REGULATORY REQUIREMENTS ON

PROCESS VALIDATION
(GENERAL)
21
st
August 2009
Mokhzanni Mustapa,
Center For Product Registration,
National Pharmaceutical Control Bureau
OUTLINE
History
Law and Regulations
Principle
The 3 approaches
Option 1, 2 or 3?
PIC/S
Typical Content of Process Validation
Re-validation
Common Mistake
P3.4 Process Validation
Guidelines & References


WHY PV?:- HISTORY
1963 :FD&C were approved; Process Validation has been a legal requirement.

<1980 : Injuries and death still took place
Quality assurance based on massive sampling of Finished product
Taking legal action against violative batches (Reactive vs. Preventive)
Large parenteral manufacturer facing complaints even though have QC programs and
negative sterility test.

1974 : Ted Byers Paper Presentation: Design for Quality emphasis attention on
process.

1987 : Guideline on General Principles of Process Validation took place.

1990 : FDA filing several injunction cases against manufacturer.

1993 : Court affirmed the requirement for PV in the cGMP

Malaysia/NPCB
1
st
Jan 2000 : Imported Injectable Products
1
st
June 2000 : Local Injectable Products
1
st
July 2007 : Galenicals
1
st
Jan 2008 : Tablet/Capsule/liquid/Patches/Eye Drops/Others



*Robert A. Nash; Pharmaceutical process Validation; 3
rd
Ed.
3
WHY PV? :- SAMPLING
Pharmaceutical Process Validation 3
rd
Ed. Robert A Nash
LAW AND REGULATIONS
Poison Act 1952
Sales of Drug Act 1952
Control of Drugs and
Cosmetics Regulations
1984
WHAT THE GUIDELINES SAY ON PV?
PRINCIPLE
a. PIC/S
PI 006-3 (25 September 2007)
6.1 Principle

PV is the means of ensuring, and providing
documentary evidence that processes (within
their specified design parameters) are capable
of repeatedly and reliably producing a finished
product of the required quality.


PRINCIPLE
b. ASEAN Guidelines on Process validation

PV is a means of ensuring that manufacturing
processes are capable of consistently
producing a finished product of the required
quality.

It involves providing documentary evidence
that the key steps in the manufacturing process
are consistent and reproducible.

PRINCIPLE
c. EMEA
Note for Guidance on Process Validation. (1
st
March
2001)

Validation is the act of demonstrating and
documenting that a procedure operates effectively.

PV is the means of ensuring the providing
documentary evidence that the processes (within
their specified parameters) are capable of
consistently producing a finished product of the
required quality.

PRINCIPLE
d. CDER: Guideline on General Principles of
Process Validation (May 1987)

PV is establishing documented evidence which
provides a high degree of assurance that a
specific process will consistently produce a
product meeting its pre-determined
specifications and quality characteristics.
ALL GUIDELINES AGREED THAT PV MEANS
Process which are Reliable, Repeatable, &
under control
Repeatable (Normally 3 consecutive
batches)
Must investigate failures
The rationale should be documented if
experimental method is changed
document deviations, decisions and reasoning
Does not improve processes
Should not validate bad processes

11
Prospective Validation
Concurrent Validation
Retrospective Validation
PROSPECTIVE VALIDATION
PIC/S: PI 006-3. Clauses

6.3.3: Document elements:
a. A description of the process
b. A description of the experiment.
c. Details of the equipment/facilities to be used (including measuring/recording equipment)
together with its calibration status.
d. The variables to be monitored.
e. The samples to be taken where when, how and how many.
f. The product performance characteristic/attributes to be monitored, together with the test
method.
g. The acceptable limits.
h. Time Schedules
i. Personnel responsibilities.
j. Details of methods for recording and evaluating results, including statistical analysis.

6.3.4: - All equipment, the production environment and analytical test methods to be used
have been fully validated (IQ/OQ).
- Staff have been properly trained.


PROSPECTIVE VALIDATION.
(CONTINUED)
6.3.6: - Sufficient number of runs and observation.
- Generally accept 3 consecutive batches.

6.3.7: - Batches made should be the same size as full scale production.

6.3.8: - Extensive testing should be performed on the product at various stages.
- Detailed testing should be done on the final product and its package.

6.3.9: - DOCUMENT it and include it in Validation report!
a. A description of the process.
b. Detailed Summary of results (in-process, final testing, including failed test). Raw
data or reference of sources.
c. Additional work or deviation should be noted and explained.
d. A review and comparison with those expected.
e. Formal acceptance/rejection of the work by the team/persons.
CONCURRENT VALIDATION
Clause 6.4.4
Documentation requirements are the same as
specified for Prospective Validation

and the testing to be carried out in-process and on
the finished product will be as specified in approved
protocols.

The completed protocols and reports should be
reviewed and approved before product is release for
sale or supply.

CONCURRENT VALIDATION
Acceptable in the case of orphan drugs,
when the number of production batches per
year is expected to be low.

Should seek prior consent from DRA.

RETROSPECTIVE VALIDATION
Can be performed for existing non-sterile products
which already in the market for some time.
Involves trend analysis of Historical manufacturing
and QC data.

Must meet following condition.
i. No change in formulation.
ii. No change in manufacturing process or analytical
method.
iii. No change in equipment or site(s) of manufacturing
iv. CpK >1.33 based on 10 20 batches


PROCESS VALIDATION CHALLENGES THE
Facility
Environment
Services & Utilities
Equipment and machines
Personnel
Standard Procedures and Operating
conditions (the process)
19
TYPICAL CONTENT OF PV
ROBERT A NASH; PHARMACEUTICAL PROCESS VALIDATION 3
RD
ED.
Safety Instruction
Environmental Restriction
Equipment
Raw Materials
Process Flow Charts
Critical Process Parameters & Related means of controls
Responsibilities of each participating group
Cleaning validation & verification requirements
Master batch component; percentage by weight
Production batch component
Process batch record
Product testing
Formulation
Validation sampling & testing
Definition of validation criteria.
20
ASEAN GUIDELINE:
CONTENT OF VALIDATION (SCHEME)
a) A short Description of the manufacturing process in a schematic
drawing or flow chart.
b) A summary of critical process, control variables and justification for
their selection.
c) Finished Product specification
d) Details analytical methods (reference to the dossier)
e) In process control proposed and with acceptance criteria.
f) Additional testing intended to be carried out (eg with proposed
acceptance criteria and analytical validation appropriate).
g) Sampling Plan where, when and how samples are taken.
h) Details of method for recording and evaluation of results.
i) Proposed time frames for carrying out the studies.

21
ASEAN GUIDELINE:
CONTENT OF VALIDATION (REPORT)
a) Summary
b) Introduction
c) Batches used for Validation
d) Manufacturing Equipment
e) Critical Process Steps and parameters
f) Acceptance criteria.
g) Sampling Plan
h) Tabulation of test results.
i) Batch Analysis
j) Evaluation of Data, and where applicable. Including statistical
process control analysis.
k) Evaluation of data including comparison against acceptance criteria.
l) Discussion on deviations and out of specification results.
m) Conclusion and recommendation.
22
PROCESS VALIDATION SCHEME


Information Remark
Short description of the Process. -summary of the critical processing steps
-critical parameters to be monitored during
validation.
Finished product specification

- release
Details of analytical methods.

- References to the dossier
In Process Controls proposed with acceptance
criteria.

Additional testing intended to be carried out.

-Proposed acceptance criteria
-Analytical validation
Sampling Plan -Where, when and how the samples are taken.

Details of method for recording and evaluation
of results.
Proposed timeframe
OPTION (ASEAN GUIDELINES)
Option Documentation
Option 1 i. Validation report for 3 consecutive batches

Option 2 i. Pharmaceutical Development report.
ii. Validation report on 1 pilot batch OR
Validation scheme.
iii. Commitment to conduct Validation study.

Option 3 i. Validation document from reference country.
ii. Commitment to conduct validation study.

Pilot Batch:
10% of commercial batch, OR 100,000s OR whichever is higher.
Retrospective:
Previous data of 10 20 consecutive batches.
PROCESS TO BE VALIDATED
(EXAMPLE)
Non Sterile Sterile
Wet/Dry Granulation
Drying
Mixing/Blending
Compression
Encapsulation
Coating
Filtration
Filling
Packing

Mixing
Filling
Sterilization
Filtration
Lyophilization
Moist Heat
Dry Heat
Radiation
Ethylene Oxide
Filling simulation (Media Fill)

PRE-REQUISITES FOR PROCESS VALIDATION
Facility and controlled environment(s) -
qualified.
Critical services and Utilities - qualified.
Equipment -calibrated and qualified.
GMP-related computer system - qualified.
Test method - validated.
Personnel - trained.
Master batch documentation -approved for
use.
Critical process parameters - known and
documented.
27
VALIDATION
Exercise 1
You are given a tablet
manufacturing flow chart
to study,.
I. List the critical steps that are
required to be validated
II. List the critical equipment
required to be qualified
III. Identify the variables and
construct a table as directed
IV. Discuss Worst Case scenario
for this process.
28
I) CRITICAL STEP
29
B) CRITICAL EQUIPMENT
No Equipment Model Type Qualification
Status
1 Granulator MG300 300L DQ-IQ-OQ-PQ
2 Fluidized Bed Dryer FBD01 - DQ-IQ-OQ-PQ

3 Cube Blender CB250 250L DQ-IQ-OQ-PQ

4 Compression CMB4 Rotary 25
station
DQ-IQ-OQ

5 Coater Thai
Coater
60 DQ-IQ-OQ-PQ

30
PROCESS VARIABLE
INPUT: Critical process
Parameters
Process OUTPUTS: Critical
Quality Attributes
(Variables)
i. Speed,
ii. Fluid amount,
iii. Time,
iv. Sieve Diameter,
Blend & Wt Granulation
LOD
Granules Uniformity
i. Air temp,
ii. Product Temp,
iii. Time
Fluid Bed Dryer
Particle size
LOD
i. Blender dimension,
ii. Speed, load, time,

Blending
Blend uniformity
Flow properties
i. Comp. Speed,
ii. Force,
iii. Feed rate
Compression
Weight control
Disintegration/Hardness,
Assay
Etc,
i. Inlet temp,
ii. Bed Temp,
iii. Exhaust Temp.
iv. Coating Pan RPM,
v. Nozzles No.
vi. Spraying rate.
vii. Spray rate,
Coating
Appearance,
Dimension,
Dissolution rate
Weight,
Hardness
Assay,
Etc.
31
C) WORST CASE SCENARIO
Process INPUT: Critical process
Parameters
Min Max
Blend & Wt
Granulation
i. Speed,
ii. Fluid amount,
iii. Time,
iv. Sieve Diameter,
200rpm
5L
20minute
300rpm
6L
30 minute
Fluid Bed
Dryer
i. Air temp,
ii. Product Temp,
iii. Time
55-75
o
C

2hrs
55-75
o
C

4 hrs
Blending
i. Blender dimension,
ii. Speed, load,
iii. time,
iv. Holding time


5 minute


10 minute
Compression
i. Comp. Speed,
ii. Force,
iii. Feed rate
iv. Holding time
300rpm
12 tonnes
400rpm
40 tonnes

Coating
i. Inlet temp,
ii. Bed Temp,
iii. Exhaust Temp.
iv. Coating Pan RPM,
v. Nozzles No.
vi. Spraying rate.
vii. Spray rate,
viii. Holding time

55 deg C

40 rpm

1 Liter per hr.

70 deg C

50 rpm

2 liter per hr
32
CHANGE CONTROL RE-VALIDATION
A repeat of the process validation to provide an
assurance that changes in process/equipment
introduced in accordance with change control
procedures do not adversely affect process
characteristics and product quality.

PIC/S Code of GMP Annex 15 Glossary
34
RE-VALIDATION DUE TO CHANGES
a) Manufacturing Process
Change to Master Processing Instructions (Methods)
b) Formulation
Change of Bill of Materials, formulation or batches proportions
Change in raw material suppliers or components
c) Equipment
Significant alteration to processing equipment
Introduction of new equipment or utilities
e) Environment
Significant change in processing conditions or environment
After extensive preventive or running maintenance work.
f) Methods & Specifications
Major changes in quality control methods or specifications
If in-process or quality control results are outside pre-set limits.
If in-process or quality control data indicates a significant process shift or change in process
capability.
35
PIC/S PI 006-3 CLAUSE 6.7.4
Changes that are likely to require Re-Validation are as follows:
a) Changes of Raw Materials (physical properties such as density,
viscosity, particle size distribution may affect the process or product.
b) Change of starting material manufacturer.
c) Changes of Packaging material (e.g.: substituting plastic for glass).
d) Changes in the process (E.g.: mixing times, drying temperatures),
e) Changes in the equipment (E.g.: addition of automatic detection
systems). Changes of equipment which involved the replacement of
equipment on a like for like basis would not normally require re-
validation.
f) Production area and support system changes (e.g.: rearrangement of
areas, new water treatment method).
g) Transfer of process to another site.
h) Unexpected changes (e.g.: those observed during self inspection or
during routine analysis of process trend data).
COMMON MISTAKE

Frequency
Criticality
A
B
C D
A) ALWAYS BUT NOT CRITICAL







Type Example
Missing information.

-Pre-requisite status?
-Raw Material, Packaging Material, Equipment,
Facilities, Operators?
-Location & Address,
-Missing pages
-Blur & Low resolution document.

Typo error.

-Color description,
-Parameters, (Temp, time, etc)
-Instruction,

Wrong document.

-Different strength.
-Old processes.
-Old/Different Plant

Incomplete Document -Protocol not submitted
-Report/Summary not submitted

B) SELDOM AND NOT CRITICAL




Type Example
Submitting unnecessary
documents.
-DQ, IQ, OQ.
-Media Fill Report for terminal process.

C) SELDOM AND CRITICAL



Type Example
-Totally different process.

-Wet granulation Vs. Dry granulation.
-Different media fill approach
(powder filling vs. liquid filling)

- Poor GMP practices.

-Poor aseptic control.
-Renovated plant.

- Unjustified PV approach. - Retrospective or Concurrent instead of Prospective.

- Different Formulation

-New formulation.
-Different product strength
-Different coating material.
-Different ingredients quantity.

D) ALWAYS AND CRITICAL



Type Example
-Re-validation condition

-
-Inconsistency with proposed
manufacturing process.
- Load, Speed, Temperature, time, distance, holding time,
pressure, etc.

- Undocumented important evidence. -Observed Equipment/process parameters
-In-Process Manufacturing

-Different equipment

-Type of blender,
-Load size,
-Single punch vs. Rotary Punch

-Different materials.

-Unapproved sources.

-Unapproved Documents. -Signature,
-Conclusion

-Different product Specification - Color, dimension,
3 Batches
Controversy!
DO CGMPS REQUIRE THREE SUCCESSFUL PROCESS VALIDATION BATCHES BEFORE A NEW ACTIVE
PHARMACEUTICAL INGREDIENT (API) OR A FINISHED DRUG PRODUCT IS RELEASED FOR DISTRIBUTION?
Sources: http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm124782.htm
No.
Neither the CGMP regulations nor FDA policy specifies a minimum number of batches to
validate a manufacturing process. The current industry guidance on APIs (see ICH Q7A for APIs)
also does not specify a specific number of batches for process validation.

FDA recognizes that validating a manufacturing process, or a change to a process, cannot be
reduced to so simplistic a formula as the completion of three successful full scale batches. The
agency acknowledges that the idea of three validation batches has become prevalent, in part
due to language in its own guidance documents. However, FDA is now clarifying current
expectations on process validation. The 1987 Guideline of General Principles of Process
Validation is currently being revised to address this issue. The emphasis for demonstrating
validated processes is placed on the manufacturers process design and development studies in
addition to its demonstration of reproducibility at scale, a goal that has always been expected.

However, a minimum number of conformance (a.k.a. validation) batches
necessary to validate the manufacturing processes is not specified.
The manufacturer is expected to have a sound rationale for its choices in this
regard.
The agency encourages the use of science based approaches to process
validation.

CURRENT & FUTURE?
Cleaning Validation
Computer & Software Validation
Modern Process
Glove Box
Isolators
Restricted Access Barrier System (RABs)
Blow, Fill and Seal / Form, Fill & Seal
Robotic controlled
Worldwide Harmonization


Market holder responsibilities
1. Option & Approach selection.
2. Document Submission
3. Details of Validation
1. OPTION AND APPROACH.
Option ASEAN Guidelines Process Validation Approach
Option 1
i. Validation Report for 3 consecutive batches.

Prospective Validation
3 consecutive successful batches or more
Option 2
i. Pharmaceutical Development report.
ii. Validation report on 1 pilot batch OR
Validation scheme.
iii. Commitment to conduct Validation study.

Concurrent Validation
3 consecutive batches or more
Option 3
i. Validation Document from reference country.
ii. Commitment To conduct Validation Study

Retrospective Validation
Previous data of 10-20* consecutive batches
*
ASEAN Guidelines On Process validation

2. DOCUMENT SUBMISSION



Document Checkbox Remark
A Development Pharmaceutical Report

Option 2
B Validation Scheme / Protocol

C Validation Report
Pilot Batch
Full production batch





Option 2
Option 1
D Supporting documents.
Cleaning validation

3. DETAILS OF VALIDATION
a) Know your product.



b) Know the Validation details.
Approach : Prospective / Concurrent / Retrospective ?.


Product ,
Name,
Strength,
Dosage
Form
Primary
Packing
Proposed
Commercial
Batch size
Manufacturer Country
No Batch
No
Mfg Date Batch Type Validated
Batch Size
Manufacturer Country
Experiment?

Pilot?

Commercial?

Question:
If the validation data submitted for 3 consecutive production batches
showed that they fully comply with specifications but do not fulfil the
process validation acceptance criteria, would they be approved for
marketing?
Answer
The onus is on the manufacturer to ensure that the manufacturing process is
well controlled prior to manufacturing the batches for marketing. The
manufacturer should provide justification for not meeting the acceptance criteria
of process validation and may need to re-validate the process before releasing
the said product batches which meet the quality specification for sale.
Sources: ASEAN Guidelines on Process Validation (Q&A)
http://www.hsa.gov.sg/publish/etc/medialib/hsa_library/health_products_regulation/western_medicines/files
_guidelines.Par.20042.File.dat/ASEAN_Guideline_on_Process_Validation_Q&A_Version2_Jul07.pdf

REFERENCES
A) PIC/S:
http://www.picscheme.org
e.g.: i) PI 006-3 : Recommendations on Validation Master Plan Intallation and Operational
Qualification Non Sterile Process Validation Cleaning validation
ii) PI 007-1: Recommendation on Validation of Aseptic Processes
iii) PI 009-8 (Annexes)

B) EMEA:
http://www.tga.gov.au/docs/html/euguide/euad_qual.htm#qualitymedicinal
e.g.: i) Note for Guidance on Process validation

C) Singapore (HSA):
http://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/GMP/guidelines.html
e.g.: i) Non Sterile Process Validation
ii) Validation of Aseptic Process
iii) Validation of Terminal Moist Heat Sterilization


REFERENCES
D) ASEAN:
http://www.bpfk.gov.my/
E.g.: i) ASEAN Guideline on Process Validation (29 KB)
ii) ASEAN Guideline on Process Validation Q&A
http://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/western_medicines/guidelines.html

E) FDA/CDER
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm064971.ht
m
eg: i) General Principles of Process Validation
ii) Sterile Drug Products Produced by Aseptic Processing - cGMP

F) International Conference on Harmonisation - Quality (ICH-Q)
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm065005.ht
m

eg: i) Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients
ii) Q8(R1) Pharmaceutical Development Revision 1
iii) Q9 Quality Risk Management
iv) Q10 Pharmaceutical Quality System

G) Global Harmonization task Force


mokhzanni@bpfk.gov.my
THANK YOU