1

Regulatory Basis for

Process Validation

John M. Dietrick
U.S. Food and Drug Administration, Rockville, Maryland, U.S.A.
Bernard T. Loftus
U.S. Food and Drug Administration, Washington, D.C., U.S.A.

I. INTRODUCTION

Bernard T. Loftus was director of drug manufacturing in the Food and Drug
Administration (FDA) in the 1970s, when the concept of process validation was
first applied to the pharmaceutical industry and became an important part of
current good manufacturing practices (CGMPs). His comments on the develop-
ment and implementation of these regulations and policies as presented in the
first and second editions of this volume are summarized below [1].

II. WHAT IS PROCESS VALIDATION?

The term process validation is not defined in the Food, Drug, and Cosmetic Act
(FD&C) Act or in FDA’s CGMP regulations. Many definitions have been of-
fered that in general express the same idea—that a process will do what it
purports to do, or that the process works and the proof is documented. A June
1978 FDA compliance program on drug process inspections [2] contained the
following definition:

This chapter was written by John M. Dietrick in his private capacity. No official support or endorse-
ment by the Food and Drug Administration is intended or should be inferred.

Copyright © 2003 Marcel Dekker, Inc.

 A validated manufacturing process is one which has been proved to do what
it purports or is represented to do. The proof of validation is obtained
through the collection and evaluation of data, preferably, beginning from
the process development phase and continuing through the production
phase. Validation necessarily includes process qualification (the qualifica-
tion of materials, equipment, systems, buildings, personnel), but it also in-
cludes the control on the entire process for repeated batches or runs.
The first drafts of the May 1987 Guideline on General Principles of Process
Validation [3] contained a similar definition, which has frequently been used in
FDA speeches since 1978, and is still used today: “A documented program which
provides a high degree of assurance that a specific process will consistently pro-
duce a product meeting its pre-determined specifications and quality attributes.”

III. THE REGULATORY BASIS FOR

PROCESS VALIDATION

Once the concept of being able to predict process performance to meet user
requirements evolved, FDA regulatory officials established that there was a le-
gal basis for requiring process validation. The ultimate legal authority is Section
501(a)(2)(B) of the FD&C Act [4], which states that a drug is deemed to be
adulterated if the methods used in, or the facilities or controls used for, its
manufacture, processing, packing, or holding do not conform to or were not
operated or administrated in conformity with CGMP. Assurance must be given
that the drug would meet the requirements of the act as to safety and would
have the identity and strength and meet the quality and purity characteristics
that it purported or was represented to possess. That section of the act sets the
premise for process validation requirements for both finished pharmaceuticals
and active pharmaceutical ingredients, because active pharmaceutical ingredi-
ents are also deemed to be drugs under the act.
The CGMP regulations for finished pharmaceuticals, 21 CFR 210 and
211, were promulgated to enforce the requirements of the act. Although these
regulations do not include a definition for process validation, the requirement is
implicit in the language of 21 CFR 211.100 [5], which states: “There shall be
written procedures for production and process control designed to assure that
the drug products have the identity, strength, quality, and purity they purport or
are represented to possess.”

IV. THE REGULATORY HISTORY OF

PROCESS VALIDATION

Although the emphasis on validation began in the late 1970s, the requirement
has been around since at least the 1963 CGMP regulations for finished pharma-
ceuticals. The Kefauver-Harris Amendments to the FD&C Act were approved

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 in 1962 with Section 501(a)(2)(B) as an amendment. Prior to then, CGMP and
process validation were not required by law. The FDA had the burden of prov-
ing that a drug was adulterated by collecting and analyzing samples. This was
a significant regulatory burden and restricted the value of factory inspections of
pharmaceutical manufacturers. It took injuries and deaths, mostly involving
cross-contamination problems, to convince Congress and the FDA that a revi-
sion of the law was needed. The result was the Kefauver–Harris drug amend-
ments, which provided the additional powerful regulatory tool that FDA re-
quired to deem a drug product adulterated if the manufacturing process was not
acceptable. The first CGMP regulations, based largely on the Pharmaceutical
Manufacturers Association’s manufacturing control guidelines, were then pub-
lished and became effective in 1963. This change allowed FDA to expect a
preventative approach rather than a reactive approach to quality control. Section
505(d)(3) is also important in the implementation of process validation require-
ments because it gives the agency the authority to withhold approval of a new
drug application if the “methods used in, and the facilities and controls used
for, the manufacture, processing, and packing of such drug are inadequate to
preserve its identity, strength, quality, and purity.”
Another requirement of the same amendments was the requirement that
FDA must inspect every drug manufacturing establishment at least once every
2 years [6]. At first, FDA did this with great diligence, but after the worst
CGMP manufacturing situations had been dealt with and violations of the law
became less obvious, FDA eased up its pharmaceutical plant inspection activi-
ties and turned its resources to more important problems.
The Drug Product Quality Assurance Program of the 1960s and 1970s
involved first conducting a massive sampling and testing program of finished
batches of particularly important drugs in terms of clinical significance and
dollar volume, then taking legal action against violative batches and inspecting
the manufacturers until they were proven to be in compliance. This approach
was not entirely satisfactory because samples are not necessarily representative
of all batches. Finished product testing for sterility, for example, does not assure
that the lot is sterile. Several incidents refocused FDA’s attention to process
inspections. The investigation of complaints of clinical failures of several prod-
ucts (including digoxin, digitoxin, prednisolone, and prednisone) by FDA found
significant content uniformity problems that were the result of poorly controlled
manufacturing processes. Also, two large-volume parenteral manufacturers ex-
perienced complaints despite quality control programs and negative sterility test-
ing. Although the cause of the microbiological contamination was never proven,
FDA inspections did find deficiencies in the manufacturing process and it be-
came evident that there was no real proof that the products were sterile.
What became evident in these cases was that FDA had not looked at the
process itself—certainly not the entire process—in its regulatory activities; it
was quality control- rather than quality assurance-oriented. The compliance offi-

Copyright © 2003 Marcel Dekker, Inc.

 cials were not thinking in terms of process validation. One of the first entries
into process validation was a 1974 paper presented by Ted Byers, entitled “De-
sign for Quality” [7]. The term validation was not used, but the paper described
an increased attention to adequacy of processes for the production of pharma-
ceuticals. Another paper—by Bernard Loftus before the Parenteral Drug Associ-
ation in 1978 entitled “Validation and Stability” [8]—discussed the legal basis
for the requirement that processes be validated.
The May 1987 Guideline on General Principles of Process Validation [3]
was written for the pharmaceutical, device, and veterinary medicine industries.
It has been effective in standardizing the approach by the different parts of the
agency and in communicating that approach to manufacturers in each industry.

V. UPDATE

As discussed in the preceding sections, process validation has been a legal re-
quirement since at least 1963. Implementation of the requirement was a slow
and deliberate process, beginning with the development and dissemination of an
agency policy by Loftus, Byers, and others, and leading to the May 1987 guide-
line. The guideline quickly became an important source of information to phar-
maceutical manufacturers interested in establishing a process validation pro-
gram. Many industry organizations and officials promoted the requirements as
well as the benefits of validation. Many publications, such as Pharmaceutical
Process Validation [1] and various pharmaceutical industry journal articles,
cited and often expanded on the principals in the guideline. During the same
period, computer validation—or validation of computer controlled processes—
also became a widely discussed topic in both seminars and industry publications.
The regulatory implementation of the validation requirement was also a
deliberate process by FDA. During the 1980s, FDA investigators often reported
processes that had not been validated or had been inadequately validated. Batch
failures were often associated with unvalidated manufacturing processes. The
FDA issued a number of regulatory letters to deficient manufacturers citing the
lack of adequate process validation as a deviation from CGMP regulations
(21CFR 211.100), which causes the drug product to be adulterated within the
meaning of Section 501(a)(2)(B) of the federal FD&C Act. Process validation
was seldom the only deficiency listed in these regulatory letters. The failure of
some manufacturers to respond to these early warnings resulted in FDA filing
several injunction cases that included this charge in the early 1990s. Most of
these cases resulted in consent decrees, and ultimately the adoption of satisfac-
tory process validation programs by the subject manufacturers. One injunction
case filed in 1992, however, was contested in court and led to a lengthy written
order and opinion by the U.S. District Court in February of 1993 [9]. The court

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 affirmed the requirement for process validation in the current good manufactur-
ing regulations, and ordered the defendants to perform process validation studies
on certain drug products, as well as equipment cleaning validation studies. This
case and the court’s ruling were widely circulated in the pharmaceutical industry
and became the subject of numerous FDA and industry seminars.
The court also criticized the CGMP regulations for their lack of specific-
ity, along with their ambiguity and vagueness. Responding to this criticism,
FDA drafted revisions to several parts of these regulations. The proposed revi-
sions were published in the Federal Register on May 3, 1996 [10]. One of the
main proposed changes was intended to emphasize and clarify the process vali-
dation requirements. The proposal included a definition of process validation
(the same definition used in the 1987 guideline), a specific requirement to vali-
date manufacturing processes, and minimum requirements for performing and
documenting a validation study. These were all implied but not specific in the
1978 regulation. In proposing these changes, FDA stated that it was codifying
current expectations and current industry practice and did not intend to add new
validation requirements. Comments from all interested parties were requested
under the agency’s rule-making policies, and approximately 1500 comments
were received. Most of the responses to the changes regarding process validation
supported the agency’s proposals, but there were many comments regarding the
definitions and terminology proposed about which processes and steps in a pro-
cess should or should not require validation, the number of batches required for
process validation, maintenance of validation records, and the assignment of
responsibility for final approval of a validation study and change control deci-
sions. Because of other high-priority obligations, the agency has not yet com-
pleted the evaluation of these responses and has not been able to publish the
final rule. In addition to the official comments, the proposed changes prompted
numerous industry and FDA seminars on the subject.
Process validation is not just an FDA or a U.S. requirement. Similar re-
quirements are included in the World Health Organization (WHO), the Pharma-
ceutical Inspection Co-operation Scheme (PIC/S), and the European Union (EU)
requirements, along with those of Australia, Canada, Japan, and other interna-
tional authorities.
Most pharmaceutical manufacturers now put substantial resources into
process validation for both regulatory and economic reasons, but despite contin-
ued educational efforts by both the agency and the pharmaceutical industry,
FDA inspections (both domestically and internationally) continue to find some
firms manufacturing drug products using unvalidated or inadequately validated
processes. Evidently there is still room for improvement, and continued discus-
sion, education, and occasional regulatory action appears warranted.
The future of process validation is also of great interest, especially with
the worldwide expansion of pharmaceutical manufacturing and the desire for

Copyright © 2003 Marcel Dekker, Inc.

 harmonized international standards and requirements. Many manufacturers are
also working on strategies to reduce the cost of process validation and incorpo-
rate validation consideration during product design and development. New tech-
nologies under development for 100% analysis of drug products and other inno-
vations in the pharmaceutical industry may also have a significant effect on
process validation concepts and how they can be implemented and regulated.

REFERENCES

1. Loftus, B. T., Nash, R. A., ed. Pharmaceutical Process Validation. vol. 57. New
York: Marcel Dekker (1993).
2. U.S. Food and Drug Administration. Compliance Program no. 7356.002.
3. U.S. Food and Drug Administration. Guideline on General Principles of Process
Validation. Rockville, MD: FDA, 1987.
4. Federal Food Drug and Cosmetic Act, Title 21 U.S. Code, Section 501 (a)(2)(B).
5. Code of Federal Regulations, Title 21, Parts 210 & 211. Fed Reg 43, 1978.
6. U.S. Code, Federal Food Drug and Cosmetic Act, Title 21, Section 510 (h).
7. Byers, T. E. Design for quality, Manufacturing Controls Seminar, Proprietary Asso-
ciation, Cherry Hill, NJ, Oct. 11, 1974.
8. Loftus, B. T. Validation and stability, meeting of Parenteral Drug Association,
1978.
9. U.S. v. Barr Laboratories, Inc., et al., Civil Action No. 92-1744, U.S. District Court
for the District of New Jersey, 1973.
10. Code of Federal Regulations, Title 21, Parts 21 & 211, Proposed Revisions, Fed
Reg (May 3, 1996).

Copyright © 2003 Marcel Dekker, Inc.