Synopsis: FDA Process Validation Guidance

LOGFILE Nr.
3 / Februar 2011 Maas & Peither AG – GMP-Verlag
Synopsis:
FDA Process Validation Guidance
This synopsis is a comparison of the draft version 2008 and the final version 2011 of the U.S.
FDA Guidance “Process Validation: General Principles and Practices”. The synopsis illus-
trates the differences between the two versions. This document helps you to get a quick
overview of the changes in detail.
Legend:
Yellow underlaid paragraphs have been revised or are new.
Underlined parts have been added compared to the prior version.
Cancelled parts in the prior version have been deleted in the new version.
Guidance for Industry

Process Validation: General Principles and Practices
Final Version January 2011 Draft 2008
I. INTRODUCTION I. INTRODUCTION
This guidance outlines the general principles This guidance outlines the general principles
and approaches that FDA considers appro- and approaches that FDA considers to be
priate elements of process validation for the appropriate elements of process validation
manufacture of human and animal drug and for the manufacture of human and animal
biological products, including active pharma- drug and biological products, including active
ceutical ingredients (APIs or drug sub- pharmaceutical ingredients (API or drug sub-
stances), collectively referred to in this guid- stance), collectively referred to in this guid-
ance as drugs or products. This guidance ance as drugs or products. This guidance
incorporates principles and approaches that incorporates principles and approaches that
all manufacturers can use to validate manu- all manufacturers can use in validating a
facturing processes. manufacturing process.
This guidance aligns process validation This guidance aligns process validation activ-
activities with a product lifecycle concept ities with the product lifecycle concept and
2
and with existing FDA guidance, including with existing FDA guidance.
the FDA/International Conference on Har-
monisation (ICH) guidances for industry, 2
See the FDA/International Conference on Har-
Q8(R2) Pharmaceutical Development, Q9 monisation (ICH) guidances for industry: Q8
Quality Risk Management, and Q10 Pharma- Pharmaceutical Development, Q9 Quality Risk
ceutical Quality System.2 Although this guid- Management, and when finalized, Q10 Pharma-
ance does not repeat the concepts and prin- ceutical Quality System (a notice of availability for
ciples explained in those guidances, FDA the May 2007 ICH draft guidance, Q10 Pharma-
encourages the use of modern pharmaceuti- ceutical Quality System, published in the Federal
Register on July 13, 2007 (72 FR 38604)). We
cal development concepts, quality risk man-
http://www.gmp-verlag.de
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agement, and quality systems at all stages of update guidance documents periodically. To
the manufacturing process lifecycle. make sure you have the most recent version of a
guidance, check the CDER guidance page at
2 http://www.fda.gov/cder/guidance/index.htm, the
To make sure you have the most recent version
of a guidance, check the CDER guidance page at CBER guidance page at
http://www.fda.gov/Drugs/GuidanceComplianceR http://www.fda.gov/cber/guidelines.htm, or the
egulatoryInformation/Guidances/default.htm, the CVM guidance page at
CBER guidance page at http://www.fda.gov/cvm/Guidance/published.htm.
http://www.fda.gov/BiologicsBloodVaccines/Guida
nceComplianceRegulatoryInforma-
tion/Guidances/default.htm, or the CVM guidance
page at
http://www.fda.gov/AnimalVeterinary/GuidanceCo
mplianceEnforce-
ment/GuidanceforIndustry/default.htm
The lifecycle concept links product and The lifecycle concept links product and
process development, qualification of the process development, qualification of the
commercial manufacturing process,3 and commercial manufacturing process, and
maintenance of the process in a state of con- maintenance of the process in a state of con-
trol during routine commercial production. trol during routine commercial production.
This guidance supports process improve- This guidance promotes modern manufactur-
ment and innovation through sound science. ing principles, process improvement, innova-
tion, and sound science.
3
In this guidance, the term commercial manufac-
turing process refers to the manufacturing
process resulting in commercial product (i.e., drug
that is marketed, distributed, and sold or intended
to be sold). For the purposes of this guidance, the
term commercial manufacturing process does not
include clinical trial or treatment IND material.
This guidance covers the following The following categories of drugs are within
categories of drugs: the scope of this guidance:
• Human drugs • Human drugs

• Veterinary drugs • Veterinary drugs
• Biological and biotechnology products • Biological and biotechnology products
• Finished products and active pharma • Finished products and active pharma-
ceutical ingredients (APIs or drug sub ceutical ingredients (API or drug sub-
stances)4 3
stance)
• The drug constituent of a combination
• The drug constituent of a combination
(drug and medical device) product
(drug and medical device) product
4
Separate current good manufacturing practice 3
Separate current good manufacturing practice
(CGMP) regulations for drug components such as
(CGMP) regulations for drug components such as
APIs (drug substances) and intermediates have
APIs (drug substances) and intermediates have
not published as of the date of this guidance, but
not published as of the date of this guidance, but
these components are subject to the statutory
these components are subject to the statutory
CGMP requirements of section 501(a)(2)(B) of CGMP requirements of section 501(a)(2)(B) of

the Federal Food, Drug, and Cosmetic Act (the the Federal Food, Drug, and Cosmetic Act (the
Act) (21 U.S.C. 351(a)(2)(B)). Process validation Act) (21 U.S.C. 351(a)(2)(B)). Process validation
for APIs is discussed in the FDA/ICH guidance for for APIs is discussed in the FDA/ICH guidance for
industry, Q7 Good Manufacturing Practice Guid- industry, Q7A Good Manufacturing Practice
ance for Active Pharmaceutical Ingredients (ICH Guidance for Active Pharmaceutical Ingredients
Q7), available on the Internet at (ICH Q7A), available on the Internet at
http://www.fda.gov/Drugs/GuidanceComplianceR http://www.fda.gov/cder/guidance/index.htm. Sec-
egulatoryInformation/Guidances/default.htm. Sec- tion XII of ICH Q7A describes in detail the prin-
tion XII of ICH Q7 describes in detail the principles to be followed in validating API processes.
ciples for validating API processes.
This guidance does not cover the following The following categories of products are not
types of products: covered by this guidance:
• Type A medicated articles and medi- • Type A medicated articles and medi-
cated feed cated feed
• Medical devices5 • Medical devices
• Dietary supplements • Dietary supplements
• Human tissues intended for transplan- • Human tissues intended for transplan-
tation regulated under section 361 of tation regulated under section 361 of
the Public Health Service Act6 the Public Health Service Act
4
5
Guidance on process validation for medical 4
See the FDA guidance for industry, Validation of
devices is provided in a separate document,
Procedures for Processing of Human Tissues
Quality Management Systems – Process Valida-
Intended for Transplantation, available on the
tion, edition 2, available at
Internet at
http://www.ghtf.org/sg3/sg3-final.html. See infra
http://www.fda.gov/cber/guidelines.htm.
note 6.
6
See the FDA guidance for industry, Validation of
Procedures for Processing of Human Tissues
Intended for Transplantation, available on the
Internet at
http://www.fda.gov/BiologicsBloodVaccines/Guida
nceComplianceRegulatoryInforma-
tion/Guidances/default.htm.
This guidance does not specify what infor- This guidance does not specify what informa-
mation should be included as part of a reg- tion should be included as part of a regulato-
ulatory submission. Interested persons can ry submission. Interested persons can refer
refer to the appropriate guidance or contact to the appropriate guidance or contact the
the appropriate Center in determining the appropriate Center in determining what in-
type of information to include in a sub- formation should be included in a submis-
mission. sion.
This guidance also does not specifically dis- This guidance also does not specifically dis-
cuss the validation of automated process cuss the validation of automated process
control systems (i.e., computer hardware and control systems (i.e., computer hardware and
software interfaces), which are commonly software interfaces), which are commonly
integrated into modern drug manufacturing integrated into modern drug manufacturing
equipment. This guidance is relevant, how- equipment. This guidance is relevant, how-
ever, to the validation of processes that in- ever, to the validation of processes that in-
clude automated equipment in processing. clude automated equipment in processing.
FDA’s guidance documents, including this FDA's guidance documents, including this
guidance, do not establish legally enforcea- guidance, do not establish legally enforcea-
ble responsibilities. Instead, guidances de- ble responsibilities. Instead, guidances de-
scribe the Agency’s current thinking on a scribe the Agency's current thinking on a
topic and should be viewed only as recom- topic and should be viewed only as recom-
mendations, unless specific regulatory or mendations, unless specific regulatory or
statutory requirements are cited. The use of statutory requirements are cited. The use of
the word should in Agency guidances means the word should in Agency guidances means
that something is suggested or recommend- that something is suggested or recommend-
ed, but not required. ed, but not required.
II. BACKGROUND II. BACKGROUND
In the Federal Register of May 11, 1987 (52 In the Federal Register of May 11, 1987 (52
FR 17638), FDA issued a notice announcing FR 17638), FDA issued a notice announcing
the availability of a guidance entitled Guide- the availability of a guidance entitled Guide-
line on General Principles of Process Valida- line on General Principles of Process Valida-
tion (the 1987 guidance).7 Since then, we 5
tion (the 1987 guidance). Since then, we
have obtained additional experience through
have obtained additional experience through
our regulatory oversight that allows us to our regulatory oversight that allows us to
update our recommendations to industry on
update our recommendations to industry on
this topic. This revised guidance conveys this topic. This revised guidance conveys
FDA’s current thinking on process validation
FDA’s current thinking on process validation
and is consistent with basic principles first and is consistent with basic principles first
introduced in the 1987 guidance. The revised introduced in the 1987 guidance. This guid-
guidance also provides recommendations
ance also provides recommendations that
that reflect some of the goals of FDA’s initia-
reflect some of the goals of FDA’s initiative
tive entitled “Pharmaceutical CGMPs for the
entitled “Pharmaceutical CGMPs for the 21st
21st Century ― A Risk-Based Approach,”
Century – A Risk-Based Approach,” particu-
particularly with regard to the use of technol- larly with regard to the use of technological
ogical advances in pharmaceutical manufac-
advances in pharmaceutical manufacturing,
turing, as well as implementation of modern
as well as implementation of modern risk
risk management and quality system tools management and quality system tools and
and concepts.8 This revised guidance rep- concepts. When finalized, this guidance will
laces the 1987 guidance. replace the 1987 guidance.
7
The 1987 guidance was prepared by a working 5
The 1987 guidance was prepared by a working
group that included representation from the Cen-
group that included representation from the Cen-
ter for Devices and Radiological Health (CDRH).
ter for Devices and Radiological Health (CDRH).
Since that time, CDRH elected to reference a
Since that time, CDRH elected to publish its own
process validation guidance prepared in coopera-
tion with the Global Harmonization Task Force process validation guidance through the Global
(GHTF). The principles and recommendations in Harmonization Task Force. The principles and
that document, Quality Management Systems – recommendations in that document, Quality Man-
Process Validation, edition 2 (available on the agement Systems – Process Validation, edition 2
Internet at http://www.ghtf.org/sg3/sg3-final.html) (available on the Internet at
are also useful to consider for drug manufacturing http://www.ghtf.org/sg3/sg3final.html), are also
processes. useful to consider for drug manufacturing
processes.
8
See “Pharmaceutical cGMPS for the 21st Cen-
tury — A Risk-Based Approach: Second Progress
Report and Implementation Plan,” available at
http://www.fda.gov/Drugs/DevelopmentApprovalP
ro-
cess/Manufacturing/QuestionsandAnswersonCurr
entGoodManufacturingPracticescGMPfor-
Drugs/ucm071836.htm.
FDA has the authority and responsibility to FDA has the authority and responsibility to
inspect and evaluate process validation per- inspect and evaluate process validation per-
formed by manufacturers. The CGMP regula- formed by manufacturers. The CGMP regula-
tions for validating pharmaceutical (drug) tions for validating pharmaceutical (drug)
manufacturing require that drug products be manufacturing require that drug products be
produced with a high degree of assurance of produced with a high degree of assurance of
meeting all the attributes they are intended to meeting all the attributes they are intended to
possess (21 CFR 211.100(a) and possess (21 CFR 211.100(a) and
211.110(a)). 211.110(a)).
A. Process Validation and Drug Quality
Effective process validation contributes sig- Effective process validation contributes sig-
nificantly to assuring drug quality. The basic nificantly to assuring drug quality. The basic
principle of quality assurance is that a drug principle of quality assurance is that a drug
should be produced that is fit for its intended should be produced that is fit for its intended
use. This principle incorporates the under- use; this principle incorporates the under-
standing that the following conditions exist: standing that the following conditions exist:
• Quality, safety, and efficacy are de- • Quality, safety, and efficacy are de-
signed or built into the product. signed or built into the product.
• Quality cannot be adequately assured • Quality cannot be adequately assured
merely by in-process and finished- merely by in-process and finished-
product inspection or testing. product inspection or testing.
• Each step of a manufacturing process • Each step of a manufacturing process
is controlled to assure that the finished is controlled to assure that the finished
product meets all quality attributes in- product meets all design characteristics
cluding specifications. and quality attributes including specifi-
cations.
B. Approach to Process Validation
For purposes of this guidance, process vali- For purposes of this guidance, process vali-
dation is defined as the collection and evalu- dation is defined as the collection and evalu-
ation of data, from the process design stage ation of data, from the process design stage
through commercial production, which estab- throughout production, which establishes
lishes scientific evidence that a process is scientific evidence that a process is capable
capable of consistently delivering quality of consistently delivering quality products.
product. Process validation involves a series Process validation involves a series of activi-
of activities taking place over the lifecycle of ties taking place over the lifecycle of the
the product and process. This guidance product and process. This guidance de-
describes process validation activities in scribes the process validation activities in
three stages. three stages.
• Stage 1 – Process Design: The com- • Stage 1 – Process Design: The com-
mercial manufacturing process is de- mercial process is defined during this
fined during this stage based on know- stage based on knowledge gained
ledge gained through development and through development and scale-up ac-
scale-up activities. tivities.
• Stage 2 – Process Qualification: During • Stage 2 – Process Qualification: During
this stage, the process design is eva- this stage, the process design is con-
luated to determine if the process is firmed as being capable of reproducible
capable of reproducible commercial commercial manufacturing.
manufacturing. • Stage 3 – Continued Process Verifica-
• Stage 3 – Continued Process Verifica- tion: Ongoing assurance is gained dur-
tion: Ongoing assurance is gained during routine production that the process
ing routine production that the process remains in a state of control.
remains in a state of control.
This guidance describes activities typical of This guidance describes activities typical in
each stage, but in practice, some activities each stage, but in practice, some activities in
might occur in multiple stages. different stages might overlap.
Before any batch from the process is com- Before any batch from the process is com-
mercially distributed for use by consumers, a mercially distributed for use by consumers, a
manufacturer should have gained a high de- manufacturer should have gained a high de-
gree of assurance in the performance of the gree of assurance in the performance of the
manufacturing process such that it will con- manufacturing process such that it will con-
sistently produce APIs and drug products sistently produce APIs and drug products
meeting those attributes relating to identity, meeting those attributes relating to identity,
strength, quality, purity, and potency. The strength, quality, purity, and potency. The
assurance should be obtained from objective assurance should be obtained from objective
information and data from laboratory-, pilot-, information and data from laboratory-, pilot-,
and/or commercial-scale studies. Information and/or commercial scale studies. Information
and data should demonstrate that the com- and data should demonstrate that the com-
mercial manufacturing process is capable of mercial manufacturing process is capable of
consistently producing acceptable quality consistently producing acceptable quality

products within commercial manufacturing products within commercial manufacturing
conditions. conditions, including those conditions that
pose a high risk of process failure.
A successful validation program depends A successful validation program depends

upon information and knowledge from prod- upon information and knowledge from prod-
uct and process development. This know- uct and process development. This know-
ledge and understanding is the basis for es- ledge and understanding is the basis for es-
tablishing an approach to control of the man- tablishing an approach to control that is ap-
ufacturing process that results in products propriate for the manufacturing process.
with the desired quality attributes. Manufacturers should:
Manufacturers should: • understand the sources of variation
• Understand the sources of variation • detect the presence and degree of var-
• Detect the presence and degree of variation
iation • understand the impact of variation on
• Understand the impact of variation on the process and ultimately on product
the process and ultimately on product attributes
attributes • control the variation in a manner com-
• Control the variation in a manner commensurate with the risk it represents to
mensurate with the risk it represents to the process and product
the process and product
Each manufacturer should judge whether it Each manufacturer should judge whether it
has gained sufficient understanding to pro- has gained sufficient understanding to pro-
vide a high degree of assurance in its manu- vide a high degree of assurance in its manu-
facturing process to justify commercial distri- facturing process to justify commercial distri-
bution of the product. Focusing exclusively bution of the product. Focusing on qualifica-
on qualification efforts without also under- tion efforts without understanding the manu-
standing the manufacturing process and as- facturing process may not lead to adequate
sociated variations may not lead to adequate assurance of quality. After establishing and
assurance of quality. After establishing and confirming the process, manufacturers must
confirming the process, manufacturers must maintain the process in a state of control
maintain the process in a state of control over the life of the process, even as mate-
over the life of the process, even as materials, equipment, production environment,
rials, equipment, production environment, personnel, and manufacturing procedures
6
personnel, and manufacturing procedures change.
change.9
6
9 The statute and regulations described in section
The statute and regulations described in section
III of this guidance explain the requirement that III of this guidance explain the requirement that
the methods and facilities used for the manufac- the methods and facilities used for the manufac-
turing of drugs be operated and administered turing of drugs be operated and maintained under
under control sufficient to assure that the identity, control sufficient to assure that the identity,
strength, purity, and quality of a drug are as they strength, purity, and quality of a drug are as they
purport or are represented to possess. purport or are represented to possess.
Manufacturers should use ongoing programs

to collect and analyze product and process
data to evaluate the state of control of the
process. These programs may identify
process or product problems or opportunities
for process improvements that can be eva-
luated and implemented through some of the
activities described in Stages 1 and 2.
Manufacturers of legacy products can take

advantage of the knowledge gained from the
original process development and qualifica-
tion work as well as manufacturing expe-
rience to continually improve their processes.
Implementation of the recommendations in
this guidance for legacy products and
processes would likely begin with the activi-
ties described in Stage 3.
III. STATUTORY AND REGULATORY RE- III. STATUTORY AND REGULATORY RE-
QUIREMENTS FOR PROCESS VALIDA- QUIREMENTS FOR PROCESS VALIDA-
TION TION
Process validation for drugs (finished phar- Process validation for drugs (finished phar-
maceuticals and components) is a legally maceuticals and components) is a legally
enforceable requirement under section enforceable requirement under section
501(a)(2)(B) of the Act (21 U.S.C. 501(a)(2)(B) of the Act, which states the fol-
351(a)(2)(B)), which states the following: lowing:
A drug . . . shall be deemed to be adulterated A drug . . . shall be deemed to be adulterated

. . . if . . . the methods used in, or the facilities . . . if . . . the methods used in, or the facilities
or controls used for, its manufacture, or controls used for, its manufacture,
processing, packing, or holding do not con- processing, packing, or holding do not con-
form to or are not operated or administered in form to or are not operated or administered in
conformity with current good manufacturing conformity with current good manufacturing
practice to assure that such drug meets the practice to assure that such drug meets the
requirements of this Act as to safety and has requirements of this Act as to safety and has
the identity and strength, and meets the qual- the identity and strength, and meets the qual-
ity and purity characteristics, which it purity and purity characteristics, which it pur-
ports or is represented to possess. ports or is represented to possess.
FDA regulations describing current good FDA regulations describing current good
manufacturing practice (CGMP) for finished manufacturing practice (CGMP) are provided
pharmaceuticals are provided in 21 CFR in 21 CFR parts 210 and 211.

parts 210 and 211.
The CGMP regulations require that manufac- Process validation is required, in both gener-
turing processes be designed and controlled al and specific terms, by the CGMP regula-
to assure that in-process materials and the tions in parts 210 and 211. The foundation
finished product meet predetermined quality for process validation is provided in §
requirements and do so consistently and 211.100(a), which states that "[t]here shall be
reliably. Process validation is required, in written procedures for production and
both general and specific terms, by the process control designed to assure that the
CGMP regulations in parts 210 and 211. The drug products have the identity, strength,
foundation for process validation is provided quality, and purity they purport or are
in § 211.100(a), which states that “[t]here represented to possess" (emphasis added).
shall be written procedures for production This regulation requires that manufacturers
and process control designed to assure that design a process including operations and
the drug products have the identity, strength, controls that will result in a product meeting
quality, and purity they purport or are these attributes. Product quality in the con-
represented to possess...” (emphasis added). text of process validation means that product
This regulation requires manufacturers to performance is consistent from batch-to-
design a process, including operations and batch and unit-to-unit. Many products are
controls, which results in a product meeting single-source or involve complicated
these attributes. processes to manufacture. Validation also
offers assurance that a process is reasonably
safeguarded from sources of variability af-
fecting production output, the loss of which
can cause supply problems, thereby nega-
tively affecting public health.
Other CGMP regulations define the various Other CGMP regulations define the various
aspects of validation. For example, § aspects of validation. Section 211.110(a),
211.110(a), Sampling and testing of in- Sampling and testing of in-process materials
process materials and drug products, re- and drug products, requires that control pro-
quires that control procedures “. . . be estab- cedures “. . . be established to monitor the
lished to monitor the output and to validate output and to validate the performance of
the performance of those manufacturing those manufacturing processes that may be
processes that may be responsible for caus- responsible for causing variability in the cha-
ing variability in the characteristics of in- racteristics of in-process material and the
process material and the drug product” (em- drug product" (emphasis added). This regula-
phasis added). Under this regulation, even tion establishes the requirement that even
well-designed processes must include in- well-designed processes must include in-
process control procedures to assure final process control procedures to assure final
product quality. In addition, the CGMP regu- product quality.
lations regarding sampling set forth a number
of requirements for validation: samples must
represent the batch under analysis (§
211.160(b)(3)); the sampling plan must result
in statistical confidence (§ 211.165(c) and

(d)); and the batch must meet its predeter-
mined specifications (§ 211.165(a)).
In addition to sampling requirements, the CGMP regulations require that batch sam-
CGMP regulations also provide norms for ples represent the batch under analysis (see,
establishing in-process specifications as an e.g., § 211.160(b)(3)) and that the sampling
aspect of process validation. Section plan result in statistical confidence (§
211.110(b) establishes two principles to fol- 211.165(c) and (d)) that the batch meets its
low when establishing in-process specifica- predetermined specifications (§ 211.165(a)).
tions. The first principle is that “. . . in-process Section 211.110(b) provides two principles to
specifications for such characteristics [of in- follow when establishing in-process specifi-
process material and the drug product] shall cations. The first principle is that “. . . in-
be consistent with drug product final specifi- process specifications for such characteris-
cations . . . .” Accordingly, in-process materi- tics [of in-process material and the drug
al should be controlled to assure that the product] shall be consistent with drug product
final drug product will meet its quality re- final specifications . . . .” Accordingly, in-
quirements. The second principle in this process material should be controlled to as-
regulation further requires that in-process sure that the final drug product will meet its
specifications “. . . shall be derived from pre- quality requirements. The second principle in
vious acceptable process average and this regulation further requires that in-process
process variability estimates where possible specifications “. . . shall be derived from pre-
and determined by the application of suitable vious acceptable process average and
statistical procedures where appropriate.” process variability estimates where possible
This requirement, in part, establishes the and determined by the application of suitable
need for manufacturers to analyze process statistical procedures where appropriate.”
performance and control batch-to-batch va- This requirement, in part, establishes the
riability.10 need for manufacturers to analyze process
performance and control batch-to-batch va-
10 7
The Agency further explains this principle in the
preamble to the final rule on “Current Good
riability.
Manufacturing Practice in Manufacture, 7
Processing, Packing, or Holding” (43 FR 45013 at In the Federal Register of September 29, 1978
45052, September 29, 1978) (available on the (43 FR 45013 at 45052), FDA published a final
Internet at http://www.fda.gov/cder/dmpq/ rule on “Current Good Manufacturing Practice in
preamble.txt). Manufacture, Processing, Packing, or Holding”
(available on the Internet at
http://www.fda.gov/cder/dmpq/preamble.txt). In
the preamble of the final rule, the Agency further
explains this principle.
The CGMP regulations also describe and The CGMP regulations also describe and
define activities connected with process de- define activities connected with process de-
sign, development, and maintenance. Sec- sign, development, and maintenance. Sec-
tion 211.180(e) requires that information and tion 211.180(e) requires that information and
data about product quality and manufacturing data about product performance and manu-
experience be periodically reviewed to de- facturing experience be periodically reviewed
termine whether any changes to the estab- to determine whether any changes to the
lished process are warranted. Ongoing feed- established process are warranted. Ongoing
back about product quality and process per- feedback about product performance is an
formance is an essential feature of process essential feature of process maintenance.
maintenance.
In addition, the CGMP regulations require In addition, the CGMP regulations require
that facilities in which drugs are manufac- that facilities in which drugs are manufac-
tured be of suitable size, construction, and tured be of suitable size, construction, and
location to facilitate proper operations (§ location to facilitate proper operations (21
211.42). Equipment must be of appropriate CFR 211.42). Equipment must be of appro-
design, adequate size, and suitably located priate design, adequate size, and suitably
to facilitate operations for its intended use (§ located to facilitate operations for its intended
211.63). Automated, mechanical, and elec- use (21 CFR 211.63). Automated, mechani-
tronic equipment must be calibrated, in- cal, and electronic equipment must be cali-
spected, or checked according to a written brated, inspected, or checked according to a
program designed to assure proper perfor- written program designed to assure proper
mance (§ 211.68). performance (21 CFR 211.68).
In summary, the CGMP regulations require In summary, the CGMP regulations require
that manufacturing processes be designed that manufacturing processes be designed
and controlled to assure that in-process ma- and controlled to assure that in-process ma-
terials and the finished product meet prede- terials and the finished product meet prede-
termined quality requirements and do so termined quality requirements and do so
consistently and reliably. consistently and reliably.
IV. RECOMMENDATIONS IV. RECOMMENDATIONS
In the following sections, we describe general

considerations for process validation, the
recommended stages of process validation,
and specific activities for each stage in the
product lifecycle.
A. General Considerations for Process A. General Considerations for Process

Validation Validation
In all stages of the product lifecycle, good In all stages of the product lifecycle, good
project management and good archiving that project management and good archiving that
capture scientific knowledge will make the capture scientific knowledge will make the
process validation program more effective process validation program more effective
and efficient. The following practices should and efficient. These practices should ensure
ensure uniform collection and assessment of uniform collection and assessment of infor-
information about the process and enhance mation about the process, reduce the chance
the accessibility of such information later in for redundant information gathering and
the product lifecycle. analysis, and enhance the accessibility of
• We recommend an integrated team such information later in the product lifecycle.
8
approach11 to process validation that • We recommend an integrated team
includes expertise from a variety of dis- approach to process validation that in-
ciplines (e.g., process engineering, in-
cludes expertise from a variety of dis-
dustrial pharmacy, analytical chemistry,
ciplines, including process engineering,
microbiology, statistics, manufacturing,
industrial pharmacy, analytical chemi-
and quality assurance). Project plans,
along with the full support of senior stry, microbiology, statistics, manufac-
management, are essential elements turing, and quality assurance. Project
for success. plans, along with the full support of se-
• Throughout the product lifecycle, vari- nior management, are essential ele-
ous studies can be initiated to discover, ments for success.
observe, correlate, or confirm informa-
tion about the product and process. All • Throughout the product lifecycle, various
studies should be planned and con- studies can be initiated to discover, ob-
ducted according to sound scientific serve, correlate, or confirm information
principles, appropriately documented, about the product and process. All stu-
dies should be planned and conducted
and approved in accordance with the
according to sound scientific principles,
established procedure appropriate for
appropriately documented, and should
the stage of the lifecycle. be approved in accordance with the es-
• The terms attribute(s) (e.g., quality, tablished procedure appropriate for the
product, component) and parameter(s) stage of the lifecycle.
(e.g., process, operating, and equip-
ment) are not categorized with respect 8
This concept is discussed in more detail in
to criticality in this guidance. With a li- FDA’s guidance for industry, Quality Systems
fecycle approach to process validation Approach to Pharmaceutical Current Good Manu-
that employs risk based decision mak- facturing Practice Regulations, available on the
ing throughout that lifecycle, the per- Internet at http://www.fda.gov/cder/guidance/
index.htm.
ception of criticality as a continuum ra-
ther than a binary state is more useful.
All attributes and parameters should be
evaluated in terms of their roles in the
process and impact on the product or
in-process material, and reevaluated as
new information becomes available.
The degree of control over those
attributes or parameters should be
commensurate with their risk to the
process and process output. In other
words, a higher degree of control is
appropriate for attributes or parameters
that pose a higher risk. The Agency re-
cognizes that terminology usage can
vary and expects that each manufac-
turer will communicate the meaning
and intent of its terminology and cate-
gorization to the Agency.

• Many products are single-source or in-
volve complicated manufacturing
processes. Homogeneity within a batch
and consistency between batches are
goals of process validation activities.
Validation offers assurance that a
process is reasonably protected
against sources of variability that could
affect production output, cause supply
problems, and negatively affect public
health.
11
This concept is discussed in more detail in
FDA’s guidance for industry, Quality Systems
Approach to Pharmaceutical Current Good Manu-
facturing Practice Regulations, available at
http://www.fda.gov/Drugs/GuidanceComplianceR
egulatoryInformation/Guidances/default.htm.
B. Specific Stages and Activities of Proc-

ess Validation in the Product Lifecycle
The following subsections describe the rec-

ommended stages and specific activities.
B. Stage 1 ― Process Design Stage 1– Process Design
Process design is the activity of defining the

commercial manufacturing process that will
be reflected in planned master production
and control records. The goal of this stage is
to design a process suitable for routine
commercial manufacturing that can consis-
tently deliver a product that meets its quality
attributes.
Building and Capturing Process Know- Building and Capturing Process Know-
ledge and Understanding ledge and Understanding
Process design is the activity of defining the

commercial manufacturing process that will
be reflected in the master production and
control records. The goal of this stage is to
design a process suitable for routine com-
mercial manufacturing that can consistently
deliver a product that meets its critical quality
attributes.
Generally, early process design experiments Generally, early process design experiments
do not need to be performed under the do not need to be performed under CGMP
CGMP conditions required for drugs intended conditions. They should, however, be con-
for commercial distribution that are manufac- ducted in accordance with sound scientific
tured during Stage 2 (process qualification) methods and principles, including good do-
and Stage 3 (continued process verification). cumentation practices. This recommendation
is consistent with ICH guidance for industry,
9
They should, however, be conducted in ac-
Q10 Pharmaceutical Quality System. Deci-
cordance with sound scientific methods and
sions and justification of the controls should
principles, including good documentation
be sufficiently documented and internally
practices. This recommendation is consistent
reviewed to verify and preserve their value
with ICH Q10 Pharmaceutical Quality Sys-
for use later in the lifecycle of the process
tem12. Decisions and justification of the con-
and product.
trols should be sufficiently documented and
internally reviewed to verify and preserve 9
A notice of availability for this draft ICH guid-
their value for use or adaptation later in the ance published in the Federal Register on July
lifecycle of the process and product. 13, 2007 (72 FR 38604). When finalized, this
12
guidance will represent FDA’s current thinking on
Available at this topic.
http://www.fda.gov/Drugs/GuidanceComplianceR
egulatoryInformation/Guidances/default.htm.
Although often performed at small-scale la- There are exceptions, however. For example,
boratories, most viral inactivation and impuri- viral and impurity clearance studies have a
ty clearance studies cannot be considered direct impact on drug safety and should be
early process design experiments. Viral and performed under CGMP conditions, even
impurity clearance studies intended to eva- when performed at small scale. The quality
luate and estimate product quality at com- unit should be involved with these studies as
mercial scale should have a level of quality is typical during commercial production.
unit oversight that will ensure that the studies
follow sound scientific methods and prin-
ciples and the conclusions are supported by
the data.
Product development activities provide key Product development activities provide key
inputs to the process design stage, such as inputs to the design stage, such as the in-
the intended dosage form, the quality tended dosage form, the quality attributes,
attributes, and a general manufacturing and a general manufacturing pathway.
pathway. Process information available from Process information available from the prod-
product development activities can be leve- uct development stage can be leveraged in
raged in the process design stage. The func- the process design stage. However, the full
tionality and limitations of commercial manu- spectrum of input variability typical of com-
facturing equipment should be considered in mercial production is not generally known at
the process design, as well as predicted con- this stage. The functionality and limitations of
tributions to variability posed by different commercial manufacturing equipment should
component lots, production operators, envi- be considered, as well as the contributions of
ronmental conditions, and measurement sys- variability by different component lots, pro-
tems in the production setting. However, the duction operators, environmental conditions,
full spectrum of input variability typical of and measurement systems in the production
commercial production is not generally setting. Laboratory or pilot-scale models de-
known at this stage. Laboratory or pilot-scale signed to be representative of the commer-
models designed to be representative of the cial process can be used to estimate varia-
commercial process can be used to estimate bility. However, it is not a regulatory expecta-
variability. tion that the process be developed and
tested until it fails, but rather that a process
be controlled within commercial manufactur-
ing conditions, including those combinations
of conditions posing a high risk of process
failure.
Designing an efficient process with an effec- Designing an efficient process with an effec-
tive process control approach is dependent tive process control approach is dependent
on the process knowledge and understand- on the process knowledge and understand-
ing obtained. Design of Experiment (DOE) ing obtained. Design of Experiment (DOE)
studies can help develop process knowledge studies can help develop process knowledge
by revealing relationships, including multiva- by revealing relationships, including multifac-
riate interactions, between the variable inputs torial interactions, between the variable in-
(e.g., component characteristics13 or process 10
puts (e.g., component characteristics inter-
parameters) and the resulting outputs (e.g., mediates, or the final product). Risk analysis
in-process material, intermediates, or the tools can be used to screen potential va-
final product). Risk analysis tools can be
riables for DOE studies to minimize the total
used to screen potential variables for DOE
number of experiments conducted while
studies to minimize the total number of expe- maximizing knowledge gained. The results of
riments conducted while maximizing know-
DOE studies can provide justification for es-
ledge gained. The results of DOE studies can
tablishing ranges of incoming component
provide justification for establishing ranges of
quality, equipment parameters, and in
incoming component quality, equipment pa-
process material quality attributes.
rameters, and in-process material quality
attributes. FDA does not generally expect 10
“Component means any ingredient [raw ma-
manufacturers to develop and test the terial] intended for use in the manufacture of a
process until it fails. drug product, including those that may not appear
in such drug product” (21 CFR 210.3(b)(3)).
13
“Component means any ingredient [raw ma-
terial] intended for use in the manufacture of a
drug product, including those that may not appear

in such drug product” (§ 210.3(b)(3)).
Other activities, such as experiments or Other activities, such as experiments or

demonstrations at laboratory or pilot scale, demonstrations at laboratory or pilot scale,
also assist in evaluation of certain conditions allow evaluation of certain conditions and
and prediction of performance of the com- prediction of performance of the commercial
mercial process. These activities also provide process. These activities also provide infor-
information that can be used to model or si- mation that can be used to model or simulate
mulate the commercial process. Computer- the commercial process. Computer-based or
based or virtual simulations of certain unit virtual simulations of certain unit operations
operations or dynamics can provide process or dynamics can provide process under-
understanding and help avoid problems at standing and avoid problems at commercial
commercial scale. It is important to under- scale. It is important to understand the de-
stand the degree to which models represent gree to which models represent the commer-
the commercial process, including any differ- cial process, including any differences that
ences that might exist, as this may have an might exist, as this may have an impact on
impact on the relevance of information de- the relevance of information derived from the
rived from the models. studies.
It is essential that activities and studies re- It is essential that activities and studies re-
sulting in process understanding be docu- sulting in product understanding be docu-
mented. Documentation should reflect the mented. Documentation should reflect the
basis for decisions made about the process. basis for decisions made about the process.
For example, manufacturers should docu- For example, manufacturers should docu-
ment the variables studied for a unit opera- ment the variables studied for a unit opera-
tion and the rationale for those variables tion and the rationale for those variables
identified as significant. This information is identified as significant. This information is
useful during the process qualification and useful during the process qualification and
continued process verification stages, includ- continued process verification stages, includ-
ing when the design is revised or the strategy ing when the design is revised or the strategy
for control is refined or changed. for control is refined or changed.
Establishing a Strategy for Process Con- Establishing a Strategy for Process Con-
trol trol
Process knowledge and understanding is the Process knowledge and understanding is the
basis for establishing an approach to process basis for establishing an approach to process
control for each unit operation and the control for each unit operation and the
process overall. Strategies for process con- process overall. Strategies for process con-
trol can be designed to reduce input varia- trol can be designed to reduce input varia-
tion, adjust for input variation during manu- tion, adjust for input variation during manu-
facturing (and so reduce its impact on the facturing (and so reduce its impact on the
output), or combine both approaches. output), or combine both approaches.
Process controls address variability to assure Process controls address variability to assure
quality of the product. Controls can consist of quality of the product. Controls can consist of
material analysis and equipment monitoring material analysis and equipment monitoring
at significant processing points (§ at significant processing points designed to
211.110(c)). Decisions regarding the type assure that the operation remains on target
and extent of process controls can be aided and in control with respect to output quality.
by earlier risk assessments, then enhanced Special attention to control of the process
and improved as process experience is through operational limits and in-process
gained. monitoring is essential
FDA expects controls to include both exami- (1) where the product attribute is not readily
nation of material quality and equipment measurable due to limitations of sampling or
monitoring. Special attention to control the detectability (e.g., viral clearance or microbial
process through operational limits and in- contamination), or
process monitoring is essential in two possi-
ble scenarios: (2) when intermediates and products cannot
be highly characterized and well-defined
1. When the product attribute is not readily quality attributes cannot be identified.
measurable due to limitations of sampling or
detectability (e.g., viral clearance or microbial These controls are included in the master
contamination) or production and control records (see 21 CFR
211.186(a) and (b)(9)).
2. When intermediates and products cannot
be highly characterized and well-defined
quality attributes cannot be identified.
These controls are established in the master

production and control records (see §
211.186(a) and (b)(9)).
More advanced strategies, which may in- More advanced strategies, such as process
volve the use of process analytical technolo- analytical technology (PAT), use timely anal-
gy (PAT), can include timely analysis and ysis and control loops to adjust the
control loops to adjust the processing condi- processing conditions so that the output re-
tions so that the output remains constant. mains constant. Manufacturing systems of
Manufacturing systems of this type can pro- this type can provide a higher degree of
vide a higher degree of process qualification process control. In the case of PAT strategy,
will differ from that used in other process the approach to process qualification will be
designs. Further information on PAT different from that for other process designs.
processes can be found in FDA’s guidance Further information on PAT processes can
for industry on PAT ― A Framework for In- be found in FDA’s guidance for industry on
novative Pharmaceutical Development, Man- PAT – A Framework for Innovative Pharma-
ufacturing, and Quality Assurance.14 ceutical Development, Manufacturing, and
Quality Assurance (available on the Internet
14
Available at at
http://www.fda.gov/Drugs/GuidanceComplianceR http://www.fda.gov/cder/guidance/index.htm).
egulatoryInformation/Guidances/default.htm. Oth-
er references that may be useful include ASTM
E2474-06 “Standard Practice for Pharmaceutical
Process Design Utilizing Process Analytical

Technology” and ASTM E2476-09 “Standard
Guide for Risk Assessment and Risk Control as it
Impacts the Design, Development, and Operation
of PAT Processes for Pharmaceutical Manufac-
ture.”
The planned commercial production and con- The planned commercial production and con-
trol records, which contain the operational trol records, which contain the operational
limits and overall strategy for process control, limits and overall strategy for process control,
should be carried forward to the next stage should be carried forward to the next stage
for confirmation. for confirmation.
C. Stage 2 ― Process Qualification Stage 2 – Process Qualification
During the process qualification (PQ) stage During the process qualification stage of
of process validation, the process design is process validation, the process design is
evaluated to determine if it is capable of re- confirmed as being capable of reproducible
producible commercial manufacture. This commercial manufacture. This stage has two
stage has two elements: (1) design of the elements: (1) design of the facility and quali-
facility and qualification of the equipment and fication of the equipment and utilities, and (2)
utilities and (2) process performance qualifi- performance qualification (PQ). During this
cation (PPQ). During Stage 2, CGMP- stage, CGMP-compliant procedures must be
compliant procedures must be followed. Suc- followed and successful completion of this
cessful completion of Stage 2 is necessary stage is necessary before commercial distri-
before commercial distribution.15 Products 11
bution. Products manufactured during this
manufactured during this stage, if accepta- stage, if acceptable, can be released.
ble, can be released for distribution.
11
15 As discussed in section III of this guidance,
As discussed in section III of this guidance, process validation (including process qualifica-
process validation (including process qualification) is legally enforceable under section
tion) is legally enforceable under section 501(a)(2)(B) of the Act. FDA regulations require
501(a)(2)(B) of the Act. FDA regulations require that process validation procedures be established
that process validation procedures be established and followed (21 CFR 211.100) before a batch
and followed (§ 211.100) before a batch can be can be distributed (21 CFR 211.22 and 211.165).
distributed (§§ 211.22 and 211.165).
1. Design of a Facility and Qualification of Design of a Facility and Qualification of

Utilities and Equipment Utilities and Equipment
Proper design of a manufacturing facility is Proper design of a manufacturing facility is

required under part 211, subpart C, of the required under 21 CFR part 211, subpart C,
CGMP regulations on Buildings and Facili- of the CGMP regulations on Buildings and
ties. It is essential that activities performed to Facilities. It is essential that activities per-
assure proper facility design and commis- formed to assure proper facility design and
sioning precede PPQ. Here, the term qualifi- commissioning precede PQ. Activities under-
cation refers to activities undertaken to dem- taken to demonstrate that utilities and pieces
onstrate that utilities and equipment are suit- of equipment are suitable for their intended
able for their intended use and perform prop- use and perform properly is referred to in this
erly. These activities necessarily precede guidance as qualification. These activities
manufacturing products at the commercial necessarily precede manufacturing products
scale. at the commercial scale.
Qualification of utilities and equipment gen- Qualification of utilities and equipment gen-
erally includes the following activities: erally includes the following activities:
• Selecting utilities and equipment con- • Selecting utilities and equipment con-
struction materials, operating prin- struction materials, operating prin-
ciples, and performance characteristics ciples, and performance characteristics
based on whether they are appropriate based on whether they are appropriate
for their specific uses. for their specific use.
• Verifying that utility systems and • Verifying that utility systems and
equipment are built and installed in equipment are built and installed in
compliance with the design specifica- compliance with the design specifica-
tions (e.g., built as designed with prop- tions (e.g., built as designed with prop-
er materials, capacity, and functions,
er materials, capacity, and functions,
and properly connected and cali-
and properly connected and cali-
brated).
brated).
• Verifying that utility systems and
equipment operate in accordance with • Verifying that the utility system and
the process requirements in all antic- equipment operate in accordance with
ipated operating ranges. This should the process requirements in all antic-
include challenging the equipment or ipated operating ranges. This should
system functions while under load include challenging the equipment or
comparable to that expected during system functions while under load
routine production. It should also in- comparable to that expected during
clude the performance of interventions, routine production. It should also in-
stoppage, and start-up as is expected clude the performance of interventions,
during routine production. Operating stoppage, and start-up as is expected
ranges should be shown capable of be- during routine production. Operating
ing held as long as would be necessary ranges should be shown capable of be-
during routine production. ing held as long as would be necessary
during routine production.
Qualification of utilities and equipment can Qualification of utilities and equipment can
be covered under individual plans or as part be covered under individual plans or as part
of an overall project plan. The plan should of an overall project plan. The plan should
consider the requirements of use and can consider the requirements of use and can
incorporate risk management to prioritize incorporate risk management to prioritize
certain activities and to identify a level of ef- certain activities and to identify a level of ef-
fort in both the performance and documenta- fort in both the performance and documenta-
tion of qualification activities. The plan should tion of qualification activities. The plan should
identify the following items: identify
1. the studies or tests to use, (1) the studies or tests to use,
2. the criteria appropriate to assess out- (2) the criteria appropriate to assess out-
comes, comes,
3. the timing of qualification activities, (3) the timing of qualification activities,
4. the responsibilities of relevant departments (4) responsibilities, and

and the quality unit, and
(5) the procedures for documenting and ap-
5. the procedures for documenting and ap- proving the qualification.
proving the qualification.
It should also include the firm’s requirements
The project plan should also include the for the evaluation of changes. Qualification
firm’s requirements for the evaluation of activities should be documented and summa-
changes. Qualification activities should be rized in a report with conclusions that ad-
documented and summarized in a report with dress criteria in the plan. The quality control
conclusions that address criteria in the plan. unit must review and approve the qualifica-
The quality control unit must review and ap- tion plan and report (21 CFR 211.22).
prove the qualification plan and report (§
211.22).
2. Process Performance Qualification Performance Qualification Approach
The process performance qualification (PPQ) The PQ is the second element of stage 2,
is the second element of Stage 2, process process qualification. The PQ combines the
qualification. The PPQ combines the actual actual facility, utilities, equipment (each now
facility, utilities, equipment (each now quali- qualified), and the trained personnel with the
fied), and the trained personnel with the commercial manufacturing process, control
commercial manufacturing process, control procedures, and components to produce
procedures, and components to produce commercial batches. A successful PQ will
commercial batches. A successful PPQ will confirm the process design and demonstrate
confirm the process design and demonstrate that the commercial manufacturing process
that the commercial manufacturing process performs as expected.
performs as expected.
Success at this stage signals an important Success at this stage signals an important
milestone in the product lifecycle. A manufac- milestone in the product lifecycle and needs
turer must successfully complete PPQ before to be completed before a manufacturer
commencing commercial distribution of the commences commercial distribution of the
drug product.16 The decision to begin com- 12
drug product. The decision to begin com-
mercial distribution should be supported by
mercial distribution should be supported by
data from commercial-scale batches. Data data from commercial batches. Data from
from laboratory and pilot studies can provide
additional assurance that the commercial laboratory and pilot studies can provide addi-
manufacturing process performs as ex- tional assurance.
pected.
12
See section III of this guidance, Statutory and
16
See section III of this guidance, Statutory and Regulatory Requirements for Process Validation.
Regulatory Requirements for Process Validation.
The approach to PPQ should be based on The approach to PQ should be based on

sound science and the manufacturer’s overall sound science and the manufacturer’s overall
level of product and process understanding level of product and process understanding.
and demonstrable control. The cumulative The cumulative data from all relevant studies
data from all relevant studies (e.g., designed (e.g., designed experiments; laboratory, pilot,
experiments; laboratory, pilot, and commer- and commercial batches) should be used to
cial batches) should be used to establish the establish the manufacturing conditions in the
manufacturing conditions in the PPQ. To PQ. For example, to have sufficient under-
understand the commercial process suffi- standing of the commercial process, the
ciently, the manufacturer will need to consid- manufacturer will need to consider the effects
er the effects of scale. However, it is not typi- of scale; however, it is not typically neces-
cally necessary to explore the entire operat- sary to explore the entire operating range at
ing range at commercial scale if assurance commercial scale if assurance can be pro-
can be provided by process design data. vided by other data. Previous credible expe-
Previous credible experience with sufficiently rience with sufficiently similar products and
similar products and processes can also be processes can also be considered. In addi-
helpful. In addition, we strongly recommend tion, we strongly recommend firms employ
firms employ objective measures (e.g., statis- objective measures (e.g., statistical metrics),
tical metrics) wherever feasible and meaning- wherever feasible and meaningful to achieve
ful to achieve adequate assurance. adequate assurance.
In most cases, PPQ will have a higher level In most cases, PQ will have a higher level of
of sampling, additional testing, and greater sampling, additional testing, and greater
scrutiny of process performance than would scrutiny of process performance. The level of
be typical of routine commercial production. monitoring and testing should be sufficient to
The level of monitoring and testing should be confirm uniform product quality throughout
sufficient to confirm uniform product quality the batch during processing. This greater
throughout the batch. The increased level of scrutiny accompanied by a higher level of
scrutiny, testing, and sampling should con- sampling should continue through the
tinue through the process verification stage process verification stage, as appropriate.
as appropriate, to establish levels and fre-
quency of routine sampling and monitoring
for the particular product and process. Con-
siderations for the duration of the heightened
sampling and monitoring period could in-
clude, but are not limited to, volume of pro-
duction, process complexity, level of process
understanding, and experience with similar
products and processes.
The extent to which some materials, such as The extent to which some materials, such as
column resins or molecular filtration media, column resins or molecular filtration media,
can be re-used without adversely affecting can be re-used without adversely affecting
product quality can be assessed in relevant product quality can be assessed in relevant
laboratory studies. The usable lifetimes of laboratory studies, and their usable lifetime
such materials should be confirmed by an should be confirmed by an ongoing PQ pro-
ongoing PPQ protocol during commercial tocol during commercial manufacture.
manufacture.
A manufacturing process that uses PAT may A manufacturing process that uses PAT may
warrant a different PPQ approach. PAT warrant a different PQ approach. Such a
processes are designed to measure in real process is one that is designed to measure in
time the attributes of an in-process material real time the attributes of an in-process ma-
and then adjust the process in a timely con- terial and then adjust the process in a timely
trol loop so the process maintains the desired control loop so the process maintains the
quality of the output material. The process desired quality of the output material. The
design stage and the process qualification process design stage and the process quali-
stage should focus on the measurement sys- fication stage should have as a focus the
tem and control loop for the measured measurement system and control loop. Re-
attribute. Regardless, the goal of validating gardless, the goal remains the same: estab-
any manufacturing process is the same: to lishing scientific evidence that the process is
establish scientific evidence that the process reproducible and will consistently deliver
is reproducible and will consistently deliver quality products.
quality products.
3. PPQ Protocol Performance Qualification Protocol
A written protocol that specifies the manufac- A written protocol that specifies the manufac-
turing conditions, controls, testing, and ex- turing conditions, controls, testing, and ex-
pected outcomes is essential for this stage of pected outcomes is essential for this stage of
process validation. We recommend that the process validation. We recommend that the
protocol discuss the following elements: protocol discuss:
• The manufacturing conditions, includ- • The manufacturing conditions including
ing operating parameters, processing operating parameters, processing lim-
limits, and component (raw material) its, and component (raw material) in-
inputs. puts.
• The data to be collected and when and • The data to be collected and when and
how it will be evaluated. how it will be evaluated.
• Tests to be performed (in-process, re- • Tests to be performed (in-process, re-

lease, characterization) and accep- lease, characterization) and accep-
tance criteria for each significant tance criteria for each significant
processing step. processing step.
• The sampling plan, including sampling • The sampling plan including sampling
points, number of samples, and the points, number of samples, and the
frequency of sampling for each unit op- frequency of sampling for each unit op-
eration and attribute. The number of eration and attribute. The number of
samples should be adequate to provide samples should be adequate to provide
sufficient statistical confidence of quali- sufficient statistical confidence of quali-
ty both within a batch and between ty both within a batch and between
batches. The confidence level selected batches. The confidence level selected
can be based on risk analysis as it re- can be based on risk analysis as it re-
lates to the particular attribute under lates to the particular attribute under
examination. Sampling during this examination. Sampling during this
stage should be more extensive than is stage should be more extensive than is
typical during routine production. typical during routine production.
• Criteria and process performance indi- • Criteria that provide for a rational con-
cators that allow for a science- and clusion of whether the process consis-
risk-based decision about the ability of tently produces quality products. The
the process to consistently produce criteria should include:
quality products. The criteria should
include:
o A description of the statistical me-
thods to be used in analyzing all col-
o A description of the statistical me- lected data (e.g., statistical metrics
thods to be used in analyzing all col- defining both intra-batch and inter-
lected data (e.g., statistical metrics batch variability).
defining both intra-batch and inter-
batch variability).
o Provision for addressing deviations
from expected conditions and han-
o Provision for addressing deviations dling of nonconforming data. Data
from expected conditions and han- should not be excluded from further
dling of nonconforming data. Data consideration in terms of PQ without
should not be excluded from further a documented, science-based justi-
consideration in terms of PPQ with- fication.
out a documented, science-based
justification.17
• Design of facilities and the qualification • Design of facilities and the qualification
of utilities and equipment, personnel of utilities and equipment, personnel
training and qualification, and verifica- training and qualification, and verifica-
tion of material sources (components tion of material sources (components
and container/closures), if not previous- and container/closures), if not previous-
ly accomplished. ly accomplished.
• Status of the validation of analytical • Status of the validation of analytical
methods used in measuring the methods used in measuring the
process, in-process materials, and the process, in process materials, and the
product. product.
• Review and approval of the protocol by • Review and approval by appropriate
appropriate departments and the quali- departments and the quality unit.
ty unit.
17
For additional guidance regarding out-of-
specification results, see FDA’s Guidance for
Industry, Investigating Out-of-Specification
(OOS)Test Results for Pharmaceutical Produc-
tion, available at http://www.fda.gov/downloads/
Drugs/GuidanceComplianceRegulatoryInformatio
n/Guidances/ucm070287.pdf.
4. PPQ Protocol Execution and Report Protocol Execution and Report
Execution of the PPQ protocol should not Protocol execution should not begin until the
begin until the protocol has been reviewed protocol has been reviewed and approved by
and approved by all appropriate depart- all appropriate departments, including the
ments, including the quality unit. Any depar- quality unit. Departure from the established
tures from the protocol must be made ac- protocol must be made according to estab-
cording to established procedure or provi- lished procedure or provisions in the proto-
sions in the protocol. Such departures must col. Such departures must be justified and
be justified and approved by all appropriate approved by all appropriate departments and
departments and the quality unit before im- the quality unit before implementation (§
plementation (§ 211.100). 211.100).
The commercial manufacturing process and The commercial manufacturing process and
routine procedures must be followed during routine procedures must be followed (§§
PPQ protocol execution (§§ 211.100(b) and 211.100(b) and 211.110(a)). The PQ lots
211.110(a)). The PPQ lots should be manu- should be manufactured under normal condi-
factured under normal conditions by the per- tions by personnel expected to routinely per-
sonnel routinely expected to perform each form each step of each unit operation in the
step of each unit operation in the process. process. Normal operating conditions should
Normal operating conditions should include cover the utility systems (e.g., air handling
the utility systems (e.g., air handling and wa- and water purification), material, personnel,
ter purification), material, personnel, envi- environment, and manufacturing procedures.
ronment, and manufacturing procedures.
A report documenting and assessing adhe- A report documenting and assessing adhe-
rence to the written PPQ protocol should be rence to the written protocol should be pre-
prepared in a timely manner after the compared in a timely manner after the completion
pletion of the protocol. This report should: of the protocol. This report should:
• Discuss and cross-reference all as- • Discuss and cross-reference all as-
pects of the protocol. pects of the protocol.
• Summarize data collected and analyze • Summarize data collected and analyze
the data, as specified by the protocol. the data, as specified by the protocol.
• Evaluate any unexpected observations • Evaluate any unexpected observations
and additional data not specified in the and additional data not specified in the
protocol. protocol.
• Summarize and discuss all manufactur- • Summarize and discuss all manufactur-
ing nonconformances such as devia- ing nonconformances such as devia-
tions, aberrant test results, or other in- tions, aberrant test results, or other in-
formation that has bearing on the va- formation that has bearing on the va-
lidity of the process. lidity of process.
• Describe in sufficient detail any correc- • Describe in sufficient detail any correc-
tive actions or changes that should be tive actions or changes that should be
made to existing procedures and con- made to existing procedures and con-
trols. trols.
• State a clear conclusion as to whether • State a clear conclusion as to whether
the data indicates the process met the the data indicates the process met the
conditions established in the protocol conditions established in the protocol
and whether the process is considered and whether the process is considered
to be in a state of control. If not, the re- to be in a sufficient state of control. If
port should state what should be ac- not, the report should state what should
complished before such a conclusion be accomplished before such a conclu-
can be reached. This conclusion sion can be reached. This conclusion
should be based on a documented jus- should be based on a documented jus-
tification for the approval of the tification for the approval of the
process, and release of lots produced process, and release of lots produced
by it to the market in consideration of by it to the market in consideration of
the entire compilation of knowledge the entire compilation of knowledge
and information gained from the design and information gained from the design
stage through the process qualification stage through the process qualification
stage. stage.
• Include all appropriate department and • Include all appropriate department and
quality unit review and approvals. quality unit review and approvals.
D. Stage 3 ― Continued Process Verifica- Stage 3 – Continued Process Verification

tion
The goal of the third validation stage is conti- The goal of the third validation stage is to
nual assurance that the process remains in a continually assure that the process remains
state of control (the validated state) during in a state of control (the validated state) dur-
commercial manufacture. A system or sys- ing commercial manufacture. A system or
tems for detecting unplanned departures systems for detecting unplanned departures
from the process as designed is essential to from the process as designed is essential to
accomplish this goal. Adherence to the accomplish this goal. Adherence to the
CGMP requirements, specifically, the collec- CGMP requirements, specifically including
tion and evaluation of information and data the collection and evaluation of information
about the performance of the process, will and data about the performance of the
allow detection of undesired process varia- process (see below), will allow detection of
bility. Evaluating the performance of the process drift. The evaluation should deter-
process identifies problems and determines mine whether action must be taken to pre-
whether action must be taken to correct, an- vent the process from drifting out of control (§
ticipate, and prevent problems so that the 211.180(e)).
process remains in control (§ 211.180(e)).
An ongoing program to collect and analyze An ongoing program to collect and analyze
product and process data that relate to prod- product and process data that relate to prod-
uct quality must be established (§ uct quality must be established (§
211.180(e)). The data collected should in- 211.180(e)). The data collected should in-
clude relevant process trends and quality of clude relevant process trends and quality of
incoming materials or components, in- incoming materials or components, in-
process material, and finished products. The process material, and finished products. The
data should be statistically trended and re- data should be statistically trended and re-
viewed by trained personnel. The information viewed by trained personnel. The information
collected should verify that the quality collected should verify that the critical quality
attributes are being appropriately controlled attributes are being controlled throughout the
throughout the process. process.
We recommend that a statistician or person We recommend that a statistician or person

with adequate training in statistical process with adequate training in statistical process
control techniques develop the data collec- control techniques develop the data collec-
tion plan and statistical methods and proce- tion plan and statistical methods and proce-
dures used in measuring and evaluating dures used in measuring and evaluating
process stability and process capability.18 process stability and process capability. Pro-
Procedures should describe how trending cedures should describe how trending and
and calculations are to be performed and calculations are to be performed. Procedures
should guard against overreaction to individ- should guard against overreaction to individ-
ual events as well as against failure to detect ual events as well as against failure to detect
unintended process variability. Production process drift. Production data should be col-
data should be collected to evaluate process lected to evaluate process stability and ca-
stability and capability. The quality unit pability. The quality unit should review this
should review this information. If properly information. If done properly, these efforts
carried out, these efforts can identify variabili- can identify variability in the process and/or
ty in the process and/or signal potential product; this information can be used to alert
process improvements. the manufacturer that the process should be
improved.
18
Some references that may be useful include
the following: ASTM E2281-03 “Standard Practice
for Process and Measurement Capability Indices,”
ASTM E2500-07 “Standard Guide for Specifica-
tion, Design, and Verification of Pharmaceutical
and Biopharmaceutical Manufacturing Systems
and Equipment,” and ASTM E2709-09 “Standard
Practice for Demonstrating Capability to Comply
with a Lot Acceptance Procedure.” This is not a
complete list of all useful references on this topic.
Many industry standards, books, and guides on
these topics are available.
Good process design and development Good process design and development
should anticipate significant sources of varia- should anticipate significant sources of varia-
bility and establish appropriate detection, bility and establish appropriate detection,
control, and/or mitigation strategies, as well control, and/or mitigation strategies, as well
as appropriate alert and action limits. How- as appropriate alert and action limits. How-
ever, a process is likely to encounter sources ever, a process is likely to encounter sources
of variation that were not previously detected of variation that were not previously detected
or to which the process was not previously or to which the process was not previously
exposed. Many tools and techniques, some exposed. Many tools and techniques, some
statistical and others more qualitative, can be statistical and others more qualitative, can be
used to detect variation, characterize it, and used to detect variation, characterize it, and
determine the root cause. We recommend determine the root cause. We recommend
that the manufacturer use quantitative, statis- that the manufacturer use quantitative, statis-
tical methods whenever appropriate and tical methods whenever feasible. We also
feasible. Scrutiny of intra-batch as well as recommend that it scrutinize intra-batch as
inter-batch variation is part of a comprehen- well as inter-batch variation as part of a com-
sive continued process verification program prehensive continued process verification
under § 211.180(e). program.
We recommend continued monitoring and We recommend continued monitoring and/or

sampling of process parameters and quality sampling at the level established during the
attributes at the level established during the process qualification stage until sufficient
process qualification stage until sufficient data is available to generate significant va-
data are available to generate significant riability estimates. Once the variability is
variability estimates. These estimates can known, sampling and/or monitoring should
provide the basis for establishing levels and be adjusted to a statistically appropriate and
frequency of routine sampling and monitoring representative level. Process variability
for the particular product and process. Moni- should be periodically assessed and sam-
toring can then be adjusted to a statistically pling and/or monitoring adjusted accordingly.
appropriate and representative level. Process
variability should be periodically assessed
and monitoring adjusted accordingly.
Variation can also be detected by the timely Variation can also be detected by the timely
assessment of defect complaints, out-of- assessment of defect complaints, out-of spe-
specification findings, process deviation re- cification findings, process deviation reports,
ports, process yield variations, batch records, process yield variations, batch records, in-
incoming raw material records, and adverse coming raw material records, and adverse
event reports. Production line operators and event reports. Production line operators and
quality unit staff should be encouraged to quality unit staff should be encouraged to
provide feedback on process performance. provide feedback on process performance.
We recommend that the quality unit meet Operator errors should also be tracked to
periodically with production staff to evaluate measure the quality of the training program;
data, discuss possible trends or undesirable to identify operator performance issues; and
process variation, and coordinate any correc- to look for potential batch record, procedural,
tion or follow-up actions by production. and/or process improvements that could help
to reduce operator error. We recommend that
the quality unit meet periodically with produc-
tion staff to evaluate data, discuss possible
trends or drifts in the process, and coordinate

any correction or follow-up actions by pro-
duction.
Data gathered during this stage might sug- Data gathered during this stage might sug-
gest ways to improve and/or optimize the gest ways to improve and/or optimize the
process by altering some aspect of the process by altering some aspect of the
process or product, such as the operating process or product such as the operating
conditions (ranges and set-points), process conditions (ranges and set-points), process
controls, component, or in-process material controls, component, or in-process material
characteristics. A description of the planned characteristics. A description of the planned
change, a well-justified rationale for the change, a well-justified rationale for the
change, an implementation plan, and quality change, an implementation plan, and quality
unit approval before implementation must be unit approval before implementation must be
documented (§ 211.100). Depending on how documented (21 CFR 211.100). Depending
the proposed change might affect product on the significance to product quality, modifi-
quality, additional process design and cations may warrant performing additional
process qualification activities could be war- process design and process qualification
ranted.19 13
activities.
19
Certain manufacturing changes may call for 13
Certain manufacturing changes may call for a
formal notification to the Agency before imple-
formal notification to the Agency before imple-
mentation, as directed by existing regulations
mentation, as directed by existing regulations and
(see, e.g., 21 CFR 314.70 and 601.12).
filing guidance (i.e., documents that describe
procedures for filing information to an applica-
tion).
Maintenance of the facility, utilities, and Maintenance of the facility, utilities, and
equipment is another important aspect of equipment is another important aspect of
ensuring that a process remains in control. ensuring that a process remains in control.
Once established, qualification status must Once established, qualification status must
be maintained through routine monitoring, be maintained through routine monitoring,
maintenance, and calibration procedures and maintenance, and calibration procedures and
schedules (21 CFR part 211, subparts C and schedules (21 CFR part 211, subparts C and
D). The equipment and facility qualification D). The data should be assessed periodically
data should be assessed periodically to de- to determine whether re-qualification should
termine whether re-qualification should be be performed and the extent of that re-
performed and the extent of that re- qualification. Maintenance and calibration
qualification. Maintenance and calibration frequency should be adjusted based on
frequency should be adjusted based on feedback from these activities.
feedback from these activities.
V. CONCURRENT RELEASE OF PPQ V. CONCURRENT RELEASE OF PER-

BATCHES FORMANCE QUALIFICATION BATCHES
In most cases, the PPQ study needs to be In most cases, the PQ protocol needs to be
completed successfully and a high degree of completed before the commercial distribution
assurance in the process achieved before of a product. In special situations, the PQ
commercial distribution of a product. In spe- protocol can be designed to release a PQ
cial situations, the PPQ protocol can be de- batch for distribution before completion of the
signed to release a PPQ batch for distribution protocol. The conclusions about the manu-
before complete execution of the protocol facturing process should be made when the
steps and activities, i.e., concurrent release. protocol is completed and the data is fully
FDA expects that concurrent release will be evaluated. FDA expects that concurrent re-
used rarely. lease will be used rarely.
Concurrent release might be appropriate for Concurrent release might be appropriate for
processes used infrequently for various rea- processes used infrequently because of li-
sons, such as to manufacture drugs for which mited demand for the product (e.g., orphan
there is limited demand (e.g., orphan drugs, drugs), processes with necessarily low pro-
minor use and minor species veterinary duction volume per batch (e.g., radiopharma-
drugs) or which have short half lives (e.g., ceuticals, including positron emission tomo-
radiopharmaceuticals, including positron graphy drugs), and processes manufacturing
emission tomography drugs). Concurrent medically necessary drugs to alleviate a
release might also be appropriate for drugs short supply, which should be coordinated
that are medically necessary and are being with the Agency.
manufactured in coordination with the Agen-
cy to alleviate a short supply.
Conclusions about a commercial manufactur-

ing process can only be made after the PPQ
protocol is fully executed and the data are
fully evaluated. If Stage 2 qualification is not
successful (i.e., does not demonstrate that
the process as designed is capable of repro-
ducible performance at commercial scale),
then additional design studies and qualifica-
tion may be necessary. The new product and
process understanding obtained from the
unsuccessful qualification study(ies) can
have negative implications if any lot was al-
ready distributed. Full execution of Stages 1
and 2 of process validation is intended to
preclude or minimize that outcome.
Circumstances and rationale for concurrent

release should be fully described in the PPQ
protocol. Even when process performance
assessment based on the PPQ protocol is
still outstanding, any lot released concurrent-
ly must comply with all CGMPs, regulatory

approval requirements, and PPQ protocol lot
release criteria. Lot release under a PPQ
protocol is based upon meeting confidence
levels appropriate for each quality attribute of
the drug.
When warranted and used, concurrent re- When warranted and used, concurrent re-
lease should be accompanied by a system lease should be accompanied by a system
for careful oversight of the distributed batch for careful oversight of the distributed batch
to facilitate rapid customer feedback. For to facilitate rapid customer feedback. For
example, customer complaints and defect example, customer complaints and defect
reports should be rapidly assessed to deter- reports should be rapidly assessed to deter-
mine root cause and whether the process mine root cause and whether the process
should be improved or changed. Concurrent- should be improved or changed. We recom-
ly released lots must also be assessed in mend that each batch in a concurrent release
light of any negative PPQ study finding or program also undergo stability testing and
conclusions and appropriate corrective action that this test data be promptly evaluated to
must be taken (§§ 211.100(a), 211.180(e), ensure rapid detection and correction of any
and 211.192). We recommend that each problems.
batch in a concurrent release program be
evaluated for inclusion in the stability pro-
gram. It is important that stability test data be
promptly evaluated to ensure rapid detection
and correction of any problems.
VI. DOCUMENTATION VI. DOCUMENTATION
Documentation at each stage of the process Documentation at each stage of the process
validation lifecycle is essential for effective validation lifecycle is essential for effective
communication in complex, lengthy, and mul- communication in complex, lengthy, and mul-
tidisciplinary projects. Documentation is im- tidisciplinary projects. Documentation is im-
portant so that knowledge gained about a portant so that knowledge gained about a
product and process is accessible and com- product and process is accessible and com-
prehensible to others involved in each stage prehensible to others involved in each stage
of the lifecycle. Information transparency and of the lifecycle. In addition to being a funda-
accessibility are fundamental tenets of the mental tenet of following the scientific me-
scientific method. They are also essential to thod, information transparency and accessi-
enabling organizational units responsible and bility are essential so that organizational units
accountable for the process to make in- responsible and accountable for the process
formed, science-based decisions that ulti- can make informed, science-based decisions
mately support the release of a product to that ultimately support the release of a prod-
commerce. uct to commerce.
The degree and type of documentation re- The degree and type of documentation re-
quired by CGMP vary during the validation quired by CGMP is greatest during stage 2,
lifecycle. Documentation requirements are process qualification, and stage 3, continued
greatest during Stage 2, process qualifica- process verification. Studies during these
tion, and Stage 3, continued process verifica- stages must conform to CGMPs and must be
tion. Studies during these stages must con- approved by the quality unit in accordance
form to CGMPs and must be approved by the with the regulations (see 21 CFR 211.22 and
quality unit in accordance with the regula- 211.100). Viral and impurity clearance stu-
tions (see §§ 211.22 and 211.100). Viral and dies, even when performed at small scale,
impurity clearance studies, even when per- also require full quality unit oversight as is
formed at small scale, also require quality necessary during routine commercial produc-
unit oversight. tion.
CGMP documents for commercial manufac- CGMP documents for commercial manufac-
turing (i.e., the initial commercial master turing (i.e., the initial commercial master
batch production and control record (§ batch production and control record (21 CFR
211.186) and supporting procedures) are key 211.186) and supporting procedures) are key
outputs of Stage 1, process design. We rec- outputs of stage 1, process design. We rec-
ommend that firms diagram the process flow ommend that firms diagram the process flow
for the full-scale process. Process flow dia- for the full-scale process. Process flow dia-
grams should describe each unit operation, grams should describe each unit operation,
its placement in the overall process, monitor- its placement in the overall process, monitor-
ing and control points, and the component, ing and control points, and the component,
as well as other processing material inputs as well as other processing material inputs
(e.g., processing aids) and expected outputs (e.g., processing aids) and expected outputs
(i.e., in-process materials and finished prod- (i.e., in-process materials and finished prod-
uct). It is also useful to generate and pre- uct). It is also useful to generate and pre-
serve process flow diagrams of the various serve process flow diagrams of the various
scales as the process design progresses to scales as the process design progresses to
facilitate comparison and decision making facilitate comparison and decision making
about their comparability. about their comparability.
VII. ANALYTICAL METHODOLOGY VII. ANALYTICAL METHODOLOGY
Process knowledge depends on accurate Process knowledge is dependent on accu-

and precise measuring techniques used to rate and precise measuring techniques that
test and examine the quality of drug compo- are used to test and examine the quality of
nents, in-process materials, and finished drug components, in-process materials, and
products. Validated analytical methods are finished products. For data to have value in
not necessarily required during product- and predicting process outcomes, it is essential
process-development activities or when used that the analytical tests be scientifically
in characterization studies. Nevertheless, sound (as required under 21 CFR 211.160).
analytical methods should be scientifically While validated analytical methods are not
sound (e.g., specific, sensitive, and accurate) required during product- and process-
and provide results that are reliable. There development activities, methods should be
should be assurance of proper equipment scientifically sound (e.g., specific, sensitive,
function for laboratory experiments. Proce- and accurate), suitable, and reliable for the
dures for analytical method and equipment specified purpose. There should be assur-
maintenance, documentation practices, and ance of proper equipment function for labora-
calibration practices supporting process- tory experiments. Procedures for analytical
development efforts should be documented method and equipment maintenance, docu-
or described. New analytical technology and mentation practices, and calibration practices
modifications to existing technology are con- supporting process-development efforts
tinually being developed and can be used to should be documented or described. Analyti-
characterize the process or the product. Use cal methods supporting clinical supply pro-
of these methods is particularly appropriate duction, particularly stage 2 and 3 studies,
when they reduce risk by providing greater must follow appropriate CGMPs in parts 210
understanding or control of product quality. and 211.
However, analytical methods supporting
commercial batch release must follow
CGMPs in parts 210 and 211. Clinical supply
production should follow the CGMPs appro-
priate for the particular phase of clinical stu-
dies.
GLOSSARY
Capability of a process: Ability of a process

to produce a product that will fulfill the re-
quirements of that product. The concept of
process capability can also be defined in
statistical terms. (ISO 9000:2005)
Commercial manufacturing process: The

manufacturing process resulting in commer-
cial product (i.e., drug that is marketed, dis-
tributed, and sold or intended to be sold). For
the purposes of this guidance, the term
commercial manufacturing process does not
include clinical trial or treatment IND material.
Concurrent release: Releasing for distribu-

tion a lot of finished product, manufactured
following a qualification protocol, that meets
the lot release criteria established in the pro-
tocol, but before the entire study protocol has
been executed.
Continued process verification: Assuring

that during routine production the process
remains in a state of control.
Performance indicators: Measurable val-

ues used to quantify quality objectives to
reflect the performance of an organization,
process or system, also known as perfor-
mance metrics in some regions. (ICH Q10)
Process design: Defining the commercial

manufacturing process based on knowledge
gained through development and scale-up
activities.
Process qualification: Confirming that the

manufacturing process as designed is capa-
ble of reproducible commercial manufactur-
ing.
Process validation: The collection and

evaluation of data, from the process design
stage through commercial production,
which establishes scientific evidence that a
process is capable of consistently deliver-
ing quality products.
Quality: The degree to which a set of inhe-

rent properties of a product, system, or
process fulfils requirements. (ICH Q9)
State of control: A condition in which the

set of controls consistently provides assur-
ance of continued process performance
and product quality. (ICH Q10)
REFERENCES REFERENCES
FDA, (CBER), Validation of Procedures for FDA, 1987 (CDER, CBER, and Center for
Processing of Human Tissues Intended for Devices and Radiological Health (CDRH)),
Transplantation, guidance for industry, May Guideline on General Principles of Process
2002. Validation, guidance for industry, May 1987.
FDA, (CDER), Investigating Out-of- FDA, 2002 (CBER), Validation of Procedures

Specification (OOS) Test Results for Phar- for Processing of Human Tissues Intended
maceutical Production, guidance for industry, for Transplantation, guidance for industry,
October 2006. May 2002.
FDA, (CDER, CVM, and ORA), PAT — A FDA, 2004 (CDER, CVM, and ORA), PAT —
Framework for Innovative Pharmaceutical A Framework for Innovative Pharmaceutical
Development, Manufacturing, and Quality Development, Manufacturing, and Quality
Assurance, guidance for industry, September Assurance, guidance for industry, September
2004. 2004.
FDA, (CDER, CBER, CVM, and ORA), Quali- FDA, 2006 (CDER, CBER, CVM, and ORA),
ty Systems Approach to Pharmaceutical Cur- Quality Systems Approach to Pharmaceutical
rent Good Manufacturing Practice Regula- Current Good Manufacturing Practice Regu-
tions, guidance for industry, September lations, guidance for industry, September
2006. 2006.
FDA/Global Harmonization Task Force FDA/Global Harmonization Task Force

(GHTF; medical devices), Quality Manage- (GHTF; medical devices), 2004, Quality
ment Systems – Process Validation, edition Management Systems – Process Validation,
2, guidance, January 2004. edition 2, guidance, January 2004.
FDA/ICH, (CDER and CBER), Q7 Good FDA/ICH, 2001 (CDER and CBER), Q7A
Manufacturing Practice for Active Pharma- Good Manufacturing Practice, Guidance for
ceutical Ingredients, guidance for industry, Active Pharmaceutical Ingredients, ICH guid-
August 2001. ance for industry, August 2001.
FDA/ICH, (CDER and CBER), Q8(R2) Phar- FDA/ICH, 2006 (CDER and CBER), Q8A
maceutical Development, guidance for indus- Pharmaceutical Development, ICH guidance
try, November 2009. for industry, May 2006.
FDA/ICH, (CDER and CBER), Q9 Quality FDA/ICH, 2006 (CDER and CBER), Q9A
Risk Management, guidance for industry, Quality Risk Management, ICH guidance for
June 2006. industry, June 2006.
FDA/ICH (CDER and CBER) Q10 Pharma- FDA/ICH (CDER and CBER) Q10 Quality
ceutical Quality System, guidance for indus- Systems, ICH draft guidance for industry,
try, April 2009. May 2007 (when finalized, this guidance will
convey FDA’s current thinking on this topic).
ASTM E2474-06 Standard Practice for
Pharmaceutical Process Design Utilizing
Process Analytical Technology.
ASTM E2476-09 Standard Guide for Risk

Assessment and Risk Control as it Impacts
the Design, Development, and Operation of
PAT Processes for Pharmaceutical Manufac-
ture.
ASTM E2281-03 Standard Practice for

Process and Measurement Capability Indic-
es.
ASTM E2500-07 Standard Guide for Specifi-

cation, Design, and Verification of Pharma-
ceutical and Biopharmaceutical Manufactur-
ing Systems and Equipment.
ASTM E2709-10 Standard Practice for De-

monstrating Capability to Comply with a Lot
Acceptance Procedure.
The synopsis has been compiled by:
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3 / Februar 2011 Maas & Peither AG – GMP-Verlag

Guidance for Industry

Final Version January 2011 Draft 2008

• Human drugs • Human drugs

CGMP requirements of section 501(a)(2)(B) of CGMP requirements of section 501(a)(2)(B) of

II. BACKGROUND II. BACKGROUND

A. Process Validation and Drug Quality

B. Approach to Process Validation

consistently producing acceptable quality consistently producing acceptable quality

A successful validation program depends A successful validation program depends

Manufacturers should use ongoing programs

Manufacturers of legacy products can take

A drug . . . shall be deemed to be adulterated A drug . . . shall be deemed to be adulterated

pharmaceuticals are provided in 21 CFR in 21 CFR parts 210 and 211.

in statistical confidence (§ 211.165(c) and

IV. RECOMMENDATIONS IV. RECOMMENDATIONS

In the following sections, we describe general

A. General Considerations for Process A. General Considerations for Process

gorization to the Agency.

B. Specific Stages and Activities of Proc-

The following subsections describe the rec-

B. Stage 1 ― Process Design Stage 1– Process Design

Process design is the activity of defining the

Process design is the activity of defining the

drug product, including those that may not appear

Other activities, such as experiments or Other activities, such as experiments or

These controls are established in the master

Process Design Utilizing Process Analytical

C. Stage 2 ― Process Qualification Stage 2 – Process Qualification

1. Design of a Facility and Qualification of Design of a Facility and Qualification of

Proper design of a manufacturing facility is Proper design of a manufacturing facility is

1. the studies or tests to use, (1) the studies or tests to use,

3. the timing of qualification activities, (3) the timing of qualification activities,

4. the responsibilities of relevant departments (4) responsibilities, and

2. Process Performance Qualification Performance Qualification Approach

The approach to PPQ should be based on The approach to PQ should be based on

3. PPQ Protocol Performance Qualification Protocol

• Tests to be performed (in-process, re- • Tests to be performed (in-process, re-

4. PPQ Protocol Execution and Report Protocol Execution and Report

D. Stage 3 ― Continued Process Verifica- Stage 3 – Continued Process Verification

process remains in control (§ 211.180(e)).

We recommend that a statistician or person We recommend that a statistician or person

We recommend continued monitoring and We recommend continued monitoring and/or

trends or drifts in the process, and coordinate

V. CONCURRENT RELEASE OF PPQ V. CONCURRENT RELEASE OF PER-

Conclusions about a commercial manufactur-

Circumstances and rationale for concurrent

ly must comply with all CGMPs, regulatory

VI. DOCUMENTATION VI. DOCUMENTATION

VII. ANALYTICAL METHODOLOGY VII. ANALYTICAL METHODOLOGY

Process knowledge depends on accurate Process knowledge is dependent on accu-

Capability of a process: Ability of a process

Commercial manufacturing process: The

Concurrent release: Releasing for distribu-

Continued process verification: Assuring

remains in a state of control.

Performance indicators: Measurable val-

Process design: Defining the commercial

Process qualification: Confirming that the

Process validation: The collection and

Quality: The degree to which a set of inhe-

State of control: A condition in which the

2002. Validation, guidance for industry, May 1987.