Process Validation

This article Reprinted from The Official Journal of ISPE

outlines the PHARMACEUTICAL ENGINEERING® May/June 2002, Vol. 22 No. 3
scope of process
validation for
biotech Active Requirements for Process
Pharmaceutical
Ingredient (API) Validation of Biotech Active
manufacturing.
Definitions, Pharmaceutical Ingredients (APIs)
validation
approaches, and
requirements for by Dr. Reiner Kirrstetter
validation
documents are
Introduction fied to read as follows (as item 12.40):
described.

P
rocess validation of Active Pharmaceuti-
cal Ingredients (APIs) is still one of the “Process validation is the documented evi-
most challenging topics for both pharma- dence that the process, operated within
This article is ceutical industry and regulatory authorities. It established parameters, can perform ef-
is the clear expectation of regulatory authori- fectively and reproducibly to produce an
dedicated to Dr. ties, especially the FDA and EMEA, that pro- intermediate or API meeting its pre-de-
Walter Dürckheimer duction processes, cleaning procedures, ana- termined specification and quality at-
on the occasion of his lytical methods, computer and utility systems tributes.”
that have an impact on product quality and
70th birthday.
purity are validated. Facilities and equipment Approaches to Process Validation
used in conjunction with production and testing of Biotech APIs
of APIs must be qualified. The principles of A very rational approach for the control of a
validation are progressively applied from devel- biotech API production process is one that re-
opment through to full-scale production. For quires application of appropriate GMP controls
new products normally, process validation must for all steps beginning with the establishment
be completed at the time of launching the prod- and maintenance of master and working cell
uct into the market. For biologics filed with the banks, and with validation of those steps, dur-
Center for Biologics Evaluation and Research ing fermentation, isolation, and purification,
(CBER), the FDA expects that process valida- identified to be critical to the quality and purity
tion is finalized prior to the license submission. of the final API. These critical steps should not
be limited to the final stages of the process, but
Definitions of Process Validation should include also those steps that could intro-
The “classical definition” for process validation duce or remove impurities or contaminants, or
is presented in an FDA Guideline (Guideline on change a physical parameter of the final API.
General Principles of Process Validation, 1987): This approach also may require data to demon-
strate that a particular step is not critical to the
“Process validation means establishing manufacturing process. General principles of
documented evidence which provides a API process validation are shown in Figure 1.
high degree of assurance that a specific Before starting process validation activities,
process will consistently produce a prod- appropriate qualification of equipment and fa-
uct meeting its pre-determined specifica- cilities, and validation of utilities systems, like
tions and quality characteristics.” water and air systems, must be completed. This
includes Design Qualification (DQ), Installa-
In the ICH Guideline Q7A “GMP for APIs,” tion Qualification (IQ), Operational Qualifica-
issued as a final version in November 2000, this tion (OQ), and Performance Qualification (PQ),
definition of process validation is slightly modi- as defined in the ICH Guideline Q7A. Success-
ful process validation programs do
Figure 1. General principles of
General Principles of API Process Validation normally cover DQ/IQ/OQ/PQ. It
API process validation.
should be mentioned that DQ is the
Apply controls to all manufacturing steps, beginning with the use of
starting materials, or master cell bank first element of the qualification of
new facilities and equipment, and
Increase controls as process proceeds to the final isolation and requested for prospective qualifica-
purification steps.
tion according to the ICH Guide Q7A.
Validate all process steps identified to be critical to quality and DQ is the documented verification
purity of the final API. that the proposed design of the facili-

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Process Validation

are manufactured under replicated conditions.

Retrospective validation is only acceptable for an exist-
ing API process that has not been previously validated and no
significant changes have been made in the raw materials,
equipment, systems, facilities, or the production process itself.
According to the ICH Guideline Q7A, this validation approach
may be used where:

• critical quality attributes and critical process parameters

have been identified

• appropriate in-process acceptance criteria and controls have

been established

• there have not been significant process/product failures

attributable to causes other than operator error or equip-
Figure 2. Key elements of a successful process validation.
ment failures unrelated to equipment suitability; and
ties or equipment is suitable for the intended purpose. DQ
includes the review of the specific requirements for equipment • impurity profiles have been established for the existing API
and facilities design, specifications, construction, and perfor-
mance up to the point of purchase to ensure that user require- Batches selected for this validation approach should be repre-
ments and functional specifications are met. Other key elements sentative of all batches made during the review period, includ-
for a successful process validation are presented in Figure 2. ing any batch that failed to meet specifications. A sufficient
Concerning the performance of process validation, there are number of batches (normally 10 to 30) should be considered to
three specific approaches: demonstrate process consistency.

• Prospective Validation Change Control and Revalidation

In theory, a validation exercise needs to be carried out only once
• Concurrent Validation for a given process. However, in practice, the process rarely
remains static. Changes occur in components (raw materials,
• Retrospective Validation intermediates, packaging materials), equipment is modified,
or the process environment may change. Therefore, an effective
Prospective validation is the preferred approach and should change control system needs to be in place to evaluate the
be conducted for all new API processes or after major changes impact on the API quality and purity after the changes. The
of older API processes. For prospective validation, “it is gener- changes must be documented and approved, and the need for
ally considered acceptable that three consecutive batches within revalidation assessed. There is no regulatory requirement to
the finally agreed parameters, would constitute a validation of revalidate at a specific time interval. The requirement is that
the process.”2 facilities, systems, equipment, and processes are periodically
Concurrent validation can be performed in situations evaluated to verify that they are still operating in a valid
where a single or limited number of API batches are produced manner.
for commercial production. The decision to carry out concur-
rent validation should be justified, documented, and approved Validation Documentation
by the quality unit. This procedure involves obtaining data The company’s overall policy, intentions, and approaches to
from thorough monitoring and extensive in-process and end validation should be described in a site-specific Validation
product testing to demonstrate that each batch meets the Master Plan (VMP). This overall plan should include the
established specifications and quality attributes. Process vali- following topics as a minimum:
dation should be completed when additional commercial batches
• overall validation policy of the company
Main Contents of a Validation Protocol
• organizational structure of and responsibilities for valida-
- scope and objective tion activities
- responsibilities and accountabilities
• summary of facilities, equipment, systems, and processes to
- validation strategy and rationale
be qualified or validated
- brief description of the process
- critical process steps identified • plans and schedules for validation activities
- acceptance criteria
• validation approaches for different products including the
- variables to be monitored, samples to be taken documentation formats for protocols and reports
- time schedules
• revalidation requirements as dictated by time or by changes
- details of methods for recording and evaluating results
• definition of terms used in the master plan
Figure 3. Main contents of a validation protocol.

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 Process Validation

“ “In process validation, there’s a lot of common sense. You need to fully
understand the process you use to make your product.” (FDA)
“
In cases of larger projects, separate validation master plans presented in Figure 4.
can be created. As mentioned before, process validation of biologics should
Process validation must not take place until a written be completed prior to the submission to CBER.
validation protocol is established which specifies how valida-
tion will be performed for a particular process. This protocol Specific Requirements for Process Validation
needs to be reviewed and approved by the quality unit before it Although the same validation principles, approaches, and
can be executed. The specific content of a validation protocol procedures apply as for all APIs, some differences exist for the
depends on the complexity of the process. Main contents are process validation of biotech APIs because the technology is
presented in Figure 3. different. The term “biotech process” refers to the use of
The batches under validation have to be documented com- organisms or cells which were generated or modified by recom-
prehensively in a validation report with cross references to the binant DNA, hybridoma (cell clone), or other similar technol-
validation protocol. A detailed summary of the results obtained ogy to produce APIs. These APIs normally consist of high
from in process and final testing, commenting on any devia- molecular weight substances, e.g., proteins or polypeptides.
tions observed, should lead to the conclusion that the process Their production involves biological processes, such as cultiva-
is considered to be validated. Any variations from the approved tion of cells or isolation and purification of materials from
validation protocol need to be documented and justified with a living organisms. The raw materials used (media or buffer
rationale. In the event of failure of a validation study, an components) may lead to microbiological contamination. There-
investigation should be conducted to determine the cause of the fore, the control of bioburden, endotoxins, and viral contamina-
failure. Conclusions should be drawn including a statement in tion during the manufacturing process is essential. In addi-
the report on resolution. Validation cannot be considered tion, appropriate controls for equipment, utility systems (wa-
finalized until an approved validation report is available. An ter, air, nitrogen, steam), and the microbiological environment
overview of validation timelines for APIs and Drug Products are necessary to minimize the risk of contamination. Equip-
(DPs) in relation to regulatory submission and launch is ment sterilization is an area which must be studied in depth

Figure 4. Validation timelines for Active Pharmaceutical Ingredients (APIs) and Drug Products (DPs).

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Process Validation

and fully understood in the validation process for biotech APIs. activity, efficacy, and safety. The acceptance criteria for these
The acceptance criteria for environmental control and the impurities should be based on data obtained from batches used
frequency of monitoring should depend on the production in preclinical and clinical studies and as consistency batches.
conditions (open, closed, contained systems), and on the stage
in production. Compared to other APIs, the amount of process Contaminants include all adventitiously introduced materi-
validation activities for biotech APIs should be higher during als not intended to be part of the manufacturing process, such
process development and the scale-up period and therefore as chemical and biochemical materials (e.g., microbial pro-
performed earlier in the timeline. The general process controls teases), and/or microbial species.
to be considered for biotech APIs are presented in Figure 5. Contaminants must be strictly avoided and/or suitably
Before starting process validation of a biotech API, qualifi- controlled with appropriate in-process acceptance criteria or
cation of the facilities, equipment, and utility systems includ- additional limits for API specifications.
ing microbiological aspects have to be performed. Elements
associated with process validation, such as controlled areas, Viral removal and viral inactivation steps are critical pro-
filter systems, sterilization procedures, cleaning validation cessing steps for some biotech processes and should be included
including holding times before/after cleaning and sterilization, in the validation process as appropriate.
stability of intermediates, and computer validation must be It also is important to identify and define critical process
addressed thoroughly. The main focus of the process validation parameters and critical variables as early as possible for a
program is to demonstrate and document the: biotech process. In principle, each step in the fermentation and
purification process could be viewed as critical. But, as a
• removal of host cell proteins and other process-related typical biotech process contains hundreds of operational vari-
impurities ables, all of which are important, the identification of the
critical variables is essential, and they must be addressed
• removal and control of product-related impurities during process validation.
An adequate change control program and the concept of
• consistent product quality and purity revalidation also apply for biotech products to maintain the
process in a controlled and validated state.
• consistent process yields, and
The Importance of Process Validation -
• avoidance of contamination A Conclusion
Process validation is a basic cGMP requirement and expected
The following issues, process-related and product-related impu- to be in place for a launched product. The pharmaceutical
rities, contaminants, and viral removal, are of great importance manufacturer must evaluate which validation activities are
to be considered during process validation of a biotech API. needed to demonstrate and to prove control of the critical
aspects of the manufacturing operations. When processes are
Process-related impurities are derived from the manufac- validated, products are repeatedly produced under a state of
turing process, i.e., cell substrates (e.g., host cell proteins, host control which ensures operational consistency over a long time
cell DNA), cell culture (e.g., inducers, antibiotics, or media period.
components), or downstream processing (e.g., oxidizing or One statement from Robert C. Coleman, National Drug
reducing agents, cyanogen bromide, guanidine, inorganic salts, Expert of the FDA, indicates that performance of process
column leachables). validation is also a good business practice - Figure 6:

Product-related impurities (e.g., precursors, certain degra- “In process validation, there’s a lot of common sense.
dation products) are molecular variants arising during produc- You need to fully understand the process you use to
tion and/or storage. They normally do not have comparable make your product.”
properties to those of the desired product with respect to
References
1. ICH Harmonized Tripartite Guideline Q7A: GMP
Process Control Principles for Biotech APIs Guide for Active Pharmaceutical Ingredients, Final Ver-
- proper establishment and maintenance of Master and Working sion, November, 2000 (Chapter 12 on Validation).
Cell Bank
- controlled inoculation and expansion of the culture 2. EU Guide to GMP, Annex 15: Qualification and Valida-
tion, Final Version, July 2001.
- defined critical variables and steps during fermentation
- monitoring of the cell growth process 3. CPMP Note for Guidance on Process Validation,
- harvesting steps and purification procedure to remove cells or
March 2001 (valid from September 2001).
cellular components while minimizing degradation and contami-
nation 4. FDA Guideline on General Principles of Process
- monitoring of bioburden and endotoxin levels, where necessary
Validation, May 1987 (reprinted February 1993).

- viral removal and viral inactivating steps, where needed 5. Berry, I.R., and Harpez, D., (editors), Validation of Ac-
tive Pharmaceutical Ingredients, IHS Health Group,
Figure 5. Process control principles for biotech APIs. Denver, Colorado 2001, ISBN 1-57491-119-8.

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 Process Validation

17. “The Gold Sheet”: Biologic Process Validation Challenges,

Validation as Good Business Practice
Gold Sheet, Vol. 35, January 2001, pp. 1-30.
It is Good Business Practice, because it ...
- is also Good Scientific Practice 18. Martin-Moe, S.W., Kelsey, W.H., Ellis, J., and Kamarck,
M.E., “Process Validation in Biopharmaceutical Manufac-
- is a helpful tool to predict and control the manufacturing results
turing,” in Biopharmaceutical Process Validation, ed-
- helps to keep the process under a “state of control” ited by Sofer, G. and Zabriskie, D.W., Dekker, New York,
- is a requirement by regulatory authorities 2000, pp. 287-298.

Figure 6. Validation as good business practice. 19. Seely, R.J. Hutchins, H.V., Luscher, M.P., Sniff, K.S., and
Hassler, R., “Defining Critical Variables in Well-Charac-
6. Lanese, J., “Three Times is Not Even the Beginning,” terized Biotechnology Processes,” Bio. Pharm., April 1999,
Validation Technology, Vol. 7, Feb. 2001, pp. 124-129. pp. 33-36.

7. Amer, G., “Process Validation Issues - A Discussion with 20. Vincent, D.V., and Revie Nabi, D.R., “The Validation Life
Robert C. Coleman,” Validation Technology, Vol. 6, May Cycle of a Biotechnology Derived Drug,” Part I-III, Valida-
2000, pp. 665-675. tion Technology, Vol. 5, February 1999, pp. 167-188; May
1999, pp. 272-293; August 1999, pp. 365-402.
8. Amer, G., “Validation and Change Control,” Validation
Technology, Vol. 5, August 1999, pp. 302-309. About the Author
Dr. Reiner Kirrstetter studied chemistry
9. Gibson, W., and Powell-Evans, K., Validation Funda- and pharmacology and took his doctorate from
mentals - How to, What to, When to Validate, the Department of Organic Chemistry of the
Interpharm Press,Inc., Buffalo Grove, Illinois, 1998, ISBN University of Heidelberg in October 1976. Af-
1-57491-070-1. ter that, he spent about three years at the
University of Kiel as Post Doc and Assistant
10. Rivera Martinez, E., “An FDA Perspective on Bulk Phar- Professor before he joined Hoechst AG in April
maceutical Chemical GMPs, Control and Validation,” Phar- 1980. After several years in pharmaceutical
maceutical Engineering, Vol. 14, 1994, pp.8-14. research, process development, and API production in Hoechst
AG, he transferred to the GMP/Inspections Department of
11. Sawyer, Ch. J., and Stotz, R.W., “Validation Requirements Hoechst AG in September 1988. Since that time, he has gained
for Bulk Pharmaceutical Chemical Facilities,” Pharma- experience in the GMP and regulatory compliance area. In July
ceutical Engineering, Vol. 12, 1992, pp. 44-52. 1992, he became Head of Quality Assurance/APIs, and then in
July 1996 Head of QA/QC for Active Pharmaceutical Ingredi-
12. For specific biotech guidance see Reference 1, Chapter 18. ents of Hoechst Marion Roussel Germany. In June 1999, he
joined the Global Quality Operations/International Quality
13. ICH Harmonized Tripartite Guideline Q6B: Specifica- Assurance organization. In December 1999, he became the
tions: Test Procedures and Acceptance Criteria for global head of Process Development Quality Management in
Biotechnical/Biological Products, Final Version, March Aventis Pharma AG, and in July 2001, he joined a global
1999. Aventis project to represent Quality Management. Dr. Reiner
Kirrstetter has published about 45 scientific articles, submit-
14. FDA Biotechnology Inspection Guide, November 1991. ted 15 patent applications, and was/is a member of different
working groups dealing with GMPs of APIs. He was involved
15. Amicetti, V., and Lyda, J., “Process Validation for Biologic in eight FDA inspections, heading three as a team leader.
and Biotechnology Products,” PDA Letter, November 2001, Aventis Pharma AG, Global Quality Operations, 65926
pp. 38-43. Frankfurt/Main, Germany, tel: 69-305-2160, reiner.
kirrstetter@aventis.com.
16. Murphy, R., Seely, R.J., Validation of Biotechnology
Active Pharmaceutical Ingredients, in Reference 5,
Chapter 17, 2001, pp. 451-474.

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