23-24 February 2017, Hamburg, Germany Page 1

Modern Validation
Implementation of EU GMP Annex 15
and FDA requirements

History of Validation
Dr Jean-Denis Mallet
23 February 2017, Hamburg
23-24 February 2017, Hamburg, Germany Page 2

Senior Technology Partner, NNE (PHARMAPLAN)

Compliance Director, SNC Lavalin Services
Auditor at the International Red-Cross
Senior GMP Consultnat at (NNE) Pharmaplan
Head of Pharmaceutical Inspection (Afssaps)
GMP Compliance Consultant at Pharmaplan
Quality Assurance Director at Beaufour-Ipsen
Quality Director at Janssen-Cilag, France
GMP inspector at the French Medicines Agency
Dr J-D Mallet
Production Director at Pharmygiene-Scat
Quality Assurance Manager at Janssen-Cilag
Technical Assistant at Roussel-Diamant Morocco

Pharmacist, IPI Paris, MBA (1978-1985).

23-24 February 2017, Hamburg, Germany Page 3

• Introduction
• The inception of good manufacturing practices (60s)
• Was the validation concept part of these GMP ? (70s)
• Emergence of the validation principles (80s)
• Consolidation of the validation approach (90s)
• The turn of the validation guidances (Y2Ks)
• Modern validation (10s)
• And tomorrow ?
 Introduction
23-24 February 2017, Hamburg, Germany Page 4

1937 : DEG in sulfanilamide 1941

tainted sulfathiazole
 Introduction
23-24 February 2017, Hamburg, Germany Page 5

1962 : thalidomide tragedy

23-24 February 2017, Hamburg, Germany Page 6

• Introduction
• The inception of good manufacturing practices (60s)
• Was the validation concept part of these GMP ? (70s)
• Emergence of the validation principles (80s)
• Consolidation of the validation approach (90s)
• The turn of the validation guidances (Y2Ks)
• Modern validation (10s)
• And tomorrow ?
 (c)GMP Inception
23-24 February 2017, Hamburg, Germany Page 7

The reverberations of the early sixities’ thalidomide tragedy, while

involving that drug in foreign countries, but not in the USA, oriented
the change in the US legislation

All legislative experts agree that if the thalidomide tragedy would

had not occurred, the US legislation on drugs in the Senate would
not have emerged in 1962

The Kefauver-Harris Drugs Amendments allowed the innovative

statutatory requirements for (current) good manufacturing practices
(GMP) to be issued in June 1963 by the FDA.
 (c)GMP Inception
23-24 February 2017, Hamburg, Germany Page 8

Part 133, Drugs, Current Good Manufacturing Practice in

Manufacture, Processing, packing, or Holding (June 1963)
 (c)GMP Inception
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These GMP regulations were then considered as a successful

« balanced approach » combining the forces of : 1°) scientific
knowledge, 2°) self-regulation and 3°) regulatory enforcement

133.1 Definitions 133.8 Mfg Procedures

133.2 Current gmp 133.9 Product containers
133.3 Buildings 133.10 Packaging & Labeling
133.4 Equipment 133.11 Laboratory records
133.5 Personnel 133.12 Distribution records
133.6 Components 133.13 Stability
133.7 Master formula & batch records 133.14 Complaint files.
 (c)GMP Inception
23-24 February 2017, Hamburg, Germany Page 10
 (c)GMP Inception
23-24 February 2017, Hamburg, Germany Page 11

In 1967, the Twentieth World Health Assembly requested the WHO

Director General to take a number of measures to assist Member
States in their efforts to improve the quality control of drugs
In particular, it called for the
formulation, as soon as
possible, of principles for
quality control procedures
that should be applied to
drug manufacturing practice
on the basis of the annex
issued in 1965 in TRS 307.
This was effective in 1969
into the TRS 418 (22nd report).
 (c)GMP Inception
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THE FDA GUIDE (1963) THE WHO GUIDE (1969)

133.1 Definitions 1. General Considerations

133.2 Current gmp 2. Defintions
133.3 Buildings 3. Personnel
133.4 Equipment 4. Premises
133.5 Personnel 5. Equipment
133.6 Components 6. Sanitation
133.7 Master formula & BR 7. Starting Materials
133.8 Mfg Procedures 8. Manufacturing Operations
133.9 Product containers 9. Labelling and Packaging
133.10 Packaging & Labeling 10. The Quality Control System
133.11 Laboratory records 11. Self-inspection
133.12 Distribution records 12. Distribution Records
133.13 Stability 13. Complaints & Reports of AR.
133.14 Complaint files
 (c)GMP Inception
23-24 February 2017, Hamburg, Germany Page 13

1969
Australia 1971
United Kingdom
23-24 February 2017, Hamburg, Germany Page 14

• Introduction
• The inception of good manufacturing practices (60s)
• Was the validation concept part of these GMP ? (70s)
• Emergence of the validation principles (80s)
• Consolidation of the validation approach (90s)
• The turn of the validation guidances (Y2Ks)
• Modern validation (10s)
• And tomorrow ?
 Validation Concept ?
23-24 February 2017, Hamburg, Germany Page 15

In 1970-1971, the Atlanta CDC investigated about an US- wide

outbreak following the use of intravenous fluids. The nosocomial
infection concerned 25 hospitals and 378 cases of septicaemia.
However, the « epidemic » organism was not systematic and, for
example, was found only in 6 of 1054 random samples …
 Validation Concept ?
23-24 February 2017, Hamburg, Germany Page 16

[…] Something might be wrong with the process and all the
quality control and all the finished product sampling and testing
in the production might not disclose the problem at the
manufacturing step. Indeed, the ordinary finished product
sampling and testing schedule had been followed including the
sterility testing and the lots have been released as acceptable…
 Validation Concept ?
23-24 February 2017, Hamburg, Germany Page 17

[…] All the quality control had been done meticulously.

But the process was at fault and the sampling did not showed it...
Bernard T. Loftus, FDA Director of Drug Manufacturing

It became obvious to FDA that the only way to assure the quality
of LVPs was if the companies validated their processes […]
 Validation Concept ?
23-24 February 2017, Hamburg, Germany Page 18

Following that outbreak, several other contamination alerts arose

in the United States and in Europe that were related with non
homogeneous LVP manufactured batches :

- USA,1970-1975, 17 LVP recalls from several established

manufacturing companies for contaminated batches
- UK, 1972, the Devonport Disaster (contaminated Dextrose)
- France, 1975, the Nancy Accident (contaminated Dextrose)
- and probably a lot more still relatively unknown …

(while a 1980 B.T. Loftus paper also mentioned similar problems

with the failing sterility some oil based injectable products and
the assay of some digitoxin tablets related with processes that
were not sufficiently checked or, in other words, that the
concerned processes were not proven to work homogeneiously
)
 Validation Concept ?
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At that point, the author would like to put some emphasis on the fact
that his lecture cannot be considered as a fully documented because
a number of information cannot be retrieved from the 70s period
which just preceeded the start of the digitalization of data …

info

Ted Byers’ lecture ?

time
XVII° XVIII° XIX° XX° XXI°
 Validation Concept ?
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As an example, the then new proposal for LVP good manufacturing

practice, proposed by the FDA in 1976, but that was never been
promulgated was quite difficult to collect from the Internet …
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Finally, it is only in 1978 that the word « validation » and the verb
« validate » (but not the term process validation) have been put into
the cGMP revision …

211.68 (b) … validation data …

211.84 (d)(2) … appropriate validation…

211.84 (d)(3) … appropriate validaiton …

211.110 (a) … to validate the performance …

211.113 (b) … validation of […] sterilization …

211.165 (e) … [methods] validation …

23-24 February 2017, Hamburg, Germany
Validation Concept ? Page 22

211.68 (b) Appropriate controls shall be exercised over computer or

related systems to assure that changes in master production and
control records or other records are instituted only by authorized
personnel Input to and output from the computer or related system of
formulas or other records or data shall be checked for accuracy. A
backup file of data entered into the computer or related system shall
be maintained except where certain data, such as calculations
performed in connection with laboratory analysis, are eliminated by
computerization or other automated processes. In such instances a
written record of the program shall be maintained along with
appropriate validation data. Hard copy or alternative systems, such
as duplicates, tapes, or microfilm, designed to assure that backup
data are exact and complete and that it is secure from alteration,
inadvertent erasures, or loss shall be maintained.
23-24 February 2017, Hamburg, Germany
Validation Concept ? Page 23

211.84 (d) (2) Each component shall be tested

for conformity with all appropriate written
specifications for purity, strength, and quality.
In lieu of such testing by the manufacturer, a
report of analysis may be accepted from the
supplier of a component. provided that at least
one specific identity test is conducted on such
component by the manufacturer, and provided
that the manufacturer establishes the reliability
of the supplier's analyses through appropriate
validation of the supplier's test results at
appropriate intervals.
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Validation Concept ? Page 24

211.84 (d)(3) Containers and closures shall be tested

for conformance with all appropriate written
procedures. In lieu of such testing by the manufacturer,
a certificate of testing may be accepted from the
supplier, provided that at least a visual identification is
conducted on such containers/closures by the
manufacturer and provided that the manufacturer
establishes the reliability of the supplier's test results
through appropriate validation of the supplier's test
results at appropriate intervals.
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Validation Concept ? Page 25

211.110 (a) To assure batch uniformity and integrity of drug products, written
procedures shall be established and followed that describe the in-process
controls, and tests, or examinations to be conducted on appropriate samples
of in-process materials of each batch. Such control procedures shall be
established to monitor the output and to validate the performance of those
manufacturing processes that may be responsible for causing variability in the
characteristics of in-process material and the drug product. Such control
procedures shall include, but are not limited [to …]
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Validation Concept ? Page 26

211.113 (b) Appropriate written procedures, designed to prevent

microbiological contamination of drug products purporting to be
sterile, shall be established and followed. Such procedures shall
include validation of any sterilization process.

Technical Report n°1, 1978

Validation of steam sterilization

Technical Report n°2, 1980

Validation of filtration sterilization

Technical Report n°3, 1981

Validation of dry heat sterilization
23-24 February 2017, Hamburg, Germany
Validation Concept ? Page 27

211.165 (e) The accuracy, sensitivity, specificity,

and reproducibility of test methods employed by
the firm shall be established and documented.
Such validation and documentation may be
accomplished in accordance with §
211.194(a)(2).
23-24 February 2017, Hamburg, Germany Page 28

• Introduction
• The inception of good manufacturing practices (60s)
• Was the validation concept part of these GMP ? (70s)
• Emergence of the validation principles (80s)
• Consolidation of the validation approach (90s)
• The turn of the validation guidances (Y2Ks)
• Modern validation (10s)
• And tomorrow ?
23-24 February 2017, Hamburg, Germany
Emergence of V. principles Page 29

After two officials of the FDA, T.E. Byers and B.T. Loftus, frequently
advocated in the 1970s for the developpement and implementation
of a validation approach as being part of the cGMP requirements, a
number of other papers and conferences were shared in the 1980s

… but the development of the validation requirements in

the GMP guidelines was very progressive from the
1970s to the XXI° Century …

Quotes 30
28
26

19

10

0 0 0
Ed.
1971 1974 1977 1983 1989 1996 2003 2008
23-24 February 2017, Hamburg, Germany
Emergence of V. principles Page 30

A number of publications then appeared in the 1980s, both from the

leading authorities (FDA, FIP/WHO, PIC) and from the professional
associations like the Parenteral Drug Association that led the
validation methodology and « standards » for the sterile processes :
.
- FIP Guidelines for Good Validation Practices, March 1980

- PIC Seminar on Validation, Dublin, Ireland, June 1982

- Draft Guideline on Process Validation, FDA, 1983

- The PAR approach to process validation, K. Chapman, 1984

- Guideline on Principles of Process Validation, FDA, 1987

- Analytical Validation, EEC, CPMP, 1989

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Emergence of V. principles Page 31

The most impacting document was probably the May 1987 FDA
Guideline on General Principles of Process Validation (still
effective until 2011) that clearly put the process validation as a
regulatory requirement and delivered the following definition :

« Process validation 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 »
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Emergence of V. principles Page 32

The Guideline on General Principles of Process Validation

included the following elements :
The basic principles of quality assurance have their goal in the
production of articles that are fit for their intended use :
1. quality, safety and effectiveness must be designed / embedded
2. quality cannot be inspected or tested into (100% of the) product
3. each step of the process must be controlled

The manufacturer should prepare a written validation protocol

specifying the data to be collected. That protocol should state a
number of process runs to demonstrate reproducibility within set limits

Analysis of the data will establish whether or not the equipment and process
controls are adequate to assure that product specifications are met.
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Emergence of V. principles Page 33

The Guideline on General Principles of Process Validation

described the following steps of process validation :

A. Prospective validation : before a new product is introduced

1.Equipment and Process
a) Equipment : Installation Qualification
b) Process Performance Qualification
c) Product Performance Qualification
2. Timely Revalidation
3. Documentation

B. Retrospective Process Validation : in some measures

23-24 February 2017, Hamburg, Germany Page 34

• Introduction
• The inception of good manufacturing practices (60s)
• Was the validation concept part of these GMP ? (70s)
• Emergence of the validation principles (80s)
• Consolidation of the validation approach (90s)
• The turn of the validation guidances (Y2Ks)
• Modern validation (10s)
• And tomorrow ?
23-24 February 2017, Hamburg, Germany
Consolidation of V. rules Page 35

Following the 1980s where the FDA clearly fixed validation objectives
to the regulated pharmaceutical industries, the term « validation »
entered in some good manufacturing guidances like the EU-GMP
guide which is unchanged here since 1991 :

- Validation studies should reinforce GMP and be conducted in

accordance with defined procedures …

- When any new formula or method is adopted, steps should be

taken to demonstrate its suitability for routine processing …

- Significant amendments should be validated …

- Processes should undergo periodic critical revalidation …

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Consolidation of V. rules Page 36

More documentation has been issued by the regulators during the

1990s, with the intent to enlarge the scope of validation including, for
example, the critical cleaning validation or analytical validation :

- WHO Guidelines on the Validation of Manufacturing Processes, 1993

- FDA Inspection Guide, Validation of Cleaning Processes (7/93)

- ICH, Validation of Analytical Procedures, Q2A, Oct. 1994

- FDA Guidance* for Industry : Sterilization Process Validation, Nov. 1994

- PIC Draft documentation for IQ and OQ of equipment, 11/1994

- PIC/S Recommendations on Validation, PH 1/96, January 1996

- FDA Proposed Amendment of CGMP, May 1996

- WHO GMP for Vaccines, Validation, 1997

23-24 February 2017, Hamburg, Germany
Consolidation of V. rules Page 37

One of the most complete and useful document issued during the
1990s was the PIC/S Recommendations on Validation which dealt
with the four following subjects :

- Validation Master Plan

- Installation and Operational Qualification

- Non-Sterile Process Validation

- Cleaning Validation

This quite detailed document was the basis for the Annex 15 of the EU-GMP
guide which finally was simplified compared to this PIC/S document …
23-24 February 2017, Hamburg, Germany
Consolidation of V. rules Page 38

Another aspect of validation, and logically, the firt of all validation is

the validation of analytical procedure. The ICH (Pharmaceutical)
International Conference on Harmonization issued it in 1994 :
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Consolidation of V. rules Page 39

On May 1996, the US FDA proposed in the Federal Register a series

of amendments to the CGMPs. The project was mainly to clarify the
expectations of this agency with regards of the validation tasks and
some definitions. But, finally, this proposal has been withdrawn.

- Validation protocol means a written plan describing the process to be

validated, including production equipment, and how he validation will be
conducted including tests […] and specifications

- Process Validation means estabishing, through documented evidence, a

high degree of assurance that a specific process will consistently produce
a product that meet is specifications

- Methods validation means establishing, through documented evidence, a

high degree of assurance that an analytical method will consistently yield
results refecting the product tested

- Equipment suitability is the established capacity of the equipment to

operate consistently with establihed limits and tolerance.
23-24 February 2017, Hamburg, Germany Page 40

• Introduction
• The inception of good manufacturing practices (60s)
• Was the validation concept part of these GMP ? (70s)
• Emergence of the validation principles (80s)
• Consolidation of the validation approach (90s)
• The turn of the validation guidances (Y2Ks)
• Modern validation (10s)
• And tomorrow ?
23-24 February 2017, Hamburg, Germany
The turn of validation guides Page 41

Undoubtedly, the various documents published from various

authorities, even if they can appear to be different, are converging
because being based and inspired from common roots …

- EMEA, Note for Guidance on Process Validation, March 2001

- EMA, Annex 15 to the EU Guide to GMP, July 2001

- Health Canada, A series of validation guides 2001-2006

- WHO, Supplementary Guidelines on Validation, TRS 937, 2006

- Draft FDA Guidline on General Principles of Validation, 2008

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The turn of validation guides Page 42

The EMeA Committee for Proprietary Medicinal Products (CPMP)

issued its « Note for Guidance on Process Validation » in March 2001 :

1. Introduction
2. Scope
3. Relationship Dev. & Manufacture
4. Data Submission
5. Scale-Up
6. Change Control

CPMP/QWP/848/96 … a tool for applicants

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The turn of validation guides Page 43

Another (European) validation tool was the Annex 15 to the EU-GMP

guide : « Qualification and Validation » which is inspired (as a
simplified inspiration) from the PIC/S PH 1/96 document :

1. Qualification and Validation

2. Planning for Validation
3. Documentation
4. Qualification
(DQ, IQ, OQ, PQ)
5. Process Validation
(Prospective, Concurrent, Retrospective)
6. Cleaning Validation
7. Change Control
8. Revalidation
July 2001
9. Glossary
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The turn of validation guides Page 44

Health Canada (Santé Canada) published, in the early 2000 years,

a series of process validation guides on a number of topics
including some useful « original » documents like this one, for BFS :
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The turn of validation guides Page 45

The TRS (Technical Report Series) n°937 from the World Health
Organization is (was) compatible with other Validation guides but, in
addition, provide us with a lot of useful templates :
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The turn of validation guides Page 46

One of the last published in that decade announced a real change in

the validation approach : the new (draft) 2008 FDA validation guide :
23-24 February 2017, Hamburg, Germany Page 47

• Introduction
• The inception of good manufacturing practices (60s)
• Was the validation concept part of these GMP ? (70s)
• Emergence of the validation principles (80s)
• Consolidation of the validation approach (90s)
• The turn of the validation guidances (Y2Ks)
• Modern validation (10s)
• And tomorrow ?
23-24 February 2017, Hamburg, Germany
Modern Validation Page 48

At the turn of the Century (or of the Millenium) we observed that the
concept of the good manufacturing practice has been adopted in
most regions, together with the Concept of Validation ….

Quite all the major guides that have been published were more or less inspired
from the (1963) very first FDA guide. And the tide of GMP history did not stop
with the XX° Century ...
23-24 February 2017, Hamburg, Germany
Modern Validation Page 49

In January 2011, the FDA published the « final » version of its

Process Validation Guide (General Principles and Practices) ….

… which really
changed the
approach, with the
introduction of the …

Continued
Process
Verification

… and bring us a The collection and evaluation of data, from the process
modified definition of design stage through commercial production, which
establishes scientific evidence that a process is
process validation : capable of consistently delivering quality products.
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Modern Validation Page 50

One of the most « recent » document is the revised and quite long
awaited EU-GMP Annex15 « Qualification and Validation » ….
1. Organising and Planning
2. Documentation, VMP
3. Qualification Stages
4. Re-Qualification
5. Process Validation
Retrospective
General (prospective)
Concurrent (exceptional)
Continuous process verification
Hybrid approach
Ongoing process verification during lifecycle
6. Verification of transportation
7. Validation of packaging
8. Qualification of Utilities
9. Validation of Test Methods
10. Cleaning Validation
11. Change Control
12. Glossary
23-24 February 2017, Hamburg, Germany Page 51

• Introduction
• The inception of good manufacturing practices (60s)
• Was the validation concept part of these GMP ? (70s)
• Emergence of the validation principles (80s)
• Consolidation of the validation approach (90s)
• The turn of the validation guidances (Y2Ks)
• Modern validation (10s)
• And tomorrow ?
23-24 February 2017, Hamburg, Germany
And tomorrow ? Page 52

Brazil A documented act the certifies that any procedure, process,

equipment, material, activity or system actually and consistently leads
to the expected results.

Canada The documented act of demonstrating that any procedure,

process, and activity will consistently lead to the expected results.
Includes the qualification of systems and equipment.

China A series of actions of proving that any operation procedure (or

method), manufacturing process or system actually leads to the
expected results.
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And tomorrow ? Page 53

EU (1991) Action of proving, in accordance with the principles of Good

Manufacturing Practice, that any procedure, process, equipment,
material, activity or system actually leads to the expected results.

EU (2015) Process Validation : The documented evidence that the

process, operated within established parameters, can perform effectively
and reproducibly to produce a medicinal product meeting its
predetermined specifications and quality attributes.

Hong Kong The documented act of proving that any procedure,

process, equipment, material, activity or system actually leads to
the expected results.

ICH (Q7) A documented program that provides a high degree of

assurance that a specific process, method, or system will consistently
produce a result meeting pre-determined acceptance criteria.
23-24 February 2017, Hamburg, Germany
And tomorrow ? Page 54

Japan Validation means to verify and document that the buildings

and facilities of the manufacturing site, proceduees, processes and
other procedures of the manufacturing control and quality control
provide the anticipated results.

Turkey A documented program that provides a high degree of

assurance that a specific process, method, or system will consistently
produce a result meeting pre-determined acceptance criteria.

WHO Action of proving, in accordance with the principles of GMP, that

any procedure, process, equipment, material, activity or system actually
leads to the expected results (see also qualification).
23-24 February 2017, Hamburg, Germany
And tomorrow ? Page 55

FDA (1987) Validation : Establishing documented evidence which

provides a high degree of assurance that a specific process will
consistently produce a product meeting is pre-determined specifications
and quality attributes

FDA (2011) 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
delivering quality products.
23-24 February 2017, Hamburg, Germany Page 56
23-24 February 2017, Hamburg, Germany Page 57

:z
23-24 February 2017, Hamburg, Germany Page 58

THANK YOU VERY MUCH

jdma@nne.com