procedures will contribute to assuring that only "approved for
release"
devices are distributed from their firm. This flexibility is allowed
by
section 820.5 of the GMP regulation.
 Many manufacturers mark their released finished devices or
identify
them by location or packaging so that a simple visual check is
sufficient to indicate whether the product is acceptable for release
for
distribution. For example, for radiationemitting electronic products
subject to a performance standard, the application of the
certification
label is often the last step in approving product release for
distribution; and, the label is used to distinguish such devices.
This
type of operation may preclude the need for a written procedure.

For interstate contract sterilization, section 801.150(e) of the

labeling regulations requires a written procedure to help prevent the
 erroneous release of packaged and labeled "sterile" but not yet
sterilized devices that appear to be but are not ready for release.
Regardless of whether 801.150(e) applies, the GMP regulation requires
controls as necessary to prevent mixups in complex situations such as
contract sterilization. For consistency, a contract as described by
801.150(e) is commonly used by manufacturers for interstate and
intrastate contracts. Such a contract and compliance with it
satisfies
the applicable GMP requirements.

Sometimes manufacturers need to ship "finished devices" that have

not
been officially released because the final test data is not yet
available. The most common example occurs when a firm is waiting for
the
results from biological indicator tests. Manufacturers may ship such
devices to their own controlled warehouses or to other finished-
device
manufacturers where the devices may be readily recalled if the need
arises. Firms are not allowed to ship non-released devices to routine
distributors. Non-released products or products on "hold" for any
quality reason must be controlled to prevent release. A suitable
control
is quarantine or a label on the units, pallets, etc., to indicate the
status.

Warehouse Storage

Storage should always take place under systematic, orderly

conditions (820.40). Manufacturers must use a first-in, first-out
(FIFO)
distribution system when fitness for use of a device deteriorates
over
time (820.150).

When a controlled environment is necessary to prevent abnormal

deterioration, the environment must be specified, controlled and
monitored according to sections 820.46 and 820.60 (see chapter 4).
Environmental specifications, such as storage temperature, must be
included in the device master record.

A designated person(s) should be responsible for storage and

handling of devices to be distributed (820.25). These activities may
be
extensive. For example, damaged, recalled, or returned devices must
be
suitably marked and segregated from devices acceptable for release.
Also, note that returned defective devices must be formally
investigated
according to 820.162 and any associated complaints investigated
according to 820.198. Therefore, firms will need controls to assure
that
 returned defective devices do not dead-end in the warehouse, but are
expeditiously routed to the appropriate department for investigation,
conclusions and followup (see chapter 14, Complaints, etc.).

Distribution Records

GMP section 820.184, Device History Record, requires

manufacturers
of noncritical devices to maintain basic distribution records for the
quantity distributed, and any control number used. These may be the
same
as, or part of, the normal business records. Generation of a separate
record is not required unless the business records are not readily
available, e.g., not maintained at the same establishment as the
device
history record. For purposes of recall, repairs, etc., a firm may
elect
to keep more records than specified by the GMP regulation such as the
date shipped and consignee information.
 In addition to the requirements for noncritical devices,
manufacturers of critical devices must maintain distribution records
that contain:

o consignee name,
o consignee address,
o quantity shipped,
o date shipped, and
o control number.

Many firms, regardless of whether their devices are critical,

keep
distribution records containing the detailed information listed above
for billing and market survey purposes.

Manufacturers of radiological electronic products listed in 21

CFR
1001.61 must maintain distribution records that will enable them to
trace specific products or production lots to distributors, or to
dealers in those instances in which the manufacturer distributes
directly to dealers (See 21 CFR 1002.30, Records to be Maintained by
Manufacturers).

Distribution records must be kept for a period of time equivalent

to
the design life and expected life of the device, but in no case less
than 2 years from the date of release for commercial distribution by
the
manufacturer. The intent of this requirement is support for potential
repairs, corrective actions, and recalls. The intent of the
regulation
is not to require the retention of distribution records for the
entire
life of devices such as stretchers. Thus, after 2 years, each
manufacturer must make a prudent decision whether to discard records
or
keep them for a longer period. When requested, distribution records
must
be made available to FDA investigators for review and copying during
normal business hours.

DEVICE INSTALLATION

Section 820.152, Installation, applies to medical device systems

and
complex devices that must be set up and adjusted at the location
where
they are to be used. For example, before a diagnostic x-ray machine
can
be used, it must be installed, adjusted, and the performance checked.
Cardiopulmonary bypass machines must be set up and adjusted at the
user
 location. Manufacturers of such devices must:

o install the device, or have it installed by a

representative;

o inspect the device after installation to assure the device

will perform as intended; or,

o provide adequate instructions and procedures for proper

installation.

These instructions and procedures for proper installation by the

firm's representative, user, or third party (820.152) must include an
appropriate means for and instructions on how to determine that the
installed device is safe, performing satisfactorily, and ready for
use.
Such procedures and instructions are part of the device master record
and generally include a checklist for the installer to make certain
that
all necessary installation and checkout activities have been
performed
correctly. If available to the manufacturer, the filled-in checklist
or
 other installation records are part of the device history record.

Safety checks at this stage refer to safety aspects directly

related
to the installation and setup activities and not to intrinsic safety
features that have already been checked during final testing at the
factory.

EXHIBITS

Various forms to show that devices are finished and may be

released
or stopped from release are briefly described below and then
exhibited.

Finished Product Release Form

This exhibit shows a finished product release form which is

actually
a checklist for the manufacturing and QC department of an in vitro
diagnostic firm to show that all required processes have been
completed.
The checklist acts as a reminder of the forms that are needed for a
product and has space for the manufacturing and QC people to indicate
that these forms have been completed and reviewed. Finally there is
space for the designees to approve or disapprove the lot for release
and
for comments, if needed.

Release To Finished Goods/Shipping

This exhibit is a release form as described above except that it

is
for various hardware products. The employee writes in the
specification
for the product being released.

Product Shipping Hold

This exhibit is an example of a form used to stop the shipping of

a
finished device for reasons related to safety, performance,
reliability,
regulatory compliance, or other quality requirements.

Release From Product Shipping Hold

This is a form used to release a finished device from a stop

shipment order. Because stop orders are always significant, this
release
form requires a signature by all key management.
 FINISHED PRODUCT RELEASE FORM

Title: AMYLASE SET Form No: Rev:

Sheet 1 of
1

Form Approval: Date:

(Circle One)
Catalog No.
Packaging LOT # XXXX-01
XXXX-10

=========================================================================
====
==
The following device history documents were reviewed.
MFG QC

1. Form No. 9926 Product Flow Sheet[ ][ ]

 2. Form No. 1077 or 1078 Iodine Solution[ ][ ]
(circle one)

3. Form No. 1082 Substrate Solution[ ][ ]

4. Form No. 1083 Substrate Tube Filling Sheet[ ][ ]

5. Form No. 1084 or 1085 Iodine Filling Sheet[ ][ ]

(circle one)

6. Form No. 1086 Packaging Record[ ][ ]

7. Form No. QC-PB-007 Finished Goods Specification[ ][ ]

QC-CO-001
(circle one)

Disapproved [ ] Approved [ ]

Comments:

Designee for Manufacturing

Disapproved [ ] Approved [ ] for Release

Comments:

Designee for Quality Control

gmp 1-4: 4/22/91

TITLE QA FORMREV. LEVEL

RELEASE OF FINISHED GOODS/SHIPPING110

APPROVAL DATESHEET 1 0f 1

TYPE OF PRODUCT

[ ] CABLE [ ] INSTRUMENT [ ] SPARE/REPLACEMENT

PARTS

PRODUCT DESCRIPTION

PART NUMBER ________________ SERIAL NO. ______________

INSPECTION SPEC. ________________ REVISION ______________

QUANTITY REL. ________________

STATUS
 CIRCLE EITHER YES OR NO

1. NO YES Final Inspection complete per standards set forth

in the
QC manual and device inspection spec.
 2. NO YES Device History packet present.

If the answer to No. 1 or 2 is NO, return the lot to the Production

Department.
3. NO YES Has Final Inspection performed a functional test
on the
product?

3.1 NO YES If Final Inspection has not performed a functional

test
on the unit, is a final test data sheet with the
unit?

COMMENTS

___________________________ Approves the release of the product to

finished Inspector's Signature goods or shipping.

___________________________ Date

<Product Shipping Hold Form>

<Release From Product Shipping Hold Form>

 GMP - CHAPTER 14 - COMPLAINTS AND FAILURE INVESTIGATIONS

CHAPTER 14 COMPLAINTS AND FAILURE INVESTIGATIONS

INTRODUCTION
Complaint Handling System
Complaint Responsibility
Death and Injury Complaints
Complaint Records
Investigation Records
File Accessibility and Location
Non-medical Complaints
Trend Analysis
GMP SECTIONS RELATED TO COMPLAINTS
DEVICE FAILURE ANALYSIS
FEEDBACK FOR QA SYSTEM
COMPLAINT SOURCES
Service or Repair
Parts shipping trends
MEDICAL DEVICE REPORTING
Who Should Report
When To Report
EXHIBITS
Customer Feedback Cards
Complaint Processing Procedure
Complaint Data Forms

INTRODUCTION

A complaint is any indication of the failure of a device to meet

customer or user expectations for quality or to meet performance
specifications. All medical device manufacturers are subject to the
complaint requirements in 21 CFR Part 820, Good Manufacturing
Practices
(GMP) regulation and to the reporting requirements in 21 CFR Part 803,
Medical Device Reporting (MDR) regulation. GMP section 820.198
Complaint
Files, states that, "Written and oral complaints relative to the
identity, quality, durability, reliability, safety, effectiveness, or
performance of a device shall be reviewed..." A complaint may be
lodged
against any finished device that had been released for distribution
and
fails to meet its company specifications for identity, quality,
 durability, reliability, safety, effectiveness or performance, and,
as
such, is subject to the provisions of 21 CFR 820.198.

Claims do not always have to be written -- they may be implied.

For
example, a defibrillator shipped without any labeling is expected to
perform defibrillation on typical patients in normal clinical
environments.
Manufacturers are required to review and investigate complaints,
 establish ways to perform these activities, and designate someone to
perform these tasks. Complaints concerning death, serious injury or
malfunctions, as defined in the MDR regulation, must be reported to
FDA
as discussed later. Manufacturers of any class of medical devices are
never exempted from the GMP complaint requirements (820.198) nor the
general record requirements (820.180) which allow FDA to review and
copy
records. Complaint file requirements are necessary to make certain
manufacturers have adequate systems for investigating complaints and
taking corrective action. Access to complaint files, device-related
injury reports, and complaints about device defects enables FDA to
determine if a manufacturer's quality assurance system and
corrective
actions are adequate and if any exemption granted to a given firm
from
other sections of the GMP is still appropriate.

Manufacturers can identify problems with device and component

quality by several methods. To meet all GMP requirements, including
820.20(a)(3), and otherwise be adequate, these identification
methods
should include a review and investigation of complaints, failed
devices, and service or repair requests. Complaints and service or
repair requests are important sources of feedback information for a
quality assurance system. Finished devices that are returned for
service
or repair may meet the complaint requirements identified in section
820.198; therefore, these service or repair requests must be treated
as
complaints. Service or repair data should be periodically reviewed
[820.20(a)(3)] to identify systematic problems and problems that may
qualify as complaints. When these problems are identified they
should
be processed as complaints according to the requirements in 820.198.

Complaint data, in conjunction with product audits, QA systems

audits, operational analyses, inspection and test data, etc., is
used
by the quality assurance organization to:

o identify poor performance in the overall quality assurance

system, particularly faulty design of devices, and faulty
manufacturing processes;

o aid in implementing solutions to these quality problems;

o verify confidence in, and improve the performance of the

quality assurance system;

o improve the safety and performance of devices;

 o reduce medical device reporting;

o reduce costs and improve production schedules;

o reduce employee confusion and improve morale;

o improve customer relations by reducing the frequency of

problems, complaints, and recalls; and,

o assure compliance with device regulations and consensus

standards.

One of the problems facing firms in the United States today is

that
 too many managers fail to understand their customer's needs or what
it
takes to manufacture a quality product. Often, the assumption is that
a
loss of sales is due to poor marketing strategy, rather than a low-
quality or outdated product line. Companies must do their best to
design
quality into their products and processes, and to build quality into
their products; however, don't stop there! There is always the
possibility of a mistake in a delivered device. Companies must be
prepared to deal with every eventuality. Remember that a complaint
handling system is one of the best sources available for use-related
information about product performance, safety, durability, and
changing
customer preferences.

Complaint Handling System

The GMP regulation requires in section 820.20 that each

manufacturer
have a formally established and documented quality assurance program
of
which complaint handling is an important element. Even if
manufacturers
have never received complaints, they must be prepared to receive and
process them. Using written procedures for handling complaints
increases
confidence that all complaints will be handled properly.
Manufacturers
should determine the need for written procedures for processing
complaints the same way as they determine the need for procedures
for
any other operation: Is there a reasonable probability that these
written procedures will solve or prevent quality problems? Written
procedures usually are provided to employees to facilitate
communication, maintain consistency, and reduce quality problems. A
written procedure is recommended for processing complaints in order
to
meet the extensive GMP requirements for complaint handling and to
meet
the documented QA program requirements of 820.20. The written
procedure
should specify: authority; responsibilities; and the process to
follow
in receiving, reviewing, and investigating complaints. However, for
very small firms where division of work is minimal, and authorities
and
responsibilities are obvious, the GMP requirements as detailed in
820.198 and 820.20(a) in conjunction with appropriate forms may be
sufficient as a protocol for handling complaints.

Although FDA does not specify a standard complaint handling

system,
 the GMP regulation does specify certain required actions that must
be
included in any system. Manufacturers must:

o review, evaluate, and file all complaints;

o formally designate a unit or individual to perform these
activities;
o determine if an investigation is necessary;
o record the reason if no investigation is made; and,
o assign responsibility for deciding when not to investigate.

Complaint Responsibility

Manufacturers must formally assign responsibility for maintaining

complaint files and conducting complaint investigations to
individuals
or an organizational unit. Regardless of the approach used, the
duties
of those responsible must be clearly delineated and thoroughly
understood by them (820.25). These employees must have the proper
education and training to process complaints. Any difficulty noted
in
employees performing required tasks for proper complaint handling
may
be an indication that additional training is needed. Any training
programs must be documented.
 The person(s) assigned to review complaints should have a
thorough
knowledge of the product line in order to make an informed,
reasonable
decision as to the severity and significance of a complaint and to
decide whether an investigation is necessary. If it is decided that
an
investigation is not necessary, a record must be made of the
rationale
used to arrive at this decision.

Death and Injury Complaints

Section 820.198(b) specifically requires that any complaint

involving the possible failure of a device to meet its performance
specifications must be reviewed, evaluated, and investigated. Also,
section 820.198(b) further specifies that any complaint pertaining
to
injury, death, or any hazard to safety shall be immediately reviewed,
evaluated, and investigated by a designated individual(s), and shall
be
maintained in a separate portion of the complaint file. However, for
trend analysis by product, a firm should duplicate these serious
complaints in the regular complaint file. Trend analysis is a means
of
identifying quality problems, although it is not specifically
required
by section 820.20(a). A single event, of course, may also be a
pointer
to a quality problem.

Complaint Records

FDA does not specify a standard method for recording or

retrieving
complaint information. Each manufacturer should develop a method for
maintaining records of complaints and investigations that: is easy
to
use and economical, meets company needs, and meets requirements of
the
GMP regulation. A form, usually two-sided if a hardcopy, is commonly
used to help process complaints. One side or page is used to record
complaint information such as: sequential number of the complaint;
origin of the complaint; customer information; product information;
any
corrective actions already taken; details of the complaint; and
dates,
signatures, assignments, etc.

The other side is used to record: instructions; investigations;

analyses; conclusions; corrective action with respect to the product
and to the customer; and dates, signatures, etc. Typical forms are
 exhibited at the end of this chapter. The completed forms are stored
in
the complaint file which may be a physical or electronic location.

Investigation Records

The designated unit or person(s) responsible for maintaining the

complaint file(s) must prepare a written record of any
investigations.
This record must include:

o the device name;

o control number, if any;
o name of complainant;
o nature of complaint; and,
o reply to complainant.

For convenience, these files would usually include dates, phone

number, user location, etc. Section 820.198(c) requires the record
of
investigation to include a reply to the complainant. A reply is
important in many cases to prevent further misuse, injury or other
adverse situation. FDA is also interested in learning how a
manufacturer
follows up complaints. However, because of the nature of the
complaint,
 there may be cases where a reply is not necessary. In such cases,
the
record should state that no reply was made and the reason for not
replying.

File Accessibility and Location

The GMP states in 820.180, General Requirements, that "All

records
required by this part shall be maintained at the manufacturing
establishment or other location that is reasonably accessible to
responsible officials of the manufacturer and to employees of the
Food
and Drug Administration ...". "All records" includes complaint files
and
records of investigations. For complaint processing, responsible
officials are general managers, complaint processors, QA managers,
R& D
and process engineers, and others who receive, process, investigate,
and correct problems associated with complaints.

Complaint files must be reasonably accessible to FDA for review

and
copying. FDA has clear authority under Section 704(e) of the Food,
Drug, and Cosmetic Act to inspect and copy all records required
under
section 519 or 520(g). Because the GMP regulation was promulgated
under
the authority of Sections 519 and 520(g), the regulation provides FDA
with authority to inspect, review and copy any complaints on devices
manufactured on or after December 18, 1978, the publication date of
the
final GMP regulation.

Complaints and records of investigation must be maintained in the

complaint file and be readily available at the manufacturing site.
The
GMP regulation requires that complaint files be located with a
formally
designated unit. If the unit or individual(s) designated as
responsible
for investigating complaints is located away from the actual
manufacturing site, a copy of the investigation record must be filed
[820.198(d)] at the actual manufacturing site.

When devices are produced for a firm by a contract manufacturer,

the
firm must forward to the contractor copies of complaints and
investigations that pertain to operations performed by the contractor.
The CONTRACTOR must maintain a complaint file as discussed herein
for
the primary manufacturer.
 RELABELERS, IMPORTERS, and OTHERS who distribute under their own
name must forward complaints to the actual manufacturer,
including foreign manufacturers. The GMP regulation (820.180)
requires
that records be reasonably accessible to responsible officials. In
most
cases, the responsible officials that can resolve complaints are
located
at the facility(ies) of the actual manufacturer of the devices. This
also includes foreign manufacturing sites.

Non-medical Complaints

If a firm's product is used as a medical device and for non-

medical
uses, complaints received from non-medical users do not necessarily
have to be included in complaint files. However, if the non-medical
product fails to meet specifications, then that report should be in
the
firm's complaint file. This action would help assure compliance with
820.20 (a)(3), which requires identifying, recommending, or
providing
solutions for quality assurance problems and verifying
implementation
of such solutions. The person receiving such complaints must be
trained
(820.25) to identify complaints that also affect those units used as
medical devices.
 Trend Analysis

To facilitate detection of failure or defect trends, complaint

files
should be arranged in a manner that permits correlating present and
past
complaints for a particular product or product line. Thus, files are
usually organized according to product or product lines.
Manufacturers
who do not organize complaint files by product or product line must
search several files to find similar complaints or indications to
identify problem trends. A single event, of course, may be an
indicator
of a quality problem. Complaints may be maintained in a computer
file
so that complaint data on a specific device or type of complaint can
be
readily accessed and analyzed.

GMP SECTIONS RELATED TO COMPLAINTS

Following are excerpts from several sections of the Good

Manufacturing Practices regulation which deal directly or indirectly
with complaint files.

820.5 Quality Assurance Program: "Every finished device

manufacturer
shall prepare and implement a quality assurance
program ..."
This is discussed in chapter 2.

820.20 Organization: "Each manufacturer shall have in place an

adequate organizational structure and sufficient personnel
to
assure the following functions are performed: ...
identifying,
recommending, or providing solutions for quality assurance
problems ..." See chapter 2.

820.25 Personnel: "Each manufacturer shall have sufficient

personnel
with the necessary education, background, training, and
experience ..." See chapter 2.

820.162 Failure Investigation: "After a device has been released

for
distribution, any failure of that device or any of its
components to meet performance specifications shall be
investigated." Discussed in this chapter.

820.198 Complaint Files: "Written and oral complaints relative to

the
 identity, quality, ... of a device shall be reviewed,
evaluated, and maintained by a formally designated unit."

Note that there is a close relationship between the sections of

the
GMP regulation that deal specifically with complaints and those that
deal with the prevention or solution of quality problems. Complaints
often arise from real quality problems, and, therefore, these must
be
adequately analyzed and resolved to meet the requirements of the:
company; customer; Food, Drug, and Cosmetic Act; and GMP sections
820.198, 820.162, and 820.20. In addition to the direct requirements
in
820.198, Complaint Files, and 820.162, Failure Investigation, the
general quality assurance program in 820.20(a)(3) contains a
fundamental
and important requirement for identifying, recommending, or providing
solutions for quality assurance problems. The evidence that a
problem
exists and the information to identify it may arise through a
complaint
and the resulting investigations of the complaint and failed medical
device.
 DEVICE FAILURE ANALYSIS

Section 820.198(b) of the complaint file requirements applies to

the
investigation of complaints involving the possible failure of a
device
to meet performance specifications, to determine if there actually
is a
device failure. This requirement to investigate the possible failure
of
a device to meet specifications is similar to requirements in section
820.162, Failure Investigation, which requires that, after a device
has
been released for distribution, any actual failure of the device or
its
components to meet performance specifications shall be investigated
and
any followup and conclusions recorded. Thus, section 820.162 refers
to
actual failure analysis, i.e., the determination of the device
failure
mechanism, and whether it is related to design, components,
manufacturing, packaging, or shipping.
Failure analysis should be conducted by appropriately trained and
experienced personnel (820.25). They should use a written protocol to
assure that the process of device handling and analysis will not
compromise the determination of the cause of the device failure. A
written protocol, however, is a general GMP requirement from 820.20
and
not a specific requirement. The failure investigation and analysis
must
determine the actual failure mechanism to the objective level
necessary
to correct the problem. When systematic failure has been diagnosed
and
corrective action established, a manufacturer need not analyze all
additional devices that are returned with the same symptoms.

If a failure is determined to be related to safety and

effectiveness, the deficiency must be determined, corrected and
documented. If an investigation verifies a particular device
deficiency
and that this deficiency may exist in other products, the
investigation
must extend to determining the effect on other medical products.

FEEDBACK FOR QA SYSTEM

In order for a quality assurance system to be dynamic or self

correcting, data on quality problems from all sources must be fed
back
into the system. Complaints are a valuable source of data that can
 point to corrective actions. The more comprehensive a QA system is,
the
lower the probability of receiving complaints. As noted in chapter 2,
a
QA system to be effective must, at the minimum, include all the GMP
requirements. Besides the GMP requirements covering packaging and
label
design, design transfer, manufacturing control, packaging, labeling,
installation, complaints and failure analysis, a truly satisfactory
QA
system should also cover customer needs, design, design evaluation,
and
all aspects of repairs.

Feedback data should flow into all operations that could be

affected
by the data and should be used to aid in device and process design
evaluation and/or redesign, and to aid in improving the overall
quality
assurance program.

Regardless of the size of the formal QA system, the feedback data

path in any company should be the same, that is, the data should
flow
into all affected operations even if some of these are not covered
by
the formal QA system.

Because feedback is an important element in a quality assurance

system, and because the GMP requirements for complaints are
versatile
in that the degree of investigation may be varied to fit the nature
of
 the complaint, some firms actively solicit feedback information on
quality problems from their customers by shipping customer feedback
data
cards with finished devices. Customer feedback cards are also a
valuable public relations tool. Although the use of the forms is
optional, complaints received by the feedback forms should be
processed
according to a complaint handling procedure that meets the
requirements
of 820.198 and any additional company requirements.
COMPLAINT SOURCES

Complaints that must be processed according to the GMP

requirements
may be received from:

o customers by letter, credit memo, returned goods form, or

phone;
o firm's representative, or other employees;
o the United States Pharmacopoeia (USP);
o a service or repair request;
o journal articles; or
o the FDA.

Complaints from any source must be equally addressed by and be

processed according to the company complaint policy and procedure.
The
company must make certain that market, sales, engineering,
manufacturing, regulatory, installation, and service personnel report
complaints. These employees must be made aware of this requirement
according to section 820.25(a). It bears repeating -- all complaints
from all sources must be processed; and, it is best if they are all
processed according to the same procedure.

Service or Repair

All devices that are serviced or repaired because they no longer

perform as intended, i.e., they fail to meet specifications, are
subject
to the requirements of 820.162, Failure Investigations. Also, some
service and repair requests may meet the requirements for a complaint
per section 820.198. All repair or service requests resulting from
failure of a device to perform its intended function due to
inadequate
design, design defects, unanticipated component failure,
manufacturing
defect, or other causes of a nonroutine maintenance nature, whether
the
devices are under warranty or not, MUST be evaluated as candidates
for
the complaint file. Therefore, all service and repair requests MUST
be
 screened for complaints and the need to conduct failure
investigations.
For those selected, that is, devices that are serviced or repaired
due
to failure to meet specifications, investigations MUST be conducted;
and, a written record of the investigation, including conclusions and
followup, MUST be made.

Routine service requests for maintenance, adjustment, or repair

of
damage or failure resulting from long use, misuse or accident,
usually
do not need to be considered as complaints. Some requests for service
may appear to be routine when, in fact, they may be for unusual
conditions that warrant a complaint. For example, service requests
because of rapid wear, unusual problems, unusual maintenance, or
development of hazardous conditions should be considered complaints.
Enough information should be obtained from the customer to determine
whether the request is for routine maintenance or the device is being
returned or serviced for other reasons. The information must be
evaluated to determine if it meets the requirements of section
820.198,
and, if so, it must be handled as a complaint. Manufacturers are
 responsible for their decision NOT to investigate per 820.162.

As mentioned, manufacturers should maintain records of repairs

and
include the repair data when calculating reliability and performing
trend analysis to meet the quality problem identification
requirements
of 820.20 (a)(3).

Parts shipping trends

Appropriate manufacturers should periodically (e.g., monthly)

examine shipping records for repair parts. Any increases in shipment
of
specific parts due to unknown reasons should be analyzed to determine
if
a significant failure problem exists. Such increases may be an
"automatic trend analysis." Manufacturers have identified quality
problems by this simple, low-cost technique.

MEDICAL DEVICE REPORTING

In addition to the GMP requirements covering complaint handling

and
failure investigations, device firms must also comply with the
Medical
Device Reporting (MDR) regulation, 21 CFR Part 803.

Who Should Report

The MDR regulation requires that manufacturers and importers of

medical devices notify FDA when they become aware of a death or
serious
injury that may have been caused by one of their marketed devices
and/or
any malfunction in one of their devices which, if it were to recur,
could reasonably be expected to cause a death or serious injury.
These
are essentially the same complaints that the GMP regulation requires
a
firm to place in a special file -- the death/injury/hazardous
complaint
file [820.198(b)]. The MDR regulation is intended to supplement the
GMP
regulation -- it is not meant to replace the GMP complaint and
failure
investigation requirements.

When to Report

There are specific time limits within which the MDR reports must
be
 made. Any report of a death or serious injury must be made by phone
no
later than 5 calendar days from the initial receipt of the
information.
Malfunction reports must be made by phone or letter no later than 15
working days from the initial receipt of the information. In all
cases a
phone report must be followed by a written report within 15 working
days
from the initial receipt of the information by the firm. To meet
these
requirements, firms must have an information handling system to
assure
that data are screened to determine what must be reported to FDA.
This
system must also be able to follow up this information quickly and
accurately in order to comply with the MDR regulation. Firms which
have
a good system for processing complaint and failure investigations
such
as described in this chapter will have the organization and data
processing capabilities to meet the MDR requirements.

gmp 1-3 5/22/91

EXHIBITS

Several exhibits are briefly described below. The exhibits follow

in
 the order described.

Customer Feedback Cards

Some firms solicit customer feedback information to help improve

the
quality of their products and labeling. Two examples of feedback
cards
to solicit use-related information follow. A description of their
use
appears above the first card.

Complaint Processing Procedure

This sample procedure is used to establish and help implement a

system for processing routine complaints for noncritical devices. The
customer complaint form mentioned in the sample procedure is
essentially
the same as the form, "customer complaints" in the next exhibit.
Nowadays the complaint log shown on sheet 4 of 4 is easily maintained
on
a computer. The firm that developed this procedure used a slightly
different procedure for handling complaints about serious hazards
because these were reported to the corporate offices. The procedure
for
hazardous complaints is not reprinted here.

Complaint Data Forms

Three examples of complaint recording forms follow the complaint

processing procedure.

The first form titled "Customer Complaint" was developed and used
to
record routine complaints regarding complex electronic and
electromechanical devices.

The second form (double-sided) titled "Product Hazard Incident

Report" is used for recording and investigating complaints regarding
hazards associated with these same complex devices. The GMP
regulation
requires that these complaints be filed in a separate file. To
simplify
trend analysis, both should be filed by product line.

The third form (double-sided) titled "Device Complaint Report"

was
developed and used to record complaints regarding relatively simple
devices, some of which may be sterile. This form may be used to
record
complaints covering routine or hazardous faults if each type of
complaint is correctly identified and correctly recorded.
 These sample forms do not have a blank for recording "reason for
no
investigation" because the company intent is for all complaints
received
to be appropriately investigated.

If they match a firm's needs, these complaint forms may be used

as
is. Also, they may be modified to meet specific needs. If a form is
modified or a new one developed, a firm must make sure the resulting
form is consistent with the GMP requirements and consistent with any
complaint handling policy and/or procedures being used at the firm.

CUSTOMER FEEDBACK CARDS

The objective of a quality assurance system is the production of

quality products or services. However, if this objective is not
achieved
for a given device, it is important to have various programs to
detect,
identify, and correct the deficiency in the device; and to identify
and
 correct any related deficiency in the quality assurance systems
[820.20(a)(3)]. One means of encouraging customers to feedback
information on minor quality problems is to supply a self-addressed
and
stamped feedback card or form. The customer will probably report
major
problems on their own initiative.

Although the use of these forms is optional, complaints received

on
the feedback forms should be processed according to a complaint
handling procedure that meets the requirements of 820.198 and any
additional company requirements. The GMP requirements for complaints
are
versatile in that the degree of investigation may be varied to fit
the
nature of the complaint. This versatility encourages the use of
feedback
forms to obtain information on minor quality problems. Customer
feedback
forms are also valuable public relations tools.

Two samples of feedback forms follow. The small card exhibited

below
is for a relatively simple device. The large folding form is for a
complex system of medical devices. Both forms have standard "business
reply mail and postage nomenclature" on the side not shown.

<CUSTOMER FEEDBACK CARD (Example 1)>

<Customer Feedback Card (Front) (Example 2)>

Company logo Procedure No: _____________________

Sheet: 1 of 4
Issue Date: ____________ Rev: _____
SUBJECT:
Complaint Processing
App: ______________________________
President
PURPOSE:

To establish and implement a system for recording customer

complaints as a basis for analysis, response, and corrective
action.

POLICY:

It is the policy of your FIRM NAME that all

 complaints regarding safety, efficacy, reliability, or quality
of
products or services will be subject to management review and/or
investigation and will result in prompt response and corrective
action where indicated.

SCOPE:

A "complaint" is any indication of the failure of a device to

meet
customer or user expectations for quality or to meet performance
specifications. Thus, any written, oral, or returned goods
expression of dissatisfaction relative to the identity, quality,
durability, reliability, safety, effectiveness, or performance
of
any device manufactured by this firm would be considered a
complaint. (See Policy/Procedure No. XXX for handling complaints
covering hazardous faults.)
 Types of complaints intended to be covered by this policy are as
follows:

1. PRODUCT PERFORMANCE: the product in some way does not perform to

user's expectation or to any level of performance conveyed to the
customer by printed labeling or verbally by company employees.

2. PRODUCT SAFETY: all safety complaints are covered by this

procedure
with the exception of "hazardous complaints" which are covered by
Policy/ Procedure No. XXX.

3. PRODUCT RELIABILITY: failure rate or need for service

adjustments
greater than user expectation, i.e. beyond the tolerable level of
expected wear or malfunction.

4. PRODUCT APPEARANCE: visual defects inconsistent with the user's

expectations for a medical device.
5. GENERAL COMPLAINTS: order or shipping error, delayed or
unacceptable response to problems, unfulfilled promises, etc.

This policy is applicable to and must be complied with by all

personnel who receive a customer complaint, including personnel in
Sales, Field Service, and any other department.

Sheet 2 of 4

FORMS USED

1. Customer Complaints

2. Complaint Log (on sheet 4)

PROCEDURE: Upon receipt of a customer complaint as defined in this

policy, recipient fills out the "ORIGINATOR" section of a CUSTOMER
COMPLAINT form and if the complaint is in writing, attaches the
complaint letter to the form. The recipient then gives the form,
with
any attachments, by the next day to the Director, Quality Assurance.

IMPORTANT COMPANY POLICY: Where a complaint requires immediate

corrective action or response to a customer, the complaint recipient
must either take the required action or communicate with the proper
person to take the required action. It is the responsibility of the
recipient of any complaint to see that the customer receives a
response
-- nothing in the following procedure relieves him or her of this
responsibility.
 Quality Assurance:

1. Assigns a sequential complaint number and enters the complaint

into
the Complaint Log.

2. Records date received and product code on the complaint form.

3. As appropriate, distributes a copy of the in-process complaint

form
to:
 Regional Sales Manager

Regional Service Manager

District Sales Manager

Sales Personnel

Service Personnel

4. Determines and notes on the in-process form the person to whom

the
complaint is to be assigned for investigation and/or corrective
action
and the date a response is required from the assignee.

5. Notes on the reverse of the in-process form any specific

instruction
to the assignee.

6. Makes 2 copies of both sides of the in-process form and

attachments,
and distributes:

Original to the Assignee.

One copy to the "UNDER INVESTIGATION" complaint folder.

One copy into a followup folder under the requested response date.

Sheet 3 of 4

The Assignee:

1. Performs the investigation and/or corrective actions as per

Policy/Procedure No. XXX and the instructions from QA. Record the
results on the in-process form.

2. Details his or her findings and any corrective action taken on

the
"ASSIGNEE" section of the in-process form.

3. Make copies and retains a copy of the in-process form and any
attachments.

4. Returns the original of the in-process form to QA.

Quality Assurance:

1. Records on the lower "QA" portion on the reverse of the in-

process
form:
 Any additional corrective action taken or directed by QA.

The nature and date of any response made to the originator or the
customer. If this response is in writing, the communication is
appended
to the in-process form.

The final disposition of the complaint. If no action is taken,

the
reason for inaction should be recorded on the in-process form.

QA signature and date.

 2. Notes in the "DISTRIBUTION" section the names of those to whom
copies of the completed complaint forms are to be sent.

3. Distributes copies where appropriate. Involved field personnel

should be copied.

4. Records the final disposition or assessment of the complaint on

the
complaint log.

5. Files the completed form in the appropriate complaint file for

the
product or product-group involved; and removes and discards the copy
previously filed in the "UNDER INVESTIGATION" complaint folder.

6. Submits monthly to Corporate QA a copy of the complaint log for

the
current month, plus any prior months for which complaints remain
unresolved.

7. Distributes the complaint log monthly to Staff and specifically

involved departments. This log should include a trend analysis of
complaints for the month correlated with trends noted in previous
months.

COMPLAINT LOG

Sheet 4 of 4
Month _______, 19_____

Seq. Date Product

No. Rec'd. Code Complaint Disposition
----- ------- --------- ------------------------------ --------------
-

<Customer Complaint (Front)>

<PRODUCT HAZARD INCIDENT REPORT (Front)>

<DEVICE COMPLAINT RECORD (1 of 2)>

 GMP - CHAPTER 15 - QA SYSTEM AUDITS

CHAPTER 15 QA SYSTEM AUDITS

INTRODUCTION
AUDIT REQUIREMENTS
Procedure
Audit Schedule
Independent Auditor
Employee Training
Evaluation Criteria
Results and Corrective Actions
Audit Certification
EXHIBITS
Policy/Procedure for GMP Audit
Quality Assurance Audit Procedure
Vendor Survey Form

INTRODUCTION

Section 820.5 of the Good Manufacturing Practices (GMP)

regulation
requires that "every finished device manufacturer shall prepare and
implement a quality assurance program that is appropriate to the
specific device manufactured and meets the requirement of this
part."
Section 820.20 outlines the quality assurance requirements of the GMP
regulation. As discussed in Chapter 2, every quality assurance (QA)
system should include: management policies; objectives; an
organization; documentation; performance of tasks according to
policies; and monitoring of the system (feedback). Section 820.20(b)
requires that the QA system be monitored through audits. The
analysis
and use of feedback data from audits, complaints, and other sources
is
a necessary part of a QA program in order for a QA system to be self
correcting. Thus, the quality audit of a QA system is one of the most
important requirements of the GMP regulation.

A quality audit is a documented independent inspection and review

of
a QA system. The audit is performed in accordance with written
procedures on a periodic basis. The objective is to verify, by
examination and evaluation of objective evidence, the degree of
compliance with those elements of the quality assurance program under
review. These audits are an essential part of every medical device
 manufacturer's effort to assure safe and effective devices.
Regardless
of how well a quality assurance program is planned, monitoring of
the
program is required if the QA program is to be effective in assuring
that finished devices meet specifications. Manufacturers who do not
have an adequate quality audit system usually do not have adequate QA
programs. An evaluation of approximately 2400 firms that had
received
GMP inspections by FDA showed that firms with an adequate quality
audit
system were in compliance with approximately 96 percent of the GMP
 requirements, while those that did not have an adequate audit system
were in compliance with approximately 70 percent.

If conducted properly, a quality audit can detect QA program

defects. Isolation of unsatisfactory trends and correction of factors
that cause defective products prevent the production of unsafe or
non-
conforming devices. Without an effective quality audit function, the
quality assurance program is incomplete -- there is no assurance that
a
manufacturer is consistently in a state-of-control. In addition, the
proper implementation of a QA audit system can result in cost
savings
by identifying and correcting problem areas. Without an audit, the
quality assurance system becomes an open loop with no feedback to
management. Without management support, the QA program will
eventually
become ineffective and, as history has shown, ignored.

AUDIT REQUIREMENTS

The GMP regulation requires that planned and periodic audits of

the
quality assurance program shall be implemented to verify compliance
with
the quality assurance program requirements. The audits are to be
performed in accordance with written procedures by appropriately
trained
individuals who do not have direct responsibility for the matters
being
audited. Audit results shall be documented in written audit reports,
which must be reviewed by management personnel who have
responsibility
for the matters audited. Followup corrective action, including
reaudit
of deficient matters, shall be taken when indicated. Upon request of
a
designated FDA employee, a responsible official of the manufacturer
shall certify in writing that the audits have been performed and
documented and that any required corrective action has been taken.

To assure that company quality goals will be routinely met and to

comply with the GMP regulation, quality assurance system audits
should:
measure the effectiveness of the quality assurance program; provide
objective evidence that adequate controls are in place; and, assure
that
products and processes conform with specifications.

Where practical, manufacturers should include audits of their

vendors, calibration laboratories, and contractors as part of a QA
audit. Manufacturers should audit vendor to assure that they have
 adequate QA controls for components received by the manufacturers
under
certification (certificate of compliance with specifications) by
vendors. An example of a detailed vendor survey (audit checklist)
form
is in the Exhibits.

Procedure

All manufacturers must have a written quality audit procedure,

although the details will vary with the firm size and nature of the
manufacturing operations. An audit procedure should include:

o an objective,
o audit scope,
o an audit schedule,
o assignment of responsibilities, and
o evaluation criteria.

Before writing their audit procedure, some firms may find it

helpful
 to rearrange the key GMP requirements for an audit in a structured
format as shown below:

o Who? Designee
o What? QA system
o When? X months
o How? Per checklist
o Results? Report/review
o Actions? Corrective

This structured format helps lead authors into covering key

requirements and "getting straight to the point when writing
procedures". Thus, this format tends to reduce the length and
increase
the clarity of written procedures.

Formal procedures should start with an objective. In this case,

the
audit objective was discussed in the opening paragraphs of this
chapter -- to monitor the QA system. The audit scope must include all
functions that significantly impact on whether devices will meet
specifications. There functions include personnel training,
facilities,
environment, device master and history records, equipment calibration,
vendors, label control, validation, complaint files, data feedback,
preparation for FDA GMP inspections, etc. Firms that have a total QA
system composed of a design QA system and a manufacturing QA system
should audit the entire system, otherwise, it is no longer a total QA
system! Audits should cover all buildings and operations as necessary
to
make certain that the desired or required quality assurance program
is
properly implemented.

The quality audit required by the GMP regulation is not intended

to
be a product audit. However, the adequacy of procedures used to
determine product acceptability must be reviewed (audited)
periodically.
Product audits and review of the device master record are desirable
as
independent evaluations of product quality to determine the product's
fitness for use and conformance to specification; and, these may be
acceptable in satisfying most quality audit requirements when product
and process are very simple. As products and processes become more
complex, evidence from inspection and testing of products no longer
provides full assurance that the manufacturing system will
consistently
produce quality products. Instead, full GMP/QA system audits are
required to insure that the established QA system is adequate for
producing devices that consistently meet the device master record
requirements and that all system requirements are being met.
 Audit Schedule

Manufacturers are responsible for deciding the frequency of audits.

The frequency should depend upon previous audit findings, any
indications of problems, and known stability of the manufacturing
process. If an audit reveals no problems, the audit intervals could
be
lengthened -- if problems are identified, audits may need to be
conducted more often. Audits are usually conducted every 6 to 12
months,
but should not exceed 12 months. Some companies split their audit
into
parts, and perform one or more parts per month or quarter, or audit
one
or more operations per month or quarter. This approach is valuable
because it tends to direct attention toward problems that can be
resolved within reasonable time limits and existing budgets. However,
such segmented audits may fail to identify company-wide problems.
Thus,
reviewers of segmented audit reports should look for indications of
 company-wide problems.

Independent Auditor

The GMP regulation requires that QA system audits be conducted by

individuals not having direct responsibility for the matters being
audited. This requirement may be satisfied by an audit team
consisting
of persons representing product development and manufacturing. Then,
when the product development area is being audited, the manufacturing
persons should have the lead responsibility and vice versa. For any
element of the quality assurance system being audited, at least one
member of the team should not have direct responsibility for the
element
being audited. Management should designate one member as team leader
for
a given audit in order to support consistency, timeliness,
completeness,
and uniform response. Of course, a consultant, corporate, or other
independent auditor may be used.

The requirement for an independent audit must generally be met;

however, if a very small manufacturer, particularly one in which
everyone is directly involved in daily production activities,
concludes
that independent audits would be unduly burdensome or impractical,
the
requirement for independence may be waived. However, if FDA finds, as
a
result of inspection or other means, this waiver has compromised the
quality assurance program, FDA may require an independent audit,
increase the frequency of FDA GMP inspections, or take other
appropriate
regulatory action.

Employee Training

Individual(s) responsible for conducting audits must be

sufficiently
trained and experienced to detect variations and problems in the
quality
assurance system [820.20(b), 820.25]. An auditor is expected to
objectively compare existing manufacturing processes, records,
test/inspection activities, label control systems, feedback, etc.,
against what they should be. To do this, the individual(s) must have
a
working knowledge of:

o how the device(s) is made,

o the manufacturing processes,
o quality assurance principles that apply, and
o the human relations aspect of auditing.
 As with any GMP training, a record should be maintained of the
training given each employee.

Because the GMP requires a written audit report, auditors must

have
sufficient writing skills to effectively communicate findings and
recommendations.

Evaluation Criteria

Each firm must determine the criteria to be used for conducting

the
audit. In general, medium to large firms will need extensive
documentation outlining the areas to be audited and the acceptable
criteria for each of these areas. The GMP requirements can form a
basis
for the evaluation criteria; however, because the GMP regulation is
broad, each firm must tailor the criteria to the operations they are
actually performing. Small manufacturers may need only minimal
 documentation, and this may consist of a checklist with appropriate
ancillary instructions to assure that all aspects of the QA system
are
covered.

An audit checklist may be a series of questions, phrases, trigger

words, or any combination of these that will prompt auditors to cover
the entire quality assurance system. Checklists should cover
requirements of the GMP regulation applicable to company products,
operations, and other areas company management has decided are
included
in their total quality assurance system. If operations or devices
change, evaluation criteria and check-lists must be appropriately
updated.

Results and Corrective Actions

A QA system audit program that has been established in accordance

with the GMP regulation and implemented in sufficient depth can
detect
undesirable variations and trends in operating procedures. Management
awareness of these undesirable variations should lead to corrections
and
help prevent production of unsafe, unreliable, or ineffective devices.

The GMP regulation requires followup corrective action, including

reaudit. When in-dicated, audit results must be given to individuals
responsible for each of the operations audited, especially if
deficiencies are found. Audit results must be reviewed by all key
management personnel, especially those responsible for the matters
audited.
An audit should never be used as a disciplinary tool. This use will
lead to ineffective audits because employees may become reluctant to
reveal any possible problems for fear of retribution.

Audit Certification

FDA has authority to review and copy all records required by the
GMP
regulation; however, FDA has elected not to routinely review audit
reports. The one exception to FDA's policy of not seeking access to
reports of audits of quality assurance programs is that FDA may seek
production of these reports in litigation under applicable procedural
rules, as for other otherwise confidential documents. Thus, a copy of
the current audit report should be maintained by the firm. FDA policy
was established because the agency does not wish to prejudice audits
by
having auditors concerned that their comments will be reviewed by FDA
investigators. Although FDA investigators do not have routine access
to
audit reports, they can request manufacturers to certify that audits
have been conducted and the results documented; however,
investigators
 do not routinely request certification. If requested, a responsible
official of the firm must certify, in writing, that the firm has
complied with the audit requirements of the GMP regulation.
Investigators usually will ask questions regarding the audit report,
such as who prepared the report, when was the report written, who
reviewed the report, was corrective action taken based on the audit
result, etc. If investigators suspect audits are not being conducted,
questions to determine consistency in answers may be addressed to
those
individuals who should have reviewed these reports. FDA investigators
will routinely review audit procedures and audit checklists.

EXHIBITS
 Two examples of audit procedures and three checklists, are
included
in this chapter. These may be modified to match individual operations
as
appropriate or used as guidelines.

Policy/Procedure for GMP Audit

In response to requests by small manufacturers, DSMA developed

this
procedure an example of a minimum procedure for GMP Quality Assurance
system audits. Following the procedure are comments to aid small
manufacturers in completing the procedure and developing a checklist
that must be used with it.

No details are given for the format of the audit "report" because
the format generally is not important for the small firm -- employees
of
small firms communicate daily with each other. In fact, the "report"
may
be the list of findings neatly noted on the audit checklist. As noted
in
the procedure, however, summaries of the audit findings and
corrective
actions are recommended. The format Who, When, etc. discussed in the
text, was used to develop this example procedure. The first three
items
in this format are reflected in item 1 of the example and the
remaining
three are reflected in items 2, 3 and 4 of the example. The scope is
the
entire quality assurance system.

Quality Assurance Audit Procedure

Quality Assurance Audit Procedure is an audit procedure that can

be
used by a medium to large firm. In comparison to the small company,
there are more people on the audit team, more audits per year, and
the
reports are distributed to more managers, some of which may be at
corporate headquarters. Therefore, this procedure contains more
details
than the one suggested for the small company. For example, the
procedure
dictates the format of the audit report for the benefit of the
managers
who may review reports for many different operations per year.

Vendor Survey Form

The vendor survey form is applicable to a vendor or contractor or

 may be modified and used as an internal audit checklist. This vendor
survey form is divided into areas of concern such as raw material and
component control, manufacturing, quality control/assurance, etc.
Also,
it is a more conventional checklist in that there are places to check
off answers to the questions. This form includes a header with space
for
firm name, address, date prepared, etc., and general information
about
the firm such as, annual sales, years in business, other plant
locations, etc. Your firms can look at these two styles of checklists
and decide to use one or the other, a combination of both, or a
totally
different format.

gmp 1-2: 4/22/91

Page 15-7

Sheet 1 of 4

Title: POLICY/PROCEDURE FOR GMP AUDITNo. _____ Rev. ______

 Approved byDate

1. A general audit of the entire quality assurance system shall be

performed by_________________________every _____ months (an audit
team
may be used).

2. The latest company approved audit checklist (number) ___________

shall be used. The audit checklist shall be updated as required and
approved by ________________________to reflect our current QA
program
needs.

3. The completed checklist and audit results summary report shall be

reviewed with the following managers, as appropriate, who are
responsible for the matters audited: ,
and . Minutes of the
review
meeting, including a list of attendees and desired corrective
actions,
shall be taken, distributed and filed by . This
same
procedure shall be used when reviewing the findings of GMP
inspections
by FDA investigators.

4. Corrective actions shall be taken by all affected persons as

discussed in the review meeting. ( will
coordinate
the corrective actions and keep management informed. A summary report
of
the status of the corrective actions, as determined by a reaudit of
the
affected areas or other appropriate means, will be written by
and filed with the original audit report. The status
report shall be updated at least bimonthly if there are any
uncompleted
corrective actions.

* * * * * * * * * *

Comments on the Policy/Procedure

A. "Rev." is the revision level of the latest company approved

procedure.

B. The above blanks should be completed with employee position

titles
and, if desired, employee names.

C. An audit checklist may be a detailed series of questions, phrases,

trigger words or any combination of these to assure that the auditor
 covers the entire quality assurance system. The checklist should
cover
the requirements of the GMP regulation applicable to each company's
products and operations plus other areas that company management had
decided are included in the total quality assurance system. A
suggested
way to develop a question-type checklist is to refer to the table of
contents of the GMP regulation and the chapters of this manual. Then
generate questions for each topic as applicable to specific products
and
operations of the firm. If an operation or devices change, the
checklist
must be updated. A small portion of a quality audit checklist follows.

Sheet 2 of 4

SPECIFICATION CONTROLS YES NO

COMMENTS
 1. Is an adequate system in place to control
all engineering drawings, specifications
and other related documentation?

2. Does the system require adequate review,

and approval of all new documentation and
changes to documents?
3. Does the system require controlled,
timely distribution of new specifications
and specifications changes?

4. Are procedures provided and adequately

implemented to assure collection of obsolete documentation?

5. Are all specifications used in production

approved, dated, and current?

6. Etc.

PROCESS CONTROLS YES NO

COMMENTS

1. Are current, approved process specifications

procedures such as work instruction, etc., used
to define each process?

2. Are process changes made according to a

formal change system and documented?

3. Are process changes communicated in a

timely manner?

4. Do process specifications and procedures

properly reflect the work to be
accomplished?

5. Are adequate acceptance and rejection

criteria provided for the output of each
process?

6. Are in-process and rejected items ade-

quately identified and/or segregated to
prevent mix-ups?

7. Etc.

Sheet 3 of 4

PERSONNEL YES NO COMMENTS

1. Are there sufficient personnel having the
necessary education,background, training,
and experience to assure that all manufacturing
operations are correctly
performed?
2. Where training programs are necessary to
assure that personnel have a thorough
 understanding of their jobs, are such
programs conducted and documented?

3. Are all employees made aware of device

defects which may occur from the improper
performance of their specific jobs?

4. Are all employees including salepersons

made aware that they must report all
complaints received from any source to
the company complaint department?

5. Are QA personnel made aware of defects

and errors likely to be encountered as
part of their individual QA function?

5. Are personnel in contact with the device

or its environment appropriately:

a. clean?
b. healthy?
c. attired?

6. Etc.

QUALITY ASSURANCE FUNCTIONS YES NO COMMENTS

1. Does the quality assurance unit do

the following?

a. review production records

b. approve or reject components
c. approve or reject manufacturing materials
d. approve or reject in-process materials
e. approve or reject packaging materials
f. approve or reject labeling
g. approve or reject finished devices
h. approve or reject devices manufactured by
another company

Sheet 4 of 4

i. approve or reject devices processed by

another company
j. approve or reject devices packaged by
another company
k. approve or reject devices held under
contract by another company
l. help provide solutions for QA problems
m. verify implementation of solutions for
quality assurance problems
n. assure that all QA checks are appropriate
and adequate
o. assure that all quality assurance checks
are performed correctly
 2. Are periodic audits of the QA program
conducted to verify compliance with QA
program requirements?

3. Are audits of the QA program:

a. performed in accordance with written

procedures?
b. conducted by appropriately trained
individuals?
c. conducted by individuals who do not have
direct responsibility for matters being
audited?

4. Are audit results:

a. documented in written audit reports?

b. reviewed by management having
responsibility for the matters audited?

5. Does company have a copy of last the

audit report on file?

6. Is followup corrective action, including

re-audit of deficient areas, taken when
indicated?

7. Etc.

QUALITY ASSURANCE AUDIT PROCEDURE

Sheet 1 of 2 No.
Rev. Approved Date _________
ECN History
___________________________________________________________________

________________________________________________________________________
___
POLICY: Periodic and planned audits of systems, processes, and
product
flow shall be performed to assure compliance with regulatory and
company requirements for current Good Manufacturing Practices (QA
system).

SCOPE: All facilities, operations, and product lines.

PROCEDURAL GUIDE: Routine quality audits of selected areas shall be

 conducted each month. The entire operation shall be covered during a
12-month cycle. An area may be audited more than once. An "Action
Audit" may be initiated by the Manager of Quality Assurance at any
time
if a special problem arises.

The teamwork approach shall be utilized to identify and correct

deficiencies.
 The audit team shall consist of the Senior Quality Auditor (team
leader)
plus one or more individuals from other disciplines who have no
direct
responsibility for the area being audited. A team auditing an
Operations
unit should include an R& D representative. A team auditing a
Quality
Control unit should include an Operations representative.

The Manager of Quality Assurance selects the team member in

consultation
with the Department Managers.

A. AUDIT PREPARATION - The Quality Auditor (team leader) reviews

standard manufacturing procedures, device histories, complaint
history,
device labels and inserts, previous audits with results, followup
audits, plus any other document relative to the audit.

B. AUDIT INITIATION - The Quality Auditor prepares an audit

checklist
for systematic examination of the area to be audited, informs the
Manager of the department being audited at the start of the audit,
and
reviews observations with the Department Manager.

C. AUDIT ANALYSIS - The Quality Auditor reviews the data gathered,

verifies important details, and writes an audit report according to
the
format delineated in the attached audit report outline.

D. ISSUANCE OF AUDIT REPORT - The Quality Auditor issues the written

audit report to the President and Department managers within 3
working
days following completion of the audit. If conditions are critical,
the
Director of Quality Assurance shall verbally brief appropriate staff
members within 12 hours following audit completion. Audit reports
shall
be stamped "Confidential".

Sheet 2 of 2

E. CORRECTIVE ACTION - The appropriate Management staff member shall

be
responsible for developing a schedule for correcting deficiencies
cited
in the audit report and submitting same within 5 working days to the
 Quality Assurance Manager. Included in the correction schedule shall
be
the responsible individual, and the date when corrective action is to
be
effected. The Manager of Quality Assurance shall act as arbiter, if
necessary, to judge validity of the deficiency, responsible
individual,
and reasonable date to complete the corrective action.

F. AUDIT FOLLOWUP - The Quality Auditor maintains a log listing

deficiencies, responsible individual, target date for corrective
action,
and actual date of correction. If the same deficiency occurs on a
second
followup audit, the President shall be notified in writing by the
Quality Assurance Manager.

G. LOG OF AUDITS AND FOLLOWUP AUDITS - The master log shall be

maintained by the Senior Quality Auditor. The audit log file shall
include a copy of current audits, list of areas to be audited during
the
12-month period, and list of areas audited to date (i.e., part of the
Master Log).

H. REPORT NUMBERS - Audit numbers shall be composed of the date

followed by the sequential number of the audit being reported (e.g.,
 88-4 for the 4th audit during 1988).

AUDIT REPORT COVER DATA

Area Audited ____________________________ Audit No. Date:

__________

Audit Team Members:

__________________________________________________________
__________________________________________________________
__________________________________________________________

Sr. Auditor's Sign:

__________________________________________________________ (Team
Leader)

REPORT OUTLINE

1. PURPOSE AND AREA DESCRIPTION - Describe initiating factors for

the
audit, limitations of audit, and area being audited.

2. MAJOR FACTS - Summarize for management review the most

undesirable
con- ditions and practices in order of their relative importance.
3. OBSERVATIONS AND FACTUAL DETAILS - Give a detailed account of the
current practices and the deficiencies listed in 4 below.

4. DEFICIENCIES - List deficiencies in procedures, standards,

documentation, safety, etc., along with identity of relevant
regulation,
SMP, SOP, etc.

5. FOLLOWUP - State plans for followup review to establish

individual
responsibilities and completion dates.

<VENDOR SURVEY FORM (1 of 4)>

 GMP - CHAPTER 16 - FACTORY INSPECTIONS

CHAPTER 16 FACTORY INSPECTIONS

INTRODUCTION
AUTHORITY AND COVERAGE
Inspection Plan
Inspection Refusals
Inspection Preliminaries
Conduct During the Inspection
Close-out Meeting
After the Inspection
BASIC POINTS FOR AN INSPECTION PLAN
REGULATORY SANCTIONS
Adulteration
Misbranding
Management Letter
Warning Letter
Seizure
Detention
Restraining Orders and Injunctions
Citations
Recalls
Penalties
EXHIBITS
Notice of Inspection
Receipt for Samples
Affidavits
List of Observations
Establishment Inspection Report
Warning Letter

INTRODUCTION

FDA determines compliance with the Good Manufacturing Practices

(GMP) regulation primarily by factory inspections. An FDA inspection
of
an establishment, however, can be initiated for a number of reasons.
The reasons may be general, such as routine scheduling or a need to
obtain data on industries new to FDA; or, the reasons may be specific,
such as investigation of a consumer or trade complaint, a product
defect report, an adverse reaction, or a death. FDA also conducts
inspections under the Government-Wide Quality Assurance Program
(GWQAP)
on behalf of the Veterans Administration (VA), Department of Defense
(DOD) and Health Resources and Services Administration (HRSA). Upon
arrival, the investigator presents his/her credentials and issues a
Notice of Inspection form FDA 482. At the end of the inspection,
observations are recorded on FDA 483, List of Observations, and
 discussed with the firms management. Later the investigator will
write
an Establishment Inspection Report (EIR), which is a detailed record
of
the inspection and findings.
 AUTHORITY AND COVERAGE

Section 704(a) of the Food, Drug, and Cosmetic (FD& C) Act gives
FDA
the authority to conduct GMP inspections of medical device
manufacturers. During these inspections, facilities, manufacturing
processes records, and corrective action programs are examined by an
FDA investigator. The results provide information necessary to
evaluate
a firm's compliance with the device GMP regulation (21 CFR 820).

Anyone who manufactures, labels, packages, imports, or stores a

medical device can be inspected. A manufacturer is any person,
including a repackager or relabeler, who writes specifications for,
manufactures, fabricates, assembles, or processes a medical device.

Inspection Plan

This chapter offers ideas on ways that a firm might prepare for,
undergo, and respond to an FDA inspection. First and foremost, it is
important to plan ahead! Before being visited by an FDA investigator,
a
firm should have in place an inspection procedure which takes into
account, and prepares a firm for, any eventuality. It should detail
company policy regarding such an inspection; and, very importantly,
designate those individual(s) who are to work with the FDA
investigator. Try to anticipate situations and have written
procedures
covering them. These procedures will provide continuity from one
inspection to another and help assure that corporate policies are
followed by employees receiving and accompanying the investigator.

Each person designated as an FDA contact should be chosen

carefully
and be thoroughly familiar with the inspection procedure and company
operations. An inspection will take longer if the contact person
cannot
answer questions without continually referring to the written
procedures. The contact should be familiar with FDA regulations and
practices and be able to anticipate problems or requests. FDA
contacts
must be knowledgeable about plant operations, and able to answer or
obtain answers to the investigator's questions. Other individuals,
with
similar qualifications, should be designated to fill in during
absences
of the primary contact. A firm might want secondary contacts to
accompany the FDA investigator even when the primary contact is
present
in order for the secondary contact to become familiar with FDA
methods
and procedures.
 Along with the designated contact, the firm may want operations
managers to accompany the investigator, such as the production
manager,
QA manager, etc. These individuals must be familiar with the plant
operations and company policy, and be able to answer questions about
procedures and processes. However, a firm should keep the number of
individuals accompanying the investigator to a minimum to prevent
problems such as contradictory statements.

Receptionists should be informed that an FDA investigator will

eventually visit and have procedures to follow when they arrive.
These
procedures should include instructions to call the FDA contact
person
and what to do or who to contact when that person is not available.

Inspection Refusals

As noted above, Section 704(a) of the FD& C Act gives FDA clear
authority to conduct inspections. It is bad policy to refuse an
 inspection because this sets up an adversarial situation and arouses
an
investigator's suspicions regarding the firm's compliance with the
GMP
regulation. If a firm refuses an inspection without a valid reason,
FDA
usually obtains a warrant which grants entry for an inspection.
Refusal
is noted in the firm's file maintained by FDA and may be interpreted
as
a lack of cooperation.

There may be instances, however, when a firm needs to ask the

investigator to return at a later time to conduct the inspection.
Explain why it is best that an inspection be done at a later time.
For
instance, if the FDA contact person(s) is not in the factory and no
one
knowledgeable about the firm's operations is available, ask the
investigator to come back. However, FDA investigators do expect to
be
admitted if a device factory is operating. The rationale is that if
a
factory is operating, someone must be in charge and that individual
should understand factory operations and procedures. If the factory
is
not in operation or if not yet manufacturing any medical devices,
this
should be explained to the investigator. This FDA representative may
still want to go through the factory to make sure it is not in
operation -- firms should have a policy covering this situation. It
is
advisable, in this situation, to allow the investigator to walk
through
the factory to verify later that it is not in operation. If the
factory
is not in operation, advise the investigator when operations will
begin. The investigator will consider the request and circumstances,
then determine whether to proceed with the inspection.

Inspection Preliminaries

Before an inspection begins, an investigator will display

credentials. The credentials have a picture of the investigator and
identify him/her as a representative of the FDA.

After presenting credentials, the investigator will issue form

FDA
482, Notice of Inspection. This form is issued to the owner, operator,
or agent in charge of the factory or to the designated FDA contact.
The
bottom portion of the Notice of Inspection contains excerpts from
 Section 704 of the FD& C Act. The investigator will complete the top
portion of the form by filling in the firm name, address, name of
the
individual given the signed form, date, and time of inspection. The
investigator then signs the form.
The FDA contact person should always be prompt. An investigator
may
become suspicious if kept waiting and may wonder if the firm is
busily
correcting GMP deficiencies. After suspicions are aroused, a firm may
receive a more comprehensive inspection because the investigator may
be
looking for areas that have been corrected or temporarily corrected.

Conduct During the Inspection

Awareness of what is going on at all times by the contact person

of
the firm during the inspection is important. Therefore, once started,
the inspection should be given priority. If the contact person is
distracted by other business, the inspection may be prolonged and the
investigator's questions concerning suspected deficiencies may go
unanswered. Familiarity with the circumstances surrounding any
deficiencies listed on form FDA 483 (the list of deviations presented
at
the close of the inspection) is vital in discussion of these with the
investigator.
 During inspections, the FDA contact person must deal with many
issues such as viewing of records, copying, photos, tape recordings,
differences of opinion, immediate corrections, promises, samples,
notes,
etc. All of these issues should be addressed by a company procedure.

There should be a procedure for responding to requests for

production records, change control records, complaint files, and
shipping records. All records required by the GMP regulation must be
made available to the investigator for review and copying (820.180).
Therefore, device master records, production records, and complaint
files must be readily accessible. However, shipping records are not
required by the GMP regulation for noncritical devices; therefore,
firms
have the option of allowing access to these records unless these
records are the only source that shows compliance with the
requirements
in 820.184 for quantity released to distribution, control numbers,
etc.
The procedures covering review of records by the investigator should
identify who will retrieve records, the investigator or one of your
employees; how many records can be reviewed at one time; and, who
should be present to answer questions raised by the investigator.

Because all records required by the GMP regulation must be

available
for copying, management should decide on a policy concerning record
copying during inspections. The following questions need to be
answered
in this policy and the answers recorded in the inspection procedure.

o Will company employees photocopy the records? If so, will

FDA
be billed for copying charges? FDA is authorized to pay for
any photocopies made on the company machine or when
the company pays for a commercial photocopier.

o If the company does not have a photocopying machine or does

not want the investigator to use it, will the investigator
be
permitted to make copies outside the plant? If so,
a
plant employee should accompany the investigator.

In all situations, the contact should make duplicate copies and

keep
these together as a record of the documents that the investigator
copied.

If any records copied by an investigator contain confidential

information, it should be identified, i.e., by a confidential stamp.
This identification does not automatically prevent release of these
records under the Freedom of Information (FOI) Act; however, the FOI
 officer filling a request is then made aware that the firm considers
the
information confidential. Confidential information is not released
under FOI.

CAUTION: do not mark every page of a document as confidential. Be

specific and mark only those items that are genuinely confidential.
Marking everything confidential forces the FOI officer to review
each
page and independently make the determination of what is
confidential.

As with photocopying of records, management should decide on a

policy regarding picture taking by the investigator during an
inspection
(FDA feels that picture taking is a normal inspectional activity).
Include this policy in the inspection procedure.

If your firm disagrees with any observation made by the

 investigator, be sure to discuss with the investigator the reason for
the observation. You may find that there was a misunderstanding that
can easily be corrected. When explaining a situation or answering
questions, be honest. Don't make up answers as this could lead to
additional problems. If you don't know the answer, say so. There is
no
FDA penalty for not knowing an answer and there is no requirement
that
a firm answer hypothetical or "what if" questions. If questions arise
about photocopying, photography, records, or any other topic, it is
best
not to force a confrontation. Arguments about an investigator's
observations may lead to loss of dialogue. The participants should
refer to the FDA regulations and guidelines, whenever possible,
rather
than base discussions and disagreement on personal opinion.

If there are questions for which you don't have an immediate

answer,
promise to research the question. A list of these unanswered
questions
is a reminder to get the answers and give them to the investigator.
The
investigator usually records the questions, and resolving unanswered
questions may avoid negative items on form FDA 483 and in the
establishment inspection report prepared by the investigator at the
end
of the inspection.

If possible, any GMP deficiencies that the investigator notes and

with which you agree should be corrected immediately. The
investigator
should be made aware of these corrections as this will show intent to
comply with the regulations and commitment to quality assurance. All
corrective actions will be documented in the investigator's EIR.
If correction cannot be made during the inspection, management
may
want to consider providing an estimated timetable for correction.
However, the firm should not present or commit to a timetable that
may
be difficult or impossible to meet. If a timetable cannot be
immediately developed, try to get one to FDA as soon as possible.

As with any production change, it is a good idea to discuss

possible
corrective actions with affected company personnel before promising
correction to FDA. This concept was discussed in chapter 6, Device
Master Record, and chapter 7, Change Control, and may prevent
promises
that have adverse effects on other areas of production. Hastily
conceived corrections can cause greater problems in the long run.
 Any commitments made to FDA should have top management
concurrence.
It can be detrimental to the firm to be committed to a course of
action
that cannot be completed or that management refuses to pursue.
Therefore, only persons with the authority to do so should make
commitments.

Occasionally during an inspection, investigators collect samples.

These may be used to:

o verify conditions in the factory;

o establish interstate movement of finished devices and their
components; or,
o to fulfill a request from FDA's Center for Devices and
Radiological Health (CDRH).

CDRH may request samples for a number of reasons, such as surveys

of
device manufacturers and investigation of user complaints. Whenever
an
investigator collects samples, duplicate samples should be collected
and stored by your firm. If problems are uncovered by FDA, testing
of
 these duplicate samples by your firm may confirm FDA results or form
a
basis for discussion of FDA findings.

Before leaving your premises with a sample, the investigator will

issue a form FDA 484, Receipt for Samples. This receipt is a record
of
the samples that were taken. Where indicated, interstate movement of
the shipments from which these samples were taken will be documented
by
the investigator with copies of shipping records. The investigator
will
then prepare an affidavit (forms FDA 463a, 463, 1664a or 1664b)
referencing these documents. A responsible firm individual will be
asked
to verify, by signature, that the documents referenced in the
affidavit
pertain to the shipment(s) in question. This action is to formally
document interstate receipt or distribution of medical devices.
Therefore, your firm should include in its inspection procedure the
company policy on the signing of affidavits. Refusal to sign an
affidavit is usually noted on the affidavit and in the EIR.

Having accurate and complete knowledge of what an investigator

has
done is an important part of handling an FDA inspection. Good notes
record this information. Comments and suggestions made by the
investigator, unanswered questions, and promises should all be
recorded. General information on the areas of the plant the
investigator
visited, to whom he spoke, etc., can help when commenting on form
FDA
483 items, making corrections to the facilities or QA system, or
advising top management of the results of an inspection.

Notes will also be useful in fulfilling promises or obtaining

answers to previously unanswered questions. When the items on the
FDA
483 are presented, accurate notes help to prevent surprises. Good
notes
can also help to prepare well thought out and adequate answers to
FDA
483 items even before these items are presented at the close-out
meeting.

Close-out Meeting

At the end of an FDA GMP inspection, the investigator conducts a

close-out meeting. It is usually held immediately after the
inspection,
but may take place a day or so later, especially if the completed
form
 FDA 483 is long. During this meeting, the investigator discusses
with
company management the observations recorded on form FDA 483.

Representatives of the firm will be given a copy of the completed

form FDA 483 which should be checked for accuracy and completeness
against notes. Misunderstandings may have occurred during the
inspection that gave the investigator the false impression that
deficiencies existed. Close-out meetings present an opportunity for
all
parties to correct such misunderstandings. Top management should be
present at the close-out meeting to answer questions about any
corrective actions to be taken and schedules for these actions.

The investigator should be reminded of any corrections that have

been made. Corrections that have been made during the inspection will
be
documented in the investigator's establishment inspection report
(EIR),
but these observations will still appear on the FDA 483. Mention
your
plans to make corrections, and provide a timetable for these future
actions. Answers given at this meeting will be recorded by the
investigator. Again, it is important that the company individual
promising corrections and setting up timetables have the authority
to
do so. Future inspections will cover those areas where correction was
 promised as well as other appropriate areas.

After the Inspection

Completion of the inspection by FDA should signal the start of

certain activities by the firm, such as discussion of deficiencies
with
appropriate departments and employees to advise them of corrections
to
be made and time frames involved.

Unresolved form FDA 483 items should be reviewed by company

technical and legal personnel. If a decision is made that corrective
action is not needed and there is disagreement with the
investigator's
opinion regarding the deficiency, state this, along with the
rationale,
in a letter to the FDA District Office responsible for inspection of
your firm. Even if a firm agrees with all the items on the FDA 483,
it
is a good idea to respond to each item in a letter, along with
documentation showing how the corrections have been implemented, to
the
District Office. This reply shows a commitment to quality assurance
and
"officially" presents the company's case to FDA. This reply should
help
resolve any doubts that the inspection report might raise about a
firm.

The final step for a firm is to determine what can be learned

from
the inspection, so that the business can operate in a better state
of
control, improve quality assurance, and assure future GMP compliance.

The following is a concise summary of the major points made in

this
chapter. This summary should help your firm formulate an inspection
plan.

BASIC POINTS FOR AN INSPECTION PLAN

1. Be prepared for the eventual inspection by trying diligently to

comply with applicable medical device regulations and preparing
an
inspection plan. If needed, assistance is available from DSMA,
phone 800-638-2041 and other offices of the Center for Devices
and
Radiological Health.

2. Receptionists should know who to call when an FDA investigator

visits.
 3. Determine that an FDA investigator is calling by examining his
credentials.

4. Receptionists or initial contact persons should inform all key

employees that an FDA investigator is present.

5. Someone, but not a large number of individuals, should accompany

the
investigator and be with the investigator at all times.

6. If the investigator is not familiar with the firm, describe the

product line and operations before entering the manufacturing area.

7. At the beginning, review with the investigator all company

policies
and programs. Employees should accentuate positive aspects of these
programs.

8. Employees should be cooperative, avoid conflict, and know when to

terminate discussions with the investigator. Base discussions on
regulations, guidelines, etc.
 9. Don't start an argument with, get up-tight with, or lie to the
FDA
investigator.

10. Understand the investigator's questions before answering. If

needed,
ask for an explanation. Refer each question to the most suitable
employee.

11. Don't state that a particular event is impossible with your

product -- the investi gator may have a report that covers the
impossible event.

12. Don't try to compromise the compliance role of the FDA

investigator
or threaten to call their supervisor.

13. Deviations should be corrected as soon as possible.

14. Keep duplicate copies or samples of material given to the FDA

investigator.

15. During the exit interview, make sure that all deviations are
adequately discussed. If there is disagreement, present all of
the
company information and any regulations and official
interpretations that support your viewpoint.

16. Immediately submit to the local FDA District office a written

reply
to the FDA 483. Make sure you address all of the observations.
State how and when you expect to make corrections. If you disagree
with an observation, give reasons and references to regulations,
guidelines, etc., for your position.

17. Be reasonable in setting schedules for corrective actions --

don't
state impossible deadlines or drag out completion schedules.

18. A followup report covering findings and corrections should be

distributed to appropriate company employees.

REGULATORY SANCTIONS

Responsible officials who are in positions of authority in

regulated
firms have a primary legal duty to implement whatever measures are
necessary to ensure that their products, facilities, and operations
are
in compliance with the law. The law presumes these individuals are
fully aware of their responsibilities.
 Whenever FDA determines, as a result of an inspection,
investigation, complaint or other source, that a product is or may
become adulterated or misbranded, several actions may be taken.
These
actions may be in the form of a warning letter to the firm; or result
in the seizure or detention of a product or an injunction; or result
in
prosecution of the firm. The actions vary depending on the degree of
danger to the public, or willingness of the manufacturer to correct
violations. [Following are several sections of the Food, Drug, and
Cosmetic (FD& C) Act commonly used in misbranding or adulteration
charges. In this reprint, some key words are bolded for emphasis.
Added
notes are in brackets.]
 Adulteration

Section 501 (351). A drug or device shall be deemed to be adulterated

--
(a)(1) If it consists in whole or in part of any filthy, putrid, or
decomposed substance; or

(2)(A) If it has been prepared, packed, or held under insanitary

conditions whereby it may have been contaminated with filth,
or
whereby it may have been rendered injurious to health;

(c) If it is not subject to the provisions of paragraph 9(b) of

this
section* and its strength differs from, or its purity or
quality
falls below, that which it purports or is represented to
possess. [* Paragraph 9(b) refers to drugs].

(h) If it is a device and the methods** used in, or the facilities

or
controls used for its manufacture, packing, storage, or
installation are not in conformity with applicable requirements under
Section 520(f)(l) or an applicable condition prescribed by an
order under Section 520f(2).

[** refers to Device Good Manufacturing Practices, Part 820 of the

Code
of Federal Regulations].

Misbranding

Section 502 (352). A drug or device shall be deemed to be misbranded

--

(a) If its labeling is false or misleading in any particular.

If in a package form unless it bears a label containing (1)

the
name and place of business of the manufacturer, packer, or
distributor; and (2) an accurate statement of the quantity of
the contents in terms of weight, measure, or numerical count ...

(f) Unless its labeling bears (1) adequate direction for use; and
(2)
such adequate warnings against use in those pathological
conditions or by children where its use may be dangerous to
health, or against unsafe dosage or methods of duration of
administration or application, in such manner and form, as are
necessary
for the protection of users ...

(j) If it is dangerous to health when used in the dosage or manner,

 or with the frequency or duration prescribed, recommended, or
suggested
in the labeling thereof.

A device may be considered misbranded for other administrative

reasons such as failure to register the firm, formally list the
product, or failure to submit a premarket notification (21 CFR Part
807).

When it is consistent with the public interest, it is FDA's

policy
to: advise regulated firms of potentially violative products,
practices,
or conditions; advise firms of violations requiring correction; and,
give firms an opportunity to make corrections voluntarily before
initiating legal or administrative action.

Management Letter
 When top management is not present during the issuance of the
FDA-483 at the end of the inspection, FDA may send a Management
Letter
to top management such as the president, CEO, etc., of the firm to
assure that top management has a copy of the FDA-483. Because the
Management Letter is only a brief transmittal letter, it is not to be
considered or confused with the Warning Letter described below.

It is imperative that the firm respond to any recommendations or

observations made by the FDA investigator or other official. A
written
response to the FDA-483 along with documentation to show how the
firm
has or intends to remove or correct the objectionable conditions or
practices can assure the FDA that the firm has corrected or intends
to
correct listed violations. A clear, quick response will demonstrate
the
firm's intent to comply with the medical device regulations. You
should
prepare such a response even if you do not hear from FDA in writing.
To
repeat, a plan of corrective action is very important. You may also
request a meeting with district management to discuss violations and
the
firm's proposed courses of action. This approach will give you a
first
hand opportunity to present your case to FDA.

Warning Letter

A Warning Letter is a specifically worded and formatted

enforcement
letter written by top management of an FDA field or headquarters
unit
to top management of a firm. The letter is sent by FDA to a firm
primarily to draw the company's attention to violations and, thereby,
obtain prompt correction. A Warning Letter is intended to effect
correction of deficiencies noted: during an inspection; from an
investigation of a product complaint; or from information received
from
other sources. A purged Warning Letter is reprinted at the end of
this
chapter.

A Warning Letter may be issued by FDA instead of immediately

seizing
product or obtaining an injunction. The Warning Letter contains a
formal warning to the firm that specific sections of the law have
been
violated and, unless corrective action is taken, the FDA is prepared
to
impose legal and/or administrative sanctions. Sanctions include
 seizure, prosecution, injunction, and civil penalties. Unless
otherwise
indicated, within 15 working days, after receiving a Warning Letter,
a
formal response must be made by the firm to FDA. State the specific
steps your firm has taken to correct noted violations, including an
explanation of each step taken to prevent the recurrence of similar
violations. If corrective action cannot be completed within 15
working
days, state the reason for the delay and the time within which the
corrections will be completed.

A Warning Letter is also a prior warning and notification to

responsible company officials of possible civil or criminal action
to
be taken by FDA. The Warning Letter replaces the Notice of Adverse
Findings and Regulatory letters that were used previously.

Responsible individuals should not assume they will always

receive a
Warning Letter before FDA initiates administrative action or
recommends
an injunction, seizure, civil penalty and/or criminal proceeding.
Before initiating formal regulatory action, FDA is under no legal
obligation to warn firms or individuals that they or their products
are
in violation of the law. For example, the FDA ordinarily will not
issue
a Warning Letter but will take other action such as seizure and
injunction when:
 o the violation reflects a recent history of repeated or
continuous conduct of a similar or substantially similar
nature during which time the firm and/or individual(s) have
been notified of a similar or substantially similar
violation;

o the violation is intentional or flagrant; or,

o the violation represents a reasonable possibility of injury

or
death.

Remember, the issuance of a Warning Letter to a firm by FDA does

not
preclude the initiation of other concurrent action, such as seizure
or
administrative detention as part of an overall enforcement strategy.

Seizure

A seizure is a civil court action against a specific quantity of

goods whereby FDA seeks to remove these goods from commercial
channels.
After seizure, no one may tamper with the goods except by permission
of
the court. The owner or claimant of the seized merchandise is
usually
given approximately 30 days by the Court to decide on a course of
action. If no action is taken, the Court will recommend disposal of
the
goods. If it is decided to contest the Government's charges, the
case
will be scheduled for trial. A third option allows the owner of the
goods to request permission of the court to bring the goods into
compliance with the law. The owner of the goods is required to
provide a
bond (money deposit) to assure that the orders of the Court will be
performed; and the owner must pay for FDA supervision of any
activities
by the company to bring the goods into compliance.

Detention

An administrative detention prohibits the distribution or use of

adulterated or misbranded devices encountered during inspections. The
detention usually lasts up to 30 days, possibly longer, until FDA
has
considered what action it should take concerning the devices, or has
initiated legal action if appropriate. During the detention, detained
devices may not be used, moved, altered, or tampered with in any
manner
by any person.
 Restraining Orders and Injunctions

A Temporary Restraining Order (TRO) is sought by FDA before an

injunction and is designed to stop the alleged violative practice
until
the court can hear evidence that may lead to an injunction. A TRO
imposes restraint upon a defendant for not more than 10 days; and
this
period may be extended by the courts.

An injunction is a court order that restrains a person or firm

from
violating the law, e.g., to prevent interstate distribution of
violative products, and to correct conditions in the establishment
in
which the violation occurred. It is not mandatory for FDA to
demonstrate
the law has been violated to obtain an injunction, but only to show
that
there is a good probability it may be violated. Injunctions are
 considered and sought by FDA when imminent health hazards have been
identified.

In regard to legal actions, temporary restraining orders and

injunctions have the highest priority within FDA because these are
used
to stop imminent health hazards.

Citations

A citation is a notice that the agency is instituting criminal

proceedings -- it is not a warning. A citation provides the person
against whom such proceeding is contemplated an opportunity to
present
his views. Citations are only used when a prosecution recommendation
is
definitely being considered by the agency.

Recalls

The Food and Drug Administration prefers to promote compliance by

means other than through the courts. Recall by the manufacturer of
violative products from the market is generally the fastest and most
effective way to protect the public. A recall may be initiated by the
manufacturer or shipper of the product, or initiated by FDA. The
first
step in a product recall is for the manufacturer or distributor to
contact the nearest FDA field office for guidance. FDA can provide
technical assistance to small and large manufacturers on how to
conduct
an effective recall.
It is recommended that manufacturers develop plans which can be
put
into effect immediately if a recall emergency arises. Accurate and
complete product and shipping records are vital to the success of a
product recall. Products should be labeled (direct or by code) to
show
date and place of manufacture.

Recently, FDA has observed that when a firm discovers a risk

presented by a medical device, they often voluntarily notify
appropriate persons of this risk in order to reduce or eliminate it.
In
some cases these notifications meet the definition of recall in 21
CFR
Part 7.3(g). Because of concern that a notification might be
classified
as a recall, firms have sometimes delayed issuing a notification
while
discussions are held with FDA. To try to eliminate delays in
situations
where public health might be at risk, FDA published, "Medical Device
 Notification and Voluntary Safety Alert Guideline," in March 1984,
which
contains procedures that firms should use in notifying or alerting
health professionals who prescribe or use a medical device. These
procedures also describe the steps used by FDA in the notification
and
safety alert process.

Penalties

FDA has authority to impose civil penalties. Manufacturers are

liable for a maximum of $15,000 per violation of the FD& C Act, with
a
cap of $1,000,000 per proceeding. See Section 303 of the FD& C Act
for
details of additional penalties. Also, see the Safe Medical Devices
Act
of 1990 for more details on FDA's authority to impose penalties.

EXHIBITS

Associated with inspections are various FDA forms. Examples of

forms
are included in the following pages. The form (FDA) numbers are in
the
 lower left corner of each sheet.

Notice of Inspection

The first form is the FDA 482 (Notice of Inspection) which is

issued
at the beginning of the inspection. It includes blanks for basic
information on the firm, the investigators name, and contains a
reprint
of applicable sections of the FD& C Act and Public Health Service Act.
This form is to be signed by the investigator and given to the
individual noted on the form.

Receipt for Samples

If an investigator collects samples, a Form FDA 484 (Receipt for

Samples) will be issued to the company agent. This form contains
blanks
for the name of the individual given the form, information on the
firm,
and a description of the item sampled. The investigator then signs
the
form and issues it to the individual noted on the form.

Affidavits

The next four forms are used where interstate movement of devices
is
documented by collection of shipping records. The investigator
prepares
an affidavit (Forms FDA 463a, 1664a, or 1664b) referencing these
shipping records. A brief statement is included along with space for
a
description of the documents that relate to the interstate movement
of
the sample in question. Each form is to be signed by the investigator
and the person giving the information. On one of the sample forms
FDA
463a, the individual giving the information refused to sign the
affidavit; and in this case the investigator added a statement to
explain the lack of a signature.

List of Observations

During an inspection, an investigator will note what is

considered
to be GMP deviations, or deviations from a firm's established
procedures. These observations comprise the Form FDA 483 (List of
Observations) which is issued to the company. The observations are
listed in the large blank area of the form, and the form is signed by
the investigator.

Establishment Inspection Report

 The final example is the "Establishment Inspection Report". After
completion of an inspection, an investigator prepares a
comprehensive
EIR covering a firm's operations, items on the FDA 483, plus the
details that support the FDA 483 and any corrective actions taken by
the firm. A firm may receive an unpurged copy of their EIR report
under
the Freedom of Information (FOI) Act by requesting the report in
writing
from their local FDA District Office. Copies of EIR's requested by
other than the inspected firm through FOI will be purged of
confidential or trade secret information. The fictitious sample EIR
near
the end of this chapter has certain lines highlighted to simulate
purging. An actual EIR that had been PURGED would have these lines
BLACKED out. The normally purged material is left in the simulated
EIR
to show the type of information that would be purged.

Warning Letter
 In this purged sample Warning Letter. blank lines replace
normally
blacked-out words.

<Example Notice of Inspection-FDA 482>

<Example Receipt for Sample-FDA 484>

<Example Affidavit-FDA 463a (1 of 2)>

<Example Affidavit-FDA 463a (2 of 2)>

<Example Affidavit-FDA 1664a>

<Example Affidavit-FDA 1664b>

<Example List of Observations-FDA 483>

<Example Establishment Inspection Report, Purged (1 of 15)>

May 30, 1991

WARNING LETTER

VIA CERTIFIED MAIL

RETURN RECEIPT REQUESTED

BOS-1-91W

_______________________________
_______________________________
_______________________________

Dear Mr. _________________________:

On April 16-25, 1991 an inspection was performed at your facility.

 Serious violations of the Federal Food, Drug, and Cosmetic Act (FD&
C
Act) were noted as follows:

Section Brief Description

501(h) A medical device is deemed to be adulterated insofar as

 the methods used in, or the facilities or controls used
for its manufacture, packing, or storage are not in
conformity with Good Manufacturing Practices for Medical
Device Regulations, [Title 21 Code of Federal Regulations
(CFR), Part 820], specifically:

- Failure to have written procedures for audits of the

quality assuranceprogram and failure to perform audits,
as required by 21 CFR 820.20(b),including audits of
contract sterilizers and contract manufacturers.

- Failure to provide adequate space to prevent mix-ups

and
to assure the orderly handling of incoming components,
finished product, testing,labeling and packaging, as
required by 21 CFR 820.40.

- Failure to have written cleaning procedures, as

required
by 21 CFR 820.56.

- Failure to have written schedules for maintenance of

equipment, as required by 21 CFR 820.60(a), or a record
of the inspection of the _______________ thermal sealer.

- Failure to have written procudures for calibration of

measurement equipment, such as a table scale, as
requred
by 21 CFR 820.61.

- Failure to have written procedures for the acceptance

of
components, as required by 21 CFR 820.80, or to have a
record of component acceptance and rejection.

- Failure to have a formal approval procedure for any

change in the manufacturing process of a device, as
required by 21 CFR 820.100(b)(3).

- Failure to have a record of label materials examination

in the device history record, as required by 21 CFR
820.120.

- Failure to have validation protocols and studies

available from your contact sterilizers, as required by
21 CFR 820.100.

- Failure to have written procedures for warehouse

control
and distribution, as required by 21 CFR 820.150.

- Failure to have a written record of complaint

investigations, as required by 21 CFR 820.198(c).
 - Failure to be able to produce device master records to
cover the ___________ devices manufacturerd by your
firm, as required by 21 CFR 820.181. Some records
produced lacked labeling specifications.

- Failure to be able to produce device history records

for
___________ devices manufacturerd by your firm, as
required by 21 CFR 820.184. Device history records did
not document that all required activities werecompleted.

This letter as well as the "List of Inspectional Observations" which

 was presented to and discussed with you at the close of the
inspection
are not meant to be all inclusive. It is your responsibility to
ensure
that all products manufactured and distributed by your firm are in
compliance with the provisions of the Act. Until these violations are
corrected, Federal agencies will be informed that FDA recommends
against the award of contracts for affected products. Failure to
achieve prompt correction may result in enforcement action without
further notice.

We understand that many of the above noted deviations occured due to

extraordinary circumstances which transpired at your firm in early
___________ and which caused you to recall all the sterile
___________
devices manufactured by your firm prior to ___________. We are
concerned that prior to resumption of the manufacture/distribution of
medical devices by your firm, you must assure compliance with all
aspects of the GMP regulations.

We request that you come in to the District Office and meet with
Compliance Officer, __________. The purpose of the meeting is to
discuss the above findings and for you to present your corrective
actions to assure that your firm is now in compliance. A tentative
date for the meeting is ___________ at ____________.

If that time is not acceptable, please call _____________ Compliance

Officer, at _____________. Your response should include corrections
taken to prevent recurrence of similar violations, a time within
which
correction will be completed, and any documentation you have to show
correction.

A copy of this letter, except for any confidential personal or

commercial information, will be placed on public display at this
office no earlier than thirty days after the date of this letter.
Your
response will also be placed on public display with any confidential
personal or commercial information purged.

Sincerely,

Edward J. McDonnell
District Director
Boston District Office

cc: ________________
 GMP - CHAPTER 17 - APPENDIXES
TABLE OF CONTENTS

CHAPTER 17. APPENDIXES

Good Manufacturing Practices Regulation . . . . . . . . . . .

17-2
Advisory and Guideline List of Critical Medical Devices . . .
17-12
Good Manufacturing Practices Preamble . . . . . . . . . . . .
17-21
Summary of Requirements Spreadsheet . . . . . . . . . . . . .
17-42
Preproduction Quality Assurance Planning: Recommendations
for Medical Device Manufacturers . . . . . . . . . . . . . .
17-43
Guideline on General Principles of Process Validation . . . .
17-61
Government-Wide Quality Assurance Program . . . . . . . . . .
17-73

GOOD MANUFACTURING PRACTICES REGULATION

GOOD MANUFACTURING PRACTICES REGULATION 21 CFR PART 820

ADVISORY LIST OF CRITICAL DEVICES -- 1988

[Published in the Federal Register, Vol. 53, No. 52, March 17, 1988]

CFR or Classification Device No.

on
FR Cite Name of Device Original
List

PART 868 -- ANESTHESIOLOGY DEVICES

1. 868.1200 Indwelling blood oxygen partial pressure

(P (o2)) analyzer 5
2. 868.2375 Breathing frequency monitor --
3. 868.5090 Emergency airway needle 43
4. 868.5160(a) Gas machine for anesthesia 42
5. 868.5240 Anesthesia breathing circuit 19
6. 868.5400 Electroanesthesia apparatus 6, 62
7. 868.5440 Portable oxygen generator 32
8. 868.5470 Hyperbaric chamber (Monoplace) --
9. 868.5610 Membrane lung for long term pulmonary support 41
10. 868.5650 Esophageal obturator 2
11. 868.5720 Bronchial tube 66
12. 868.5730 Trachealtube 67
13. 868.5740 Tracheal/bronchial differential ventilation 68
tube
14. 868.5750 Inflatable tracheal tube cuff 27
15. 868.5800 Tracheostomy tube and tube cuff 69
16. 868.5810 Airway connector 25
17. 868.5830 Autotransfusion apparatus 9
18. 868.5895 Continuous ventilator 73, 56
19. 868.5905 Noncontinuous ventilator (IPPB) 75
20. 868.5915 Manual emergency ventilator 58, 70
21. 868.5925 Powered emergency ventilator 70
22. 868.5935 External negative pressure ventilator 74
 PART 870 -- CARDIOVASCULAR DEVICES

23. 870.1025 Arrhythmia detector and alarm 29

24. 870.1330 Catheter guide wire --
25. 870.1360 Trace microsphere --
26. 870.1750 External programmable pacemaker pulse 34
generator
27. 870.1800 Withdrawal-infusion pump 54
28. 870.3250 Vascular clip 22
29. 870.3260 Vena cava clip 23
30. 870.3300 Arterial embolization device --
31. 870.3375 Cardiovascular intravascular filter 31
32. 870.3450 Vascular graft prosthesis of less than 6 47, 52
millimeters diameter
33. 870.3460 Vascular graft prosthesis of 6 millimeters 47, 52
and greater diameter
34. 870.3470 Intracardiac patch or pledget made of --
polypropylene, polyethylene terephthalate,
or polytetrafluoroethylene
35. 870.3535 Intra-aortic balloon and control system 10
36. 870.3545 Ventricular bypass (assist) device 15
37. 870.3600 External pacemaker pulse generator 33
38. 870.3610 Implantable pacemaker pulse generator 35
39. 870.3620 Pacemaker lead adaptor --
40. 870.3650 Pacemaker polymeric mesh bag --
41. 870.3670 Pacemaker charger --
42. 870.3680 Cardiovascular permanent or temporary 30
pacemaker electrode
43. 870.3700 Pacemaker programmers --
44. 870.3710 Pacemaker repair or replacement material --
45. 870.3800 Annuloplasty ring --
46. 870.3850 Carotid sinus nerve stimulator --
47. 870.3925 Replacement heart valve 71
48. 870.4320 Cardiopulmonary bypass pulsatile flow --
generator
49. 870.4350 Cardiopulmonary bypass oxygenator 44
50. 870.4360 Nonroller-type cardiopulmonary bypass blood 13
pump
51. 870.4370 Roller-type cardiopulmonary bypass blood pump 14
52. 870.5200 External cardiac compressor 24, 57
53. 870.5225 External counter-pulsating device 26
54. 870.5300 DC-defibrillator (including paddles) 28
55. 870.5550 External transcutaneous cardiac pacemaker 45
(noninvasive)
56. --- Percutaneous transiuminal coronary --
angioplasty (PTCA) balloon dilation catheter
57. --- Automatic implanted cardioverter --
defibrillator system

PART 872 -- DENTAL DEVICES

58. 872.3640 Endosseous implant --

PART 874 -- EAR, NOSE, AND THROAT DEVICES

59. 874.3620 Ear, nose and throat synthetic polymer --
material
60. 874.3695 Mandibular implant facial prosthesis --
61. 874.3730 Laryngeal prosthesis (Taub design) 49
62. 874.3820 Emdolymphatic shunt --
63. 874.3850 Endolymphatic shunt tube with valve --
64. 874.3930 Tympanostomy tube with semipermeable membrane --
65. --- Ear, nose, throat natural polymer-collagen --
material

PART 876 -- GASTROENTEROLOGY-UROLOGY DEVICES

66. 876.3350 Penile inflatable implant --

67. 876.5270 Implanted electrical urinary continence device --
68. 876.5540 A-V shunt cannula --
69. 876.5630 Peritoneal dialysis system and accessories 46
70. 876.5820 Hemodialysis system and accessories, 36
dialysate concentrate, h6ilow fiber capillary
dialyzers, disposable dialyzers, high
permeability dialyzers, parallel flow
dialyzers, single coil dialyzers, twin coil
dialyzers, single needle dialysis set,
dialysate delivery systems
71. 876.5870 Sorbent hemoperfusion system 7
72. 876.5880 Isolated kidney peifusion and transport --
system and accessories
73. 876.5955 Peritoneo-venous shunt --
74. 46 FR 7566 Urethral sphincter prosthesis 51
(1/23/81)
75. 46 FR 7566 Urethral replacement 55
(1/23/81)

PART 878 -- GENERAL AND PLASTIC SURGERY DEVICES

(The following are class III devices. See 21 U.S.C. 360j(1).)

76. 42 FR 63474 Absorbable Surgical sutures 64

(12/16/77)
77. 42 FR 63474 Nonabsorbable surgical Sutures 64
(12/16/77)
78. 879.4520 Polytetrafluoroethylene (Teflon) injectable --

(The following are proposed classifications as discussed in

the January 19, 1982 FEDERAL REGISTER, 47 FR 2810.)

79. 878.3300 Surgical mesh --

80. 878.3500 Polytetrafluoroethylene with carbon fibers --
composite implant material
81. 878.3530 Inflatable breast prosthesis --
82. 878.3540 Silicone gel-filled breast prosthesis --
83. --- Implanted mammary prosthesis of composite --
saline and gel-filled design
84. 878.3610 Esophageal prosthesis 48
85. 878.3720 Tracheal prosthesis 50
86. 878.4300 Implantable clip --
87. 878.4750 Implantable staple --
88. --- Maxillofacial prosthesis --
 PART 880 -- GENERAL HOSPITAL AND PERSONAL USE DEVICES

89. 880.5130 Infant radiant warmer 12

90. 880.5400 Neonatal incubator 37
91. 880.5410 Neonatal transport incubator --
92. 880.5725 Infusion pump 53
 93. --- Implanted infusion pump --

PART 882 -- NEUROLOGICAL DEVICES

94. 882.5030 Methyl methacrylate for aneurysmorrhaphy --

95. 882.5150 Intravascular occluding catheter 17
96. 882.5200 Aneurysm clip 20
97. 882.5225 Implanted malleable clip --
98. 882.5250 Burr hole cover --
99. 882.5300 Methyl methacrylate for cranioplasty --
100. 882.5320 Preformed alterable cranioplasty plate --
101. 882.5330 Preformed nonalterable cranioplasty plate --
102. 882.5360 Cranioplasty plate fastener --
103. 882.5550 Central nervous system fluid shunt and 59
components
104. 882.5820 Implanted cerebellar stimulator 60
105. 882.5830 Implanted diaphragmatic/phrenic nerve 61
stimulator
106. 882.5840 Implanted intracerebral/subcortical 63
stimulator for pain relief
107. 882.5850 Implanted spinal cord stimulator for bladder --
evacuation
108. 882.5860 Implanted neuromuscular stimulator --
109. 882.5870 Implanted peripheral nerve stimulator for --
pain relief
110. 882.5880 Implanted spinal cord stimulator for pain --
relief
111. 882.5880 Epidural spinal electrode --
112. 882.5900 Preformed craniosynostosis strip --
113. 882.5910 Dura substitute --
114. 882.5950 Artificial embolization device 65
115. --- Lyophilized human (cadaver) dura mater --
116. --- Stabilized epidural spinal electrode --
117. --- Implanted intracranial pressure monitor --
118. --- Totally implanted spinal cord stimulator for --
pain relief

PART 884 -- OBSTETRICAL AND GYNECOLOGICAL DEVICES

119. 884.5360 Contraceptive intrauterine device (IUD) and 38

introducer
120. 884.5380 Contraceptive tubal occlusion device (TOD) 11, 21,
21
and introducer

PART 886 -- OPHTHALMIC DEVICES

121. 886.3300 Absorbable implant (scieral buckling method) --

122. 886.3400 Keratoprosthesis 39
123. 886.3600 Intraocular lens 40
124. 886.3920 Eye valve implant --

PART 888 -- ORTHOPEDIC DEVICES

125. 888.3000 Bone Cap --
126. 888.3010 Bone fixation cerclage --
127. 888.3020 Intramedullary fixation rod --
128. 888.3025 Passive tendon prosthesis --
129. 888.3027 Polymethylmethacrylate (PMMA) bone cement --
130. 888.3030 Single/MLIltiple component metallic bone --
fixation appliance and accessories --
131. 888.3040 Smooth or threaded metallic bone fixation --
fastener
132. 888.3050 Spinal interlaminal fixation orthosis --
133. 888.3060 Spinal intervertebral body fixation orthosis --
134. 888.3100 Ankle joint metal/composite semi-constrained --
cemented prosthesis
135. 888.3110 Ankle joint metal/polymer semi-constrained --
cemented prosthesis
136. 888.3120 Ankle joint metal/polymer non-constrained --
cemented prosthesis
137. 888.3150 Elbow joint metal/metal or metal/polymer --
constrained cemented prosthesis
138. 888.3160 Elbow joint metal/polymer semi-constrained --
cemented prosthesis
139. 888.3170 Elbow joint radial (hemi-elbow) polymer --
prosthesis
140. 888.3180 Elbow joint humeral (hemi-elbow) metallic --
uncemented prosthesis
141. 888.3200 Finger joint metal/metal constrained --
uncemented prosthesis
142. 888.3210 Finger joint metal/metal constrained cemented --
prosthesis
143. 888.3220 Finger joint metal/polymer constrained --
cemented prosthesis
144. 888.3230 Finger joint polymer constrained prosthesis --
145. 888.3300 Hip joint metal constrained cemented or --
uncemented prosthesis
146. 888.3310 Hip joint metal/polymer constrained cemented --
or uncemented prosthesis
147. 888.3320 Hip joint metal/metal semi-constrained, with --
a cemented acetabular component, prosthesis
148. 888.3330 Hip joint metal/metal semi-constrained, with --
an uncemented acetabular component, prosthesis
149. 888.3340 Hip joint metal/composite semi-constrained --
cemented prosthesis
150. 888.3350 Hip joint metal/polymer semi-constrained --
cemented prosthesis
151. 888.3360 Hip joint femoral (hemi-hip) metallic --
cemented or uncemented prosthesis
152. 888.3370 Hip joint (hemi-hip) acetabular metal --
cemented prosthesis
153. 888.3380 Hip joint femoral (hemi-hip) trunnion-bearing --
metal/polyacetal cemented prosthesis
154. 888.3390 Hip joint femoral (hemi-hip) metal/polymer --
cemented or uncemented prosthesis
155. 888.3400 Hip joint femoral (hemi-hip) metallic --
resurfacing prosthesis
156. 888.3410 Hip joint metal/polymer semi-constrained --
resurfacing cemented prosthesis
157. 888.3480 Knee joint femorotibial metallic constrained --
cemented prosthesis
158. 888.3490 Knee joint femorotibial metal/composite --
non-constrained cemented prosthesis
159. 888.3500 Knee joint femorotibial metal/composite --
 semi-constrained cemented prosthesis
160. 888.3510 Knee joint femorotibial metal/polymer --
constrained cemented prosthesis
161. 888.3520 Knee joint femorotibial metal/polymer --
non-constrained cemented prosthesis
162. 888.3530 Knee joint femorotibial metal/polymer --
 semi-constrained cemented prosthesis
163. 888.3540 Knee joint patellofemoral polymer/metal --
semi-constrained cemented prosthesis
164. 888.3550 Knee joint patellofemorotibial --
polymer/metal/metal constrained cemented
prosthesis
165. 888.3560 Knee joint patellofemorotibial --
polymer/metal/polymer semi-constrained
cemented prosthesis
166. 888.3570 Knee joint femoral (hemi-knee) metallic --
uncemented prosthesis
167. 888.3580 Knee joint patellar (hemi-knee) metallic --
resurfacing uncemented prosthesis
168. 888.3590 Knee joint tibial (hemi-knee) metallic --
resurfacing uncemented prosthesis
169. 888.3640 Shoulder joint metal/metal or metal/polymer --
constrained cemented prosthesis
170. 888.3650 Shoulder joint metal/polymer non-constrained --
cemented prosthesis
171. 888.3660 Shoulder joint metal/polymer semi-constrained --
cemented prosthesis
172. 888.3680 Shoulder joint glenoid (hemi-shoulder) --
metallic cemented prosthesis
173. 888.3690 Shoulder joint humeral (hemi-shoulder) --
metallic uncemented prosthesis
174. 888.3720 Toe joint polymer constrained prosthesis --
175. 888.3730 Toe joint phalangeal (hemi-toe) polymer --
prosthesis
176. 888.3750 Wrist joint carpal lunate polymer prosthesis --
177. 888.3760 Wrist joint carpal scaphoid polymer prosthesis --
178. 888.3770 Wrist joint carpal trapezium polymer --
prosthesis
179. 888.3780 Wrist joint polymer constrained prosthesis --
180. 888.3790 Wrist joint metal constrained cemented --
prosthesis
181. 888.3800 Wrist joint metal/polymer semi-constrained --
cemented prosthesis
182. 888.3810 Wrist joint ulnar (hemi-wrist) polymer --
prosthesis

<SUMMARY OF REQUIREMENTS FOR SE MEDICAL DEVICES>

federal register

FRIDAY, JULY 21, 1978

PART II

DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE

Food and Drug Administration

MANUFACTURE, PACKING, STORAGE AND INSTALLATION OF MEDICAL DEVICES

Regulations Establishing Good Manufacturing Practices

[4110-03]

Title 21--Food and Drugs

 CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH,
EDUCATION, AND WELFARE

[Docket No. 75N-0140]

PART 809--IN VITRO DIAGNOSTIC PRODUCTS FOR HUMAN USE

PART 820--GOOD MANUFACTURING PRACTICE FOR MEDICAL DEVICES: GENERAL

Regulations Establishing Good Manufacturing Practices for the

Manufacture, Packing, Storage, and Installation of Medical Devices

AGENCY: Food and Drug Administration.

ACTION: Final rule.

SUMMARY: This document establishes a good manufacturing practice

(GMP) regulation for the manufacture, packing, storage, and
installation of medical devices. This regulation implements a
provision of the Medical Device Amendments of 1976.

EFFECTIVE DATE: December 18, 1978.

FOR FURTHER INFORMATION CONTACT: Edward J. McDonnell, Bureau of

Medical Devices (HFK-130), Food and Drug Administration, Department
of
Health, Education, and Welfare, 8757 Georgia Avenue, Silver Spring,
Md. 20910, 301-427-8120.

SUPPLEMENTARY INFORMATION: On May 28, 1976, the Medical Device

Amendments of 1976 (Pub. L. 94-295) were enacted into law, amending
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 201 et seq.).
Section 520(f) of the act (21 U.S.C. 360j(f)) provides the agency
with
authority to prescribe a regulation requiring that the methods used
in, and the facilities and controls used for, the manufacture,
packing, storage, and installation of medical devices conform to
current GMP requirements, as prescribed in the regulation, to assure
that devices are safe and effective and otherwise in compliance with
the act.

The proposed device GMP regulation was published in the FEDERAL

REGISTER of March 1, 1977 (42 FR 11997). Other FEDERAL REGISTER
notices concerning this regulation are cited below in the section of
this preamble on "History of Device GMP Regulation."

The Commissioner recognizes that the medical device industry consists

of manufacturers whose devices and manufacturing processes differ
significantly. This diversity of manufacturing processes affects the
development of comprehensive GMP regulations that will apply to all
finished device manufacturers. The Commissioner believes that an
"umbrella" GMP regulation applicable to all finished device
manufacturers should not be so specific as to prescribe for each
manufacturer the precise details of what it must do and how it must
 undertake to manufacture devices. Rather, the GMP regulation should
contain general requirements in specific areas of concern applicable
to all manufacturers, specify additional requirements for certain
devices, and require each manufacturer to supply the details which
are
appropriate for its device by developing for the manufacture of each
device a detailed set of procedures which implement the GMP
regulation. FDA will examine such procedures to determine whether a
 manufacturer is complying with the regulation.

The Food and Drug Administration (FDA) expects to publish additional

GMP regulations applicable to specific types of devices. These
future
regulations will supplement the "umbrella" GMP regulation and will be
of two types: One will contain requirements that will apply only to
generic types of devices or classes of devices, e.g., pacemakers,
eyeglasses, etc.; the other will contain requirements that will apply
to certain devices or cross-class characteristics or processes, e.g.,
sterile devices, plastics, electrical properties, etc.

The "umbrella" GMP regulation imposes additional requirements on

"critical devices," defined as devices that are intended for surgical
implant into the body or devices intended to support or sustain life
and whose failure to perform when properly used can be reasonably
expected to result in significant injury to the user. Other devices
are called "noncritical" devices and are subject to provisions of the
regulation that are not limited to critical devices. The distinction
is based on the additional risks to users that are posed by defective
critical devices.

This distinction was incorporated into the proposed regulation

published in the FEDERAL REGISTER of March 1, 1977 (42 FR 11997), by
means of a two-tier approach that denotes general requirements
applicable to all devices (critical and noncritical) and specific
requirements applicable only to those devices classified as
"critical."

IMPORTANCE OF DEVICE GOOD MANUFACTURING PRACTICE REGULATION

Today, increasing numbers of Americans are experiencing the benefits

of modern medical technology in the treatment of injury and disease.
Device manufacturers, adapting advances in space and medical
technology, are producing a broad spectrum of varied and complex
life-sustaining, life-supporting devices. In addition, a growing
number of other, less sophisticated devices also have been made
available to health professionals for improved health care services
delivery. At the same time, Americans are also more likely to come
in
contact with devices. Data compiled by the American Hospital
Association show that, during 1976, there were more hospital
admissions, outpatient visits, and physician visits in the United
States than in any preceding year (Ref. 1). As a consequence, more
devices than ever before were used by and on Americans in the
diagnosis and treatment of medical conditions.

Consumers who use devices differ from other consumers in an important

respect. They are usually injured or diseased, and thus are a
population at risk. These patients, and the many health
professionals
who diagnose and treat their conditions, depend on and trust device
manufacturers to produce safe and effective devices of high quality.
Although the degree of a patient's dependence on a device varies
according to the nature of the illness, it is clear that the
application of defective devices to patients already at risk because
of illness could have a deleterious or even catastrophic effect on
their recovery.

Based on FDA's experience, the Commissioner believes that it is

vitally important that devices be manufactured in accordance with
quality assurance principles that help prevent the production of
defective products that can endanger consumers. In monitoring device
 recalls, FDA has found that, too often, device manufacturers have
fallen short in meeting the expectations of those who need and depend
upon high quality medical products. During the past several years.
FDA monitored approximately 1,000 device recalls. Many of these
resulted from manufacturers' failure to follow good manufacturing
practices. For example, of 232 device recalls monitored by the FDA
from October 1976 through November 1977, FDA believes that 198 of
them
were attributable to poor manufacturing practices.

The quality assurance program mandated by this regulation is designed

to be preventive. The device GMP regulation requires all device
manufacturers to design, implement, and continually monitor a
comprehensive quality assurance program. This quality assurance
program may be appropriately tailored to satisfy a device's special
manufacturing requirements, but it may not compromise strict quality
control standards. Based on its experience, FDA believes that
manufacturers who operate in accordance with the requirements of the
regulation will be less likely to distribute defective devices to an
unwary public than those who do not meet the requirements. Quality
assurance under this regulation will maximize the probability that
only safe and effective devices will reach the marketplace.

The device GMP regulation has been developed in accordance with basic
principles of quality assurance. (See, for example, Juran, "Quality
Control Handbook," 3d ed., McGraw-Hill (1974).) These principles have
as their goal the production of articles that are fit for their
intended uses, and may be stated as follows: (1) Quality, safety,
and
effectiveness must be designed and built into the product; (2)
quality
cannot be inspected or tested into the finished product; and (3) each
step of the manufacturing process must be controlled to maximize the
probability that the finished product meets all quality and design
specifications.

During 1977, FDA conducted approximately 300 device establishment

inspections to survey current manufacturing practices (Ref. 2).
This
survey showed that the majority of device manufacturers already had
quality assurance programs in place that complied with about half of
the provisions of the proposed device GMP regulation. This survey
also shows, however, that many firms are not adhering to procedures
that fulfill basic principles of quality assurance. As firms comply
with the requirements of the regulation, FDA expects that many device
defects and recalls can be avoided. The Commissioner believes that
promulgation of a device GMP regulation will help prevent defective
devices from reaching the marketplace and will help assure the
production of safe and effective devices.

HISTORY OF DEVICE GMP REGULATION

Since December 1973, FDA has been actively involved in the

development
of a GMP regulation for medical devices. Representatives of the
general public and industry were invited and encouraged to assist the
agency in this effort.

During the summer of 1975, a preliminary draft of a device GMP

regulation was developed by the agency. Because of the widespread
interest in this subject, the Commissioner made this draft regulation
available to the public for comment and review before a proposed
regulation was published in the FEDERAL REGISTER. A notice of
availability of the draft regulation was published in the FEDERAL
REGISTER Of August 8, 1975 (40 FR 33482). Interested persons were
 given 60 days to submit comments. In view of the interest generated
by the draft regulation and after a review of the initial comments,
FDA decided to hold public meetings on the draft regulation in four
major cities. These meetings were announced in the FEDERAL REGISTER
of
October 9, 1975 (40 FR 47530). The four public meetings were held in
November 1975 in Dallas, San Francisco, Chicago, and Washington, D.C.
Approximately 1,200 persons attended these four meetings, and all
questions and comments were recorded and transcribed (ref. 3).

In addition to reviewing the comments received at the meetings, FDA

reviewed approximately 130 written comments on the draft regulation.
Based on these comments, FDA developed a proposed GMP regulation,
which was published in the FEDERAL REGISTER of March 1, 1977 (42 FR
11997), Interested persons were given until June 29, 1977 to submit
comments and views on the proposal. Drafts of the final regulation
were made available to the public by notices published in the FEDERAL
REGISTER of October 25, 1977 (42 FR 56348) and March 7, 1978 (43 FR
9320).

DEVICE GMP ADVISORY COMMITTEE

Section 520(f)(3) of the Federal Food, Drug, and Cosmetic Act

requires
that the Commissioner of Food and Drugs establish an advisory
committee for the purpose of making recommendations to him on the
proposed regulation and the approval or disapproval of petitions
requesting exemptions or variances from GMP requirements that may be
submitted to FDA by manufacturers and referred to the committee by
FDA.

This advisory committee, known as the Device GMP Advisory Committee,

is composed of nine members. Three of the members represent Federal,
State or local government; two members represent the interests of
physicians and other health care professionals; two members represent
the interests of the device manufacturing industry; and two members
represent the interests of the general public.

A notice requesting nominations for members of the Device GMP

Advisory
Committee was published in the FEDERAL REGISTER of July 13, 1976 (41
FR 28817); a notice announcing the establishment of the committee was
published in the FEDERAL REGISTER of August 27, 1976 (41 FR 36233).

A notice in the FEDERAL REGISTER of June 28, 1977 (42 FR 32805)

announced that the Device GMP Advisory Committee would hold its first
meeting on August 4, 1977 and that a public hearing to hear views on
the proposed GMP regulation would be held on August 5, 1977.

During the first advisory committee meeting, representatives of FDA's

Bureau of Medical Devices reviewed the events which led to the
development of the proposed regulation, discussed the agency's
philosophy on good manufacturing practices, and presented a summary
of
 the comments received on the proposal (Ref. 4). The advisory
committee reviewed these comments and provided its own general and
specific comments to the agency.

At the August 5, 1977 public hearing, the Director of FDA's Bureau of

Medical Devices served as the presiding officer and was assisted by a
hearing panel, which included the Device GMP Advisory Committee and
representatives from the Bureau and regional offices.
Representatives
of five trade associations, one manufacturer, FDA, and the general
public presented comments and suggestions. This hearing was attended
 by approximately 200 persons, and transcripts of the meeting and
hearing are available (Ref. 5).

During the Advisory Committee meeting and public hearing, the

following six major issues relating to a GMP regulation were
identified as warranting further discussion:

1. Effective date of the regulation.

2. Exemption or variance procedure.
3. Applicability to foreign manufacturers.
4. Disclosure of internal audits.
5. Inflationary impact.
6. Definition of a "critical device."

The advisory committee agreed to consider each of these issues in

detail at its next meeting. The agency asked for additional written
comments from the advisory committee and agreed to prepare a draft
final rule, also to be discussed at the next meeting, reflecting the
changes made as a result of the agency's review of written comments,
public testimony, and committee recommendations.

A notice was published in the FEDERAL REGISTER of September 13, 1977

(42 FR 45960) announcing that the second Device GMP Advisory
Committee
meeting would be held on October 27-28, 1977. A notice of
availability
of the draft final regulation was published in the FEDERAL REGISTER
of
October 25, 1977 (42 FR 56348). At the meeting, the committee members
reviewed the draft final regulation, further discussed the six major
issues listed above, heard a presentation from a trade association on
the potential inflationary impact of the GMP regulation, and
discussed
FDA's inspections surveying manufacturing practices in 300 device
establishments, mentioned above. A transcript of this meeting is
available at the office of the Hearing Clerk (HFA-305), FDA (Ref. 6).

These inspections were conducted under the following FDA Compliance

Programs: "Inspection of Medical Device Manufacturers" and
"Inspection of Diagnostic Product Manufacturers" (Refs. 7 and 8).
The
report based on these inspections revealed that many device
manufacturers were not meeting the proposed device GMP requirements,
particularly proposed   820.20 Organization, 820.80 Components,
820.120 Device labeling, and 820.130 Device packaging. Although it
is
important to recognize that this report may not be representative of
the device industry as a whole, the data suggest that a number of
device manufacturers were not following important provisions of the
proposed regulation that represent current good manufacturing
practices. However, the majority of manufacturers complied with half
or more of the proposed requirements.
 In reviewing the final draft GMP regulation for devices, the
committee
suggested numerous editorial changes and made recommendations,
summarized below, on the six major issues. The comments of other
interested parties on these six major issues and the Commissioner's
treatment of these comments are found under the heading "The
Commissioner's Responses to the Public Comments." and appear below in
this preamble.

1. Effective date of the regulation. The committee recommended that

the final regulation be effective 180 days after publication and
suggested that, during the 180-day period after the effective date,
the agency exercise reasonable flexibility in implementing this
regulation to allow for appropriate adjustments by industry and FDA.
 The Commissioner agrees that industry should have a period of time
following the publication of the regulation to allow for appropriate
adjustments in manufacturing practice. The Commissioner has decided
that it is appropriate for the regulation to be effective 150 days
after publication. FDA's implementation philosophy is described
under
the heading "Implementation," which appears below in this preamble.

2. Exemption or variance procedure. The committee recommended that

exemption or variance procedures be published in the final regulation.
The committee felt that at the time the regulation was being
promulgated, the affected industry should have the opportunity to
seek
exemptions or variances from those requirements which manufacturers
felt were not appropriate to their manufacturing operations.

The Commissioner is adopting this recommendation by adding a

reference
to section 520(f)(2) of the act and 21 CFR 10.30 on citizen petitions
to FDA as procedures for applying for exemptions or variances from
device GMP requirements.

3. Applicability to foreign manufacturers. The committee expressed

concern that the GMP regulation be applied to foreign manufacturers
in
a manner which would not result in discrimination against domestic
manufacturers.

The Commissioner agrees that the device GMP regulation should apply
to
the manufacture of any device to be imported or offered for import
into the United States. This was Congress' intent in amending
section
801(a) of the act (21 U.S.C. 381(a)) to allow the Commissioner to
prohibit the importation of a device that was not manufactured in
conformance with the good manufacturing practice requirements.
Devices that appear to be unsafe or ineffective, to have been
manufactured under conditions that were not in compliance with the
GMP
regulation, or to be otherwise adulterated or misbranded will be
detained when offered for import and will not be permitted to enter
the United States until FDA is satisfied that these devices, and
where
possible the conditions under which they were manufactured, are in
full compliance with the act and FDA regulations. FDA now inspects
some foreign device firms and has plans to increase the number of
foreign inspections. FDA is also exploring, with representatives of
foreign countries, the possible development of bilateral agreements
which will provide for the uniform application of GMP requirements
and
exchange of inspectional information on the manufacturing practices
of
domestic and foreign firms. These efforts recognize the importance
of international uniformity of requirements so that foreign and
 domestic manufacturers both are treated fairly.

4. Disclosure of internal audits. The committee recommended that

FDA
not ask for a company's internal audits. The committee felt that
internal audits would not be useful or meaningful to a firm's
management as a self-inspection tool if the internal audit was
available to FDA.

A discussion of the Commission's findings on FDA's access to internal

audits is found under the heading "Organization and Personnel," which
appears elsewhere in the preamble.

5. Inflationary impact.--The committee expressed concern about the

costs to industry of implementing the regulations and the potential
inflationary impact on the cost of health care. The committee
 suggested that FDA undertake a cost-benefit analysis 1 year after the
effective date of the regulations to determine its impact on the cost
of health care.

The Commissioner recognizes the legitimacy of the concerns about the

cost of the regulation to industry and the general public. He
specifically requested comments on this issue in the proposal. The
Commissioner has placed an economic impact assessment of the final
GMP
rule on file for public review in the office of the hearing clerk
(HFA-305), Food and Drug Administration, Room 4-65, 5600 Fishers Lane,
Rockville, Md. 20857 (ref. 9).

Comments filed by affected industry members and other interested

parties revealed that reliable quantitative data on expected economic
impact of the regulation are not available and could not be readily
developed in the near future. The agency tried to estimate the
impact
of the regulation based on data submitted by the industry, which is
in
the best position to assess the impact of the regulation on current
practices. Although the data submitted by the industry were
fragmentary, ambiguous, and not representative of the industry as a
whole, the Commissioner believes that manufacturers' expressed
concerns about the cost of complying with the regulation were
legitimate and real. Chief concerns related to recordkeeping
requirements; the need for increases in personnel, the requirement
that the quality assurance unit be organizationally independent from
production units; housing and content requirements for various files;
the definition of the term "critical device"; the role of the
inspector, and the appropriateness of applying umbrella provisions to
individual segments of the industry that have their own
characteristic
needs. But most comments were more issue-oriented than cost-oriented
and reflected a primary desire that particular provisions be revised,
replaced, deleted, less ambiguously stated, or made less stringent.
The Commissioner has responded to these issue-oriented comments below.

In reviewing the comments, in light of FDA's survey of 300 device

establishments, the Commissioner notes that those industry segments
which will have to increase their quality assurance expenditures the
most to comply with the regulation also stand to gain the most from
the regulation, in terms of lower cost, by avoiding device failures,
recalls, and product liability. However, in estimating expenses,
none
of those who submitted comments gave any evidence of having factored
in these potential savings. Nor did comments estimate the savings to
society if defective devices, attendant injuries, and medical costs
can be reduced by the regulation.

In developing the draft regulation, FDA made many changes in response

to comments. These changes rendered obsolete some of the economic
estimates contained in comments on the proposed regulation. To
refine
and update the submitted comments, FDA sent a questionnaire to all
firms that had commented on the potential economic impact, asking 14
questions based on specific parts of the regulation (ref. 10). FDA
asked whether a change in a provision would alter the comment's
previous assessment of economic impact. The questionnaire also asked
commentors to determine the overall difference in cost of the
regulation if all changes in the regulation were made.

FDA compared industry comments on inflation impact of the proposal

with industry comments on inflation impact of the draft final
regulation made publicly available on October 25, 1977. Commentors
tended to scale down their original estimates, probably because
 changes in the draft final regulation would reduce compliance costs.

Because of the unavailability of a data base for estimating the cost

impact of the regulation, the agency asked for such data from four
quality assurance experts of the American Society for Quality Control.
Since these four experts participated with FDA representatives In a
series of conferences to inform the device industry of the provisions
of the GMP regulation, they were very familiar with all of the
requirements of the regulation. The cost estimates prepared by each
of
the quality assurance experts is summarized in the economic impact
assessment on file in the office of the hearing clerk.

Factors which FDA hopes will reduce the regulation's costs include
the
flexibility provided in the document, the opportunity for
manufacturers to petition for an exemption or variance from one or
more requirements, the time given industry to comply with the
regulation, and FDA's education and training programs for industry.

The Commissioner is confident that the costs imposed by the GMP

regulation will be greatly outweighed by its benefits. Although he
has no current plans to undertake the suggested cost benefit study of
the impact of GMP regulation on the cost of health care, the
Commissioner does intend to study the overall economic impact of the
medical device amendments of 1976.

6. Definition of a "critical device".--The majority of committee

members concluded that no one definition of the term "critical
device"
would be acceptable to all interested persons. Concern was expressed
about the need to retain the term "user" found in the proposed
definition rather than the term "patient," which appeared in the
draft made available on October 25, 1977. Some members believed
health professionals, such as doctors and nurses, as well as patients,
should be considered when attempting to apply this definition and
that
the term "user" was descriptive enough to include both the patient
and
the health professional who use devices.

The Commissioner recognizes that it is difficult to define the term

"critical device," but finds that the definition in the draft made
available on October 25, 1977, is sufficient to communicate the
concept of "critical device." However, the Commissioner will retain
the term "user," which was in proposed  820.3(f), because it is
broader than the term "patient."

The Committee and many comments recommended that the agency develop a
list of critical devices so that the industry and FDA field personnel
will know what devices are subject to critical device requirements.
The Commissioner agrees with the committee that a list of examples of
critical devices should be developed and made available. The process
 used by FDA to develop this list and the involvement of the Device
GMP
Advisory Committee in this effort are described below.

DEVELOPMENT OF A CRITICAL DEVICE LIST

The Commissioner agrees with these comments and has developed a list
of critical devices to serve as guidance to the industry. This list
is available and will be provided to all critical device
manufacturers
who are registered with FDA and, upon request, to any other
interested
person.

In developing a list of critical devices, FDA used the following

 definition found in the draft final regulation: "a device intended
for surgical implant into the body or to support or sustain life
whose
failure to perform when properly used in accordance with instructions
for use provided in the labeling can be reasonably expected to result
in a significant injury to the patient." FDA first compiled a list of
devices based on preliminary findings and recommendations of FDA's
device classification panels (ref. 11). The list includes those
devices that the panels designated as life-sustaining or
life-supporting and those devices that the panels had tentatively
recommended for classification into class III (those for which
premarket approval will be required)

After the August 4, 1977, meeting of the Device GMP Advisory

Committee, FDA asked committee members to review the list and
identify
devices which should be deleted from it. During the October 27-28,
1977, committee meeting, the committee suggested some revisions in
the
definition of "critical device" and recommended that the agency
consult with the device classification panels about which particular
devices meet the revised definition, because the committee believed
these panels have additional knowledge of particular devices. In
addition, individual members of the Device GMP Advisory Committee
provided the agency with additional recommendations on what should be
included in the list.

The agency then prepared a revised list of critical devices, which it

sent to one or more members of each device classification panel, with
a request for recommendations about which devices should be added to
or deleted from the list. Panel members were instructed to evaluate
each possible critical device in light of the definition of "critical
device" and their knowledge of, and experience with the device.

In developing the list of critical devices, which appears below in

this preamble, FDA has used the recommendations received from the
Device GMP Advisory Committee and the device classification panels.
This list of critical devices is based on the revised definition of
"critical device" appearing in this regulation and on the most
current
information available to FDA. FDA will revise this list periodically.
after consulting with the Device GMP Advisory Committee, as
additional
information becomes available. Revisions of the list will be
announced in the FEDERAL REGISTER and will be available from the
Bureau of Medical Devices, Division of Compliance Programs, 8757
Georgia Avenue, Silver Spring, Md. 20910. The Commissioner
emphasizes that this list of critical devices is only illustrative
and
is being provided as guidance to the industry. The list is not
intended to be definitive or exhaustive. Each manufacturer should
refer to the definition of "critical device" in determine whether the
critical device requirements apply to that manufacturer's device.
 In accordance with the registration and listing requirements in 21
CFR
Part 807, FDA will use the information submitted by manufacturers to
generate a listing of all manufacturers who make identified critical
devices. Once this information is compiled, FDA will notify each
manufacturer of such a critical device that FDA has determined that
the critical device GMP requirements apply to that device.

GUIDELINE LIST OF CRITICAL DEVICES

1. Airway, Bi-Nasopharyngeal (with connector).

2. Airway, Esophageal (obturator).
3. Airway, Nasopharyngeal (with connector).
 4. Airway, Oropharyngeal, Anesthesiology.
5. Analyzer, Oxygen, Neonatal Invasive.
6. Apparatus, Electronanesthesia.
7. Apparatus, Hemoperfusion, Sorbent.
8. Apparatus, Suturing, Stomach and Intestinal.
9. Autotransfusion Apparatus.
10. Balloon, Intra Aortic, and Control System.
11. Band, Tubal Occlusion.
12. Bed, Radiant Heat.
13. Blood Pump, Cardiopulmonary Bypass, Non-Roller.
14. Blood Pump, Cardiopulmonary Bypass, Roller Type.
15. Bypass, Ventricular (assist).
16. Catheter, Embolectomy.
17. Catheter, Intravascular Occluding.
18. Catheter, Septostomy.
19. Circuit, Breathing (w/connector, adaptor Y piece).
20. Clip, Aneurysm.
21. Clip, Tubal Occlusion.
22. Clip, Vascular.
23. Clip, Vena Cava.
24. Compressor, External, Cardiac Powered.
25. Connector, Airway (extension).
26. Counter-Pulsating Device, External.
27. Cuff, Tracheal Tube, Inflatable.
28. Defibrillator, DC-Powered (including paddles).
29. Detector and Alarm Arrhythmia.
30. Electrode, Pacemaker, Permanent and Temporary.
31. Filter, Intravascular, Cardiovascular.
32. Generator, Oxygen, Portable.
33. Generator, Pulse, Pacemaker, External.
34. Generator, Pulse, Pacemaker, External, Programmable.
35. Generator, Pulse, Pacemaker, Implantable.
36. Hemodialysis Systems (including accessories).
Dialyzers. Capillary Hollow Flber.
Dialyzers, Disposable.
Dialyzers, High Permeability.
Dialyzer, Parallel Flow.
Dialyzer, Single Coil.
Dialyzer, Twin Coil.
Set, Dialysis, Single Needle.
Systems for Dialysate Delivery.
37. Incubator, Neonatal Ventilator.
38. Intrauterine Contraceptive Device (IUD) and Introducer.
39. Keratoprosthesis, Noncustom.
40. Lens, Intraocular, Ophthalmic.
41. Lung, Membrane (for long-term respiratory support).
42. Machine, Gas Anesthesia/Analgesia, Complete Systems.
43. Needle, Emergency Airway.
44. Oxygenator, Cardiopulmonary.
45. Pacemaker, Cardiac, External Transcutaneous.
46. Peritoneal Dialysis System, Automatic Delivery.
47. Prosthesis, Arterial Graft, Synthetic.
48. Prosthesis, Esophagus.
49. Prosthesis, Laryngeal.
50. Prosthesis, Trachea.
51. Prosthesis, Urethra Sphincter.
52. Prosthesis, Vascular Graft.
53. Pump, Infusion, Cardiovascular.
54. Pump, Withdrawal/Infusion.
55. Replacement, Urethral.
 56. Respirator, Neonatal Ventilator.
57. Resuscitator, Cardiac, Mechanical.
58. Resuscitator, Pulmonary, Manual.
59. Shunt, Central Nervous System Fluid and Components.
60. Stimulator, Cerebella Implanted.
61. Stimulator, Diaphragmatic/Phrenic Nerve, Implanted.
62. Stimulator, Electroanesthesia.
63. Stimulator, Intracerebral/Subcortical Implanted (pain relief).
64. Suture, Cardiovascular.
65. Thromboemboli, Intravascular (artificial embolization device).
66. Tube, Bronchial (w/wo connector).
67. Tube, Tracheal (w/wo connector).
68. Tube, Tracheal/Bronchial, Differential Ventilation (w/wo
connector).
69. Tube, Tracheostomy (w/wo connector).
70. Unit Emergency Oxygen and Resuscitation.
71. Valve, Heart Replacement.
72. Valve, Tubal Occlusion.
73. Ventilator, Continuous (respirator).
74. Ventilator, External Body, Negative Pressure, Adult (cuirass).
75. Ventilator, Noncontinuous (respirator).

THE COMMISSIONER'S CONCLUSIONS ON THE PUBLIC COMMENTS

FDA received approximately 140 written comments on the proposed

regulation of March 1, 1977; these came from manufacturers, trade
associations, professional associations, consultants, and other
interested parties. Based on these comments, information provided at
the public hearing held on August 5, 1977, and the recommendations of
FDA's Device GMP Advisory Committee, FDA has made several changes in
the final regulation. A discussion of the comments and changes
follows:

GENERAL PROVISIONS

1. Several comments regarding the scope of the regulation in

proposed
 820.1 said the GMP regulation should apply only to finished device
manufacturers because manufacturers of components may supply only a
fraction of their production to finished device manufacturers. In
addition, it was suggested that components, e.g., transistors,
semiconductors, etc., for many finished devices are readily available
in the marketplace and are not manufactured exclusively for use in
devices. Several comments argued that devices would be more costly
if
device component suppliers have to comply with the GMP regulation.

The Commissioner agrees with the comments and has amended the final
regulation to apply to manufacture of finished devices only.
Although
the regulations do not apply to component suppliers, the Commissioner
has required manufacturers of finished devices to take the necessary
precautions to assure the quality of components. He also encourages
component manufacturers to use the regulations as a guide where
 appropriate.

The Commissioner points out that manufacturers of human blood and

blood components are subject to requirements of 21 CFR part 606 and
not to part 820. A statement to this effect has been added to  820.1.

2. Many comments suggested deletion of the reference to

"installation
of devices" in proposed  820.1 Scope, because most devices are not
installed by the manufacturer.
 The Commissioner rejects this suggestion because some devices must be
installed by the manufacturer or other qualified person before they
can be used. A new  820.152 Installation is added to the final
regulation to recognize the importance of installation to the proper
functioning of a device. Section 820.152 of the final regulation
requires that where a device is installed by the manufacturer or the
manufacturer's authorized representative, the manufacturer or
representative shall inspect the device after installation to assure
that it performs as intended. Where a device is installed by a
person
other than the manufacturer or an authorized representative, the
manufacturer is required to provide adequate instructions and
procedures for proper installation.

3. Several comments suggested that only firms required to register

with FDA be required to comply with the regulation.

The Commissioner disagrees with this suggestion because some firms

are
exempted from the requirement to register for reasons which do not
relate to the need to comply with GMP requirements. Therefore, it
would be inappropriate to exempt categorically these firms from GMP
requirements. For example, foreign manufacturers are not required to
register, but shall be required to meet GMP requirements.

4. Several comments said the proposed regulation did not represent

"current" practice and recommend deleting the term.

The Commissioner disagrees with this recommendation because the

regulation is designed to reflect present good industry practices and
provides the type of flexibility necessary to allow for changes to
reflect advances in technology and new manufacturing procedures.
Many
changes were made in response to comments on the initial draft and to
the published proposal to address the concerns of industry as to the
currentness of this regulation.

5. Several comments suggested that business firms be included in the

subparagraph on authority in proposed  820.1(a). A few of these
comments suggested that the word "manufacturer" be substituted for
"person."

The Commissioner rejects these comments because "person" in this

sense, and as defined in section 201(e) of the act (21 U.S.C.
321(e)), includes individuals, partnerships, corporations, and
associations.

6. Several comments objected that the regulation does not make

special provisions for minor violations.

The Commissioner rejects these comments because he believes they are

not pertinent to the proposed regulation. The Commissioner will
determine on a case-by-case basis which violations of the regulation
are minor and the type of regulatory followup necessary to effect
 compliance, as the Commissioner is permitted to do under section 306
of the act (21 U.S.C. 336).

7. Several comments on proposed  820.1(b) Limitation said that

because in vitro diagnostic (IVD) products are now devices. the drug
GMP regulation should no longer apply to the manufacture of IVD's.
The comments suggested that  809.20(b), which now requires
manufacturers of these products to follow the drug GMP regulation as
a
 guideline, should be modified.

The Commissioner agrees with the comments because this regulation

applies to all devices, including IVD products. The Commissioner is
amending  809.20(b) to state that IVD manufacturers shall comply
with
the device GMP regulation.

8. Many comments urged clarification of the applicability of the GMP

regulation to foreign manufacturers of devices offered for
importation
into the United States. Some of the comments said that unless FDA
plans to inspect such foreign manufacturers, there is no way the
agency can effectively regulate imports.

The Commissioner rejects these comments because FDA will continue its
longstanding practice of inspecting foreign plants and plans in the
future to conduct more inspections of foreign manufacturers of
devices
offered for importation into the United States. Such foreign
manufacturers, like domestic manufacturers, are required to comply
with the GMP requirements. Any imported device about which the
agency
has questions with respect to safety and effectiveness will be
detained upon importation until the agency is satisfied that it
complies with all applicable laws and regulations administered by FDA.
In addition, FDA will attempt to develop and implement bilateral
agreements with appropriate Government officials in other countries
to
provide greater assurance that foreign manufacturers of devices
offered for importation into the United States are adhering to the
GMP
regulation.

9. Several comments said the proposed regulation should be clarified

to provide that device GMP regulations are meant to apply to devices
intended for human use only.

The Commissioner finds it unnecessary to clarify the regulation

because proposed  820.1 Scope expressly limits the regulation to
devices intended for human use.

The Commissioner has revised proposed  820.1 by moving to new 

820.5
Quality assurance program the requirement that every device
manufacturer shall prepare and implement a quality assurance program
that is appropriate to the specific device manufactured and that
meets
the requirements of this regulation. The Commissioner is making this
change to emphasize the importance of this requirement.

DEFINITIONS

10. One comment suggested deleting the proposed definition for

 "automated quality control" since this activity was adequately
covered
by the proposed definition of "quality control unit."

The Commissioner has deleted the definition of "automated quality

control" from the final regulation because this term is adequately
described in the definition of "quality assurance" and in  820.20(a).
Additionally, the term "quality control" is replaced throughout the
regulation with the term "quality assurance" to reflect suggestions
provided in the comments and the Commissioner's belief that the term
"quality assurance" is broader and more precise than the term
"quality
control."

11. Several comments suggested changes in the proposed definition of

"component" to clarify the meaning of the phrase "will appear." Many
 comments said the reference to "appearing" raised questions about
whether components which are not visible in the finished device are
covered.

The Commissioner agrees with the comments, and the definition of

"component" is amended in the final regulation to state that
"component" means any material, substance, piece, part, or assembly
used during device manufacture that is intended to be included in the
finished device.

12. Many comments suggested changing the proposed definition of

"control number" to reflect the current industry practice of using
letters, numbers, or both.

The Commissioner agrees with the suggestion to allow letters and/or

numbers, and the definition is changed accordingly.

13. Several comments on the proposed definition of "control number"

suggested adding a provision for the use of symbols or other markings
as well because it may not be practical to use only numbers and
letters.

The Commissioner is not persuaded that there is any need for the use
of symbols and other markings other than letters and/or numbers, and
he is not making the requested change.

14. Many comments said the proposed definition of "critical

component" was too broad and could be construed to mean any component
in a critical device.

The Commissioner agrees, and the definition of "critical component"

Is
revised in the final regulation to include any component whose
failure
to perform can be reasonably expected to cause the failure of a
critical device or to affect its safety or effectiveness.

15. Many comments suggested that the proposed definition. of

"critical device" be revised to identify more accurately those
characteristics of a device which require that it be considered a
critical device. It was stated that the proposed definition could be
misinterpreted to encompass certain types of devices that the
comments
do not believe the Commissioner intended to be regarded as critical.

The Commissioner is changing the definition of "critical device" in

the final regulation to include only those devices intended for
surgical implant into the body or to support or sustain life, whose
failure to perform when properly used in accordance with instructions
for use provided in the labeling can be reasonably expected to result
in significant injury to the user.

16. Many comments indicated that the 19 device advisory

classification panels, rather than the Device GMP Advisory Committee,
 should either decide or be consulted on which devices are critical
and
which are not.

The Commissioner consulted with the device advisory classification

panels in developing the initial list of examples of critical devices.
However, the Commissioner finds that the members of the Device GMP
Advisory Committee are competent to make recommendations as to which
devices are critical. Therefore, the regulation provides for the
Commissioner to consult with the Device GMP Advisory Committee before
 identifying critical devices. The process FDA used in identifying
examples of a critical devices is described Under the heading
"Development of a Critical Device List," which appears elsewhere in
this preamble.

17. Several comments said only class III devices (those requiring
premarket approval) should be declared "critical."

The Commissioner disagrees because some life-supporting or

life-sustaining devices will not be subject to class III controls.
but rather will be subject to class II controls (devices requiring
standards).

18. Several comments said the term "implant" in the proposed

definition of "critical device" should be defined.

The Commissioner disagrees, because any decision to determine whether

a device is "critical" will not depend entirely on its being an
implant. In addition, the Commissioner has proposed a definition of
the term "implant" in the proposed regulation on device
classification
procedures published in the FEDERAL REGISTER of September 13, 1977
(42
FR 46028).

19. Several comments said the proposed definition of "critical

device" should reflect the fact that critical devices may replace or
assist nonfunctioning organs. A few comments suggested that support
of life be differentiated from sustenance of life.

The Commissioner rejects the comments because devices that replace

body organ should be treated on a case-by-case basis in determine
whether such devices are life-sustaining or life-supporting. The
Commissioner believes that if a device fails while it is in use by or
on any person, and if such failure can be reasonably expected to
result in death or a clearly diminished capacity to function as an
otherwise normal human being, then that device is life-sustaining or
life-supporting.

20. Several comments said the condition of the patient at the time a
device is used should be a factor in considering whether a device
should be considered as a "critical device."

The Commissioner rejects the comments because the diagnosis of the

"condition of the patient" is not pertinent to determine whether a
device should be regarded as "critical" for purposes of applying the
GMP regulation. The state of health of the patient is a medical
judgment or diagnosis made by physicians and health professionals.
The criticality of a device under this regulation depends on
characteristics of the product, i.e., that the device sustains or
supports life. The suggestion that FDA take into account the
condition of the patient in defining "critical device" is impractical
and unworkable because use of this additional criterion would make it
impossible for a manufacturer to identify critical devices.
 21. Several comments proposed that the definition of "critical
device" reflect the fact that user error accounts for many
device-related patient, injuries.

The Commissioner agrees with these comments, and the definition in

the
final regulation is modified to recognize the relevance and
importance
of using a device in accordance with instructions provided in the
 labeling.

22. One comment recommended that dental implants be included in the

definition of "critical device" in proposed  820.3.

The Commissioner disagrees with the comment because dental implants

that should be considered "critical" would be adequately covered by
the term "implant" and the other criteria contained in the definition
of "critical device."

23. One comment said the "permanent injury" referred to in the

proposed definition of "critical device" should be more clearly
defined.

The Commissioner is substituting "significant injury" for "permanent

injury" because he believes "significant injury" is more descriptive
of that type of hazard that requires the application of critical
device GMP controls to provide protection to the public.

24. Many comments objected to the proposed definition of "critical

device" on the ground that the definition could be interpreted to
allow the Commissioner to ignore the criteria for determining the
criticality of a device and arbitrarily designate certain devices as
critical. The comments suggested that the Commissioner should be
subject to the "definitional limitations" or criteria contained in
the
definition in designating critical devices.

The Commissioner never intended to suggest that he could ignore the

criteria and arbitrarily designate any device as "critical."
Accordingly, the Commissioner is amending the final regulation to
clarify this point. A new sentence describing the Commissioner's
role
in the identification of critical devices is added to the definition:
"Critical devices will be identified by the Commissioner after
consultation with the Device Good Manufacturing Practice Advisory
Committee authorized under section 520(f) of the act, and an
illustrative list of critical devices will be available from the
Bureau of Medical Devices, Food and Drug Administration."

25. Several comments said the definition of "critical operation" in

proposed  820.3(g) was too broad because it could be interpreted to
mean that all manufacturing operations relating to a critical device
were critical operations.

The Commissioner agrees that the definition should be clarified. The

Commissioner is revising the definition to mean any operation in the
manufacture of a critical device which, if improperly performed, can
be reasonably expected to cause the failure a critical device or to
affect its safety or effectiveness.

26. Many comments concerning the definition of "finished device" in

proposed  820.3(h) (now  820.3(j)) suggested that the phrase
"whether packaged or labeled for commercial distribution" should be
deleted because a device is not a "finished device" until it is
packaged and labeled.

The Commissioner disagrees with the comments because some

manufacturers make devices that are packaged and/or labeled by other
firms. In these instances the regulation applies to both the person
manufacturing the device and the person repackaging or relabeling the
device.
 27. Many comments objected to the definition of "manufacturer" in
proposed  820.3(i) (now  820.3(k)), which included any person who
manufactures, fabricates, assembles, or processes a device in "whole
or in part". Comments said this provision was too broad,
particularly
in the instance of suppliers (vendors) who provide general-use
components to manufacturers who use such components as parts of
devices.

The Commissioner agrees with the comments, and he is revising the

regulation to define "manufacturer" to mean any person, including any
repacker and/or relabeler, who manufacturers, fabricates, assembles,
or processes a finished device. The term does not include any person
who only distributes a finished device.

28. Several comments said the proposed definition of "manufacturer"

should be modified to eliminate the possibility that a manufacturer
might be held responsible for devices altered without the
manufacturer's knowledge.

The Commissioner advises that the definition was not intended to

suggest that Part 820 would make a manufacturer responsible for
changes in devices by others, after the device left the
manufacturer's
control. However, he believes that no change in the definition of
"manufacturer" is necessary.

29. Several comments suggested including definitions of the

following
terms: "audit," "controlled label." "device history record,"
"documented," "inspection," "master device record," "non-critical
component," "quality assurance," "quality assurance program,"
"quality
program," "quality control," and "quality control manual."

The Commissioner agrees in part and has determined that the

regulation
can be more easily understood if the terms "audit," "device history
record," "device master record," and "quality assurance" are defined.
Accordingly, the final regulation is amended to include definitions
of
these terms. The definitions for the terms "audit" and "quality
assurance" have been adapted from the "Working Draft on Quality
Systems Terminology" (ref. 12). The Commissioner has determined that
the other suggested terms do not require a definition since the
meanings provided by a dictionary are sufficient.

The Commissioner notes that the term "finished device" is used in

  820.1, 820.3, and 820.5 to clarify the intent of the regulation.
Wherever the term "device" is used elsewhere in Part 820, it should
be
understood to mean "finished device."

ORGANIZATION AND PERSONNEL

 30. Many comments on proposed  820.20 Organization said the
requirement that the quality control unit be organizationally
independent of, or separate from, units performing the manufacturing
operations was overly restrictive and unduly burdensome to small
device manufacturers. They argued that small manufacturers would be
forced to hire additional personnel because it is common practice in
a
small company for the same individual to perform both a quality
assurance and a production function. Other comments said FDA should
not concern itself with the organizational structure of a company
because the structure has nothing to do with good manufacturing
practices.
 The Commissioner is revising the requirement that a manufacturer have
in its organization a quality assurance unit that is organizationally
independent of, or separate from, units performing manufacturing
operations. The regulation now requires that each manufacturer
prepare
and implement quality assurance procedures to assure that a formally
established and documented quality assurance program is performed.
After reflecting on the concerns raised by small manufacturers on the
implications of organizational requirements, the Commissioner has
determined that it would be unwise at this time to mandate that each
manufacturer have a separate quality assurance unit. In making this
change, the Commissioner recognizes that effective quality assurance
procedures depend more on the commitment of top management to
exercise
leadership in planning, designing, implementing, and assessing the
quality assurance program than on the establishment of a separate
quality assurance unit. Although many manufacturers have determined
that an objective and accountable quality assurance process can be
achieved most effectively by establishing an independent quality
assurance unit, the Commissioner believes the desirable objectivity
and accountability can be achieved without dictating organizational
requirements. FDA is more interested in the adequacy and
appropriateness of the quality assurance program that each
manufacturer has developed than in the organizational structure of
the
company.

Because the regulation no longer requires each manufacturer to have

in
its organization a quality control unit, the Commissioner finds it
unnecessary to define the term "quality control unit," and he has
deleted the definition from the final rule.

The Commissioner has also amended the regulation to provide that,

where possible, a designated individuals) not having direct
responsibility for the performance of a manufacturing operation shall
be responsible for the quality assurance program. Although production
and quality assurance personnel share a common goal of assuring that
high quality devices are produced, their interests may sometimes
conflict in the short run as decisions are made that will affect a
company's output. The Commissioner has used the words "where
possible"
in this requirement because he recognizes that for very small
companies (one or two employees) it would be impossible for the
designated quality assurance individual not to have responsibility
for
a production function.

31. Several comments said individual employees should be able to

check and verify their own work. They argued that if such checks are
not done by the employees themselves, a production foreman or
supervisor should perform them because these individuals are more
familiar with the manufacturing operations than is an independent
quality control person.
 The Commissioner never intended that production personnel should not
be able to check or inspect their own work. Checking and inspection
activities are highly desirable and help to assure that devices are
fit for their intended use. But adherence to an adequate quality
assurance program provides a further check to assure that material
and
production specifications are met. In an effective quality assurance
program, the checking and inspection for adherence to specifications
that are done by production and quality assurance personnel alike
complement one another and provide greater assurance that high
quality
devices are produced.
 32. Several comments on proposed  820.20 suggested that the term
"quality control" be changed to "quality assurance" since the latter
term is more inclusive and familiar in industry.

The Commissioner agrees with the suggestion, and  820.20 is changed

accordingly. The Commissioner has changed the term "quality control"
to
"quality assurance" wherever the term appears in the final regulation.

33. Several comments on the proposed responsibilities of the quality

control unit under  820.20(a) said manufacturers should be
responsible only for those devices they manufacture and not for those
manufactured for them by other firms under contract.

The Commissioner disagrees with the comments and believes a

manufacturer should have adequate control measures designed and in
force to assure that any firm manufacturing a device for it under
contract complies with the GMP regulation.

34. Several comments said the quality control unit need not check
in-process production of noncritical devices because it has the
authority to reject the finished device if that should prove
necessary.

The Commissioner disagrees with these comments because he has not

mandated any in-process checks during the production of noncritical
devices. It is the manufacturer's responsibility under  820.5 to
determine whether such checks are necessary for the production of
noncritical devices. Through inspections, FDA will review these
management decisions and quality assurance procedures and communicate
to the firm its observations on the adequacy of, and the adherence to,
a manufacturer's procedure for inprocess checks.

35. Several comments said the quality control personnel have no need
to review production records, as these records, have no bearing on
the
quality of the device.

The Commissioner disagrees. An effective quality assurance program

requires a careful and periodic review of all elements of
manufacturing practice that have a bearing on the quality, safety,
and
effectiveness of a device. A careful review includes the verification
and evaluation of each quality factor that affects production to
assure that all processing and performance specifications are met. A
review of production and other records by quality assurance personnel
is fundamental to the implementation and maintenance of an effective
quality assurance program. The review of production records provides
management with feedback on the results of the production activity
and
with assurance that production, process, and performance
specifications are being met.

36. Several comments urged that the requirements of the quality

control function, as stated in proposed  820.20(a), be clarified.

The Commissioner agrees, and 820.20(a) is revised to clarify the

requirements of the quality assurance program.

37. Many comments expressed reservations about proposed  820.20(b),

which requires audits of a manufacturer's quality assurance program.
These comments objected to any provision that would require the
disclosure of internal audit reports to FDA. It was stated that any
 requirement which would result in disclosure of internal audit
reports
would lead to a weakening of the audit system because firms would be
reluctant to be candid when expressing in writing the results of
their
internal audits if this information were freely available to FDA and
to the public under the Freedom of Information Act. It was further
argued that concern about self-incrimination would result in the
preparation of "sanitized" audit reports. A few comments suggested
that, if procedures for internal audits are required, firms should
have the flexibility to provide FDA with complete summaries of the
outcome of an audit and any decision resulting from observations
uncovered during the audit. It was further stated that a summary
should be sufficient to enable FDA to determine whether audits have
been performed and to verify that appropriate action was taken by
management.

The Commissioner believes that planned and periodic audits of quality

assurance should be undertaken because the maintenance of a useful
quality assurance program requires that the program be subjected to
periodic review. In addition, the proper implementation of an audit
system for quality assurance can result in cost-savings to the
manufacturer if problem areas are identified and corrected.

The Commissioner shares the concerns of the comments and the Device
GMP Advisory Committee that general FDA access to audit reports would
tend to weaken the audit system. He believes that auditing of
quality
assurance programs is important, and he recognizes the need to
maintain a degree of confidentiality if audits are to be complete and
candid. Therefore, the Commissioner has decided that FDA must
require
each manufacturer to conduct periodic audits of its quality assurance
program and to prepare audit reports. The Commissioner has also
concluded that FDA must routinely inspect and copy manufacturers'
internal audit procedures. However, as a matter of administrative
policy, FDA will not request inspections and copying of the reports
of
audits of a manufacturer's quality assurance program when FDA
conducts
routine surveillance of a manufacturer's compliance with device GMP's.
When FDA needs to determine whether a manufacturer is conducting
audits in accordance with the regulation, a designated FDA employee
may request a responsible official of the manufacturer to certify in
writing that the manufacturer has complied with  820.20(b). Upon
receiving such a request, the official is required to submit, or to
have another responsible official of the manufacturer submit, the
certification of compliance. A person who submits a false
certification is liable to prosecution under 18 U.S.C. 1001 and 21
U.S.C. 331(q)(2).

The one exception to FDA's policy of not seeking access to reports of

audits of quality assurance programs is that FDA may seek production
of these reports in litigation under applicable procedural rules, as
 for other otherwise confidential documents.

It should be stressed that FDA's policy of not generally seeking

access to audit reports applies only to reports of periodic audits
(as
defined in  820.3(b)) of a manufacturer's quality assurance program,
not to any records concerning particular devices or any other records
concerning quality assurance or production. Records required under
other sections of part 820, e.g.,   820.161 on finished device
inspection, 820.162 on failure investigation, and 820.198 on
complaint
files, are subject to routine FDA inspection and are not governed by
the policy in  820.20(b) concerning FDA access to audit reports.
 38. Many comments on proposed  820.25 Personnel said the
requirement
that personnel have adequate educational background, training, and
experience was too restrictive and that the phrase "qualifications
and
experience" was sufficient.

The Commissioner disagrees with these comments because the stated

requirements are not too restrictive. The requirement Of "sufficient
personnel with the necessary education, background, training, and
experience to assure that all manufacturing operations are correctly
performed" is a flexible one. In the Commissioner's opinion the
suggested term "qualifications" would include education, background,
and training.

39. Many comments said training programs in proposed  820.25(a)

need
not be documented and such documentation would create unnecessary
paperwork and expense without achieving any significant benefit.

The Commissioner disagrees with the comments, but  820.25(a) is

revised in the final regulation to require that all personnel have
the
necessary training to perform their assigned responsibilities, but
only to require documented training programs where such programs are
necessary to assure that personnel have a thorough understanding of
their jobs. He believes it is essential that the manufacturer
formally
recognize any training required for the performance of specific work
by its employees. Where no training programs are necessary, the
manufacturer is not required to implement an unnecessary program.

40. Many comments objected to the requirement in proposed  820.25(a)

that a documented training program be in effect for quality control
personnel regarding defects and errors likely to be encountered in
their individual control functions.

The Commissioner agrees with these comments, and  820.25(a) is

revised in the final regulation to eliminate the need for a
documented
training program on defects and errors for quality assurance
personnel. However, he is revising and expanding this section to
require manufacturers to strive for "defect awareness" by all
employees. The final regulation requires that all employees be made
aware of device defects that may occur from the improper performance
of their specific jobs. Quality assurance personnel shall be made
aware of defects and errors likely to be encountered as part of their
individual quality assurance function.

41. Many comments said on-the-job training was more effective than a
documented training program and best served to provide the necessary
experience required by the regulation.

The Commissioner recognizes the value and desirability of on-the-job

 training programs and advises that  820.25(a) in the final
regulation
allows for such training.

42. Several comments concerning the personnel health and cleanliness

requirements in proposed  820.25(b) said this provision should apply
to sterile device manufacturers only.

The Commissioner disagrees with the comments because devices other

than sterile devices, e.g., diagnostic products, may be adversely
affected by poor personnel health and cleanliness practices. However,
he points out that the requirement applies only to the extent that
the
cleanliness, health, and attire of personnel in contact with the
 device or its environment may affect the device.

43. Several comments said proposed  820.25(b), concerning personnel

health and cleanliness, was under the purview of the Occupational
Safety and Health Administration, not FDA.

The Commissioner disagrees with the comment and has determined that
the Occupational Safety and Health Act (OSHA) regulations do not
include all of the personnel health and cleanliness requirements
needed in this regulation, which aims at protecting device users from
defective devices rather than protecting manufacturing employees from
job-related hazards. Although there are some areas of common
interest, the Commissioner believes that this regulation does not
conflict with OSHA regulations.

BUILDINGS

44. Many comments objected to the use of the word "prevent" in

proposed  820.40 Buildings in the provision that facilities provide
adequate space to prevent mixups, and in other parts of the proposal.
The comments agreed that "prevent" is an absolute and connotes an
unattainable goal. The comments suggested that the term "prevent" be
changed to "designed to prevent."

The Commissioner agrees with the suggestion and the final regulation
is changed accordingly.

45. Several comments objected to the requirement in proposed 

820.40
that buildings in which manufacturing, assembling, packaging, packing.
holding, testing, and labeling operations are conducted shall be of
suitable design and contain sufficient space to facilitate adequate
cleaning, maintenance, and other necessary operations. It was argued
that these requirements should apply only when the device itself may
be affected if a building were improperly designed or too crowded.
The comments also said the requirement was too specific.

The Commissioner rejects the comments because the failure to have a

suitably designed building with ample space for necessary operations
may affect the safety and effectiveness of virtually any device. The
requirements that buildings be of suitable design and that buildings
and facilities contain sufficient space to facilitate necessary
operations and orderly handling of manufacturing operations provide
manufacturers with flexibility and permit them to take into account
the differences among various kinds of devices.

46. Several comments objected to the proposed requirement in 

820.46
that periodic verification of environmental controls be performed and
documented. Comments suggested that verification implies
documentation
and that use of the word "documented" was redundant.

The Commissioner disagrees with the comments because verification can

 occur without documentation. Therefore, he believes it is necessary
that any verification of environmental controls be documented and
available for review.

47. Several comments suggested that verification of environmental

control for noncritical device manufacturers, as proposed in  820.46,
was unnecessary. The comments further suggested that the
requirements
for the control of environmental conditions are too specific and that
environmental conditions should be controlled only when they could
 affect the device.

The Commissioner rejects these comments. The proposed requirement

already stated that environmental conditions shall be controlled when
necessary, thereby allowing flexibility with respect to whether
environmental conditions are to be controlled and, if so, the type of
control applied. The Commissioner is clarifying  820.46 to provide
that environmental conditions at the manufacturing site shall be
controlled when such conditions could have an adverse effect on a
device's fitness for use.

48. Several comments recommended that the requirement in proposed 

820.56 that cleaning and sanitation procedures be adequate to meet
process requirements apply only when necessary.

The Commissioner rejects the comments because adequate cleaning and

sanitation procedures to meet process requirements are basic
requirements of good manufacturing practice and are necessary to
assure the safety and effectiveness of devices.

49. Several comments objected to the inclusion of proposed 

820.56(a) concerning personnel sanitation requirements. The comments
contended that the need for personnel sanitation is obvious and is
often assured by State and local laws.

The Commissioner disagrees with the comments. He does not believe

that the need for personnel sanitation is universally understood.
Moreover, no evidence was provided to establish that State and local
laws generally require that adequate sanitation facilities be present
in device establishments.

50. Several comments objected to the requirement in proposed 

820.56(b) that there be written procedures to prevent contamination
and otherwise control vermin, pests, and insects.

The Commissioner rejects the comments because It is of utmost

importance that devices be manufactured under clean, sanitary, and
pest-free conditions.

51. Several comments suggested that requirements in proposed

 820.56(b) of procedures to control vermin, pests, and insects, and
to
provide safeguards to prevent contamination by rodenticides,
insecticides, fungicides, fumigants, and hazardous substances should
apply only where appropriate. Some of these comments said the
documentation of procedures to control vermin, pests, and insects was
unnecessary.

The Commissioner disagrees with these comments. He believes that

documented procedures to control vermin, pests, insects, and chemical
contaminants are necessary and appropriate for any device
manufacturer.

52. One comment recommended deletion of the requirement concerning

sewage and refuse disposal on the ground that this provision was
adequately covered by local laws.

The Commissioner rejects the comment because not all local laws
adequately address sewage and refuse disposal in device
establishments.
 53. Many comments suggested that the requirement for written
procedures and schedules in proposed  820.56(e) be prefaced by "when
necessary" because not all cleaning procedures require written
procedures and schedules.

The Commissioner disagrees because written procedures and schedules

are generally necessary to assure that cleaning and sanitation
procedures are in place. The Commissioner notes that the
requirements
of proposed  820.56(e) have been incorporated into the introductory
paragraph of  820.56 on cleaning and sanitation.

EQUIPMENT

54. Several comments suggested deletion of the sentence In the

introductory text of proposed  820.60, which reads: "All
manufacturing materials or other substances used with such equipment
or which may come in contact with the device shall not adversely
affect the device," since paragraph (d) of the same section makes it
redundant.

The Commissioner agrees with the comments, and the sentence is

deleted
from the final regulation.

55. One comment regarding the requirements in proposed  820.60,

that
equipment be designed to facilitate maintenance, adjustment, and
cleaning, noted that manufacturers have no direct control over the
design and specifications of the equipment they buy.

The Commissioner disagrees with the comment because equipment design

and specifications can be detailed in a purchase agreement where
necessary. In other cases, the manufacturer can exercise control
over
the suitability and acceptability of any equipment the manufacturer
intends to buy.

56. Several comments argued that the requirement in proposed 

820.60(a) that schedules be visibly posted on or near each piece of
equipment was impractical for many pieces of equipment and did not
serve as an effective control function.

The Commissioner agrees that posting schedules is not always

practical, but emphasizes that  820.60(a) provides flexibility in
that schedules need not be posted on equipment if they are readily
available to personnel performing maintenance activities.

57. One comment argued that cleaning and/or adjustment may be

necessary many times during the day for certain equipment and is
routinely performed by operators as part of their jobs. Documenting
these activities as required in proposed  820.60(a) would add to
costs without providing any benefits.
 The Commissioner disagrees with the comment because he believes it is
important that cleaning and adjustment be documented to insure that
the equipment Is operating properly and within stated tolerances.
However, the regulation provides flexibility by allowing the
manufacturer to determine how the documentation requirement should be
applied to a piece of equipment that is cleaned or adjusted many
times
during a day. Proposed 4820.60(a) is rewritten to clarify its intent.

58. Many comments argued that inspections of regularly scheduled

maintenance of all equipment as required in proposed  820.60(b) is
 unnecessary. It was suggested that the phrase "where applicable"
preface the requirement.

Although the Commissioner has not adopted the specific suggestion In

these comments, he has revised the final regulation to clarify that
periodic documented inspections are required only for equipment
subject to applicable maintenance schedules.

59. Several comments objected to the requirement in proposed 

820.60(c) that any inherent limitations or allowable tolerances be
posted. Comments argued that this posting may be impractical since
this information is a function of material, operation, tool size,
speed, feed, and other factors. Comments suggested that this
information on inherent limitations and allowable tolerances be
allowed to be readily available rather than visibly posted.

The Commissioner accepts the comments, and the regulation is changed

to allow any inherent limitations or allowable tolerances to be
visibly posted on or near equipment requiring periodic adjustment, or
to be readily available to personnel performing that function.

60. Many comments suggested that the requirement in proposed 

820.60(d). for documenting the use and removal of manufacturing
materials, be limited to critical devices and critical components
because such documentation is unnecessary for noncritical devices.

The Commissioner rejects the comments because some manufacturing

materials left on a device, such as cleaning agents and lubricating
oils, may adversely affect performance of a finished device
regardless
of whether the device is critical or noncritical. However, the final
regulation only requires documentation of the removal, and not the
use. of a manufacturing material.

61. Several comments noted that for many manufacturing materials it

would be impractical to limit such materials to a specified amount as
required in the proposal.

The Commissioner rejects the comments and points out that the
manufacturer has flexibility in specifying levels of materials
allowed
on the device, provided the safety and effectiveness of the device
are
not compromised. The requirement directs the manufacturer to develop
and follow his own procedures for limiting amounts of manufacturing
materials. The Commissioner has revised this section to require that
the procedures for the removal of manufacturing materials be in
writing to assure that proper attention is directed to this activity.

62. Many comments said proposed  820.61 Measurement equipment; 

820.62 Critical devices, measurement equipment; and,  820.68
Equipment calibration were redundant and resulted in needless
duplication. It was suggested that these proposed sections be
consolidated to eliminate inconsistent terminology and duplication.
The Commissioner agrees with the comments and the requirements of
these proposed sections are consolidated into  820.61 Measurement
equipment. There are no specific requirements for critical device
measuring equipment in the final regulation because the Commissioner
believes that all measurement equipment should be properly calibrated
and maintained, regardless of the type of device being manufactured.

63. Several comments said documented periodic inspection as required

 in proposed  820.61 should not be required for all measurement
equipment. Concern was also expressed about the frequency with which
such equipment should be inspected.

The Commissioner disagrees with the comments. However, this section

is revised in the final regulations so that the manufacturer shall
have procedures that describe when measurement equipment is to be
routinely calibrated, inspected, and checked. The calibration,
inspection, and checking activities should be carried out as often as
necessary to assure that the equipment is performing properly, and
these activities are required to be documented.

64. Several comments said it is not always possible to attach a

calibration record to each piece of measuring equipment as required
in
proposed  820.68(b).

The Commissioner agrees and has amended the final regulation in 

820.61(c) to require that the necessary calibration records be
displayed or readily available for each piece of equipment requiring
calibration.

65. Several comments objected to proposed  820.68(e), which

required
a designated individual to maintain a separate record showing
calibration dates, methods, data, and by whom calibrated. It was
suggested that this requirement is unnecessary since the individual
actually performing the calibration is already required to document
this activity.

The Commissioner agrees, and  820.61(c) of the final regulation is

revised to eliminate the need to maintain duplicative records of
calibration.

66. Several comments stated that it is not always practical to trace

a calibration standard to the national standards at the National
Bureau of Standards (NBS), as required in proposed  820.62. One
comment suggested that the calibration of measuring equipment used in
testing shipping cartons does not have to be traceable to any
national
standard.

The Commissioner agrees and is changing the final regulation in 

820.61(b) to provide that calibration standards shall be traceable to
the national standards at NBS only where practical. The Commissioner
is also amending the requirement to apply to noncritical as well as
critical devices because he believes measurement equipment used to
produce noncritical devices should also be carefully calibrated,
where
practical, with national standards to assure accuracy of any
measurement operation.

CONTROL OF COMPONENTS
67. Several comments suggested that the requirement in proposed 
820.80(a) for acceptance of components be limited to components
requiring testing.

The Commissioner disagrees with the comments because appropriate

procedures should be implemented to assure that all components are
examined prior to acceptance. In some cases, the examination of
components may be visual to verify that what was ordered has actually
been received. For other components, detailed testing may be
necessary.
 68. Many comments objected to the requirement in proposed  820.80(a)
that only a designated individual could accept or reject components
and said this implied that only one named individual could perform
this function.

The Commissioner notes that he never intended that the term

"designated individual" limit a task or operation to only one named
individual. A firm may designate more than one individual to perform
this function. This is true wherever the term "designated
individual(s)" is used in the regulation.

The purpose of any requirement that a firm designate one or more

individuals to perform a function is to insure accountability for
that
function.

69. Many comments noted that visual examination of each shipping

container, as required in proposed  820.80(a), is not feasible and
suggested revising the statement to require inspections of each
shipment.

The Commissioner rejects the suggestion because there is no

indication
that such visual observation would impose an undue burden on the
manufacturer. If a large number of shipping containers are combined
in pallet form, it may be sufficient to examine visually the outside
containers as representative of the entire pallet and then undertake
visual examination of individual shipping containers when the pallet
is separated.

70. One comment said proposed  820.80(a) should not require

incoming
testing and acceptance of standard electronic components.

The Commissioner believes that components should be inspected,

sampled, and tested for conformance to specifications wherever
deviations from component specifications could result in a device
being unfit for its intended use. This requirement is rewritten to
clarify its intent.

71. Many comments suggested clarification of the requirement in

proposed  820.80(b) for records "of all obsolete and rejected
components." One comment suggested that a requirement of records "of
the disposition of obsolete or rejected components" would state more
clearly the intent of this provision.

The Commissioner agrees, and  820.80(b) is revised accordingly.

72. Several comments suggested that the stock rotation requirement

in
proposed  820.80(b) apply only where needed because some products do
not require rotation.

The Commissioner agrees with the comments, and the paragraph is

 rewritten to clarify his intention that those components whose
fitness
for use or quality deteriorates over time shall be stored in a manner
to facilitate proper stock rotation.

73. Several comments objected that the word "obsolete" is

inappropriate in proposed  820.80(b) because obsolete components are
often retained as spare parts.

The Commissioner rejects the suggestion because he believes that

 components used as spare parts are not really obsolete, as these
components will be used to repair or recondition certain devices.
The
manufacturer should maintain a record of the disposition of all
obsolete or rejected components, including those that are discarded,
but not those used as spare parts. This paragraph is revised to
clarify the intent of the requirement.

74. Many comments objected to the requirement in proposed  820.81(a)

that an individual be designated to maintain rejection percentages
for
an critical components and said the availability of raw data on
rejection records for critical components was sufficient.

The Commissioner agrees with the comments, and the requirement for a
designated individual to maintain rejection percentages for critical
components is deleted from  820.81(a). Additionally, the final
regulation clarifies that all lots of critical components shall be
representatively sampled for testing and examination. The
Commissioner believes this requirement is necessary to assure that
critical components are fit for their intended use.

75. Several comments argued that the requirement in proposed 

820.81(a) that a control number be used to identify critical
components upon receipt was unnecessary.

The Commissioner disagrees with the comments and believes it is

essential that stringent controls be exercised over the receipt and
identification of critical components.

76. Several comments noted that the reserve-sampling requirement in

proposed  820.81(a) is not necessary for some critical components.

The Commissioner agrees with the comments, but does not believe the
regulation should be changed because  820.81(a) does not impose a
general reserve-sampling requirement. For certain critical
components, such as the power source of a cardiac pacemaker, a
manufacturer should maintain a reserve sample of the component
because
experience has shown that, in a small number of instances. the
component may prematurely fail during its expected life. The
maintenance of a reserve sample provides the manufacturer with a
factual basis for determining the actual, as opposed to the expected,
life of the critical component and allows for the identification of
troublesome areas so that corrective action may be undertaken. In
developing procedures to implement  820.81(a) each manufacturer has
some flexibility to determine the quantity needed for analysis and
reserve, thus reducing the burden on manufacturers. If a
manufacturer
has good reasons to believe that it is not necessary to maintain a
reserve sample of a critical component, then the manufacturer need
not
do so. However, the manufacturer should be prepared to explain these
reasons to FDA.
 77. Several comments on proposed  820.81(a) suggested that the
wording of the proposed requirement concerning identification of
critical components could be interpreted to mean that each critical
component must be identified with control numbers upon receipt.

The Commissioner points out that  820.81(a) requires only that each
lot of critical components be identified with a control number(s)
upon
receipt.

78. One comment said the requirement in proposed  820.81(b) should

 not require that a component supplier agreement take the form of a
separate document. Several comments noted that the component
supplier
agreement is often spelled out in the purchase order specifications.

The Commissioner notes that the proposed regulations did not specify
that the written agreement must be contained in a separate document
and agrees that such agreement could be contained in a purchase order.
Therefore, he believes that no change in the regulation is necessary.

79. Many comments objected to the requirement of a component

supplier
agreement proposed in  820.81(b) because it is not always possible
to
obtain such an agreement, particularly in the instance of component
suppliers who furnish standard "off-the-shelf" components.

The Commissioner agrees with the comments and is revising the

regulation to require such an agreement only where possible.

PRODUCTION AND PROCESS CONTROLS

80. One comment suggested that manufacturing specifications and

process requirements in proposed  820.100 should not apply to all
manufacturing operations.

The Commissioner disagrees with the comment and notes that  820.5
states that the quality assurance program shall be appropriate to the
specific device manufactured. This flexible approach enables
manufacturer to exercise judgment in determining which specifications
and/or processing procedures for a particular device need to be
established, implemented, and controlled. The Commissioner is
revising the final rule for clarity.

81. One comment on proposed  820.100(a)(1) said these controls

should also apply to device labeling.

The Commissioner agrees but notes that subpart G of the final

regulation requires adequate controls for labeling.

82. Several comments suggested modification of proposed 

820.100(a)(2). which would require that specification changes,
including changes made concerning devices already distributed, shall
be subject to controls as great as or greater than those applied to
the original design before the changes. The comments suggested that
this requirement apply only to specification changes affecting device
safety or effectiveness.

The Commissioner rejects the suggestion because most specification

changes could directly or indirectly affect device safety and
effectiveness. This requirement is revised in the final regulation
to
clarify the intent. The requirement now states that specification
 changes shall be subject to controls as stringent, as those applied
to
the original design specifications of the device. Such changes shall
be approved and documented by a designated individual(s) and shall
include the approval date and the date the change becomes effective.

83. Several comments suggested that the requirement in proposed 

820.100(a)(2) to document all specification changes and
implementation
dates for such changes is too broad and would be unnecessarily
burdensome to the manufacturer.

The Commissioner disagrees with these comments because he believes it

 is important to document the relationship between the date a
specification change is approved and the date a specification change
is implemented. The Commissioner is aware of device recalls that
were
caused by the failure of manufacturers document changes made in
production specifications. The Commissioner is revising 820.100(b)(1)
to clarify the intent.

84. Several comments objected to proposed  820.100(b)(2), which

requires that there be a formal approval procedure for any change in
the manufacturing process of a device. These comments objected to
the
requirement on the ground that it is unnecessary. Many comments
recommended that approval of changes in the manufacturing process be
limited to those changes affecting device safety, performance, or
effectiveness because not all manufacturing process changes require
formal approval.

The Commissioner rejects these comments because he believes that a

formal approval procedure should be established for any change in the
manufacturing process. The Commissioner notes that the requirement
permits a manufacturer to develop a formal approval procedure that is
appropriate to the device being manufactured. The nature of the
manufacturing process and the potential impact of any change in the
device should be considered in determining an appropriate and
adequate
formal approval procedure. The Commissioner is revising this
requirement to clarify the intent.

85. Many comments suggested that the use of the term "statistical
control" in proposed  820.100(c), regarding ongoing trend analysis,
is
confusing and essentially duplicates the requirement in  820.100(b).

The Commissioner agrees that  820.100(c) duplicates  820.100(b) and

is deleting  820.100(c) from the final regulation.

86. Several comments recommended changing the requirement in

proposed
 820.101(a) to state that critical operations shall be performed by
qualified individuals or suitable equipment and shall be suitably
verified. The comment suggested that the word "qualified" is more
appropriate than the word "designated."

The Commissioner rejects the comment because the intent of proposed 

820.101(a) is to assure that manufacturers assign responsibility for
each critical operation. The Commissioner believes that although
many
individuals may be qualified to perform a critical operation, one or
more individuals should be specifically "designated" to assure
accountability for that operation.

87. Several comments suggested that the information required in

proposed  820.101(b), regarding a record of critical operations, is
 also required under proposed  820.115, regarding reprocessing of
devices and components.

The Commissioner rejects the comments. Section 820.115 Reprocessing

of devices or components establishes general requirements for all
finished devices. The requirements of  820.101(b) regarding records
of critical operations apply to critical devices only.

88. One comment objected to the requirement in proposed  820.101(b)

that the individual performing the critical operation record that
operation in the device history record as required in  820.185(a)
for
critical devices. It was noted that proposed  820.185(a) permits
the
 device history record to include or reference such operation
documentation.

The Commissioner agrees with the comments, and  820.185(a) is

revised
to state that any individual responsible for the performance of a
critical operation shall record or reference that operation in the
device history record.

89. One comment objected to the requirement in proposed  820.101(c),

that the device history record identify each critical component of
the
device. The comment suggested that it would be most difficult and
burdensome to identify each critical component in the device history
record.

The Commissioner notes that the requirement should not be interpreted

to mean that each individual critical component must be individually
identified in the device history record. He intended to provide that
a component may be identified as part of a lot, and he is amending 
820.195(b)(1) in the final regulation to clarify that a critical
component may be designated merely by a lot number. The Commissioner
has also determined that the requirement in proposed  820.101(c) is
also required by proposed  820.185(b)(1). Accordingly, the
Commissioner is deleting  820.101(c).

90. Many comments objected to the requirement in proposed 

820.115(a) that all rejected devices that are subsequently
reprocessed
be subject to another complete final inspection. The comments
suggested that the reason for rejection should determine the nature
of
the reinspection; that a device reworked for a cosmetic defect, such
as a scratched surface, does not require a complete final inspection;
and that only the rejected part or area of the device needs to be
reinspected.

The Commissioner agrees with the comments and is revising  820.115(a)

of the final regulation to state that reprocessing procedures shall
be
established, implemented, and controlled to assure that the
reprocessed device or component meets the original, or subsequently
modified and approved, specifications.

91. One comment recommended that the reinspection of a reprocessed

device, as required in proposed  820.115(b), not be required to
assure
compliance with all specifications, but only with that specification
the deviation from which necessitated the reprocessing.

The Commissioner agrees, and  820.115(b) is amended in the final

regulation to require that any device rejected during finished device
inspection and later reprocessed shall be subject to another complete
final inspection for any characteristics of the device which may be
adversely affected by such reprocessing.

92. One comment objected to the requirement in proposed  820.116(a)

that there shall be a formal approval procedure for instituting a new,
or altering an approved, reprocessing procedure. The comment noted
that the requirement implied that original specifications cannot be
changed or updated without prior written approval.

The Commissioner disagrees with the comments. Section 820.116(a) of

the final regulation permits changes in original specifications
without prior written approval if a manufacturer has established a
formal approval procedure for instituting a new, or altering an
 approved, reprocessing procedure that does not require prior written
approval.

93. Two comments recommended that the requirement in proposed 

820.116(a) that reprocessing procedures be designed so that the
reprocessed device or component meets the same or equal
specifications
as the original device or component be changed to make the
requirement
consistent with  820.115(b).

The Commissioner agrees with the comments, and  820.116(a) of the

final regulation is revised to state that any critical device or
component subject to reprocessing procedure shall conform to the
original, or subsequently modified and approved, specifications.

In addition, the Commissioner has revised  820.116(a) for clarity.

94. Several comments on proposed  820.116(b) regarding reprocessing

control suggested that all written testing and sampling procedures be
documented to assure that any reprocessed critical device or
component
conform to original specifications. It was suggested that such
written
procedures not be specifically located In the quality control manual
as required in proposed  820.116(b).

The Commissioner agrees with the comments, and  820.116(b) of the

final regulation is revised to require that these procedures be
contained or referenced in the device master record. The
Commissioner
is deleting proposed  820.190, which required the maintenance of a
quality assurance manual, because all the information required to be
included in the manual is already required to be included in the
master device record. Hence, proposed  820.190 is unnecessary.

95. Several comments on proposed  820.116(b) noted that, in some

instances, a manufacturer may not want a reprocessed device or
component to meet original specifications.

The Commissioner agrees with the comments, and  820.116(b) of the

final regulation is revised to require that reprocessed devices and
components meet the original, or subsequently modified and approved,
specifications.

96. Several comments on proposed  820.116(c), regarding failure

investigation, suggested that failure investigations be undertaken
whenever any device or any of its components fails to meet
performance
specifications, regardless of whether the failed device is critical
or
not. The comments noted that the failure of noncritical devices can
have deleterious effects on the health of a patient.
The Commissioner agrees that the protection of the public requires
that all such failures be investigated and documented, and the
requirement is amended accordingly. The Commissioner has also
determined that this requirement for failure investigation should
apply to any device that fails after the device has been released for
distribution and should be located in Subpart I--Device Evaluation.
The Commissioner is . adding new  820.162 to make this change.

PACKAGING AND LABELING CONTROL

97. Many comments on proposed  820.120(a), concerning label

integrity, suggested that requiring labels to be attached to devices
would be impractical for certain types of devices, such as ophthalmic
 lenses, pacemakers, bone screws, and dental products.

The Commissioner notes that labels may be attached to outside

containers or packages and that it is not a mandatory requirement
that
the label be attached to the device itself. Additionally, the
Commissioner is amending the final regulation to require that a
designated individuals proofread samples of labeling for accuracy
before the labels and other labeling are released to inventory. The
Commissioner finds that this requirement is necessary to assure
labeling integrity and control. This requirement will minimize the
possibility of labeling mixups, a problem which has resulted in many
device recalls.

98. Several comments suggested that proposed  820.120(b), which

requires spatial separation of the device labeling operation, is
necessary only for materials that look alike. It was stated that it
is not physically practical in many small companies to completely
separate assembly, labeling, and packaging areas. The Commissioner
does not intend and is not requiring that labeling operations be
separated from packaging or assembly operations. However, the
Commissioner believes that labeling operations for different devices
should be separated from similar labeling operations in a manner
designed to prevent mixups. Therefore, he is retaining the
requirement.

99. Many comments on proposed  820.120(b) argued that the

requirement for the separation of packaging and labeling operations
could be met by using methods or procedures other than physical or
spatial separation.

The Commissioner rejects the comments. Physical or spatial separation

of packaging or labeling operations for different devices is the most
effective means of preventing mixups.

100. Several comments objected to proposed  820.120(c) regarding

area inspection and containing requirements for inspection of
packaging and labeling areas. It was suggested that it would be
burdensome for a manufacturer to require that the area be reinspected
by a designated individual other than the operator to assure that
device labeling materials from pr,or operations do not remain in the
area.

The Commissioner agrees, and the final regulation is amended to

delete
the requirement that the designated individual not be the individual
actually responsible for the labeling operation.

101. Many comments on proposed  820.120(c) said that in

manufacturing any device, especially a large piece of equipment, the
possibility of mislabeling is remote and that recording area
inspections in the device history record would only amount to
excessive, useless recordkeeping.
The Commissioner agrees with the comments and is deleting the
requirement that a record of such inspection be maintained because he
believes that compliance with the requirements of  820.120(d) of the
final regulation will be sufficient to prevent that mixups in device
labeling.

102. Several comments on proposed  820.121 suggested that the labels

and labeling materials for critical and noncritical devices alike
 should be stored and maintained in a manner to provide proper
identification and to prevent mixups.

The Commissioner agrees that proper storage of labels and labeling

for
critical and noncritical devices is an important safeguard designed
to
prevent mixups. He is adding new  820.120(d) to the final regulation
to require that labels and labeling be stored and maintained in a
manner that provides proper identification and is designed to prevent
mixups.

103. Several comments on proposed  820.121 suggested that labeling

materials issued for both critical and noncritical devices should be
examined for identity and, where applicable, expiration dates,
control
numbers, storage instructions, handling, and additional processing
instructions.

The Commissioner agrees that labeling materials for critical and

noncritical devices alike should be examined for identity to maintain
labeling integrity and to provide necessary control. He is adding
new
 820.120(e) to the final regulation to require that labeling
materials issued for devices be examined for identity and, where
applicable, expiration dates, control numbers, storage instructions,
handling instructions, and additional processing instructions.

104. Several comments suggested that in the device master record, a

record should be maintained to document that an individual has
examined labeling materials for identity.

The Commissioner agrees that a record of such examination of labeling

materials, which includes the date and person performing the
examination, should be maintained. The Commissioner is adding new 
820.120(e) to the final regulation to make this change.

105. Several comments expressed concern that proposed  820.121,

which requires that all labeling materials be examined for the
presence of expiration dates and storage instructions, is not
appropriate for all critical devices.

The Commissioner agrees with the comments. The final regulation is

revised by adding the phrase "where applicable" to  820.120(e) so
that the requirement of compliance with the provision depends upon
the
particular characteristics of the device.

106. Many comments objected to proposed  820.121(a), which required

that statistically selected samples of critical device labels and
labeling be proofread for accuracy. It was suggested that statistical
methods are not always the best methods. It was further suggested
that
samples of all labels and labeling, not just labeling pertaining to
 critical devices, should be proofread before being released to
production.

The Commissioner accepts the comments, and the reference to a

"statistically selected sample" is deleted. He is revising 
820.121(a) of the final regulation by applying the requirement to
proofread samples of labeling to noncritical as well as critical
devices because it also is important that the labeling of noncritical
devices be accurate. In addition, the Commissioner is substituting
the term "labels" for the term "labeling materials" in  820.121(a)
to
clarify that the control number required for a critical device shall
appear on the label of the critical device.
 107. Several comments on proposed  820.121(c) restricting personnel
access to critical device labeling recommended that the restriction
apply only "where applicable."

The Commissioner disagrees with the comments because it is Important

that access to labels and labeling be limited to authorized personnel
to prevent labeling mixups.

108. A few comments questioned the necessity of destroying or

altering excess printed labels bearing control numbers as required in
proposed  820.121(d). The comments said this was costly and
sometimes
unnecessary.

The Commissioner agrees, and proposed  820.121(d) is deleted from

the
final regulation.

109. One comment suggested that proposed  820.130, regarding device

packaging and providing that "Package design, construction, and
material shall be adequate to protect the device during customary
conditions of processing, storage, handling, and shipment," be
changed
by placing the word "shipping" before the term "package design." The
comment suggested that the requirement should apply only to the
shipping package.

The Commissioner rejects the comments and points out that  820.130
on
device packaging in the final regulation applies to all packaging,
whether or not the immediate container or the shipping container, so
as to assure protection of the device during storage and shipment.

110. Several comments recommended that proposed  820.131(a),

regarding critical device package design, and requiring that the
device package be designed and constructed to protect the device from
alteration or damage by expected external factors, exclude any
reference to external energy factors since these factors were only
one
example of many factors for which provision must be made.

The Commissioner agrees with the comments, and proposed  820.131(a)

is deleted from the final regulation. The Commissioner finds that
the
requirements of  820.130 in the final regulation are sufficient to
communicate the intent of proposed  820.131(a).

111. Several comments suggested deleting proposed  820.131(b),

regarding critical device storage and handling protection and
requiring that the device containers and packages be designed to
withstand any reasonably anticipated factors to be encountered under
normal and common storage and handling conditions of the device until
ready for its intended use, because proposed  820.131(b) duplicated
the requirements of  820.130.
The Commissioner agrees with the comments, and proposed  820.131(b)
is deleted from the final regulation. The Commissioner believes that
the requirements of  820.130 are adequate to assure that device
packaging is properly controlled and that additional requirements for
critical devices are unnecessary.

HOLDING, DISTRIBUTION, AND INSTALLATION

112. Several comments objected to the wording in proposed  820.150.

which stated that there shall be written procedures for finished
 device warehouse control and distribution to assure that only those
devices authorized for release are distributed. It was suggested
that
the term "devices authorized for release" be changed to "devices
approved for release," as authorization presumes approval.

The Commissioner agrees with the comments, and the amendment is made.
Section 820.150 is also revised to clarify that the oldest approved
devices shall be distributed first where a device's quality or
fitness
for use deteriorates over time.

113. Many comments on proposed  820.151 suggested that the dealer

or
distributor of a critical device be required to record the batch or
lot number of that critical device upon sale to a user so that the
device could be more readily located in the event of a recall.

The Commissioner is not adopting the comment. The Commissioner has

decided that this regulation should not apply only to persons who
only
distribute devices, as is stated in  820.1 Scope. Dealers or
distributors may record batch or lot numbers if they believe, or they
agree with, the manufacturer that a particular device requires such
traceability. Future FDA regulations may address distributor
recordkeeping requirements.

114. Several comments objected to proposed  820.150, which required

for critical devices the maintenance of distribution records that
include the name and address of the consignee, the name and quantity
of devices, the date shipped, and the control number used. The
comments suggested that the recordkeeping requirement should be
flexible enough to permit the manufacturer to make reference to the
location of the required information.

The Commissioner agrees, and the final regulation is amended

accordingly.

DEVICE EVALUATION

115. Many comments on proposed  820.160, regarding finished device

inspection, suggested deleting the requirement that a device be
tested
under those conditions in which it is to operate. Comments noted that
such testing is part of the design verification process. They
pointed
out that design verification results in the development of testing
programs to ensure that each lot of finished devices conforms to the
design requirements; and, as long as each lot passes these tests
satisfactorily, it is unnecessary to test the device repeatedly under
normal operating conditions. Many comments suggested that it was
impossible to test a device under those conditions in which it is to
operate.
 The Commissioner agrees with the comments, and  820.160 is revised
so
that it no longer is an absolute requirement. Instead, it requires
that, where practical, a device be selected from a production run and
tested under simulated-use conditions and, where necessary, tested
for
conformance with device specifications. The Commissioner notes that

820.181 Device master record requires the manufacturer to identify
where it is necessary that a device be tested for conformance with
its specifications. Any device which requires calibration or
adjustment, to assure that It is in proper operating condition or
otherwise fit for its intended use, should be tested carefully as
part
of the finished device inspection. The manufacturer should be
prepared to explain to FDA the decisions made about the
 appropriateness and necessity of finished device testing.

116. One comment objected to the requirement in proposed  820.160

that sampling plans for testing and release of the device be
statistically validated.

The Commissioner accepts the comment, and  820.160 is revised to

require in the final regulation that sampling plans for checking and
release of a device be based on an acceptable statistical rationale,
without necessarily being statistically validated.

117. Many comments recommended deletion of the requirement in

proposed  820.161 for critical devices that a designated individual
assure that all records and documentation required for the device
history record are correct, because it was cumbersome and impractical
and would result in unnecessary duplication of effort. Further, it
was
argued that the economic burden of performing double checks is not
warranted because the device history record will already contain the
signatures of responsible individuals, thus attesting to the
correctness of the information in this record. It was suggested that
the designated individual be required only to assure that the
contents
of the device history record are "consistent with the release
criteria" for the device.

The Commissioner is responding to the comments by revising  820.161

to require in the final regulation that a designated individuals be
responsible for assuring that all records and documentation required
for the device history record are present, complete, and consistent
with the release criteria.

In addition, the Commissioner is revising  820.161 to require that a

critical device or component which does not meet its performance
specifications during finished device inspection shall be
investigated
and that a written record of the investigation, including conclusions
and followup, shall be made. The Commissioner believes that this
requirement, which was previously found in proposed  820.116(c), is
more properly located in  820.161 Critical devices, finished device
inspection.

RECORDS

118. Many comments on the general requirements in proposed  820.180

for records and reports objected to the phrase "parts 820 through
829." Comments suggested that this phrase be deleted because, of the
cited parts, only part 820 is now in existence.

The Commissioner accepts the comments, and the regulation is amended

accordingly.

119. The Commissioner is revising  820.180 to clarify the intent of

the records requirements. The Commissioner is requiring that all
records required by part 820 be maintained at the manufacturing
establishment or other reasonably accessible location. He is also
including in the regulation the requirement of section 704(e) of the
act (21 U.S.C. 374(a)) that records required to be kept regarding
devices shall be available for review and copying by FDA
representatives. This change responds to a comment asking whether FDA
would have access to inspect records required to be kept under part
820. The Commissioner notes that FDA will examine these records to
determine whether manufacturers are complying with the recordkeeping
 and documentation requirements of the regulation and with the act.

The Commissioner also notes that the principal reason for stipulating
that all records required by part 820 shall be maintained at the
manufacturing establishment or other reasonably accessible location
is
for the benefit of the manufacturer. By maintaining these records at
the manufacturing establishment or other reasonably accessible
location, responsible officials of a manufacturer can exercise
control
and accountability over the entire manufacturing process and thereby
maximize the probability that the finished device conforms to its
design specifications. The requirement helps assure that responsible
officials at the manufacturing establishment have ready access to
those documents essential for conducting self-inspections, complaint
investigations, failure analyses, and audits.

120. Several comments on proposed  820.180(b) concerning record

retention period recommended that a provision be made regarding the
record retention period for devices which have very short lifetimes.
Many of these comments also noted that there were devices with an
indefinite life expectancy. It was suggested that the period required
for record retention be left to the manufacturer.

The Commissioner concludes that the requirement on record retention

period will remain unchanged. The minimum record retention period
will continue to be 2 years, a time period consistent with the
biennial inspection requirement in section 510(h) of the act (21
U.S.C. 360(h)) for class II and class III devices. In the event that
the record retention imposes a hardship on the manufacturer, a
variance from the requirement may be requested. It should be
recognized that for devices with an indefinite life expectancy the
regulation states that such records shall be maintained "for a period
of time consistent with the design and expected life of the device."

121. Many comments suggested that proposed  820.180(b) be amended

to
provide the manufacturer with the option of retaining photostatic or
other reproductions of a record.

The Commissioner agrees and is amending this section. However, a

manufacturer must take steps to assure that any reproductions are
true
and accurate copies of the original. Where written notes, erasure
marks, or other changes are not apparent on the reproduction, a
notation of this fact should be clearly indicated on the reproduction
of the record, and the hard copy of the record should be retained for
the required length of time.

122. Several comments expressed confusion about the requirements in

proposed  820.181 on what is to be maintained in the master device
record and the requirements in proposed  820.184 on what is to be
maintained in the device history record.
 The Commissioner believes that both sections already are clear, but
has changed both sections to clarify further the intent of the
requirements.

123. Many comments on proposed  820.181, regarding the master device

record, suggested rewording to provide that references can be made to
locations within the manufacturing facility where various records are
housed. Comments noted that duplicative records for every device
would
be costly and impractical.
 The Commissioner agrees with the comments. Section 820.181 of the
final regulation is amended to state that the device master record
shall include, or refer to the location of. all specifications and
procedures for the manufacture of each type of device.

124. Several comments on proposed  820.181 objected to, the phrase

"each separate device entity" because this phrase was not clear and
could encompass devices that differ only in size, shape, packaging,
or
color. It was suggested that the intent of this requirement be
clarified.

The Commissioner agrees, and 820.181 in the final regulation is

revised to provide that the master device record shall include or
reference all specifications and procedures for each type of device.
It will be unnecessary to include in the device master record
duplicate specifications for each separate device entity. However,
the master device record shall include, or reference the location of,
any unique specifications and procedures for the manufacture of
devices which differ only in size, shape, packaging, or color.

125. Several comments on  820.180 suggested that the general

requirements regarding the master device record applicable to both
noncritical and critical devices were more inclusive than the
separate
requirements applicable to critical devices. The comments pointed
out
that the sentence, "The master device record shall include all
specifications and procedures or appropriate references for each
separate device entity" was broader than the device master record
requirements for critical devices. These comments noted that the
critical device requirements in proposed  820.182, in paragraph (a)
regarding device specification, paragraph (b) regarding production
process specifications, paragraph (c) regarding quality control
specifications, and paragraph (g) regarding packaging specifications
were merely types of specifications already required by proposed 
820.180.

The Commissioner agrees with the comments, and   820.181 and 820.182
are revised in the final regulation to clarify the intent of the
requirements and to preserve the distinction between noncritical and
critical device requirements.

126. Several comments on proposed  820.182, regarding the critical

device master record, objected to the proposed requirement that all
specifications and procedures on critical devices be included or
referenced in a single record.

The Commissioner rejects the comments. It is essential that a single

source document for each device manufactured be assembled, maintained,
and consulted when necessary by the manufacturer. The Commissioner
notes that specifications and procedures for critical devices may be
referenced in the device master record as long as they are available
for inspection at the manufacturing site or other reasonably
 accessible location.

127. Several comments on proposed  820.182(f), regarding labels and

labeling, recommended that copies of promotional material not be
included in the device master record because such material is not
part
of the manufacturing process.

The Commissioner agrees with the comments, and  820.182(f) is

deleted
from the final regulation. Although promotional materials other than
 labeling will not be required as part of the device master record,
these materials should be available to FDA representatives at the
manufacturing establishment.

128. Many comments suggested that the intent of proposed  820.184

be
clarified. The comments expressed confusion over the requirement
that sufficient records be maintained to demonstrate conformance to
specifications, and sought guidance as to what was meant by
"sufficient records."

The Commissioner agrees with the comments, and the final regulation
is
revised to require that a device history record be maintained to
demonstrate that the device is manufactured in accordance with the
device master record. The device history record shall include or
refer to the location of the following information: The dates of
manufacture, the quantity manufactured, the quantity released for
distribution, and any control number used.

129. Several comments expressed confusion about proposed  820.185

(b)(1). on control numbers used for component documentation. The
comments said it would be unnecessarily burdensome and costly to
require manufacturers to identify each critical component by a
control
number.

The Commissioner advises that he did not intend that each critical
component carry a control number. The final regulation is changed to
provide that critical components may be designated in the device
history record by a control number Identifying a particular lot of
critical components. The Commissioner has also revised  820.185 for
clarity and consistency of language.

130. Many comments recommended that proposed   820.190 and 820.191,

regarding a quality control manual, be deleted because all the
information required in the quality control manual is required in
proposed  820.181 Master device record.

The Commissioner agrees that maintenance of a quality control manual

would duplicate requirements of the device master record, and
proposed
  820.190 and 820.191 are deleted from the final regulation.

131. Several comments addressed proposed  820.195, regarding checks

of automated data processing concerning critical devices. The
comments said the requirement should be limited to data Processing
information used for manufacturing or quality assurance Purposes and
argued that it is unnecessary to apply this requirement to data
processing activities such as billing and personnel files. Several
comments said the manufacturer should not be required to make and to
store a duplicate copy of computerized information at a separate
geographical location because hard copy reports can be generated and
made available to FDA upon request.
 The Commissioner agrees with these comments, and the final regulation
is amended to apply only to automated data processing used for
manufacturing or quality assurance purposes. The Commissioner also
is
deleting the requirement for maintenance of a duplicate copy of
computerized information.

132. Many comments on proposed  820.198(a), regarding complaint

files, argued that any requirement to maintain a complaint file must
be tempered by the fact that each firm will define a complaint
 somewhat differently. The comments suggested that there are a great
many customer inquiries which do not relate to product safety or
effectiveness and, therefore, are not complaints.

The Commissioner finds that the description of what is meant by the

term "complaint" found in proposed  820.198(a) is sufficient to
communicate the kinds of complaints that must be reviewed and
maintained. However, to correct an oversight in the proposal, he has
specified that the requirement to maintain a complaint file applies
to
complaints relative to safety (as well as identity, quality,
durability, reliability, effectiveness, or performance) of a device.

133. Several comments suggested that a manufacturer should have the

flexibility to designate a unit other than the quality control unit
to
maintain, review, and investigate, where necessary, complaints made
about devices.

The Commissioner agrees, and the final regulation is amended by

substituting the term "formally designated unit" for "quality control
unit."

134. Several comments objected to the requirement in proposed

 820.198(b) that complaints about injury, death, or safety be
maintained separately from other complaints. They suggested that
there is no useful purpose for separating files and that it should be
the manufacturer's prerogative to file complaints in any manner he
sees fit.

The Commissioner disagrees with the comments because complaints

dealing with an injury deserve special attention when there is a
possibility that the failure of a device is responsible for the
injury. The Commissioner also believes that those complaints about a
device's identity, quality, durability, reliability, safety,
effectiveness, or performance are often indicative of poor
manufacturing practices requiring correction. In evaluating the
adequacy and appropriateness of a quality assurance program, the
Commissioner is interested in learning how a manufacturer
investigates
and follows up on such complaints.

To help assure that this investigation and followup occur, the

Commissioner is amending the final regulation to require that a
written record of each investigation of a complaint be maintained and
be readily available at the manufacturing site in a file designated
for device complaints. The Commissioner believes that this
requirement will facilitate the effective enforcement of the act by
assuring that complaint investigation reports are accessible to
responsible company officials and to FDA representatives who, in
turn, can determine whether necessary corrective action has been
accomplished.

The Commissioner advises that FDA representatives will routinely

 examine a manufacturer's complaint file to determine whether those
complaints that require followup have been properly investigated.

The Commissioner also is revising  820.198 to clarify the

requirements of this section.

135. Several comments said FDA should not cite section 519 of the
act
(21 U.S.C. 360i), regarding records and reports on devices, as part
of the authority for Part 820. It was argued that FDA had not met
the
 specific requirements of section 519 of the act. One comment said
that findings must be made as to how each recordkeeping and reporting
requirement satisfies section 519 of the act and that FDA cannot
incorporate recordkeeping requirements under section 519 of the act
in
a GMP regulation but must issue a separate recordkeeping regulation.
The comment also asserted that FDA could require manufacturers to
maintain GMP records, but could not inspect them. The concern was
that if the GMP regulation' was promulgated under authority of
section
519 as well as section 520(f) of the act and other provisions, FDA
would have specific authority to inspect, copy, and verify required
records under section 704(e) of the act (21 U.S.C. 374(e)).

The Commissioner rejects the comments. There is no reason why he

cannot rely on section 519 of the act in establishing GMP
recordkeeping and reporting requirements. Indeed, the legislative
history indicates that Congress expected FDA to do so (H. Rept. No.
94-853, 94th Cong., 2d sess., 23). It would be illogical for FDA to
have authority to require GMP records to be kept but not to see them.

The GMP records and reports requirements are promulgated under

sections 519, 520(f), and 701(a) of the act. Section 519 of the act
requires a manufacturer of a device to maintain such records, make
such reports, and provide such information as the Commissioner may by
regulation reasonably require to assure that such device is not
adulterated or misbranded and to otherwise assure its safety and
effectiveness. The GMP recordkeeping and reporting requirements
clearly are reasonable requirements under this general authority and,
in addition, are consistent with limits on this authority in section
519(a)(1) through (5) of the act, as explained below. Section 519
does not require the Commissioner to make any findings. (Compare, for
example, section 514(g)(2) and (3) of the act (21 U.S.C. 360d(g)(2)
and (3)).)

Section 519(a)(1) of the act prohibits recordkeeping requirements

that
are unduly burdensome to a device manufacturer, taking into account
the cost of complying with the requirements and the need for
protection of the public health and the implementation of the act.
The Commissioner has considered each recordkeeping requirement in
Part
820 and has concluded that none is unduly burdensome considering the
costs and the benefits. The FDA survey of manufacturing practices in
300 device establishments showed that 80 percent of the
establishments
inspected were already complying with the major recordkeeping
requirements of the proposed device GMP. Thus, the majority of device
manufacturers would only have to make minor changes to their current
practices to be in full compliance with the GMP recordkeeping
requirements. The more demanding recordkeeping requirements only
apply
to manufacturers of critical devices. FDA has deleted a number of
duplicative or burdensome proposed requirements in response to
 comments. Any manufacturer who believes that a requirement, as it
applies to that manufacturer, is unduly burdensome may request an
exemption or variance.

Section 519(a)(2) of the act provides that procedural regulations for

device reporting requirements shall require each FDA request for a
report or information under the regulations to state the reason or
purpose for the request and identify to the fullest extent
practicable
the desired report or information. Section 519(a)(3) of the act
applies a similar requirement to other FDA requests for submission of
a report or information on devices. Except for the provision in 
820.20(b) for FDA to request certification concerning manufacturers'
 audits of quality assurance procedures, Part 820 does not create any
procedures for FDA to request reports or information and, thus, is
not
subject to section 519(a)(2) of the act. FDA generally will rely on
the inspection procedures in section 704(e) of the act (which are
referenced in  820.180) to gain access to, and copying of, required
records. FDA does not believe that notices of inspection under
section 704 of the act are subject at section 519(a)(3) of the act,
which governs "submissions" of reports.

The procedure in  820.20(b) for requests of certification concerning

audit reports complies with section 519(a)(2) of the act.

The agency's access to patient identification In complaint files is

consistent with section 519(a)(4) of the act; this access is needed
to
determine the safety and effectiveness of devices, to verify required
records, and, in some cases, to protect the individual's medical
welfare.

Finally, the regulations comply with section 519(a)(5) of the act

because they do not require manufacturers of class I devices to
maintain records on information not in their possession. All records
required to be maintained concern the manufacturers' own
establishments and procedures. Moreover, the records are needed to
determine whether the devices are adulterated and misbranded.
Congress expected FDA to require manufacturers of class I devices to
keep records on quality control where necessary to protect the public
health (H.R. Rep., supra, 24).

136. A comment asked whether FDA would have authority to inspect

records required under Part 820.

The answer is yes. FDA already has authority in section 704(a) of

the
act (21 U.S.C. 374(a)) to inspect records concerning "restricted
devices." FDA believes that this authority clearly extends to
complaint files and other GMP records for restricted devices. It is
FDA's position that the term "restricted device" include articles
which are prescription devices under 21 CFR 801.109. However, some
device manufacturers disagree with FDA and have challenged FDA's
records inspection authority under section 704(a) of the act, in
several pending lawsuits.

In three related cases, the U.S. District Court for the Northern
District of New York, in a written opinion dated April 6, 1978,
disagreed with FDA's determination that the term "restricted device"
includes preenactment prescription devices. Becton, Dickinson and
Company v. Food and Drug Administration et al. (Civ. Action No.
77-CV-181); United States v. Becton, Dickinson and Company (Civ.
Action No. 77-CV-337); In the matter of establishment inspection of
Bard-Parker Division of Becton, Dickinson and Company (Misc. 112)
(N.D. NY). These cases are under appeal to the U.S. Court of Appeals
for the Second Circuit. A contrary result was reached by the U.S.
 District Court for the Central District of California in a decision
reinstating an inspection warrant, which was quashed by another judge
4 weeks earlier, that authorizes FDA to inspect records relating to
restricted devices (cardiac pacemakers). In the Matter of the
Establishment Inspection of American Technology, Inc., Civil Action
No. CV-1727-LEW (C.I). CA, decided June 5, 1978). The issue is also
pending in one other judicial district.

The GMP regulation, however, does not deal directly with the issues
in
 these cases (the scope of section 704(a) authority and the meaning of
"restricted devices"). After Part 820 becomes effective, FDA will
have
clear authority under section 704(e) of the act to inspect and copy
required GMP records, including complaint files, for all devices,,
whether or not restricted devices, and regardless of the outcome of
the pending cases. After the effective date, a person who refuses to
allow FDA to inspect a required GMP record, or who causes such a
refusal, will have committed an act that is prohibited under section
301 (e) and (f) of the Act (21 U.S.C. 331 (e) and (f)) and will be
subject to regulatory action under section 302 or 303 (21 U.S.C. 332
or 333). In addition, under sections 501(h) and 502(t)(2) (21 U.S.C.
351(h), 352(t)(2)), devices are adulterated and misbranded if they
are
the subject of required GMP records to which FDA is refused access.
Such devices are subject to seizure.

IMPLEMENTATION

137. Many comments expressed concern about FDA's plan for

implementing the regulation and particularly the effective date.
Comments said the regulation should become effective 180 days to 18
months after final publication in the FEDERAL REGISTER, rather than
90
days after final publication as FDA had proposed. Others cautioned
that the agency should be flexible in implementing this regulation
because of the need for industry to accomplish any necessary changes
in their manufacturing practices with minimum confusion and cost.
The
comments also suggested that a flexible implementation schedule would
provide FDA with an opportunity to train field personnel.

The Commissioner has carefully reviewed each comment on effective

date
and agrees that it is desirable for FDA to summarize and restate
clearly FDA's implementation strategy for this regulation.

This regulation has been under development for a long time. The
device
industry has had an extraordinary involvement in its development.
Since 1973 the agency has encouraged device manufacturers to examine
their manufacturing practices in light of the draft and proposed
device GMP regulations. For several years FDA has engaged in
constructive dialog with representatives of the device industry to
foster a better understanding of the agency's overall approach to
device GMP's. Simply stated, this approach recognizes the need to
develop a regulation applicable to all device manufacturers. The
regulation should not be so specific as to specify for every type of
device manufacturer exactly what it must do and how its manufacturing
practices must be accomplished; but, rather the regulation should set
forth general requirements applicable to all manufacturers, with
additional requirements for manufacturers of critical devices. These
GMP requirements are designed to be flexible so that a device
manufacturer can develop a detailed set of procedures, as required by
   820.5 and 820.20, which take into account a device's special
manufacturing needs without compromising strict adherence to quality
assurance requirements. FDA will look at these detailed procedures
and how they measure up to the requirements of Part 820 to determine
whether a manufacturer is complying with the regulation and is
operating in accordance with its own quality assurance program.

The Commissioner recognizes that certain GMP requirements may be

inappropriate when applied to certain device manufacturers. A
manufacturer who believes that a GMP requirement is not appropriate
or
possible in the manufacture of that manufacturer's devices may
petition for an exemption or variance under the procedures in
 820.1(d).

The Commissioner believes this regulation should be implemented as

soon as possible to reduce the need for many device recalls and to
upgrade existing quality assurance practices of the device industry.
Based on FDA's experience, the Commissioner believes that many device
recalls have resulted from obvious deficiencies in the manufacturing
process and could have been prevented if the manufacturer had taken
reasonable steps to follow a quality assurance program. However, the
Commissioner recognizes that it may be difficult or costly for some
manufacturers to comply with the regulation within 90 days after the
publication of the final regulation and agrees that a later effective
date should be provided. Accordingly, the Commissioner has concluded
that manufacturers will be required to comply with the regulation 150
days after its publication.

The Commissioner recognizes the concerns many manufacturers have

about
how FDA will implement this regulation and how FDA will explain the
requirements of the regulation to the affected industry. The
Commissioner recognizes that the manufacturer, not FDA, is primarily
responsible for producing high quality devices. FDA will encourage
voluntary compliance. The decisions a manufacturer makes to tailor
specific manufacturing needs to quality assurance requirements will
be
carefully evaluated by FDA. The industry should understand, however,
that this regulation has the force of law, and that violation of its
provisions are a basis for seizure, in, junction, and for prosecution.

As an initial communication effort, that agency has conducted 12 2-

day
meetings across the country to inform manufacturers about the
requirements of the regulation. These meetings were cosponsored by
the American Society for Quality Control (ASQC) and FDA's Bureau of
Medical Devices and were announced in the FEDERAL REGISTER of March 7,
1978 (43 FR 9320).

In addition to these meetings, the agency is conducting training

programs for its field personnel to assure uniformity and consistency
of application of this regulation. FDA field personnel will conduct
GMP inspections according to compliance programs developed by the
Bureau of Medical Devices. These programs will be available to the
public upon request in accordance with 21 CFR part 20, FDA's public
information regulations.

FDA has prepared and is making available to the public an analysis of

GMP deficiencies and device recalls, enforcement actions, and
complaints in recent years. This analysis shows how compliance with
the requirements of the regulation might have prevented device
defects, consumer injuries, and recalls and will aid manufacturers in
complying with the regulation. For devices which have been
tentatively recommended for classification into class I (general
controls), the Commissioner recognizes that future FDA regulations or
orders may provide for some device manufacturers to be exempt from
 certain provisions of the law, including the GMP regulation as it
applies to certain class I devices. For this reason, FDA will not
initiate any program to conduct routine inspections of manufacturers'
devices which panels have recommended for class I until final
classification regulations are published. But if it is necessary to
investigate a device manufacturer because of complaints about a
device
failure or other defect, FDA will not hesitate to make an inspection
to determine whether, among other things the manufacturer is
complying
with device GMP's.
 Where FDA investigators observe deviations from the GMP regulation,
manufacturers will have the opportunity to discuss differences of
opinion not only with the investigators but also with management in
the FDA district offices and, if necessary, the Office of the
Associate Director for Compliance in the Bureau of Medical Devices.

Background data and information on which the Commissioner relies in

promulgating this regulation have been placed on file for public
review in the office of the hearing clerk (HFA-305), Food and Drug
Administration, room 4-65, 5600 Fishers Lane, Rockville, Md. 20857. A
list of these documents follows:

REFERENCES

1. "Hospital Statistics," American Hospital Association Annual

Survey, 1977.
2. "Current Manufacturing Practices in 300 Medical Device
Establishments," prepared by Office of Compliance, Bureau of
Medical Devices, FDA, 1977.
3. Transcripts of Four Public Meetings on GMP Regulations, San
Francisco, Calif.; Dalls, Tex.; Chicago, Ill.; Washington, D.C.,
November 1975.
4. Transcript of Device GMP Advisory Committee Meeting on Device GMP
Regulations, Washington. D.C., August 4, 1977.
5. Transcript of Public Hearing on Device GMP Regulation, Washington,
D.C., August 5, 1977.
6. Transcript of Device GMP Advisory Committee Meeting on Device GMP
Regulations, Washington, D.C., October 27-28, 1977.
7. "Inspection of Medical Device Manufacturers," Compliance Program
7324.19, Compliance Program Guidance Manual, FDA, October 22,
1976.
8. "Inspection of Diagnostic Product Manufacturers," Compliance
Program 7324.18, Compliance Program Guidance Manual, FDA, March
10, 1977.
9. "Economic Impact Assessment of Final Rulemaking, Good
Manufacturing Practice Regulation for Manufacture, Packing,
Storage and Installation of Medical Devices," prepared by Food
and
Drug Administration, Department of Health, Education, and Welfare,
Bureau of Medical Devices, June 1978.
10. "Inflation Impact Assessment Questionnaire," prepared by Office
of
Compliance, Bureau of Medical Devices, FDA.
11. "List of Critical Devices," prepared by Office of Compliance,
Bureau of Medical Devices, FDA.
12. "Working Draft on Quality Systems Terminology," prepared by the
Writing Committee for the revision of ASQC A3-1971, ANSI Z1.7-
1971
(Draft 3, Rev. O, February 1, 1978).

In conjunction with the final regulation on good manufacturing

practices, the Commissioner is promulgating a conforming amendment to
21 CFR 809.20(b) relating to compliance of in vitro diagnostic
products with the drug GMP's found in 21 CFR parts 210, 211, 225, 226,
and 229. This conforming amendment reflects the new definition of
"device" which, as a result of the Medical Device Amendments of 1976
(Pub. L. 95-265), now includes in vitro diagnostic products. Because
the amendment to part 800 makes no substantive changes and is
promulgated only to conform with existing regulations, the
Commissioner finds that notice and public procedure are unnecessary.

All in vitro diagnostic products will be subject to 21 CFR part 820

 relating to GMP's for medical devices, after the effective date of
part 820.

The Food and Drug Administration has carefully considered the

environmental effects of the regulation and, because the action will
not significantly affect the quality of the human environment, has
concluded that an environmental impact statement is not required.

Therefore, under the Federal Food, Drug, and Cosmetic Act (secs. 501,
502, 518, 519, 520(f), and 701(a) as amended, 52 Stat. 1049-1051 as
amended, 1055, 90 Stat. 562-569 (21 U.S.C. 351, 352, 360h, 360i,
360j(f), 371(a))) and under authority delegated to the Commissioner
(21 CFR 5.1), chapter I of title 21 of the Code of Federal
Regulations
is amended as follows:

1. Part 809 is amended in  809.20 by revising paragraph (b) to read

as follows:

 809.20 General requirements for manufacturers and producers of in

vitro diagnostic products.

* * * * *

(b) Compliance with good manufacturing practices. In vitro

diagnostic
products shall be manufactured in accordance with the good
manufacturing practices requirements found in part 820 of this
chapter.

PREPRODUCTION QUALITY ASSURANCE PLANNING: RECOMMENDATIONS

PREPRODUCTION QUALITY ASSURANCE PLANNING: RECOMMENDATIONS FOR MEDICAL

DEVICE MANUFACTURER (MAY 1987)

PREPRODUCTION QUALITY ASSURANCE PLANNING:

RECOMMENDATIONS FOR MEDICAL
DEVICE MANUFACTURERS

May 1987

U.S. Department of Health and Human Services

Public Health Service
Food and Drug Administration
Center for Devices and Radiological Health
Office of Compliance
Division of Compliance Programs
Rockville, Maryland 20857
 PREFACE

The Food and Drug Administration (FDA) often formulates and

disseminates recommendations about matters which are authorized by,
but
 do not involve direct regulatory action under, the laws
administered
by the agency.

Accordingly, under 21 CFR 10.90(c) FDA is making available these

draft
recommendations that are acceptable to FDA but are not legal
requirements. The draft recommendations contain preproduction
practices
which are acceptable to FDA for ensuring the safety and effec-
tiveness
of device designs before their release to production. These
recommendations are intended to minimize design defects that have
resulted in device recalls.

PREPRODUCTION QUALITY ASSURANCE PLANNING:

RECOMMENDATIONS FOR MEDICAL DEVICE
MANUFACTURERS

1.0 SCOPE

These recommendations describe good design practices applicable to

the
design of medical devices and is intended to assist device
manufacturers in planning and implementing a preproduction quality
assurance program. The purpose of this program is to provide a high
degree of confidence that medical device designs are proven reliable,
safe and effective prior to releasing designs to production for
routine
manufacturing. The FDA especially recommends these good design
practices to those medical device manufacturers who have found it
necessary to recall devices from the marketplace because of defects
in
the design of a component, subassembly, or the device itself.
Likewise,
manufacturers of life-sustaining, life-supporting, or implantable
devices, particularly those that make electrical, electromechanical
or
mechanical devices, should examine these suggested practices to
determine their applicability to their product life cycle development
activities. Additionally, those manufacturers who are committed to
company-wide quality assurance programs that emphasize quality
improvement strategies to enhance product quality and productivity
while reducing quality costs should find these recommendations
helpful
in identifying the preproduction activities that FDA believes are
important. The practices described herein are applicable to the
development of new designs as well as the adaptation of existing
designs to new or improved applications.
 2.0 INTRODUCTION

The design phase is the most important phase in the life cycle of a
device. The inherent safety, effectiveness, and reliability of a
device
are established during this phase. No matter how carefully a device
may
be manufactured or how perfect the GMP program, this inherent safety
and effectiveness cannot be improved except through design
enhancement.
Therefore, it is crucial that adequate controls be established and
implemented during the design phase to assure that the safety,
effectiveness and reliability of the device are optimally enhanced
prior to manufacturing to assure that an acceptable quality level can
be
achieved during production. It is only through careful planning and
management of the preproduction process that safety, effectiveness
and
reliability can be established in a device.

A design deficiency can be very costly once a device design has been
released to production and the device is manufactured and
distributed.
 Costs may include not only replacement and redesign costs, with
resulting modifications to manufacturing, procedures, retraining, etc.
to enable manufacture of the modified device, but also liability
costs,
and loss of customer goodwill.

These recommendations were adapted from documents listed in Appendix

II -- References. The cited references include military standards,
documents developed by the National Aeronautics and Space
Administration (NASA), voluntary standards, National Bureau of
Standards
(NBS) guidelines, and others.

Analysis of recall and other adverse experience data available to FDA

indicates that one of the major causes of device failures is
deficient
design. Examples are cited herein, not as an indictment of
particular
manufacturers or industries, but as an illustration of the advantages
of
implementing a preproduction quality assurance program. The examples
used are from FDA's device recall records.

3.0 PREPRODUCTION QUALITY ASSURANCE PROGRAM

All manufacturers of medical devices should establish and implement a

program for assessing the reliability, safety, and effectiveness of
device design prior to releasing the design to production and,
ideally,
this assessment should be made as the design is developed. The
procedures for making these assessments should be defined in a
formally
established and documented preproduction quality assurance (PQA)
program. Formal protocols should be developed and agreed upon for
design verification and reliability assessment. The program should
be
sanctioned by upper management and should be considered a crucial
part
of each manufacturer's overall effort to produce only reliable, safe,
and effective devices.

3.1 Organization

The organizational elements and authorities necessary to establish

the
PQA program, to execute program requirements, and to achieve program
goals, should be specified in formal documentation. Responsibility
for
implementing the overall program and each program element should
also
be formally assigned and documented.

An audit program should be established as a permanent part of the PQA

 and audits should be conducted periodically throughout the
preproduction life cycle phase to evaluate program implementation
and
effectiveness. The program should be updated as experience is gained
and
the need for improvement is noted.

As a minimum, the PQA program should include the following:

3.2 Specifications

Prior to the design activity, the design concept should be defined or

expressed in terms of its desired characteristics, such as physical,
chemical, performance, etc. Acceptable ranges or limits should be
provided for each characteristic to establish allowable variations
and
these should be expressed in terms that are readily measurable.\1\

\1\ For example, the pulse amplitude range for an external pacemaker
could be established as .5 to 28 mA at a lead of 1000 ohms, and
pulse
duration could be .1 to 9.9 ms.
 Once these characteristics are agreed upon as those desired for the
proposed device (i.e. the design aim) they should be translated into
written design specifications. These preliminary specifications
provide
the details from which the design can be developed, and controlled,
as
well as the means by which the design can be evaluated.
Specifications
should address, as applicable, such performance characteristics as
durability/reliability, precision, stability, purity, and others
necessary to fulfill the product's intended purpose. Specifications
should be reviewed and evaluated by appropriate qualified personnel
from organization elements such as Marketing, R& D, Quality,
Reliability, and Manufacturing.

3.2.1 System Compatibility

A device's compatibility with other devices in the intended operating

system should be addressed early in the design phase, to the extent
that compatibility is necessary to assure proper functioning of the
system, e.g., IV sets with infusion pumps, breathing circuits with
ventilators, disposable electrodes with cardiac monitors. The full
operating range of within-tolerance specifications for the mating
devices(s) should be considered, not merely nominal values.\2\

\2\ For example, a disposable blood tubing set was designed and
manufactured by Company A for use with Company B's dialysis machine.
The tubing was too rigid, such that when the air-embolism occlusion
safety system on the dialysis machine was at its lowest within-
specification force, the tubing would not necessarily occlude and air
could be passed to the patient. The tubing occluded fully under the
nominal occlusion force.

3.2.2 Design Changes

Changes made to the specifications during R& D that are accepted as

design changes should be documented and evaluated to assure that
they
accomplish the intended result and do not compromise safety or
effectiveness. Manufacturers may make undocumented changes during
preproduction clinical trials in response to suggestions or
criticisms
from clinicians. In the manufacturer's haste to satisfy the user,
changes are sometimes made without an evaluation of the overall
effect
on the device. Improving one characteristic of the device may have
an
unforeseen adverse effect on another.

The documentation of changes made to a device as it is developed

provides a complete history of the product design evolution and a
means
 by which each design change can be reviewed. This documentation can
be
invaluable for conducting investigations of design deficiencies which
may not be detected until after the finished device is in commercial
distribution.

3.3 Design Review

Device design should progress through clearly defined and planned

stages. For example, a new medical device could be designed in
planned
stages including concept, detail design, prototype, and pilot
production. Each medical device manufacturer should establish and
implement, as the cornerstone of the PQA program, an independent
assessment or review of the design at each stage, as the design
 matures, to assure conformance to design criteria and to identify
design weaknesses. The objective of design review is the early
detection
and remedy of design deficiencies. The earlier design review is
initiated, the sooner problems can be identified and the less costly
it
will be to implement corrective action. The assessment should include
a
formal review of subsystems, including software, when applicable,
components, packaging, labeling and support documentation such as
drawings, test specifications and instructions. The extent and
frequency of design review depends on the complexity and significance
of
the device studied. However, the assessment should extend beyond
merely
satisfying user requirements in order to assure that safety and
effectiveness goals are met.

A detailed, documented description of the design review program

should
be established, including organizational units involved, procedures
used, flow diagrams of the process, identification of documentation
required, a schedule, and a checklist of variables to be considered
and
evaluated.

Reviews should be objective, unbiased examinations by appropriately

trained personnel which include individuals other than those
responsible for the design. For example, design review should be
conducted by representatives of Manufacturing, Quality Assurance,
Engineering, Marketing, Servicing and Purchasing, as well as those
responsible for R& D. Design review should, as applicable and at the
appropriate stage, include those designated to conduct and monitor
preclinical and clinical studies. Provisions should be prescribed for
resolving differences of technical judgment. Review results should
be
well documented in report form and signed by designated individuals
as
complete and accurate. All changes made as a result of review
findings
should be documented. Reports should include conclusions and
recommended
followup and should be disseminated in a timely manner to appropriate
organizational elements, including management.

When corrective action is required, the action should be

appropriately
monitored, with responsibility assigned to assure that a follow-up
is
properly conducted. Schedules should be established for completing
corrective action. Quick fixes should be prohibited. These include
adjustments that may allow the device to perform adequately for the
 moment, but do not address the underlying cause. All design defects
should be corrected in a manner that will assure the problem will
not
recur. Design reviews should, when applicable, include failure mode
effects analysis.

3.3.1. Failure Mode Effects Analysis

Failure mode effects analysis (FMEA) should be conducted at the

beginning of the design effort and as part of each design review to
identify potential design weaknesses. The primary purpose of FMEA is
the early identification of potential design inadequacies that may
adversely affect safety and performance. Identified inadequacies can
then be eliminated or their effect (susceptibility) minimized through
design correction or other means.\3\

\3\ For example, a design review checklist could be constructed as

follows, with the review consisting of an evaluation of the design to
assure that each checklist item, as applicable, was adequately
addressed.
 physical characteristics and constraints
regulatory and voluntary standards requirements
safety needs of the user, need for failsafe characteristics
producibility of the design
functional and environmental requirements
inspectability and testability of the design, test
requirements
permissible maximum and minimum tolerances
acceptance criteria
selection of components
packaging requirements
labeling, including warnings, identification, user
instructions
shelflife, storage, stability requirements
possible misuse of the product that can be anticipated,
elimination of human induced failures
product serviceability/maintainability

FMEA is conducted by identifying, through failure analysis techniques,

significant defects that can occur and their probability of
occurrence,
and then defining the effect of these defects on product safety and
performance. When it is likely that a defect could adversely impact
safety and effectiveness, the design should be modified to eliminate
or
minimize the defect. For those potential defects that cannot be
corrected through redesign effort, special controls such as labeling
warnings, alarms, etc. should be provided.\4\ FMEA should include an
evaluation of possible human induced failures or defects.\5\, \6\

\4\ For example, one possible failure mode for an anesthesia machine
could be a sticking valve. If the valve's sticking could result in
over
or under-delivery of the desired anesthesia gas, a failsafe feature
should be incorporated into the design to prevent the wrong delivery,
or, if this is impractical, a suitable alarm system should be
included
to alert the user in time to take corrective action.

\5\ For example, defibrillator battery packs were recalled because of

an instance when the battery pack burst while being charged. The
batteries were designed to be trickle charged, but the user charged
the
batteries using a rapid charge. The result was a rapid buildup of gas
which could not be contained by the invented batteries. If a warning
label had been provided, or the batteries vented, the incident
probably
would not have happened.

\6\ In another example, a microprocessor controlled infusion pump

required an EPROM change because of the possibility of overinfusion.
It
 was determined that if the "volume remaining" was manually set to
zero
and the "flow rate" set to less than one ML/HR, the pump would
deliver
fluids at the previous flow rate setting which could be as high as
699
ML/HR.

Each potential failure mode should be considered in light of its

probability of occurrence and characterized as to the severity of
its
effect on reliability, safety, and effectiveness. Severity or
criticality levels are useful for establishing priorities for
corrective
action or engineering changes. For example, severity classifications
can be defined as follows:

Category I - Catastrophic - a failure

which
may cause death or
significant
 injury.

Category II - Critical - a failure which

may
result in minor injury.

Category III - Minor - a failure which will

result in no injury.

Typically, two failure mode analysis techniques are used: 1) Fault

Tree
Analysis; and 2) Failure Mode Effects Criticality Analysis.

3.3.1.1. Fault Tree Analysis

Fault tree analysis (FTA) is a deductive, "top-down" approach to

failure
mode analysis. First a system failure or safety hazard is assumed,
then
through the use of detailed logic diagrams, basic defects or events
are
identified that could cause the assumed system failure or safety
hazard. FTA is especially applicable to medical devices because
human/device interfaces can be taken into consideration, i.e., a
particular kind of adverse effect on a user such as electrical shock
can be assumed. Whether or not the event can occur, either due to
device defects or operator error, can then be determined. Once
defects
are identified, computational techniques are used to analyze the
basic
defects, determine failure mode probabilities, and establish severity
of
effect levels.

3.3.1.2. Failure Mode Effects Criticality Analysis

Failure mode effects criticality analysis (FMECA) is an inductive

"bottom-up" process which assumes basic defects at the component
level
and then determines the effects at higher levels of assembly.
Failure
modes are analytically induced into each component and failure
effects
are evaluated and noted, including severity and probability of
occurrence. FMECA can be performed using either actual failure data
derived from field failures or hypothesized failure modes derived
from
design analysis or other sources. In addition to providing
information
about failure cause and effect, FMECA provides a structured method
for
 proceeding component-by-component through the system to assess
failure
effects.

FMECA is described in MIL-STD-1629A "Procedures for Performing

Failure
Mode, Effects and Criticality Analysis" and on site training is
offered
by private firms.\7\ All Failure Mode Effects Analyses should be
conducted in accordance with a written protocol, with results and
recommendations documented and provided to the appropriate personnel
in
a timely manner. When design weaknesses are identified, consideration
should be made of other distributed devices in which the design
weakness may also exist.8 Appropriate corrective action should be
taken
as necessary to correct these design deficiencies.

\7\ For example, the ITT Research Institute, Turin Road North, P.O.
Box 180, Rome N.Y., 13440, phone 315-336-2539 offers a Reliability
Design Training Course to manufacturers which includes Failure Mode
Effects Analysis and Fault Tree Analysis Techniques.

\8\ For example, an anomaly which could result in an incorrect output

was discovered in a microprocessor used in a blood analysis
diagnostic
device at the prototype testing stage. This same microprocessor was
 used in other diagnostic machines already in commercial distribution.
A
review should have been made of the application of the microprocessor
in the already distributed devices to assure that the anomaly would
not
adversely affect performance.

.4 Reliability Assessment

When appropriate and applicable, a reliability assessment should be

made
for new and modified designs and acceptable failure rates
established.
Reliability assessment is the process of prediction and
demonstration
directed towards estimating the basic reliability of a device.

Prior to distribution, reliability assessment is initiated by

theoretical and statistical methods by first determining the
reliability of each component, then progressing upward, establishing
the reliability of each subassembly and assembly, until the
reliability
of the entire device or device system is established.\9\

\9\ For example, the following references apply to predicting the

reliability of electronic devices.
a)MIL-HDBK-217B Reliability Prediction of Electronic Equipment
b)MIL-STD-785B Reliability Program for Systems and Equipment
Development and Production.
c)Study of Reliability Prediction Techniques for Conceptional
Phases
of Development, RADC-TR-74-235, Rome Air Development Center.

The process of reliability assessment goes beyond merely making a

prediction and then waiting for field experience to prove or
disprove
the assessment.

Reliability assessment is a continuous process which includes

predicting, demonstrating reliability, analyzing data, then re-
predicting, re-demonstrating reliability re-analyzing data on a
continual basis. Reliability assessment should be considered an
essential part of the PQA program and should be used to estimate the
reliability of each new and modified design.

3.5 Parts and Materials Quality Assurance

All medical device manufacturers should establish and implement a

comprehensive parts and materials (P/M) quality assurance program
for
assuring that all P/M used in device designs have the reliability
necessary to achieve their intended purposes. This program should
 encompass the selection, specification, qualification and ongoing
verification of P/M quality.

P/M should be selected on the basis of their suitability for the

chosen
application, compatibility with other P/M and the environment, and
proven reliability. Conservative choices in selection of P/M are
characteristic of reliable devices. Standard proven P/M should be
used
as much as possible in lieu of unproven P/M.\10\

\10\ For example, a manufacturer of an intravenous administration set

used an unproven plastic raw material in the initial production of
molded connectors. After distribution, reports were received of the
tubing separating from the connectors. Investigation and analysis by
the manufacturer revealed that the unproven plastic material used to
 mold the connectors deteriorated with time causing a loss of bond
strength. The devices were subsequently recalled.

The safety and effectiveness of medical devices are determined by the

reliability of the P/M used in the finished device and their
application in the device design. Conducting an aggressive P/M
qualification and applications program is essential if the inherent
reliability established in the device design is to be achieved in the
finished device. An effective program also minimizes replacement or
repair costs and enhances product life.

A preferred P/M list should be established during the preliminary

design
stage and refined as the design progresses. This list should be
placed
under formal change control once the design is released for
production.
P/M should be classified according to the severity of their effect
on
reliability, safety and effectiveness should they fail or not achieve
their intended purpose. Emphasis on the use of high reliability P/M,
qualification, inspection, test and other methods of assuring
acceptability should be based on this classification, i.e., more
emphasis should be placed on assuring the acceptability of P/M whose
failure could result in injury.

The acceptability of P/M for their selected applications should be

supported by both calculated and observed test data. The degree of
testing necessary to provide assurance of adequate P/M performance
for
the chosen application depends on the severity of use conditions and
importance of the P/M function.\11\

\11\ For example, the spring used to achieve proper spindle operation
in a volume ventilator experiences thousands of cycles of compression
and expansion. Failure of the spring could result in respiratory
arrest. Therefore, the spring's ability to perform reliably under
these
conditions must be assured through comprehensive qualification
testing.
Operator and service manuals should cover appropriate preventive
maintenance.

Existing test or qualification data may be used for proven or

standard
P/M. However, when selecting P/M previously qualified, attention
should
be given to the currentness of the data, applicability of the
previous
qualification to the intended application, and adequacy of the
existing
P/M specification. Additional qualification should be conducted as
necessary.\12\
 \12\ For example, lubricant seals previously qualified for use in an
anesthesia gas circuit containing one anesthesia gas may not be
compatible with another gas. These components should be qualified for
each specific environment.

Failure of P/M during qualification to meet expected performance,

safety
and effectiveness objectives should be investigated and the results
described in written reports. These reports should be provided to
management and other appropriate personnel in a timely manner to
assure
that only qualified P/M are used. Failure analysis, when deemed
appropriate, should be conducted to a level that the failure
mechanism
can be identified.

The selection and qualification of P/M and their inclusion on a

qualified P/M list does not assure proper application. P/M
qualification only assures that the P/M can meet established
 specifications requirements. Proper application means the P/M must be
used in an application where it is not unduly stressed mechanically,
electrically, environmentally, etc.\13\ A thorough applications
review
should be conducted during the design phase and, when necessary,
adequate margins of safety should be established.

\13\ For example, a wholebody image device was recalled because

screws
used to hold the upper detector head sheared off, allowing the
detector
head to fall to its lowest position. The screws were well within
their
tolerances for all specified attributes. However, the application was
such that the screws did not possess sufficient shear strength for
the
intended use.

3.6 Software Quality Assurance

When a design incorporates software developed in-house, a software

quality assurance program should be in place which outlines a
systematic approach to software development. The program should
include
a protocol for formal review and validation of device software to
ensure
overall functional reliability.

There are many approaches to software quality assurance (SQA) and

some
of these are described in the software source documents referenced
at
the end of this document. However, they all involve some form of
measuring the development process at each phase, verifying that each
phase satisfies the requirements of the previous phase, validating
that
the output of each phase satisfies its requirements (which may
include
testing), documenting and controlling changes that are made, and
revalidating. Major goals of SQA are correctness, reliability,
testability, and maintainability.

SQA should begin with a plan, which can be written using a guide such
as
ANSI/IEEE Standard 730-1984, Standard for Software Quality Assurance
Plans. Good SQA assures quality software from the beginning of the
development cycle by specifying up front the required quality
attributes of the completed software and the acceptance testing to be
performed. In addition, the software should be written in
conformance
with a company standard using structured programming. The SQA
 representative or department should have the authority to enforce
implementation of SQA policies and recommendations.

When device manufacturers purchase custom software from contractors,

the
SQA should assure that the contractors have an adequate SQA program
that will assure software correctness, reliability, testing and
maintainability.

When manufacturers purchase software from vendors or subcontractors,

the
SQA should assure, through appropriate testing, that the software is
adequate for its intended application prior to use in production.

3.7 Labeling

A review of labeling should be included as part of the design review

process to assure that it is in compliance with applicable laws and
regulations and that adequate directions for the product's intended
use
are easily understood by the enduser group. Labeling includes manuals,
charts, inserts, panels, display labels, software for CRT display,
etc.
 Qualification testing of the device should include verification of
the
accuracy of instructions contained in the labeling.\14\ Qualification
should also include verification that labeling intended to be
permanently attached to the device will remain attached and legible
through processing, storage and handling for the useful life of the
device.

\14\ For example, after distribution, labeling had to be corrected

for
an infusion pump because there was danger of overinfusion if certain
flow charts were used. The problem existed because an error was
introduced in the charts when the calculated flow rates were
transposed
onto flow charts.

Maintenance manuals should be provided where applicable and should

provide adequate instructions whereby a user or service activity can
maintain the device in a safe and effective condition.

3.8 Design Technical Verification

Once the design is translated into physical form, its technical

adequacy, safety and reliability should be verified through
comprehensive documented testing under simulated or actual use
conditions.\15\

\15\ For example, an infusion pump was recalled due to overinfusion.

Investigation revealed that there was a compatibility problem between
the pump and IV set cassettes. The receptacle valve actuating stud
was
too short to properly activate the valves in the IV cassette. The
result was a free flow condition. If the pump had been tested with
the
IV sets recommended for use with the pump, the recall probably could
have been avoided.

Clinical trials should not begin until the safety of the device has
been verified under simulated use conditions, particularly at the
expected performance limits. Simulated use testing should address use
with other applicable devices and possible misuse. Manufacturers of
devices that are likely to be used in a home environment and operated
by persons with a minimum of training and experience have an
obligation
to anticipate the types of operator errors most likely to occur.
These
manufacturers should design and label their products to encourage
proper use and minimize the frequency of misuse.\16\

\16\ For example, an exhalation valve used in conjunction with a

ventilator could be connected in a reverse position because the inlet
and exhalation ports were the same diameter. In the reverse position
 the user could breath spontaneously but was isolated from the
ventilator. The valve should have been designed so that it could be
connected only in the proper position.

3.9 Design Transfer/Preproduction Qualification

Once the technical adequacy of the design has been verified through
applicable testing and the design has been approved, the approved
design including components, packaging and labeling is translated
into
approved, formal specifications. The device, however, is not yet
ready
to be released to manufacturing for routine production.

Before the specifications are released for routine production, actual

 finished devices should be manufactured using the approved
specifications, the same materials and components, the same or
similar
production and quality control equipment, and the methods and
procedures
that will be used for routine production. These devices should then
be
qualified through extensive testing under actual or simulated use
conditions and in the environment, or simulated environment, in
which
the device is expected to be used.

Caution should be taken when using prototypes developed in the

laboratory or machine shop as qualification units. Prototypes may not
be like the finished production device. During R& D, conditions are
typically better controlled and personnel more knowledgeable about
what
needs to be done and how to do it than are production personnel. When
going from laboratory to scaled-up production, standards or methods
and
procedures may not be properly transferred or additional
manufacturing
processes may be added. Often changes, not reflected in the prototype,
are made in the product to facilitate the manufacturing process.
Proper
qualification of devices that are produced using the same or similar
methods and procedures as those to be used in routine production can
prevent the distribution and subsequent recall of many unacceptable
medical devices.\17\

\17\ For example, a drainage catheter using a new Teflon material was
designed, fabricated and subsequently qualified in a laboratory
setting. Once the catheter was manufactured and distributed, however,
the manufacturer began receiving complaints that the bifurcated
sleeve
was separating from the catheter shrink base. Investigation found the
separation was due to dimensional shrinkage of the Teflon and
leeching
of the plasticizers from the sleeve due to exposure to Freon during
manufacturing. Had the device been exposed to actual production
conditions during fabrication of the prototypes, the problem may have
been detected before routine production and distribution.

Typically, testing under use conditions is the clinical or in-vivo

testing stage for devices requiring an Investigational Device
Exemption
(IDE), clinical studies to support a Premarket Notification, or
Premarket Approval (PMA) submission to FDA. When practical, clinical
testing should be conducted using devices produced under expected
routine production conditions. Otherwise, the clinically qualified
device will not be truly representative of production devices. Advice
from clinicians should be sought with respect to how the device will
actually be used. Testing should include stressing the device at its
performance and environmental specification limits.\18\
 \18\ For example, for an electrical device such as a cardiac monitor,
electrical stress testing should include: device On-Off cycling,
operation in accordance with all specified operating mode upper and
lower limits and performance cycles, input voltage variance above and
below the nominal value, and, in the presence of electrical noise
from
sources such as electrical beds and electrocautery machines and
electrostatic discharge.

Testing should be performed according to a documented test plan which

specifies the performance parameters to be measured, test sequence,
evaluation criteria, test environment, etc. Once the device is
qualified, all manufacturing, and quality assurance specifications
should be placed under formal change control.

Storage conditions should be considered when establishing

environmental
 test specifications for a device.\19\, \20\

\19\ For example, a surgical staple device was recalled because it

malfunctioned. Investigation found that the device malfunctioned
because of shrinkage of the plastic cutting ring due to sub-zero
conditions to which the device was exposed during shipping and
storage.

\20\ In another example, a potassium electrode for use with a

Sodium/Potassium Analyzer was recalled because of complaints of low
potassium level readings that were in error. Investigation
determined
that the solution that bathes the potassium electrode during shipping
and storage was the cause of the errant readings.

3.10 Certification

After initial production units have successfully passed preproduction

qualification testing, a formal technical review should be conducted
to
assure adequacy of the design, production, and quality assurance
procedures, and should include a determination of the:

resolution of any differences between the procedures and

standards used to produce the design while in R& D and
those
approved for production;

resolution of any differences between the approved device

specifications and the actual manufactured product;

validity of test methods used to determine compliance with

the
approved specifications; and

adequacy of the specification change control program.

3.11 Personnel

Design activities, including design review, analysis and testing

should
be conducted by appropriately trained and competent personnel.

3.12 Test Instrumentation

All equipment used in qualification of the design should be properly

calibrated and maintained under a formal calibration and maintenance
program.

3.13 Design Quality Monitoring

Once the design has been proven safe and effective and devices are
 produced and distributed, the effort to assure that the device and
its
components have acceptable quality and are safe and effective is not
complete.

Each medical device manufacturer, in order to comply with the medical

device GMP regulation, must have an effective program for:
identification and analysis of quality problems; taking appropriate
corrective action to prevent recurrence of these problems; and, the
timely internal reporting of problems discovered either in-house or
in
the field. Specific instructions should be established to provide
direction about when and how problems are to be investigated,
analyzed,
and corrected and responsibility for assuring initiation and
completion
 of these tasks.

A special effort should be made to assure that failure data obtained

from complaint and service records are made available and reviewed
by
those responsible for design.

-THE END-
(Prepared by the Manufacturing Quality Assurance Branch, (HFZ-332),
Division of Compliance Programs)

APPENDIX I

DEFINITIONS

Certification - a documented review and approval of

all qualification and validation
documentation carried out as a
final
step in the design quality
assurance
program prior to release of the
design for production.

Characteristic - a physical, chemical, visual,

functional or any other
identifiable
property of a medical device or
part
or material. (MIL-STD-109B)

Criticality - a relative measure of the

consequences of a failure mode and
its frequency of occurrence.
(MIL-
STD-1629A)

Defect - any non-conformance of a

characteristic with specified
requirements. (MIL-STD-109B)

Design Review - a planned, scheduled, and

documented
audit of all pertinent aspects of
the design that can affect
performance, safety or
effectiveness.

Design Specifications - a description of the physical and

functional requirements for an
article. In its initial form, the
 design specification is a
statement
of functional requirements with
only
general coverage of physical and
test requirements. The design
specification evolves through the
R& D
phase to reflect progressive
refinements in performance, design,
configuration and test
requirements.

Design Transfer - the transfer of the design basis

or
baseline into specifications for
the
device, its components, packaging,
labeling, and the manufacturing
and
quality assurance procedures,
methods, specifications, etc., so
 that the device can be produced
using
production methods.

Environment - the conditions, circumstances,

influences, stresses, surrounding
and
affecting the device during
storage,
handling, transportation,
installation and use. (MIL-
STD-1629A)

Failure - an event in which a previously

acceptable article does not
perform
one or more of its required
functions within the specified
limits
under specified conditions. (MIL-
STD
781C)

Failure Analysis - the logical, systematic

examination
of an item, including its diagrams
or formulas, to identify and
analyze
the probability, causes, and
consequences of potential and real
failures.

Failure Cause - the physical or chemical process,

design defect, quality defect,
com-
ponent misapplication, or other
processes which are the basic
reason
for failure or which initiate the
physical process by which deter-
ioration proceeds to failure.
(MIL-
STD-1629A)

Failure Effect - the consequences a failure has on

the
operation, function, or status of
a
device.

Failure Mode - the manner in which a failure is

 observed. The way a failure occurs
and its impact on the device
performance. (MIL-STD-109B)

Failure Mode and Effect Analysis - the process of identifying

potential
design weaknesses reviewing
schematics, engineering drawings,
etc., to identify basic faults at
the
part/material level and determine
their effect at finished or sub-
assembly level on safety and
effectiveness. (Reliability
Design
Handbook, RDG 376, Reliability
Analysis Center, Rome Air
Development
Center)

Failure Mode Analysys - identifying through systematic,

analytical methods the
consequences
of device defects.
 Failure Pattern - the occurrence of two or more
failures of the same component or
feature in identical or
equivalent
application which are caused by
the
same basic failure mechanism.
(MIL-
STD-781C)

Fault Tree Analysis - the process of identifying

potential
design weaknesses using a highly
detailed logic diagram depicting
basic faults and events that can
lead
to system failure and/or safety
hazard. (Reliability Design
Handbook, RDG 76, Reliability
Analysis Center, Rome Air
Development
Center)

Maintainability - the quality of the combined

features
of device design and installation
which facilitates the
accomplishment
of inspection, test, check-out,
servicing, repair, and overhaul
necessary to meet operational
object-
ives with a minimum of time, skill
and resources in the planned
maintenance environments.

Non-conformance - a condition of any device or

component in which one or more
characteristics do not conform to
requirements. Includes failures,
deficiencies, defects and
malfunctions.

Producibility - a measure of the extent to which

the
design can be readily produced
using
acceptable (usually standard)
production methods.

Qualification - a documented determination that a

device (and its associated
software),
 component, packaging or labeling,
meets all prescribed design and
performance requirements.

Quality - the composite of all the

characteristics, including
performance, of an item or
product.
(MIL-STD-109B)

Quality Assurance - a planned and systematic pattern

of
all actions necessary to provide
adequate confidence that the
device,
its components, packaging and
labeling are acceptable for their
intended use. (MIL-STD-109B)
 Reliability - the characteristic of a device, or
any component thereof, expressed
as
a probability that it will perform
its required functions under
defined
conditions for specified operating
periods.

Reliability a quantitative assessment of the

reliability of a device, system or
Prediction -portion thereof. Such
assessments
usually employ mathematical
modeling,
directly applicable results of
tests
on the device, failure data,
estimated reliability figures, and
non-statistical engineering
estimates. (Reliability Design
Handbook, RDG 376, Reliability
analysis Center, Rome Air
Development Center)

Severity - the consequences of a failure mode.

Severity considers the worst
potential consequences of a
failure,
determined by the degree of injury.

System - the principal functioning entities

comprising the device, e.g.,
hardware, software. Also an
organized
and disciplined approach to
accomplish a task, e.g., a failure
reporting system.

Testing - the determination by technical or

scientific means of the properties
or
elements of a device or its
components, including functional
operation, and involving the
application of established
scientific
principles and procedures.

APPENDIX II

REFERENCES
 MILITARY STANDARDS

1. MIL-STD-1629A "Procedures for Performing Failure

Mode, Effects and Criticality
Analysis"

2. MIL-STD-785B "Reliability Program for Systems

and
Equipment Development and
Production"

3. MIL-STD-109B "Quality Assurance Terms and

Definitions"
 4. MIL-STD-217B "Reliability Prediction of
Electronic
Equipment"

5. MIL-STD-472 "Maintainability Predictions"

6. MIL-STD-1521A "Technical Reviews and Audits for

Systems, Equipments, and Computer
Programs"

7. MIL-STD-781C "Reliability Design Qualification

and
Production Acceptance Tests:
Exponential Distribution."

8. MIL-STD-483 "Configuration Management"

NATIONAL AERONAUTICS AND SPACE ADMINISTRATION

1. NASA SP-6502 "Elements of Design Review for

Space
Systems"

2. NASA SP-6504 "Failure Reporting and Management

Techniques in the Surveyor
Program"

3. NHB 5300.4(A) "Reliability Program Provisions

for
Aeronautical and Space System
Contractors"

4. N68-10120 "Parts and Materials Application

Review for Space Systems"

5. N68-20357 "An Introduction to the Assurance

of
Human Performance in Space
Systems"

VOLUNTARY STANDARDS

1. ANSI/ASQC Z-1.15-1979 "Generic Guidelines for Quality

Systems"

2. ASQC C1-1968 "Specification of General

Requirements for a Quality
Program"

3. ANSI/IEEE STD 730-1984 "IEEE Standard for Software

Quality
Assurance Plans"
4. ANSI/IEEE STD 830-1981 "Guide to Software Requirements
Specifications"

QUALITY ASSURANCE LITERATURE

1. Caplan, Frank, "The Quality System, A Source-book for Managers and

Engineers"- Chilton, Radnor, Pa.

2. Juran, J.M., "Quality Control Handbook", 3rd edition - McGraw-Hill,

N.Y.

3. Fairly, Richard E., "Software Engineering Concepts," McGraw-Hill,

N.Y.
 4. LLoyd, David K. & Lipow, Myron, "Reliability: Management, Methods,
and Mathematics; Prentice-Hall, N.J.

5. O'Conner, Patrick D.T., "Practical Reliability Engineering", John

Wiley & Sons, N.Y.

OTHER

1. RDH-376 "Reliability Design Handbook" - Reliability Analysis

Center,
Rome Air Development Center, Griffiss Air Force Base, N.Y.

2. Bassen & Silverberg et al, "Computerized Medical Devices: Usage

Trends, Problems and Safety Technology", FDA Center for Devices and
Radiological Health, Silver Spring, Md.

3. NBS Special Publication 500-98 "Planning for Software Validation,

Verification, and Testing", November 1982.

4. NBS Special Publication 500-75 "Validation, Verification, and

Testing of Computer Software", February 1981.

5. NBS Special Publication 500-56 "Validation, Verification, and

Testing for the Individual Programmer", February 1980.

NBS Federal Information Processing Standards Publications (FIPS

PUBs):

1. FIPS PUB 38 "Guidelines for Documentation of Computer Programs

and
Automated Data Systems", February 1976.

2. FIPS PUB 64 "Guidelines for Documentation of Computer Programs,

and
Automated Data Systems for the Initiation Phase", August 1979.

3. FIPS PUB 101 "Guidelines for Lifecycle Validation, Verification,

and
Testing of Computer Software", June 1983.

gmP4-3

GUIDELINE ON GENERAL PRINCIPLES OF PROCESS VALIDATION

GUIDELINE ON GENERAL PRINCIPLES OF PROCESS VALIDATION

Page 17-61

GUIDELINE ON GENERAL PRINCIPLES OF PROCESS VALIDATION

 May 1987
Prepared by: Center for Drugs and Biologics and
Center for Devices and Radiological Health
Food and Drug Administration

Maintained by: Division of Manufacturing and Product Quality

(HFN-320) Center for Drugs and Biologics
 Food and Drug Administration
5600 Fishers Lane
Rockville, Maryland 20857

GENERAL PRINCIPLES OF PROCESS VALIDATION

I. PURPOSE

This guideline outlines general principles that FDA considers to be

acceptable elements of process validation for the preparation of
human
and animal drug products and medical devices.

II. SCOPE

This guideline is issued under Section 10.90 (21 CFR 10.90) and is
applicable to the manufacture of pharmaceuticals and medical devices.
It
states principles and practices of general applicability that are
not
legal requirements but are acceptable to the FDA. A person may rely
upon this guideline with the assurance of its acceptability to FDA,
or
may follow different procedures. When different procedures are used,
a
person may, but is not required to, discuss the matter in advance
with
the FDA to prevent the expenditure of money and effort on activities
that may later be determined to be unacceptable. In short, this
guideline lists principles and practices which are acceptable to the
FDA for the process validation of drug products and medical devices;
it
does not list the principles and practices that must, in all
instances,
be used to comply with law.

This guideline may be amended from time to time. Interested persons

are
invited to submit comments on this document and any subsequent
revisions. Written comments should be submitted to the Dockets
Management Branch (HFA-305), Food and Drug Administration, Rm. 4-62,
5600 Fishers Lane, Rockville, Maryland 20857. Received comments may
be
seen in that office between 9:00 a.m. and 4:00 p.m. Monday through
Friday.

III. INTRODUCTION

Process validation is a requirement of the Current Good Manufacturing

Practices Regulations for Finished Pharmaceuticals, 21 CFR Parts 210
and 211, and of the Good Manufacturing Practices Regulations for
 Medical Devices, 21 CFR Part 820, and therefore, is applicable to
the
manufacture of pharmaceuticals and medical devices.

Several firms have asked FDA for specific guidance on what FDA
expects
firms to do to assure compliance with the requirements for process
validation. This guideline discusses process validation elements and
concepts that are considered by FDA as acceptable parts of a
validation
program. The constituents of validation presented in this document
are
not intended to be all inclusive. FDA recognizes that, because of
the
great variety of medical products (drug products and medical
devices),
processes and manufacturing facilities, it is not possible to state
in
one document all of the specific validation elements that are
applicable. Several broad concepts, however, have general
applicability
which manufacturers can use successfully as a guide in validating a
manufacturing process. Although the particular process validation
will
vary according to such factors as the nature of the medical product
 (e.g., sterile vs non-sterile) and the complexity of the process,
the
broad concepts stated in this document have general applicability
and
provide an acceptable framework for building a comprehensive approach
to
process validation.

DEFINITIONS

Installation Qualification - Establishing confidence that process

equipment and ancillary systems are capable of consistently
operating
within established limits and tolerances.

Process Performance Qualification - Establishing confidence that the

process is effective and reproducible.

Product Performance Qualification - Establishing confidence through

appropriate testing that the finished product produced by a
specified
process(es) meets all release requirements for functionality and
safety.

Prospective Validation - Validation conducted prior to the

distribution
of either a new product, or product made under a revised
manufacturing
process, where the revisions may affect the product's
characteristics.

Retrospective Validation - Validation of a process for a product

already
in distribution based upon accumulated production, testing and
control
data.

Validation - Establishing documented evidence which provides a high

degree of a high degree of assurance that a specific process will
consistently produce a product meeting its predetermined
specifications
and quality attributes.

Validation Protocol - A written plan stating how validation will be

conducted, including test parameters, product characteristics,
production equipment and decision points on what constitutes
acceptable
test results.

Worst Case - A set of conditions encompassing upper and lower

processing
limits and circumstances, including those within standard operating
procedures, which pose the greatest chance of process or product
 failure when compared to ideal conditions. Such conditions do not
necessarily induce product or process failure.

IV. GENERAL CONCEPTS

Assurance of product quality is derived from careful attention to a

number of factors including selection of quality parts and materials,
adequate product and process design, control of the process, and in-
process and end-product testing. Due to the complexity of today's
medical products, routine end-product testing alone often is not
sufficient to assure product quality for several reasons. Some end-
product tests have limited sensitivity. \1\ In some cases destructive
testing would be required to show the manufacturing process was
adequate and in other situations end-product testing does not reveal
all variations that may occur in the product that may impact on
safety
and effectiveness.\2\

\1\ For example, USP XX states: "No sampling plan for applying
 sterility tests to a specified proportion of discrete units selected
from a sterilization load is capable of demonstrating with complete
assurance that all of the untested units are in fact sterile."

\2\ As an example, in one instance a visual inspection failed to

detect
a defective structural weld which resulted in the failure of an
infant
warmer. The defect could only have been detected by using destructive
testing or expensive test equipment.

Process validation is a key element in assuring that these quality

assurance goals are met.

The basic principles of quality assurance have as their goal the

production of articles that are fit for their intended use. These
principles may be stated as follows:

(1) quality, safety, and effectiveness must be designed and

built
into the product;

(2) quality cannot be inspected or tested into the finished

product; and,

(3) each step of the manufacturing process must be controlled

to
maximize the probability that the finished product meets
all
quality and design specifications.

It is through careful design and validation of both the process and

process controls that a manufacturer can establish a high degree of
confidence that all manufactured units from successive lots will be
acceptable. Successfully validating a process may reduce the
dependence
upon intensive in-process and finished-product testing. It should be
noted that in most all cases, end-product testing plays a major role
in
assuring that quality assurance goals are met; i.e., validation and
end-product testing are not mutually exclusive.

The FDA defines process validation as follows:

Process validation is establishing documented evidence which

provides a high degree of assurance that a specific process will
consistently produce a product meeting its predetermined
specifications and quality characteristics.

It is important that the manufacturer prepare a written validation

protocol which specifies the procedures (tests) to be conducted and
the
 data to be collected. The purpose for which data are collected must
be
clear, the data must reflect facts, and the data must be collected
carefully and accurately. The protocol should specify a sufficient
number of replicate process runs to demonstrate reproducibility and
provide an accurate measure of variability among successive runs.
The
test condition for these runs should encompass upper and lower
processing limits and circumstances, including those within standard
operating procedures, which pose the greatest chance of process or
product failure compared to ideal conditions; such conditions have
become widely known as "worst case" conditions. (These are sometime
called "most appropriate challenge" conditions.) Validation
documentation should include evidence of the suitability of
materials
and the performance and reliability of equipment and systems.

Key process variables should be monitored and documented. Analysis of

 the data collected from monitoring will establish the variability of
process parameters for individual runs and will establish whether or
not the equipment and process controls are adequate to assure that
product specifications are met.

Finished product and in-process test data can be of value in process

validation, particularly in those situations where quality
attributes
and variabilities can be readily measured. Where finished (or in-
process) testing cannot adequately measure certain attributes,
process
validation should be derived primarily from qualification of each
system
used in production and from consideration of the interaction of the
various systems.

V. CGMP REGULATIONS FOR FINISHED PHARMACEUTICALS

Process validation is required in both general and specific terms, by

the Current Good Manufacturing Practice Regulation for Finished
Pharmaceuticals, 21 CFR Parts 210 and 211. Examples of such
requirements are listed below for informational purposes, and are not
all inclusive.

A requirement for process validation is set forth in general terms in

21
CFR 211.100 -- Written procedures; deviations -- which states, in
part:

"There shall be written procedures for production and process

control designed to assure that the drug products have the
identity, strength, quality, and purity they purport or are
represented to possess."

Several sections of the CGMP regulations state validation

requirements
in more specific terms. Excerpts from some of these sections are:

Section 211.110, Sampling and testing of in-process materials and

drug
products.
(a) "...control procedures shall be established to monitor the
output and VALIDATE the performance of those manufacturing
processes that may be responsible for causing variability in the
characteristics of in-process material and the drug product."
(emphasis added)

Section 211.113, Control of Microbiological Contamination.

(b) "Appropriate written procedures, designed to prevent

microbiological contamination of drug products purporting to be
sterile, shall be established and followed. Such procedures
shall
 include VALIDATION of any sterilization process." (emphasis
added)

VI. GMP REGULATION FOR MEDICAL DEVICES

Process validation is required by the medical device CGMP Regulation,

21
CFR 820. Section 820.5 requires every finished device manufacturer
to:

"...prepare and implement a quality assurance program that is

appropriate to the specific device manufactured..."

Section 820.3(n) defines quality assurance as:

 "...all activities necessary to verify confidence in the quality
of
the process used to manufacture a finished device."

When applicable to a specific process, process validation is an

essential element in establishing confidence that a process will
consistently produce a product meeting the designed quality
characteristics.

A generally stated requirement for process validation is contained in

Section 820.100:

"Written manufacturing specifications and processing procedures

shall be established, implemented, and controlled to assure that
the device conforms to its original design or any approved
changes
in that design."

Validation is an essential element in the establishment and

implementation of a process procedure, as well as in determining
what
process controls are required in order to assure conformance to
specifications.

Section 820.100(a)(1) states:

"...control measures shall be established to assure that the

design
basis for the device, components and packaging is correctly
translated into approved specifications."

Validation is an essential control for assuring that the

specifications
for the device and manufacturing process are adequate to produce a
device that will conform to the approved design characteristics.

VII. PRELIMINARY CONSIDERATIONS

A manufacturer should evaluate all factors that affect product

quality
when designing and undertaking a process validation study. These
factors may vary considerably among different products and
manufacturing technologies and could include, for example, component
specifications, air and water handling systems, environmental
controls,
equipment functions, and process control operations. No single
approach
to process validation will be appropriate and complete in all cases;
however, the following quality activities should be undertaken in
most
situations.

During the research and development (R& D) phase, the desired

 product should be carefully defined in terms of its characteristics,
such as physical, chemical, electrical, and performance
characteristics.\3\ It is important to translate the product
characteristics into specifications as a basis for description and
control of the product.

\3\ For example, in the case of a compressed tablet, physical

characteristics would include size, weight, hardness, and freedom
from
defects, such as capping and splitting. Chemical characteristics
would
include quantitative formulation/potency; performance characteristics
may include biovailability (reflected by disintegration and
dissolution). In the case of blood tubing, physical characteristics
would include internal and external diameters, length and color.
Chemical characteristics would include raw material formulation.
Mechanical properties would include hardness and tensile strength;
 performance characteristics would include biocompatibility and
durability.

The product's end use should be a determining factor in the

development
of product (and component) characteristics and specifications. All
pertinent aspects of the product which impact on safety and
effectiveness should be considered. These aspects include performance,
reliability and stability. Acceptable ranges or limits should be
established for each characteristic to set up allowable
variations.\4\
These ranges should be expressed in readily measurable terms.

\4\ For example, in order to assure that an oral, ophthalmic, or

parenteral solution has an acceptable pH, a specification may be
established by which a lot is released only if it has been shown to
have a pH within a narrow established range. For a device, a
specification for the electrical resistance of a pacemaker lead would
be established so that the lead would be acceptable only if the
resistance was within a specified range.

Documentation of changes made during development provide traceability

which can later be used to pinpoint solutions to future problems.

The validity of acceptance specifications should be verified through

testing and challenge of the product on a sound scientific basis
during
the initial development and production phase.

Once a specification is demonstrated as acceptable it is important

that
any changes to the specification be made in accordance with
documented
change control procedures.

VIII. ELEMENTS OF PROCESS VALIDATION

A. Prospective Validation

Prospective validation includes those considerations that should be

made
before an entirely new product is introduced by a firm or when there
is
a change in the manufacturing process which may affect the product's
characteristics, such as uniformity and identity. The following are
considered as key elements of prospective validation.

1. Equipment and Process

The equipment and process(es) should be designed and/or selected so

that
product specifications are consistently achieved. This should be done
with the participation of all appropriate groups that are concerned
 with assuring a quality product, e.g., engineering design,
production
operations, and quality assurance personnel.

a. Equipment: Installation Qualification

Installation qualification studies establish confidence that the

process equipment and ancillary systems are capable of consistently
operating within established limits and tolerances. After process
equipment is designed or selected, it should be evaluated and tested
to
verify that it is capable of operating satisfactorily within the
operating limits required by the process.\5\ This phase of validation
includes examination of equipment design; determination of
calibration,
maintenance, and adjustment requirements; and identifying critical
equipment features that could affect the process and product.
 Information obtained from these studies should be used to establish
written procedures covering equipment calibration, maintenance,
monitoring and control.

\5\Examples of equipment performance characteristics which may be

measured include temperature and pressure of injection molding
machines; uniformity of speed for mixers; temperature, speed, and
pressure for packaging machines; and temperature and pressure of
sterilization chambers.

In assessing the suitability of a given piece of equipment, it is

usually insufficient to rely solely upon the representations of the
equipment supplier, or upon experience in producing some other
product.\6\ Sound theoretical and practical engineering principles
and
considerations are a first step in the assessment.

\6\ The importance of assessing equipment suitability based upon how

it
will be used to attain desired product attributes is illustrated in
the
case of deionizers used to produce Purified Water, USP. In one case,
a
firm used such water to make a topical drug product solution which,
in
view of its intended use, should have been free from objectionable
microorganisms. However, the product was found to be contaminated
with
a pathogenic microorganism. The apparent cause of the problem was
failure to assess the performance of the deionizer from a
microbiological standpoint. It is fairly well recognized that
deionizers are prone to build-up of microorganisms -- especially if
the
flow rates are low and the deionizers are not recharged and sanitized
at suitable intervals. Therefore, these factors should have been
considered. In this case, however, the firm relied upon the
representations of the equipment itself, namely the "recharge" (i.e.
conductivity) indicator, to signal the time for regeneration and
cleaning. Considering the desired product characteristics, the firm
should have determined the need for such procedures based upon pre-
use
testing, taking into account such factors as the length of time the
equipment could produce deionized water of acceptable quality, flow
rate, temperature, raw water quality, frequency of use, and surface
area of deionizing resins.

It is important that equipment qualification simulate actual

production conditions, including those which are "worst case"
situations.

Tests and challenges should be repeated a sufficient number of times

to
 assure reliable and meaningful results. All acceptance criteria must
be
met during the test or challenge. If any test or challenge shows that
the equipment does not perform within its specifications, an
evaluation
should be performed to identify the cause of the failure.
Corrections
should be made and additional test runs performed, as needed, to
verify
that the equipment perform within specifications. The observed
variability of the equipment between and within runs can be used as a
basis for determining the total number of trials selected for the
subsequent performance qualification studies of the process.\7\

\7\ For example, the AAMI Guideline for Industrial Ethylene Oxide
Sterilization of Medical Devices approved 2 December 1981, states:
"The performance qualification should include a minimum of 3
successful, planned qualification runs, in which all of the
acceptance
criteria are met.....(5.3.1.2.)."
 Once the equipment configuration and performance characteristics are
established and qualified, they should be documented. The
installation
qualification should include a review of pertinent maintenance
procedures, repair parts lists, and calibration methods for each
piece
of equipment. The objective is to assure that all repairs can be
performed in such a way that will not affect the characteristics of
material processed after the repair. In addition, special post-
repair
cleaning and calibration requirements should be developed to prevent
the
inadvertent manufacture of nonconforming product. Planning during the
qualification phase can prevent confusion during emergency repairs
which could lead to use of the wrong replacement part.

b. Process: Performance Qualification

The purpose of performance qualification is to provide rigorous

testing
to demonstrate the effectiveness and reproducibility of the process.
In
entering the performance qualification phase of validation, it is
understood that the process specifications have been established and
essentially proven acceptable through laboratory or other trial
methods
and that the equipment has been judged acceptable on the basis of
suitable installation studies.

Each process should be defined and described with sufficient

specificity so that employees understand what is required. Parts of
the
process which may vary so as to affect important product quality
should
be challenged.\8\

\8\ For example, in electroplating the metal case of an implantable

pacemaker, the significant process steps to define, describe, and
challenge include the establishment and control of current density
and
temperature values for assuring adequate composition of electrolyte
and
for assuring cleanliness of the metal to be plated. In the production
of parenteral solutions by aseptic filling, the significant aseptic
filling process steps to define and challenge should include the
sterilization and depyrogenation of containers/closures,
sterilization
of solutions, filling equipment and product contact surfaces, and the
filling and sealing of containers.

In challenging a process to assess adequacy, it is important that

challenge conditions simulate those that will be encountered during
actual production, including "worst case" conditions. The challenges
 should be repeated enough times to assure that the results are
meaningful and consistent. Each specific manufacturing process should
be appropriately qualified and validated. There is an inherent danger
in relying on what are perceived to be similarities between products,
processes, and equipment without appropriate challenge.\9\

\9\ For example, in the production of a compressed tablet, a firm may

switch from one type of granulation blender to another with the
erroneous assumption that both types have similar performance
characteristics, and, therefore, granulation mixing times and
procedures need not be altered. However, if the blenders are
substantially different, use of the new blender with procedures used
for the previous blender may result in a granulation with poor
content
uniformity. This, in turn, may lead to tablets having significantly
differing potencies. This situation may be averted if the quality
assurance system detects the equipment change in the first place,
challenges the blender performance, precipitates a revalidation of
the
process, and initiates appropriate changes. In this example,
 revalidation comprises installation qualification of the new
equipment
and performance qualification of the process intended for use in the
new blender.

c. Product: Performance Qualification

For purposes of this guideline, product performance qualification

activities apply only to medical devices. These steps should be
viewed
as preproduction quality assurance activities.

Before reaching the conclusion that a process has been successfully

validated, it is necessary to demonstrate that the specified process
has not adversely affected the finished product. Where possible,
product performance qualification testing should include performance
testing under conditions that simulate actual use. Product
performance
qualification testing should be conducted using product manufactured
from the same type of production equipment, methods and procedures
that
will be used for routine production. Otherwise, the qualified product
may not be representative of production units and cannot be used as
evidence that the manufacturing process will produce a product that
meets the predetermined specifications and quality attributes. \10\

\10\ For example, a manufacturer of heart valves received complaints

that the valve-support structure was fracturing under use.
Investigation by the manufacturer revealed that all material and
dimensional specifications had been met but the production machining
process created microscopic scratches on the valve supporting
wireform.
These scratches caused metal fatigue and subsequent fracture.
Comprehensive fatigue testing of production units under simulated use
conditions could have detected the process deficiency.
In another example, a manufacturer recalled insulin syringes
because of complaints that the needles were clogged. Investigation
revealed that the needles were clogged by silicone oil which was
employed as a lubricant during manufacturing. Investigation further
revealed that the method used to extract the silicone oil was only
partially effective. Although visual inspection of the syringes
seemed
to support that the cleaning method was effective, actual use proved
otherwise.

After actual production units have successfully passed product

performance qualification, a formal technical review should be
conducted and should include:

Comparison of the approved product specifications and the

actual qualified product.

Determination of the validity of test methods used to

 determine compliance with the approved specifications.

Determination of the adequacy of the specification change

control program.

2. System to Assure Timely Revalidation

There should be a quality assurance system in place which requires

revalidation whenever there are changes in packaging, formulation,
equipment, or processes which could impact on product effectiveness
or
product characteristics, and whenever there are changes in product
 characteristics. Furthermore, when a change is made in a raw material
supplier, the manufacturer should consider subtle, potentially
adverse
differences in the raw material characteristics. A determination of
adverse differences in raw material indicates a need to revalidate
the
process.

One way of detecting the kind of changes that should initiate

revalidation is the use of tests and methods of analysis which are
capable of measuring characteristics which may vary. Such tests and
methods usually yield specific results which go beyond the mere
pass/fail basis, thereby detecting variations within product and
process specifications and allowing determination of whether a
process
is slipping out of control.

The quality assurance procedures should establish the circumstances

under which revalidation is required. These may be based upon
equipment, process, and product performance observed during the
initial
validation challenge studies. It is desirable to designate
individuals
who have the responsibility to review product, process, equipment,
and
personnel changes to determine if and when revalidation is warranted.

The extent of revalidation will depend upon the nature of the changes
and how they impact upon different aspects of production that had
previously been validated. It may not be necessary to revalidate a
process from scratch merely because a given circumstance has changed.
However, it is important to carefully assess the nature of the change
to
determine potential ripple effects and what needs to be considered
as
part of revalidation.

3. Documentation

It is essential that the validation program is documented and that

the
documentation is properly maintained. Approval and release of the
process for use in routine manufacturing should be based upon a
review
of all the validation documentation, including data from the
equipment
qualification, process performance qualification, and product/package
performance testing to ensure compatibility with the process.

For routine production, it is important to adequately record process

details (e.g., time, temperature, equipment used) and to record any
changes which have occurred. A maintenance log can be useful in
performing failure investigations concerning a specific manufacturing
lot. Validation data (along with specific test data) may also
 determine expected variance in product or equipment characteristics.

B. Retrospective Process Validation

In some cases a product may have been on the market without

sufficient
premarket process validation. In these cases, it may be possible to
validate, in some measure, the adequacy of the process by
examination
of accumulated test data on the product and records of the
manufacturing
procedures used.

Retrospective validation can also be useful to augment initial

premarket
prospective validation for new products or changed processes. In such
cases, preliminary prospective validation should have been
sufficient
to warrant product marketing. As additional data is gathered on
production lots, such data can be used to build confidence in the
adequacy of the process. Conversely, such data may indicate a
declining
 confidence in the process and a commensurate need for corrective
changes.

Test data may be useful only if the methods and results are
adequately
specific. As with prospective validation, it may be insufficient to
assess the process solely on the basis of lot by lot conformance to
specifications if test results are merely expressed in terms of
pass/fail. Specific results, on the other hand, can be statistically
analyzed and a determination can be made of what variance in data can
be expected. It is important to maintain records which describe the
operating characteristics of the process, e.g., time, temperature,
humidity, and equipment settings.\11\ Whenever test data are used to
demonstrate conformance to specifications, it is important that the
test methodology be qualified to assure that test results are
objective
and accurate.

\11\ For example, sterilizer time and temperature data collected on

recording equipment found to be accurate and precise could establish
that process parameters had been reliably delivered to previously
processed loads. A retrospective qualification of the equipment could
be performed to demonstrate that the recorded data represented
conditions that were uniform throughout the chamber and that product
load configurations, personnel practices, initial temperature, and
other variables had been adequately controlled during the earlier
runs.

IX. ACCEPTABILITY OF PRODUCT TESTING

In some cases, a drug product or medical device may be manufactured

individually or on a one-time basis. The concept of prospective or
retrospective validation as it relates to those situations may have
limited applicability, and data obtained during the manufacturing and
assembly process may be used in conjunction with product testing to
demonstrate that the instant run yielded a finished product meeting
all
of its specifications and quality characteristics. Such evaluation
of
data and product testing would be expected to be much more extensive
than the usual situation where more reliance would be placed on
prospective validation.

GOVERNMENT-WIDE QUALITY ASSURANCE PROGRAM

GOVERNMENT-WIDE QUALITY ASSURANCE PROGRAM

17-73

GOVERNMENT-WIDE QUALITY ASSURANCE PROGRAM

 The Food and Drug Administration (FDA) plays a special role
through its "Government-Wide Quality Assurance Program" (GWQAP)
regarding devices that are sold to government agencies. In the early
1970's the Office of Management and Budget (OMB) and the General
Accounting Office (GAO) conducted separate studies. Both concluded
that
to reduce duplication and costs, FDA should be the sole agency
responsible for quality assurance support of government procurement
of
medical products. Since late 1981, FDA has phased in general medical
device procurement activities under separate interagency agreements
with
 the Department of Defense (DOD), Veterans Administration (VA) and the
Health Resources and Services Administration (HRSA). Before 1981, FDA
was already supporting the procurement of in vitro diagnostic
products
and drugs under agreement with these agencies.

Firms wishing to become government suppliers:

must comply with all applicable requirements of the

medical
device amendments to the Food, Drug, and Cosmetic (FD& C)
Act,
i.e., register, list, submit a premarket notification,
operate under a good manufacturing practices (GMP) program,
etc.; and,

should contact the agency or department involved to obtain

information on the bid process. (Addresses and phone
numbers
for DOD, VA and HRSA are at the end of this article.)

In general, the government uses a solicitation process to

identify
the most responsible low bidder for a product to be purchased. The
solicitation contains a description of the desired product or
products
and any specifications which must be met by the supplier. As part of
the
solicitation process, FDA provides recommendations to the contracting
officer of the procuring agency regarding the capability of a
potential
contractor and subcontractors to supply a high quality product.
Responsibility for determining whether a firm meets contractual
requirements for such areas as finance, Equal Employment Opportunity
(EEO), etc., is still the responsibility of the purchasing agency.

The purchasing agency's contracting officer makes the final

acceptance decision for the government based on contractual
requirements
and FDA information.

The FDA information consists of an evaluation of the bidders'

ability to meet bid specifications. In the first step of this
evaluation, FDA receives a written request for evaluation of a firm
from
the purchasing agency. The request identifies the product and all
involved manufacturing and packaging locations. Each request results
in
a review of available agency information such as registration/listing,
inspection history, premarket approval information, etc. If available
information is not sufficient to make a conclusion, as might be the
case
 if previous GMP inspections were not concerned with the type of
product
being purchased, FDA may re-inspect the supplier(s) to determine
compliance with the GMP regulation.

GMP inspections requested under GWQAP are conducted by FDA

investigators using profile classes. A profile class is simply a
designation for a particular process. Metals fabrication or assembly
(abbreviated MTL) would indicate the processes used to fabricate or
assemble metal components of finished devices. Thus, if a previous
inspection did not cover the profile class or classes for the product
being purchased, a new inspection may be needed.

The latest device GMP Inspection Compliance Program CP 7378.830,

December 1989, now requires an investigator to cover all, or as many
as
possible, profile classes at a firm. This approach should reduce the
number of GWQAP initiated inspections, because it is likely that the
profile classes for the desired product will have been covered during
previous GMP
 factory inspections. The firm will be found not acceptable if
significant GMP deficiencies are noted during an inspection, and FDA
is
contemplating action such as a warning letter, seizure, injunction,
or
prosecution. If inspection determines a firm does not currently have
the
equipment and controls necessary to begin manufacturing the requested
product, FDA will
not provide an evaluation to the purchasing agency. This is not
considered a rejection of the firm -- merely a finding that FDA
cannot
properly evaluate a firm's operations.

On some occasions, FDA will not provide an evaluation to an

agency
because key information is lacking. This situation occurs mainly with
products that require expiration dating either because of an FDA
regulation, or because expiration dating is a requirement in the
contract for the particular product. When the data or additional
information is received, FDA will review the new information and
respond
to the requesting agency.

Under the GWQAP program, FDA may advise the requesting agency
that a
firm has not met all the requirements of the device regulations. If,
for
instance, a firm is not registered, FDA will advise the requesting
agency. This agency then informs the manufacture which FDA
requirement
must be met before the evaluation can continue. After the
manufacturer
has complied
with the requirement, FDA review of available information will
continue
in order to determine if the firm is or is not acceptable.

After the purchasing agency's contracting officer awards the

contract and for the duration of the contract, FDA monitors the
firm's
compliance with the bid specifications, FD& C Act and regulations. If
the
contracts for DOD are designated as "source acceptance / inspection,"
FDA is responsible for accepting the shipment(s) on behalf of the
government. This acceptance procedure can be done by an on-site visit
to
the firm or by mail at the discretion of the appropriate FDA Field
Office. On-site visits for acceptance purposes involve the
examination
of the product, labeling, packaging/packing and military markings to
ensure these comply with all contractual and FDA requirements. If the
 product complies, FDA will sign DD Form 250 which authorizes a firm
to
ship the product to government depots. If the product deviates from
contractual or FDA requirements, FDA does not sign the DD Form 250
and
reports the deficiencies to DOD. Contractual deviations are resolved
with the firm by DOD. Deviations from FDA requirements must await
final
FDA resolution, at which time an accept or reject is reported to DOD.
If
DOD contracts are designated "destination acceptance" (acceptance by
DOD
at the depot), they do not involve FDA examination. The VA and HRSA
contract shipments are accepted at the final destination.

FDA also reviews and evaluates complaints received from a

purchasing
agency. FDA evaluates complaints for validity and will follow up if
the
product appears to be in violation of the FD& C Act. FDA will
recommend
followup or testing to determine compliance with contract-related
requirements.

For further information relating to FDA's responsibilities under

this program, please contact:

Chief, Device Section

 Medical Products Quality Assurance Staff
Food and Drug Administration
5600 Fishers Lane
Rockville, Maryland 20857
301-443-3590

For information specific to the medical device regulations, you

may
contact:

Chief
Government Wide Quality Assurance Program, HFZ-331
Center for Devices and Radiological Health
1390 Piccard Drive
Rockville, Maryland 20850
301-427-1125

For information on requirements for qualification as a government

supplier, please contact:

Department of Defense
Defense Personnel Support Center
Small Business Advisor
2800 South 20th Street
Philadelphia, Pennsylvania 19101
215-737-2321

Veterans Administration
Marketing Center
Small Business Center
Hines, Illinois 60141
708-216-2438

Health Resources and Services Administration

Chief, Contracts Branch
5600 Fishers Lane
Rockville, Maryland 20857
301-443-2750