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Process Validation
An International Third Edition, Revised and Expanded
edited by
Robert A. Nash
Stevens Institute of Technology
Hoboken, New Jersey, U.S.A.
Alfred H.Wachter
Wachter P h r m a Projects
Therwil, Switzerland
MARCEL
MARCELDEKKER,
INC. NEWYORK * BASEL
DEKKER
CRC Press
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Executive Editor
James Swarbrick
PharmaceuTech, Inc
Pinehurst, North Carolina
Advisory Board
Peter G. Welling
Institut de Recherche Jouvemal
Fresnes, France
DRUGS AND THE PHARMACEUTICAL SCIENCES
Robert A. Nash
v
Contents
Preface v
Contributors ix
Introduction xiii
3. Retrospective Validation 31
Chester J. Trubinski
4. Sterilization Validation 83
Michael J. Akers and Neil R. Anderson
Peter H. Cheng New York State Research Foundation for Mental Hygiene,
New York, New York, U.S.A.
John M. Dietrick Center for Drug Evaluation and Research, U.S. Food and
Drug Administration, Rockville, Maryland, U.S.A.
William E. Hall Hall & Pharmaceutical Associates, Inc., Kure Beach, North
Carolina, U.S.A.
F. St. John Forbes Wyeth Labs, Pearl River, New York, U.S.A.
*Retired
Contributors xi
Chester J. Trubinski Church & Dwight Co., Inc., Princeton, New Jersey,
U.S.A.
Paul Von Doehren Searle & Co., Inc., Skokie, Illinois, U.S.A.
Robert A. Nash
Stevens Institute of Technology, Hoboken, New Jersey, U.S.A.
I. FDA GUIDELINES
The U.S. Food and Drug Administration (FDA) has proposed guidelines with
the following definition for process validation [1]:
Process validation is establishing documented evidence which provides a
high degree of assurance that a specific process (such as the manufacture
of pharmaceutical dosage forms) will consistently produce a product meet-
ing its predetermined specifications and quality characteristics.
The first four items listed above are directly related to the manufacture
and validation of solid dosage forms. Items 1 and 3 are normally associated
with variability in the manufacturing process, while items 2 and 4 are usually
influenced by the selection of the ingredients in the product formulation. With
respect to content uniformity and unit potency control (item 3), adequacy of
mixing to assure uniformity and homogeneity is considered a high-priority con-
cern.
Conventional quality control procedures for finished product testing en-
compass three basic steps:
1. Establishment of specifications and performance characteristics
2. Selection of appropriate methodology, equipment, and instrumenta-
tion to ensure that testing of the product meets specifications
3. Testing of the final product, using validated analytical and testing
methods to ensure that finished product meets specifications.
With the emergence of the pharmaceutical process validation concept, the fol-
lowing four additional steps have been added:
4. Qualification of the processing facility and its equipment
5. Qualification and validation of the manufacturing process through ap-
propriate means
6. Auditing, monitoring, sampling, or challenging the key steps in the
process for conformance to in-process and final product specifications
7. Revalidation when there is a significant change in either the product
or its manufacturing process [3].
It has been said that there is no specific basis for requiring a separate set of
process validation guidelines, since the essentials of process validation are em-
bodied within the purpose and scope of the present CGMP regulations [2]. With
this in mind, the entire CGMP document, from subpart B through subpart K,
may be viewed as being a set of principles applicable to the overall process of
manufacturing, i.e., medical devices (21 CFR–Part 820) as well as drug prod-
ucts, and thus may be subjected, subpart by subpart, to the application of the
principles of qualification, validation, verification and control, in addition to
change control and revalidation, where applicable. Although not a specific re-
Introduction xv
The FDA, under the authority of existing CGMP regulations, guidelines [1], and
directives [3], considers process validation necessary because it makes good
engineering sense. The basic concept, according to Mead [5], has long been
Qualification and
Subpart Section of CGMPs control documentation
A General provisions
B Organization and personnel Responsibilities of the quality con-
trol unit
C Buildings and facilities Plant and facility installation and
qualification
Maintenance and sanitation
Microbial and pest control
D Equipment Installation and qualification of
equipment and cleaning methods
E Control of components, containers Incoming component testing proce-
and closures dures
F Production and process controls Process control systems, reprocess-
ing control of microbial contami-
nation
G Packaging and labeling controls Depyrogenation, sterile packaging,
filling and closing, expire dating
H Holding and distribution Warehousing and distribution pro-
cedures
I Laboratory controls Analytical methods, testing for re-
lease component testing and sta-
bility testing
J Records and reports Computer systems and information
systems
K Return and salvaged drug products Batch reprocessing
Sterilization procedures, Air and water quality are covered in appropriate subparts of Table 1.
xvi Nash
applied in other industries, often without formal recognition that such a concept
was being used. For example, the terms reliability engineering and qualification
have been used in the past by the automotive and aerospace industries to repre-
sent the process validation concept.
The application of process validation should result in fewer product re-
calls and troubleshooting assignments in manufacturing operations and more
technically and economically sound products and their manufacturing processes.
In the old days R & D “gurus” would literally hand down the “go” sometimes
overformulated product and accompanying obtuse manufacturing procedure,
usually with little or no justification or rationale provided. Today, under FDA’s
Preapproval Inspection (PAI) program [4] such actions are no longer accept-
able. The watchword is to provide scientifically sound justifications (including
qualification and validation documentation) for everything that comes out of the
pharmaceutical R & D function.
With the exception of solution products, the bulk of the work is nor-
mally carried out at 10 × batch size, which is usually the first scale-up
batches in production-type equipment.
The following operations are normally carried out by the development function
prior to the preparation of the first pilot-production batch. The development
activities are listed as follows:
xviii Nash
A. Laboratory Batch
The first step in the scale-up process is the selection of a suitable preliminary
formula for more critical study and testing based on certain agreed-upon initial
design criteria, requirements, and/or specifications. The work is performed in
the development laboratory. The formula selected is designated as the (1 × )
laboratory batch. The size of the (1 × ) laboratory batch is usually 3–10 kg of a
solid or semisolid, 3–10 liters of a liquid, or 3000 to 10,000 units of a tablet or
capsule.
C. Pilot Production
The pilot-production phase may be carried out either as a shared responsibility
between the development laboratories and its appropriate manufacturing coun-
terpart or as a process demonstration by a separate, designated pilot-plant or
process-development function. The two organization piloting options are pre-
sented separately in Figure 1. The creation of a separate pilot-plant or process-
development unit has been favored in recent years because it is ideally suited to
carry out process scale-up and/or validation assignments in a timely manner. On
the other hand, the joint pilot-operation option provides direct communication
between the development laboratory and pharmaceutical production.
The object of the pilot-production batch is to scale the product and process
by another order of magnitude (100 × ) to, for example, 300–1,000 kg, 300–
1,000 liters, or 300,000–1,000,000 dosage form units (tablets or capsules) in
size. For most drug products this represents a full production batch in standard
production equipment. If required, pharmaceutical production is capable of scal-
ing the product/process to even larger batch sizes should the product require
expanded production output. If the batch size changes significantly, additional
validation studies would be required. The term product/process is used, since
one can’t describe a product with discussing its process of manufacture and,
conversely, one can’t talk about a process without describing the product being
manufactured.
Usually large production batch scale-up is undertaken only after product
introduction. Again, the actual size of the pilot-production (100 × ) batch may
vary due to equipment and raw material availability. The need for additional
pilot-production batches ultimately depends on the successful completion of a
first pilot batch and its process validation program. Usually three successfully
completed pilot-production batches are required for validation purposes.
In summary, process capability studies start in the development labora-
tories and/or during product and process development, and continue in well-
defined stages until the process is validated in the pilot plant and/or pharmaceu-
tical production.
An approximate timetable for new product development and its pilot
scale-up program is suggested in Table 3.
Calendar
Event months
Process validation is done by individuals with the necessary training and experi-
ence to carry out the assignment.
The specifics of how a dedicated group, team, or committee is organized
to conduct process validation assignments is beyond the scope of this introduc-
tory chapter. The responsibilities that must be carried out and the organizational
structures best equipped to handle each assignment are outlined in Table 4. The
xxii Nash
Engineering Install, qualify, and certify plant, facilities, equipment, and sup-
port system.
Development Design and optimize manufacturing process within design limits,
specifications, and/or requirements—in other words, the estab-
lishment of process capability information.
Manufacturing Operate and maintain plant, facilities, equipment, support sys-
tems, and the specific manufacturing process within its design
limits, specifications, and/or requirements.
Quality assurance Establish approvable validation protocols and conduct process
validation by monitoring, sampling, testing, challenging, and/
or auditing the specific manufacturing process for compliance
with design limits, specifications, and/or requirements.
Source: Ref. 8.
Process capability is defined as the studies used to determine the critical process
parameters or operating variables that influence process output and the range of
numerical data for critical process parameters that result in acceptable process
output. If the capability of a process is properly delineated, the process should
consistently stay within the defined limits of its critical process parameters and
product characteristics [12].
Process demonstration formerly called process qualification, represents
the actual studies or trials conducted to show that all systems, subsystems, or
unit operations of a manufacturing process perform as intended; that all critical
process parameters operate within their assigned control limits; and that such
studies and trials, which form the basis of process capability design and testing,
are verifiable and certifiable through appropriate documentation.
The manufacturing process is briefly defined as the ways and means used
to convert raw materials into a finished product. The ways and means also
include people, equipment, facilities, and support systems required to operate
the process in a planned and effectively managed way. All the latter functions
must be qualified individually. The master plan or protocol for process capabil-
ity design and testing is presented in Table 5.
A simple flow chart should be provided to show the logistical sequence
of unit operations during product/process manufacture. A typical flow chart used
in the manufacture of a tablet dosage form by the wet granulation method is
presented in Figure 2.
Table 5 Master Plan or Protocol for Process Capability Design and Testing
Figure 2 Process flow diagram for the manufacture of a tablet dosage form by wet
granulation method. The arrows show the transfer of material into and out of each of the
various unit operations. The information in parentheses indicates additions of material to
specific unit operations. A list of useful pharmaceutical unit operations is presented in
Table 6.
Introduction xxv
ment, clinical study, process development, and process validation and into pro-
duction. Working individually with separate analytical testing functions and
with little or no appropriate communication among these three vital functions is
a prescription for expensive delays. It is important to remember that the concept
illustrated in Figure 3 can still be followed even when the API is sourced from
outside the plant site or company. In this particular situation there will probably
be two separate analytical methods development functions: one for the API
manufacturer and one for the drug product manufacturer [14].
Statistical process control (SPC), also called statistical quality control and pro-
cess validation (PV), represents two sides of the same coin. SPC comprises the
various mathematical tools (histogram, scatter diagram run chart, and control
chart) used to monitor a manufacturing process and to keep it within in-process
and final product specification limits. Lord Kelvin once said, “When you can
measure what you are speaking about, and express it in numbers, then you know
something about it.” Such a thought provides the necessary link between the
two concepts. Thus, SPC represents the tools to be used, while PV represents
the procedural environment in which those tools are used.
xxvi Nash
There are three ways of establishing quality products and their manufac-
turing processes:
1. In-process and final product testing, which normally depends on sam-
pling size (the larger the better). In some instances, nothing short of
excessive sampling can ensure reaching the desired goal, i.e., sterility
testing.
2. Establishment of tighter (so called “in-house”) control limits that hold
the product and the manufacturing process to a more demanding stan-
Introduction xxvii
dard will often reduce the need for more extensive sampling require-
ments.
3. The modern approach, based on Japanese quality engineering [15], is
the pursuit of “zero defects” by applying tighter control over process
variability (meeting a so-called 6 sigma standard). Most pharmaceuti-
cal products and their manufacturing processes in the United States
today, with the exception of sterile processes are designed to meet a
4 sigma limit (which would permit as many as eight defects per 1000
units). The new approach is to center the process (in which the grand
average is roughly equal to 100% of label potency or the target value
of a given specification) and to reduce the process variability or noise
around the mean or to achieve minimum variability by holding both
to the new standard, batch after batch. In so doing, a 6 sigma limit
may be possible (which is equivalent to not more than three to four
defects per 1 million units), also called “zero defects.” The goal of 6
sigma, “zero defects” is easier to achieve for liquid than for solid
pharmaceutical dosage forms [16].
Process characterization represents the methods used to determine the
critical unit operations or processing steps and their process variables, that usu-
ally affect the quality and consistency of the product outcomes or product attri-
butes. Process ranging represents studies that are used to identify critical process
or test parameters and their respective control limits, which normally affect the
quality and consistency of the product outcomes of their attributes. The follow-
ing process characterization techniques may be used to designate critical unit
operations in a given manufacturing process.
A. Constraint Analysis
One procedure that makes subsystem evaluations and performance qualification
trials manageable is the application of constraint analysis. Boundary limits of
any technology and restrictions as to what constitutes acceptable output from
unit operations or process steps should in most situations constrain the number
of process variables and product attributes that require analysis. The application
of the constraint analysis principle should also limit and restrict the operational
range of each process variable and/or specification limit of each product attri-
bute. Information about constraining process variables usually comes from the
following sources:
• Previous successful experience with related products/processes
• Technical and engineering support functions and outside suppliers
• Published literatures concerning the specific technology under investi-
gation
xxviii Nash
Optimization techniques are used to find either the best possible quantitative
formula for a product or the best possible set of experimental conditions (input
values) needed to run the process. Optimization techniques may be employed in
the laboratory stage to develop the most stable, least sensitive formula, or in the
qualification and validation stages of scale-up in order to develop the most sta-
Introduction xxix
Trial no. X1 X2 X3 X4 X5 X6 X7 X8 X9
1 − − − − − − − − −
2 + − − − − − − − −
3 − − − + − − − − +
4 + − + − − − + − −
5 − + − + − + − + −
6 + − + − + − + − +
7 − + − + + + − + +
8 + + + − + + + + −
9 − + + + + + + + +
10 + + + + + + + + +
Worst-case conditions: Trial 1 (lower control limit). Trial 10 (upper control limit). X variables
randomly assigned. Best values to use are RSD of data set for each trial. When adding up the data
by columns, + and − are now numerical values and the sum is divided by 5 (number of +s or −s).
If the variable is not significant, the sum will approach zero.
ble, least variable, robust process within its proven acceptable range(s) of opera-
tion, Chapman’s so-called proven acceptable range (PAR) principle [20].
Optimization techniques may be classified as parametric statistical meth-
ods and nonparametric search methods. Parametric statistical methods, usually
employed for optimization, are full factorial designs, half factorial designs, sim-
plex designs, and Lagrangian multiple regression analysis [21]. Parametric
methods are best suited for formula optimization in the early stages of product
development. Constraint analysis, described previously, is used to simplify the
testing protocol and the analysis of experimental results.
The steps involved in the parametric optimization procedure for pharma-
ceutical systems have been fully described by Schwartz [22]. Optimization tech-
niques consist of the following essential operations:
1. Selection of a suitable experimental design
2. Selection of variables (independent Xs and dependent Ys) to be tested
3. Performance of a set of statistically designed experiments (e.g., 23 or
32 factorials)
4. Measurement of responses (dependent variables)
5. Development of a predictor, polynomial equation based on statistical
and regression analysis of the generated experimental data
6. Development of a set of optimized requirements for the formula based
on mathematical and graphical analysis of the data generated
xxx Nash
may be the already successfully concluded first pilot batch at 100 × size, which
is usually prepared under the direction of the organizational function directly
responsible for pilot scale-up activities. Later, replicate batch manufacture may
be performed by the pharmaceutical production function.
The strategy selected for process validation should be simple and straight-
forward. The following factors are presented for the reader’s consideration:
1. The use of different lots of components should be included, i.e., APIs
and major excipients.
2. Batches should be run in succession and on different days and shifts
(the latter condition, if appropriate).
3. Batches should be manufactured in equipment and facilities desig-
nated for eventual commercial production.
4. Critical process variables should be set within their operating ranges
and should not exceed their upper and lower control limits during
process operation. Output responses should be well within finished
product specifications.
xxxii Nash
B. Retrospective Validation
The retrospective validation option is chosen for established products whose
manufacturing processes are considered stable and when on the basis of eco-
nomic considerations alone and resource limitations, prospective validation pro-
grams cannot be justified. Prior to undertaking retrospective validation, wherein
the numerical in-process and/or end-product test data of historic production
batches are subjected to statistical analysis, the equipment, facilities and subsys-
tems used in connection with the manufacturing process must be qualified in
conformance with CGMP requirements. The basis for retrospective validation
is stated in 21CFR 211.110(b): “Valid in-process specifications for such charac-
teristics shall be consistent with drug product final specifications and shall be
derived from previous acceptable process average and process variability esti-
mates where possible and determined by the application of suitable statistical
procedures where appropriate.”
The concept of using accumulated final product as well as in-process nu-
merical test data and batch records to provide documented evidence of product/
process validation was originally advanced by Meyers [26] and Simms [27] of
Eli Lilly and Company in 1980. The concept is also recognized in the FDA’s
Guidelines on General Principles of Process Validation [1].
Using either data-based computer systems [28,29] or manual methods,
retrospective validation may be conducted in the following manner:
1. Gather the numerical data from the completed batch record and in-
clude assay values, end-product test results, and in-process data.
2. Organize these data in a chronological sequence according to batch
manufacturing data, using a spreadsheet format.
3. Include data from at least the last 20–30 manufactured batches for
analysis. If the number of batches is less than 20, then include all
manufactured batches and commit to obtain the required number for
analysis.
4. Trim the data by eliminating test results from noncritical processing
steps and delete all gratuitous numerical information.
5. Subject the resultant data to statistical analysis and evaluation.
6. Draw conclusions as to the state of control of the manufacturing pro-
cess based on the analysis of retrospective validation data.
7. Issue a report of your findings (documented evidence).
Introduction xxxiii
C. Concurrent Validation
In-process monitoring of critical processing steps and end-product testing of
current production can provide documented evidence to show that the manufac-
turing process is in a state of control. Such validation documentation can be
provided from the test parameter and data sources disclosed in the section on
retrospective validation.
xxxiv Nash
Not all of the in-process tests enumerated above are required to demon-
strate that the process is in a state of control. Selections of test parameters
should be made on the basis of the critical processing variables to be evaluated.
D. Revalidation
Conditions requiring revalidation study and documentation are listed as follows:
1. Change in a critical component (usually refers to raw materials)
2. Change or replacement in a critical piece of modular (capital) equip-
ment
3. Change in a facility and/or plant (usually location or site)
4. Significant (usually order of magnitude) increase or decrease in batch
size
5. Sequential batches that fail to meet product and process specifications
In some situations performance requalification studies may be required
prior to undertaking specific revalidation assignments.
The FDA process validation guidelines [1] refer to a quality assurance
system in place that requires revalidation whenever there are changes in packag-
ing (assumed to be the primary container-closure system), formulation, equip-
ment or processes (meaning not clear) which could impact on product effective-
ness or product characteristics and whenever there are changes in product
characteristics.
Approved packaging is normally selected after completing package perfor-
mance qualification testing as well as product compatibility and stability studies.
Since in most cases (exceptions: transdermal delivery systems, diagnostic tests,
and medical devices) packaging is not intimately involved in the manufacturing
process of the product itself, it differs from other factors, such as raw materials.
Introduction xxxv
The reader should realize that there is no one way to establish proof or
evidence of process validation (i.e., a product and process in control). If the
manufacturer is certain that its products and processes are under statistical con-
trol and in compliance with CGMP regulations, it should be a relatively simple
matter to establish documented evidence of process validation through the use
of prospective, concurrent, or retrospective pilot and/or product quality informa-
tion and data. The choice of procedures and methods to be used to establish
validation documentation is left with the manufacturer.
This introduction was written to aid scientists and technicians in the phar-
maceutical and allied industries in the selection of procedures and approaches
that may be employed to achieve a successful outcome with respect to product
performance and process validation. The authors of the following chapters ex-
plore the same topics from their own perspectives and experience. It is hoped
that the reader will gain much from the diversity and richness of these varied
approaches.
REFERENCES
14. Nash, R. A., Streamlining Process Validation, Amer. Pharm. Outsourcing May
2001.
15. Ishikawa, K., What is Total Quality Control? The Japanese Way, Prentice-Hall,
Englewood Cliffs, NJ (1985).
16. Nash, R. A., Practicality of Achieving Six Sigma or Zero-Defects in Pharmaceutical
Systems, Pharmaceutical Formulation & Quality, Oct./Nov. 2001.
17. CGMP: Amendment of Certain Requirements, FDA Federal Register, May 3,
1996.
18. Box, G. E. and Hunter, J. S., Statistics for Experimenters, John Wiley, N.Y. (1978).
19. Hendrix, C. D., What every technologist should know about experimental design,
CHEMTECH (March 1979).
20. Chapman, K. G., The PAR approach to process validation, Pharm. Tech., Dec.
1984.
21. Bolton, S., Pharmaceutical Statistics: Practical and Clinical Applications, 3rd ed.,
Marcel Dekker, New York (1997).
22. Schwartz, J. B., Optimization techniques in product formulation. J. Soc. Cosmet.
Chem. 32:287–301 (1981).
23. Butler, J. J., Statistical quality control, Chem. Eng. (Aug. 1983).
24. Deming, S. N., Quality by Design, CHEMTECH, (Sept. 1988).
25. Contino, AV., Improved plant performance with statistical process control, Chem.
Eng. (July 1987).
26. Meyer, R. J., Validation of Products and Processes, PMA Seminar on Validation
of Solid Dosage Form Processes, Atlanta, GA, May 1980.
27. Simms, L., Validation of Existing Products by Statistical Evaluation, Atlanta, GA,
May 1980.
28. Agalloco, J. P., Practical considerations in retrospective validation, Pharm. Tech.
(June 1983).
29. Kahan, J. S., Validating computer systems, MD&DI (March 1987).
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].
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.
1
2 Dietrick and Loftus
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.”
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
Regulatory Basis for Process Validation 3
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
Regulatory Basis for Process Validation 5
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
6 Dietrick and Loftus
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).
2
Prospective Process Validation
Allen Y. Chao
Watson Labs, Carona, California, U.S.A.
I. INTRODUCTION
II. ORGANIZATION
mentation file should contain all information that was generated during the en-
tire product development sequence to a validation process.
Product development usually begins when an active chemical entity has been
shown to possess the necessary attributes for a commercial product. The product
development activities for the active chemical entity, formulation, and process
form the foundation upon which the subsequent validation data are built.
Generally, product development activities can be subdivided into formula-
tion and process development, along with scale-up development.
A. Formulation Development
Formulation development provides the basic information on the active chemical,
the formula, and the impact of raw materials or excipients on the product. Typi-
cal supportive data generated during these activities may include the following:
1. Preformulation profile or characterization of the components of the
formula, which includes all the basic physical or chemical information
about the active pharmaceutical ingredients (API, or the chemical en-
tity) and excipients
2. Formulation profile, which consists of physical and chemical charac-
teristics required for the products, drug-excipient compatibility stud-
ies, and the effect of formulation on in vitro dissolution
3. Effect of formulation variables on the bioavailability of the product
4. Specific test methods
5. Key product attributes and/or specifications
6. Optimum formulation
7. Development of cleaning procedures and test methods
Formulation development should not be considered complete until all those fac-
tors that could significantly alter the formulation have been studied. Subsequent
minor changes to the formulation, however, may be acceptable, provided they
are thoroughly tested and are shown to have no adverse effect on product.
B. Process Development
Even though the process development activities typically begin after the formu-
lation has been developed, they may also occur simultaneously. The majority of
the process development activities occur either in the pilot plant or in the pro-
Prospective Process Validation 11
posed manufacturing plant. The process development program should meet the
following objectives:
1. Develop a suitable process to produce a product that meets all
a. Product specifications
b. Economic constraints
c. Current good manufacturing practices (CGMPs)
2. Identify the key process parameters that affect the product attributes
3. Identify in-process specifications and test methods
4. Identify generic and/or specific equipment that may be required
It is important to remember that cleaning procedures should at least be in the
final stages of development, as equipment and facilities in the pilot or proposed
manufacturing plant are involved, and the development of the cleaning verifica-
tion test methods must be complete.
Process development can be divided into several stages.
Design
Challenging of critical process parameters
Verification of the developed process
Typical activities in these areas are illustrated in Figure 2.
1. Design
This is the initial planning stage of process development. The design of the
process should start during or at the end of the formulation development to
define the process to a large extent. One aspect of the process development
to remember is end user (manufacturing site) capabilities. In other words, the
practicality and the reality of the manufacturing operation should be kept in
perspective. Process must be developed in such a manner that it can easily be
transferred to the manufacturing site with minimal issues. During this stage,
technical operations in both the manufacturing and quality control departments
should be consulted.
Key documents for the technical definition of the process are the flow
diagram, the cause-and-effect diagram, and the influence matrix. The details of
the cause-and-effect diagram and the influence matrix will be discussed under
experimental approach in a later section.
The flow diagram identifies all the unit operations, the equipment used,
and the stages at which the various raw materials are added. The flow diagram
in Figure 3 outlines the sequence of process steps and specific equipment to be
used during development for a typical granulation solid dosage from product.
The flow diagram provides a convenient basis on which to develop a detailed
list of variables and responses.
12
Preliminary working documents are critical, but they should never be cast
in stone, since new experimental data may drastically alter them. The final ver-
sion will eventually be an essential part of the process characterization and
technical transfer documents.
Regardless of the stage of formulation/process development being consid-
ered, a detailed identification of variables and responses is necessary for early
program planning. Typical variables and responses that could be expected in a
granulated solid dosage form are listed in Table 1. This list is by no means
complete and is intended only as an example.
4. Verification
Verification is required before a process is scaled up and transferred to produc-
tion. The timing of this verification may be critical from a regulatory point of
view, as the there is little or no room for modifying the parameter values and
16 Chao et al.
For maximum information, the process should not be altered during the verifica-
tion trials.
5. Development Documentation
The developmental documentation to support the validation of the process may
contain the following:
Process challenging and characterization reports that contain a full de-
scription of the studies performed
Development batch record
Raw material test methods and specifications
Prospective Process Validation 17
The development of the final full-scale production process proceeds through the
following steps:
Process scale-up studies
Qualification trials
Process validation runs
18 Chao et al.
A. Scale-Up Studies
The transition from a successful pilot-scale process or research scale to a full-
scale process requires careful planning and implementation. Although a large
amount of information has been gathered during the development of the process
(i.e., process characterization and process verification studies), it does not neces-
sarily follow that the full-scale process can be completely predicted.
Many scale-up parameters are nonlinear. In fact, scale-up factors can be
quite complex and difficult to predict, based only on experience with smaller-
scale equipment. In general, the more complex the process, the more complex
the scale-up effect.
For some processes, the transition from pilot scale or research scale to full
scale is relatively easy and orderly. For others the transition is less predictable.
More often than not there will be no serious surprises, but this cannot be guaran-
teed. Individuals conducting the transfer into production should be thoroughly
qualified on both small- and large-scale equipment.
The planning for scale-up should follow the same general outline followed
for process characterization and verification. It usually begins when process
development studies in the laboratory have successfully shown that a product
can be produced within specification limits for defined ranges of process param-
eters.
Frequently, because of economic constraints, a carefully selected excipient
may be used as a substitute for the expensive active chemical in conducting
initial scale-up studies. Eventually, the active chemical will have to be used to
complete the scale-up studies, however.
It is common sense that every effort will be made to conduct the final
scale-up studies under CGMP conditions, thus any product produced with speci-
fications can be considered for release as a finished salable product (for over-
the-counter products only).
B. Qualification Trials
Once the scale-up studies have been completed, it may be necessary to manufac-
ture one or more batches at full scale to confirm that the entire manufacturing
process, comprising several different unit operations, can be carried out
smoothly. This may occur prior to or after the regulatory submission, depending
on the strategy used in filing.
parameters and specifications. The validation protocol is usually the joint effort
of the following groups:
Safety instructions
Environmental restrictions
Gas or liquid discharge limitations
Solid or scrap disposal instructions
Equipment
Description
Operation
Cleaning
Raw materials
Pertinent characteristics
Acceptance limits
Analytical methods
Packaging and storage
Handling precautions
Process flow chart
Critical parameters and related means of controls
Responsibilities of each of the groups participating
Cleaning validation/verification requirements
Master batch components (percentage by weight)
Production batch component (by weight)
Process batch record
Process sequence
Process instructions
Material usage
Product testing
In-process testing and acceptance criteria
Finished product testing and acceptance criteria
Test method references
Formulation
20 Chao et al.
A. Program Scope
Defining a clear and detailed set of objectives is a necessary first step in any
experimental program. Some similarity exists between objectives for different
products and processes using similar existing technology. For products and pro-
cesses at the forefront of technology, the definition of specific experimental
objectives can be a continuing activity throughout product development.
Constraints on planning experimental programs can be classified accord-
ing to their impact on time, resources, and budget. The effect and impact of
these should be incorporated into the experimental program early to avoid com-
promising critical program objectives.
22 Chao et al.
B. Process Summary
An initial clear understanding of the formulation and/or process is important.
The following techniques can assist in summarizing current process knowledge.
1. Flow Diagram
A process flow diagram (Fig. 3) can often provide a focal point of early program
planning activities. This diagram outlines the sequence of process steps and
specific equipment to be used during development for a typical granulated prod-
uct. Flow diagram complexity will depend on the particular product and process.
The flow diagram provides a convenient basis on which to develop a detailed
list of variables and responses.
3. Cause-and-Effect Diagram
An efficient representation of complex relationships between many process and
formulation variables (causes), and a single response (effect) can be shown by
using a cause-and-effect diagram [1]. Figure 4 is a simple example.
A central arrow in Figure 4 points to a particular single effect. Branches
off the central arrow lead to boxes representing specific process steps. Next,
principle factors of each process step that can cause or influence the effect are
drawn as subbranches of each branch, until a complete cause-and-effect diagram
is developed. This should be as detailed a summary as possible. An example of
a more complex cause-and-effect diagram is illustrated in Figure 5. A separate
summary for each critical product characteristic (e.g., weight variation, dissolu-
tion, friability) should be made.
4. Influence Matrix
Once the variables and responses have been identified, it is useful to summarize
their relationships in an influence matrix format, as shown in Figure 6. Based
on the available knowledge, each process variable is evaluated for its potential
Prospective Process Validation
Many different experimental designs and analysis methods can be used in devel-
opment activities (Fig. 7). Indeed, the possibilities could fill several books. For-
tunately, in any given situation, it is not necessary to search for that single
design or analysis method that absolutely must be used; there are usually many
possibilities. In general, designs that are usable offer different levels of effi-
ciency, complexity, and effectiveness in achieving experimental objectives.
A. Types of Design
It is not possible to list specific designs that will always be appropriate for
general occasions. Any attempt to do so would be sure to be ineffective, and
the uniqueness of individual experimental situation carefully, including
Specific objectives
Available resources
Availability of previous theoretical results
Relevant variables and responses
Qualifications and experience of research team members
Cost of experimentation
It should also be determined which design is appropriate. A statistician who is
experienced in development applications can assist in suggesting and evaluating
candidate designs. In some cases, the statistician should be a full-time member
of the research team.
B. Data Analysis
The appropriate analysis of the experimental results will depend on the experi-
mental objectives, the design used, and the characteristics of the data collected
during the experiment. In many cases, a simple examination of a tabular or
Prospective Process Validation
C. Experiment Documentation
Documentation is essential to program planning and coordination, in addition to
the obvious use for the summary of activities and results. Written communica-
tion becomes important for larger complex programs, especially when con-
ducted under severe constraints on time and resources. Documentation can con-
sist of some or all of the following items:
1. Objectives; an exact statement of quantifiable results expected from
the experiment
2. Experimental design; a detailed list of the experimental conditions to
be studied and the order of investigation
3. Proposed/alternate test methods
a. A list of test methods consistent with the type of experiment be-
ing performed
b. A detailed description of the steps necessary to obtain a valid
measurement
c. Documentation supporting the accuracy, precision, sensitivity,
and so on of the test methods
4. Equipment procedures; documentation of safety precautions and step-
by-step methods for equipment setup, operation, and cleanup
5. Sampling plans; the type, number, location, and purpose of samples
to be taken during the experiment; in addition, the type and number
of all measurements to be performed on each sample
6. Protocol; a formal written experimental plan that presents the afore-
mentioned experimental documentation in a manner suitable for re-
view
7. Data records
a. Experiment log; details of events in the experiment noting process
adjustments and any unusual occurrences
b. In-process measurements; records of the magnitude of critical
process parameters during the experimental sequence
Sample measurements; recorded values of particular measure-
ments on each sample
8. Report; documentation of experiment implementation, exceptions/
modifications to the protocol, results, and conclusion
Prospective Process Validation 29
D. Program Organization
Throughout the experimental phases of the development program, it is essential
to maintain effective communication among various team members. This is fa-
cilitated by having one individual with the necessary technical and managerial
skills assume responsibility for the experimental program, including procuring
resources and informing management of progress.
In a large experimental program, the responsible individual may serve as
a project leader or manager with little or no technical involvement.
IX. SUMMARY
REFERENCES
6. Davies, O. L., ed. The Design and Analysis of Industrial Experiments. New York:
Longman Group (1978).
7. Diamond, W. J. Practical Experiment Designs for Engineers and Scientists. Bel-
mont, CA: Lifetime Learning Publications (1981).
8. Ott, E. R. Process Quality Control: Troubleshooting and Interpretation of Data.
New York: McGraw-Hill (1975).
9. Anderson, N. R., Banker, G. S., and Peck, G. E. Pharmaceutical Dosage Forms:
Tablets. vol. III. New York: Marcel Dekker (1981).
3
Retrospective Validation
Chester J. Trubinski
Church & Dwight Co., Inc., Princeton, New Jersey, U.S.A.
I. INTRODUCTION
The FDA has published a guideline for use by industry that outlines general
principles considered acceptable parts of process validation [1]. Pharmaceutical
firms have been inspected against this standard and those found wanting have
been cited or had approval to manufacture product denied. Indeed, statistics
compiled by the FDA for fiscal year 1997 show inadequate process validation
as one of the top 10 reasons for withholding approval [3]. One way for a firm
to satisfy the requirement for validated processes is to identify those products
that have been on the market for some time and use the wealth of production,
31
32 Trubinski
testing, and control data to demonstrate that the process is reliable. This strate-
gy is commonly referred to as retrospective validation. Historical data also may
be used to augment an earlier validation in cases in which the product has
changed.
ing changes to the method of manufacture and control should be fully investi-
gated before any decision is made to validate retrospectively:
1. Formulation changes involving one or more of the active ingredients
or key excipients
2. Introduction of new equipment not equivalent in every respect to that
previously in use
3. Changes in the method of manufacture that may affect the product’s
characteristics
4. Changes to the manufacturing facility
A product found to be unsuitable for retrospective validation because of a
revised manufacturing process is a likely candidate for prospective validation,
which is beyond the scope of this chapter [1]. Such a discovery, however, should
be brought to the attention of the appropriate authority. In today’s regulatory
environment ignoring the matter would be imprudent.
The third and last step in our selection process is to identify which prod-
ucts are likely to be discontinued because of a lack of marketing interest or
regulatory consideration, to be sold, or to be reformulated. The timing of these
events will dictate whether the product in question remains a viable candidate
for retrospective validation.
The foremost discussion on developing a list of suitable products for study
is summarized in Figure 1.
of data collection and analysis. The time requirements dictate that such work be
assigned to a function with discretionary time, possibly a technical services
group or a quality engineer. Management commitment is especially crucial if
disruptive influences are to be minimized. The loss of a committee member to
another project is such an example.
2. Validation Protocol
A written protocol that describes what is to be accomplished should be prepared
[5]. It should specify the data to be collected, the number of batches to be
included in the study, and how the data, once assembled, will be treated for
relevance. The criteria for acceptable results should be described. The date of
approval of the protocol by the validation organization should also be noted.
The value of a protocol is to control the direction of the study, as well as provide
a baseline in the event unanticipated developments necessitate a change in strat-
egy. A written protocol is also an FDA recommendation [1].
D. Other Considerations
Comprehensive records of complaints received either directly from the customer
or through a drug problem reporting program should be reviewed. Furthermore,
a record of any follow-up investigation of such complaints is mandatory [6] and
should be part of this file. Review of customer complaint records can furnish a
useful overview of process performance and possibly hint at product problems.
Complaint analysis should therefore be viewed as a meaningful adjunct to the
critical process step and control test selection process.
Batch yield reflects efficiency of the operation. Because yield figures are
the sum of numerous interactions, they fail in most cases to provide specific
information about process performance and therefore must be used with caution
in retrospective validation. In any event, this information should be collected,
as it can contribute to further refinement of the yield limits that appear in the
batch record.
Lot-to-lot differences in the purity of the therapeutic agent must be consid-
ered when evaluating in-process and finished-product test results. In addition to
potency such qualities as particle size distribution, bulk density, and source of
the material will be of interest. Such information should be available from the
raw material test reports prepared by the quality control laboratory for each lot
of material received. The physical characteristics of the excipients should not
be overlooked, especially for those materials with inherent variability. Metallic
stearates is a classic example. In such instances, the source of supply is desirable
information to have available.
There is value in examining logs of equipment and physical plant mainte-
nance. These documents can provide a chronological profile of the operating
environment and reveal recent alterations to the process equipment that may
have enough impact to disqualify the product from retrospective validation con-
sideration. For this reason, it is always prudent to contemplate equipment status
early in the information-gathering stage. The availability of such information
should be ascertained for yet another reason: rarely is equipment dedicated to
Retrospective Validation 37
one product. More often than not, each blender, comminutor, tablet press, and
so forth is used for several operations. Information gathered initially can there-
fore be incorporated into subsequent studies.
Retrospective validation is directed primarily toward examining the rec-
ords of past performance, but what if one of these documents is not a true
reflection of the operation performed? Suppose that changes have crept into the
processing operation over time and have gone unreported. This condition would
result in the validation of a process that in reality does not exist. It is therefore
essential to audit the existing operation against the written instructions. There is
obvious advantage to undertaking this audit before commencing data acquisi-
tion. Ideally, the manufacture of more than one batch should be witnessed, espe-
cially where multiple-shift operations are involved. The same logic would apply
to the testing performed in process and at the finished stage. If any deviation
from the written directions is noted, an effort must be made to measure its
impact. In this regard, the previously described validation organization is a logi-
cal forum for discussion and evaluation.
As a rule, batches that are rejected or reworked are not suitable for inclu-
sion in a retrospective validation study [7]. Indeed, a processing failure that is
not fully explainable should be cause to rethink the application of retrospective
validation. Nonconformance to specification that is attributable to a unique
event–operator error, for example, may be justifiably disregarded. In such cases,
the batch is not considered when the historical data are assembled.
Raw materials, both actives and excipients, can be a source of product
variability. To limit this risk, there should be meaningful acceptance specifica-
tions and periodic confirmation of test results reported on the supplier’s certifi-
cate of analysis. Also, purchases must be limited to previously qualified suppli-
ers. A determination that such controls are in place should be part of any
retrospective validation effort.
The following discussion will focus on how to apply the previously discussed
concepts to the validation of marketed products. To provide a fuller understand-
ing of this procedure, the manufacture of several dosage forms designed for
different routes of administration will be examined. For each dosage form, criti-
cal process steps and quality control tests will be identified. Useful statistical
techniques for examining the assembled data will be illustrated. It is also impor-
tant to note that not all of the collected information for a product lends itself to
this type of analysis. This will become more apparent as we proceed with the
evaluation of the five drugs under consideration.
38 Trubinski
mation: recommended blending time and blender load. The latter will be of little
interest, as only one size batch is produced for this product. Blender speed is
not specified in the batch record because it is fixed. Because mixing time has
been recognized as influencing blend uniformity, this operation will become the
first of the critical process steps for which we will want to collect historical
information [8].
The second major step is granulation. The process is controlled by the
operator, whose judgment is relied on for the appropriate end point. As no
information useful for process validation is available, we will move on to the
next step, comminution.
The batch record calls for passing the wet mix through a comminutor
using a no. 5 or 7 drilled stainless steel screen. Knife position and rotational
speed are two other factors that influence particle size; however, the step instruc-
tion is quite specific about machine setup. Therefore, only screen size is a source
of variability for this step. We will want to know the frequency of use of each
screen.
Next, the granulation is dried to a target moisture of 1%. Either a tray or
fluid bed dryer may be used, at the discretion of area supervision. Regardless
of the method, drying time will be of interest. In addition, the final moisture
content should be ascertained for each batch. The dried granulation and lubricant
are then oscillated using a no. 10 or 12 wire screen. This is the last sizing
operation of the process; it will determine the particle size distribution of the
final blend. Knowing the history of use of each screen size is thus important.
The lubricant and granulation are blended for several minutes. The elapsed
mixing time is of interest because of its impact on drug distribution and the
generally deleterious effect of the lubricant on dissolution.
Because excess moisture is thought to have a negative effect on the dosage
form, loss on drying (LOD) is determined on the final blend.
Blending is followed by tableting. During compression, online measure-
ments such as tablet weight, hardness, and disintegration are made by the pro-
cess operator in order to ensure uniformity of the tablets. The weight of the
tablets is not measured individually; rather, the average weight of 10 tablets is
recorded. Although these data are good indicators of operation and machine
performance, we would prefer to have the more precise picture provided by
individual tablet weight.
Disintegration time and tablet hardness data could be collected from the
manufacturing batch records; however, for ease of administration these figures
will be obtained from the quality control test results, which also contain individ-
ual tablet weighings.
Disintegration time was selected as a critical variable because for a drug
substance to be absorbed it must first disintegrate and then dissolve. The resis-
tance of a tablet to breakage, chipping, and so forth depends on its hardness.
40 Trubinski
Disintegration, too, can be influenced by hardness of the tablet. For these rea-
sons, hardness testing results also will be examined.
Specifications used by quality control to release drug A are found in a
laboratory procedure. In addition to the previously discussed hardness and disin-
tegration time requirements, the procedure calls for determining the average
tablet weight by the United States Pharmacopeia (USP) procedure; that is, 20
individual tablets are weighed.
The control procedure also requires assay of individual tablets. Of all the
information available, these data will be the most useful in reaching an opinion
of the adequacy of the process to distribute the therapeutic agent uniformly.
In addition, the laboratory checks the moisture content of the bulk tablets.
It will be interesting to compare these results to the LOD of the final blend to
measure the contribution of material handling.
Critical manufacturing steps and quality control tests for drug A, identified
as a result of the review, are summarized in Table 1.
can materially affect attributes of the final product. Unfortunately, having only
one batch produced by the 20-min process does not permit statistically valid
comparisons. At best, test results for the single 20-min batch can be screened
using summary data from the remainder of the study. Under different circum-
stances, batches would have been grouped by mixing time and compared by
dosage form attributes. More than likely, subsequent manipulation of the blend
would have negated any contribution, allowing us to conclude that a mixing
time of 10 to 20 min is not unreasonable.
At the wet milling step we encounter a situation similar to preblending;
that is, only two of the 30 study batches are prepared using the no. 5 drilled
screen. The no. 7 is obviously the screen of choice. The purpose of this step is
to produce particles of reasonably uniform size, which in turn will improve
drying. From the records, we also know that the no. 5 screen was used
only with batches that were tray dried. Elapsed drying time and residual
moisture were compared for the two batches from the no. 5 screen process
and the other 13 batches that were tray dried. No important differences were
detected. Still, in light of the limited use of the no. 5 screen, it would not
be inappropriate to recommend this option be eliminated from the processing
instructions.
Mean drying time for the oven tray process is 19.2 hr. All 15 batches
were dried within the specified time of 16 to 20 hr. No seasonal influence was
apparent. The average moisture content of these batches is 1.2%; the standard
deviation is 0.3%. The 15 batches dried using the fluid bed dryer had a residual
moisture of 0.8% (SD = 0.1%). Drying time is mechanically controlled and not
recorded. The statistics favor the fluid bed process; it is more efficient and
uniform. There is nothing in these data to disqualify the oven tray dryer from
further use, however.
Oscillation of the dried granulation and lubricant was accomplished in
every instance using a no. 10 wire screen. Reference to the no. 12 screen, the
alternative method for pulverizing the batch, must be deleted from the manufac-
turing instructions for the process to be validated retrospectively.
The final mix blending time was reported as either 10 or 15 min. Twenty-
one of the 30 batches were tumbled for 10 min and the remainder were mixed
for 15 min. The mixing time is not mechanically controlled or automatically
recorded; it is left to the operator to interpret elapsed time. Because of the
importance of the step to distribution of the therapeutic agent, a comparison was
made between the distribution of the percentage of relative tablet potency [(tab-
let assay/tablet weight) × 100] for the two mixing times. The frequency distribu-
tions of the two populations are shown in Figure 3.
The two histograms are visually different, with the 15-min process exhibit-
ing more dispersion. Despite this difference both populations are tightly grouped,
which is a reflection of the uniformity of the blend.
42 Trubinski
Figure 4 x̄-control chart for drug A percentage moisture at final blend step (fluid bed
process).
limit. Hardness and disintegration time are not well correlated, probably due to
rounding of test results and the need to compare averages.
On average, tablets from the fluid bed process were slightly harder. Also,
the individual batches had a greater range of hardness than batches from the
alternative drying process. Disintegration time for the fluid bed process averaged
3.0 min. Individual batches ranged from 2.0 to 4.5 min. As with the tray process,
no correlation was found between hardness and disintegration time. In summary,
tablets from the fluid bed dryer process were somewhat harder and took slightly
longer to disintegrate. (See Table 2.) These differences are considered insignifi-
cant, however. If any recommendations were made, it would be to lower the
disintegration time specification or establish an internal action limit closer to
the historical upper range of the process.
Control charts were plotted for hardness and average tablet weight (ATW)
to evaluate process performance over time. Separate charts were prepared for
the tray dryer and fluid bed processes. Hardness values are an average of 10
individual measurements. The ATW subgroups are the result of weighing 20
tablets individually. The control charts were inspected for trends and evidence
of instability using well-established methods [9]. Only the control chart for hard-
ness of tablets from the fluid bed process responded to one of the tests for
pattern instability (Fig. 5); that is, two of three consecutive points exceeded the
2-sigma limit. From the chart it is obvious the general trend toward greater
tablet hardness (from 11 to 25 SCU) is the underlying cause of the instability.
The trend to greater hardness was subsequently arrested and may have to do
Retrospective Validation 45
Figure 5 x̄-control chart for drug A tablet hardness (fluid bed process).