GUIDELINE ON GENERAL PRINCIPLES OF PROCESS
VALIDATION May, 1987
Courtesy of Kamm & Associates: fda-consultant.com
Prepared by: Center for Drugs and Biologics
and
Center for Devices and Radiological Health
Food and Drug Administration
Maintained by: Division of Manufacturing and Product
Quality (HFN-320)
Office of Compliance
Center for Drugs and Biologics
Food and Drug Administration
5600 Fishers Lane
Rockville, Maryland 20857
I. PURPOSE
This guideline outlines general
principles that FDA considers to be
acceptable elements of process
validation for the preparation of
human and animal drug products and
medical devices.
II. SCOPE
This guideline is issued under Section
10.90 (21 CFR 10.90) and is
applicable to the manufacture of
pharmaceuticals and medical
devices. It states principles and
practices of general
applicability that are not legal
requirements but are acceptable to
the FDA. A person may rely upon
this guideline with the assurance
of its acceptability to FDA, or may
follow different procedures.
When different procedures are used, a
person may, but is not
required to, discuss the matter in
advance with FDA to prevent the
expenditure of money and effort on
activities that may later be
determined to be unacceptable. In
short, this guideline lists
principles and practices which are
acceptable to the FDA for the
process validation of drug products and
medical devices; it does
not list the principles and practices
that must, in all instances,
be used to comply with law.
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This guideline may be amended
from time to time. Interested
persons are invited to submit comments
on this document and any
subsequent revisions. Written
comments should be submitted to the
Dockets Management Branch (HFA-305),
Food and Drug Administration,
Room 4-62, 5600 Fishers Lane,
Rockville, Maryland 20857. Received
comments may be seen in that office
between 9\a.m. and 4\p.m.,
Monday through Friday.
III. INTRODUCTION
Process validation is a requirement of
the Current Good
Manufacturing Practices Regulations for
Finished Pharmaceuticals,
21 CFR Parts 210 and 211, and of the
Good Manufacturing Practice
Regulations for Medical Devices, 21 CFR
Part 820, and therefore, is
applicable to the manufacture of
pharamaceuticals and medical
devices.
Several firms have asked FDA for
specific guidance on what FDA
expects firms to do to assure
compliance with the requirements for
process validation. This
guideline discusses process validation
elements and concepts that are
considered by FDA as acceptable
parts of a validation program.
The constituents of validation
presented in this document are not
intended to be all-inclusive.
FDA recognizes that, because of the
great variety of medical
products (drug products and medical
devices), processes and
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manufacturing facilities, it is not
possible to state in one
document all of the specific validation
elements that are
applicable. Several broad
concepts, however, have general
applicability which manufacturers can
use successfully as a guide
in validating a manufacturing
process. Although the particular
requirements of process validation will
vary according to such
factors as the nature of the medical
product (e.g., sterile vs
non-sterile) and the complexity of the
process, the broad concepts
stated in this document have general
applicability and provide an
acceptable framework for building a
comprehensive approach to
process validation.
Definitions
Installation qualification -
Establishing confidence that process
equipment and ancillary systems are
capable of consistently
operating within established limits and
tolerances.
Process performance qualification -
Establishing confidence that
the process is effective and
reproducible.
Product performance qualification -
Establishing confidence through
appropriate testing that the finished
product produced by a
specified process meets all release
requirements for functionality
and safety.
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Prospective validation - Validation
conducted prior to the
distribution of either a new product,
or product made under a
revised manufacturing process, where
the revisions may affect the
product's characteristics.
Retrospective validation - Validation
of a process for a product
already in distribution based upon
accumulated production, testing
and control data.
Validation - Establishing documented
evidence which provides a high
degree of assurance that a specific
process will consistently
produce a product meeting its
pre-determined specifications and
quality attributes.
Validation protocol - A written plan
stating how validation will be
conducted, including test parameters,
product characteristics,
production equipment, and decision
points on what constitutes
acceptable test results.
Worst case - A set of conditions
encompassing upper and lower
processing limits and circumstances,
including those within
standard operating procedures, which
pose the greatest chance of
process or product failure when
compared to ideal conditions. Such
conditions do not necessarily induce
product or process failure.
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IV. GENERAL CONCEPTS
Assurance of product quality is derived
from careful attention to a
number of factors including selection
of quality parts and
materials, adequate product and process
design, control of the
process, and in-process and end-product
testing. Due to the
complexity of today's medical products,
routine end-product testing
alone often is not sufficient to assure
product quality for several
reasons. Some end-product tests
have limited sensitivity.1 In
some cases, destructive testing would
be required to show that the
manufacturing process was adequate, and
in other situations
end-product testing does not reveal all
variations that may occur
in the product that may impact on
safety and effectiveness.2
The basic principles of quality
assurance have as their goal the
production of articles that are fit for
their intended use. These
1 For example, USP XXI states: "No
sampling plan for applying
sterility tests to a specified
proportion of discrete units
selected from a sterilization load is
capable of demonstrating with
complete assurance that all of the
untested units are in fact
sterile."
2 As an example, in one instance a visual
inspection failed to detect
a defective structural weld which
resulted in the failure of an
infant warmer. The defect could
only have been detected by using
destructive testing or expensive test
equipment.
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principles may be stated as
follows: (1) quality, safety, and
effectiveness must be designed and
built into the product; (2)
quality cannot be inspected or tested
into the finished product;
and (3) each step of the manufacturing
process must be controlled
to maximize the probability that the
finished product meets all
quality and design
specifications. Process validation is a key
element in assuring that these quality
assurance goals are met.
It is through careful design and
validation of both the process and
process controls that a manufacturer
can establish a high degree of
confidence that all manufactured units
from successive lots will be
acceptable. Successfully
validating a process may reduce the
dependence upon intensive in-process
and finished product testing.
It should be noted that in most all
cases, end-product testing
plays a major role in assuring that
quality assurance goals are
met; i.e., validation and end-product
testing are not mutually
exclusive.
The FDA defines process validation as
follows:
Process validation is
establishing documented evidence which
provides a high
degree of assurance that a specific process will
consistently produce
a product meeting its pre-determined
specifications and
quality characteristics.
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It is important that the manufacturer
prepare a written validation
protocol which specifies the procedures
(and tests) to be conducted
and the data to be collected. The
purpose for which data are
collected must be clear, the data must
reflect facts and be
collected carefully and
accurately. The protocol should specify a
sufficient number of replicate process
runs to demonstrate
reproducibility and provide an accurate
measure of variability
among successive runs. The test
conditions for these runs should
encompass upper and lower processing
limits and circumstances,
including those within standard
operating procedures, which pose
the greatest chance of process or
product failure compared to ideal
conditions; such conditions have become
widely known as "worst
case" conditions. (They are
sometimes called "most appropriate
challenge" conditions.)
Validation documentation should include
evidence of the suitability of
materials and the performance and
reliability of equipment and systems.
Key process variables should be
monitored and documented. Analysis
of the data collected from monitoring
will establish the
variability of process parameters for
individual runs and will
establish whether or not the equipment
and process controls are
adequate to assure that product
specifications are met.
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Finished product and in-process test
data can be of value in
process validation, particularly in
those situations where quality
attributes and variabilities can be
readily measured. Where
finished (or in-process) testing cannot
adequately measure certain
attributes, process validation should
be derived primarily from
qualification of each system used in
production and from
consideration of the interaction of the
various systems.
V. CGMP REGULATIONS FOR FINISHED PHARMACEUTICALS
Process validation is required, in both
general and specific terms,
by the Current Good Manufacturing
Practice Regulations for Finished
Pharmaceuticals, 21 CFR Parts 210 and
211. Examples of such
requirements are listed below for
informational purposes, and are
not all-inclusive.
A requirement for process validation is
set forth in general terms
in section\211.100 -- Written
procedures; deviations -- which
states, in part:
"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."
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Several sections of
the CGMP regulations state validation
requirements in more
specific terms. Excerpts from some of
these sections are:
Section 211.110, Sampling and testing of in-process
materials and drug products.
(a)
"....control procedures shall be established to monitor the
output and VALIDATE
the performance of those manufacturing
processes that may be
responsible for causing variability in the
characteristics of
in-process material and the drug product."
(emphasis added)
Section 211.113,
Control of Microbiological Contamination.
(b)
"Appropriate written procedures, designed to prevent
microbiological
contamination of drug products purporting to be
sterile, shall be
established and followed. Such procedures
shall include
VALIDATION of any sterilization process."
(emphasis added)
VI. GMP REGULATION FOR MEDICAL DEVICES
Process validation is required by the
medical device GMP
Regulations, 21 CFR Part\820.
Section 820.5 requires every
finished device manufacturer to:
"...prepare and
implement a quality assurance program that is
appropriate to the
specific device manufactured..."
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Section 820.3(n) defines quality
assurance as:
"...all
activities necessary to verify confidence in the quality
of the process used
to manufacture a finished device."
When applicable to a specific process,
process validation is an
essential element in establishing
confidence that a process will
consistently produce a product meeting
the designed quality
characteristics.
A generally stated requirement for
process validation is contained
in section\820.100:
"Written
manufacturing specifications and processing procedures
shall be established,
implemented, and controlled to assure that
the device conforms
to its original design or any approved
changes in that
design."
Validation is an essential element in
the establishment and
implementation of a process procedure,
as well as in determining
what process controls are required in
order to assure conformance
to specifications.
Section 820.100(a)(1) states:
"...control
measures shall be established to assure that the
design basis for the
device, components and packaging is
correctly translated
into approved specifications."
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Validation is an essential control for
assuring that the
specifications for the device and
manufacturing process are
adequate to produce a device that will
conform to the approved
design characteristics.
VII. PRELIMINARY CONSIDERATIONS
A manufacturer should evaluate all
factors that affect product
quality when designing and undertaking
a process validation study.
These factors may vary considerably
among different products and
manufacturing technologies and could
include, for example,
component specifications, air and water
handling systems,
environmental controls, equipment
functions, and process control
operations. No single approach to
process validation will be
appropriate and complete in all cases;
however, the following
quality activities should be undertaken
in most situations.
During the research and development
(R&D) phase, the desired
product should be carefully defined in
terms of its
characteristics, such as physical,
chemical, electrical and
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performance characteristics.3 It
is important to translate the
product characteristics into
specifications as a basis for
description and control of the product.
Documentation of changes made during
development provide
traceability which can later be used to
pinpoint solutions to
future problems.
The product's end use should be a
determining factor in the
development of product (and component)
characteristics and
specifications. All pertinent
aspects of the product which impact
on safety and effectiveness should be
considered. These aspects
3 For example, in the case of a compressed tablet,
physical
characteristics would include size,
weight, hardness, and freedom
from defects, such as capping and
splitting. Chemical
characteristics would include
quantitative formulation/potency;
performance characteristics may include
bioavailability (reflected
by disintegration and
dissolution). In the case of blood tubing,
physical attributes would include
internal and external diameters,
length and color. Chemical
characteristics would include raw
material formulation. Mechanical
properties would include hardness
and tensile strength; performance
characteristics would include
biocompatibility and durability.
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include performance, reliability and
stability. Acceptable ranges
or limits should be established for
each characteristic to set up
allowable variations.4 These
ranges should be expressed in
readily measurable terms.
The validity of acceptance
specifications should be verified
through testing and challenge of the
product on a sound scientific
basis during the initial development
and production phase.
Once a specification is demonstrated as
acceptable it is important
that any changes to the specification
be made in accordance with
documented change control procedures.
VIII. ELEMENTS OF PROCESS VALIDATION
A. Prospective Validation
Prospective validation includes those
considerations that should be
made before an entirely new product is
introduced by a firm or when
there is a change in the manufacturing
process which may affect the
product's characteristics, such as
uniformity and identity. The
following are considered as key
elements of prospective validation.
4 For example, in order to assure that an
oral, ophthalmic, or
parenteral solution has an acceptable
pH, a specification may be
established by which a lot is released
only if it has been shown to
have a pH within a narrow established
range. For a device, a
specification for the electrical
resistance of a pacemaker lead
would be established so that the lead
would be acceptable only if
the resistance was within a specified
range.
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1. Equipment
and Process
The equipment and
process(es) should be designed and/or selected
so that product
specifications are consistently achieved. This
should be done with
the participation of all appropriate groups
that are concerned
with assuring a quality product, e.g.,
engineering design,
production operations, and quality assurance
personnel.
a. Equipment: Installation Qualification
Installation qualification studies establish confidence that
the process equipment and ancillary systems are capable of
consistently operating within established limits and
tolerances. After process equipment is designed or
selected, it should be evaluated and tested to verify that
it is capable of operating satisfactorily within the
operating limits required by the process.5 This phase of
validation includes examination of equipment design;
determination of calibration, maintenance, and adjustment
requirements; and identifying critical equipment features
that could affect the process and product. Information
obtained from these studies should be used to establish
written procedures covering equipment calibration,
maintenance, monitoring, and control.
5
Examples of equipment performance characteristics which may
be measured include temperature and pressure of injection
molding machines, uniformity of speed for mixers,
temperature, speed and pressure for packaging machines, and
temperature and pressure of sterilization chambers.
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In assessing the suitability of a given piece of equipment,
it is usually insufficient to rely solely upon the
representations of the equipment supplier, or upon
experience in producing some other product.6 Sound
theoretical and practical engineering principles and
considerations are a first step in the assessment.
It is important that equipment qualification simulate actual
production conditions, including those which are "worst
case" situations.
6 The
importance of assessing equipment suitability based upon
how it will be used to attain desired product attributes is
illustrated in the case of deionizers used to produce
Purified Water, USP. In one case, a firm used such water to
make a topical drug product solution which, in view of its
intended use, should have been free from objectionable
microorganisms. However, the product was found to be
contaminated with a pathogenic microorganism. The apparent
cause of the problem was failure to assess the performance
of the deionizer from a microbiological standpoint. It is
fairly well recognized that the deionizers are prone to
build-up of microorganisms--especially if the flow rates are
low and the deionizers are not recharged and sanitized at
suitable intervals. Therefore, these factors should have
been considered. In this case, however, the firm relied
upon the representations of the equipment itself, namely the
"recharge" (i.e., conductivity) indicator, to signal the
time for regeneration and cleaning. Considering the desired
product characteristics, the firm should have determined the
need for such procedures based upon pre-use testing, taking
into account such factors as the length of time the
equipment could produce deionized water of acceptable
quality, flow rate, temperature, raw water quality,
frequency of use, and surface area of deionizing resins.
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Tests and challenges should be repeated a sufficient number
of times to assure reliable and meaningful results. All
acceptance criteria must be met during the test or
challenge. If any test or challenge shows that the
equipment does not perform within its specifications, an
evaluation should be performed to identify the cause of the
failure. Corrections should be made and additional test
runs performed, as needed, to verify that the equipment
performs within specifications. The observed variability of
the equipment between and within runs can be used as a basis
for determining the total number of trials selected for the
subsequent performance qualification studies of the
process.7
Once the equipment configuration and performance
characteristics are established and qualified, they should
be documented. The installation qualification should
include a review of pertinent maintenance procedures, repair
parts lists, and calibration methods for each piece of
equipment. The objective is to assure that all repairs can
be performed in such a way that will not affect the
7 For
example, the AAMI Guideline for Industrial Ethylene
Oxide Sterilization of Medical Devices approved 2 December
1981, states: "The performance qualification should include
a minimum of 3 successful, planned qualification runs, in
which all of the acceptance criteria are met.....(5.3.1.2.).
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characteristics of material processed after the repair. In
addition, special post-repair cleaning and calibration
requirements should be developed to prevent inadvertent
manufacture a of non-conforming product. Planning during
the qualification phase can prevent confusion during
emergency repairs which could lead to use of the wrong
replacement part.
b. Process: Performance Qualification
The purpose of performance qualification is to provide
rigorous testing to demonstrate the effectiveness and
reproducibility of the process. In entering the performance
qualification phase of validation, it is understood that the
process specifications have been established and essentially
proven acceptable through laboratory or other trial methods
and that the equipment has been judged acceptable on the
basis of suitable installation studies.
Each process should be defined and described with sufficient
specificity so that employees understand what is required.
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Parts of the process which may vary so as to affect
important product quality should be challenged.8
In challenging a process to assess its adequacy, it is
important that challenge conditions simulate those that will
be encountered during actual production, including "worst
case" conditions. The challenges should be repeated enough
times to assure that the results are meaningful and
consistent.
8 For
example, in electroplating the metal case of an
implantable pacemaker, the significant process steps to
define, describe, and challenge include establishment and
control of current density and temperature values for
assuring adequate composition of electrolyte and for
assuring cleanliness of the metal to be plated. In the
production of parenteral solutions by aseptic filling, the
significant aseptic filling process steps to define and
challenge should include the sterilization and
depyrogenation of containers/closures, sterilization of
solutions, filling equipment and product contact surfaces,
and the filling and closing of containers.
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Each specific manufacturing process should be appropriately
qualified and validated. There is an inherent danger in
relying on what are perceived to be similarities between
products, processes, and equipment without appropriate
challenge.9
c. Product: Performance Qualification
For purposes of this guideline, product performance
qualification activities apply only to medical devices.
These steps should be viewed as pre-production quality
assurance activities.
9 For
example, in the production of a compressed tablet, a
firm may switch from one type of granulation blender to
another with the erroneous assumption that both types have
similar performance characteristics, and, therefore,
granulation mixing times and procedures need not be
altered. However, if the blenders are substantially
different, use of the new blender with procedures used for
the previous blender may result in a granulation with poor
content uniformity. This, in turn, may lead to tablets
having significantly differing potencies. This situation
may be averted if the quality assurance system detects the
equipment change in the first place, challenges the blender
performance, precipitates a revalidation of the process, and
initiates appropriate changes. In this example,
revalidation comprises installation qualification of the new
equipment and performance qualification of the process
intended for use in the new blender.
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Before reaching the conclusion that a process has been
successfully validated, it is necessary to demonstrate that
the specified process has not adversely affected the
finished product. Where possible, product performance
qualification testing should include performance testing
under conditions that simulate actual use. Product
performance qualification testing should be conducted using
product manufactured from the same type of production
equipment, methods and procedures that will be used for
routine production. Otherwise, the qualified product may
not be representative of production units and cannot be used
as evidence that the manufacturing process will produce a
product that meets the pre-determined specifications and
quality attributes.10
10 For example,
a manufacturer of heart valves received
complaints that the valve-support structure was fracturing
under use. Investigation by the manufacturer revealed that
all material and dimensional specifications had been met but
the production machining process created microscopic
scratches on the valve supporting wireform. These scratches
caused metal fatigue and subsequent fracture. Comprehensive
fatigue testing of production units under simulated use
conditions could have detected the process deficiency.
In another example, a manufacturer recalled insulin syringes
because of complaints that the needles were clogged.
Investigation revealed that the needles were clogged by
silicone oil which was employed as a lubricant during
manufacturing. Investigation further revealed that the
method used to extract the silicone oil was only partially
effective. Although visual inspection of the syringes
seemed to support that the cleaning method was effective,
actual use proved otherwise.
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After actual
production units have sucessfully passed product
performance
qualification, a formal technical review should be
conducted and should
include:
o
Comparison of the approved product specifications and the
actual qualified product.
o
Determination of the validity of test methods used to
determine compliance with the approved specifications.
o
Determination of the adequacy of the specification change
control program.
2. System to
Assure Timely Revalidation
There should be a
quality assurance system in place which
requires revalidation
whenever there are changes in packaging,
formulation,
equipment, or processes which could impact on
product effectiveness
or product characteristics, and whenever
there are changes in
product characteristics. Furthermore, when
a change is made in
raw material supplier, the manufacturer
should consider
subtle, potentially adverse differences in the
raw material
characteristics. A determination of adverse
differences in raw
material indicates a need to revalidate the
process.
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One way of detecting
the kind of changes that should initiate
revalidation is the
use of tests and methods of analysis which
are capable of
measuring characteristics which may vary. Such
tests and methods
usually yield specific results which go beyond
the mere pass/fail
basis, thereby detecting variations within
product and process
specifications and allowing determination of
whether a process is
slipping out of control.
The quality assurance
procedures should establish the
circumstances under
which revalidation is required. These may
be based upon
equipment, process, and product performance
observed during the
initial validation challenge studies. It is
desirable to
designate individuals who have the responsibility
to review product,
process, equipment and personnel changes to
determine if and when
revalidation is warranted.
The extent of
revalidation will depend upon the nature of the
changes and how they
impact upon different aspects of production
that had previously
been validated. It may not be necessary to
revalidate a process
from scratch merely because a given
circumstance has
changed. However, it is important to carefully
assess the nature of
the change to determine potential ripple
effects and what
needs to be considered as part of revalidation.
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3.
Documentation
It is essential that
the validation program is documented and
that the
documentation is properly maintained. Approval and
release of the
process for use in routine manufacturing should
be based upon a
review of all the validation documentation,
including data from
the equipment qualification, process
performance
qualification, and product/package testing to ensure
compatibility with
the process.
For routine
production, it is important to adequately record
process details
(e.g., time, temperature, equipment used) and to
record any changes
which have occurred. A maintenance log can
be useful in
performing failure investigations concerning a
specific
manufacturing lot. Validation data (along with
specific test data)
may also determine expected variance in
product or equipment
characteristics.
B. Retrospective Process Validation
In some cases a product may have been
on the market without
sufficient premarket process
validation. In these cases, it may be
possible to validate, in some measure,
the adequacy of the process
by examination of accumulated test data
on the product and records
of the manufacturing procedures used.
Retrospective validation can also be
useful to augment initial
premarket prospective validation for
new products or changed
processes. In such cases,
preliminary prospective validation
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should have been sufficient to warrant
product marketing. As
additional data is gathered on
production lots, such data can be
used to build confidence in the
adequacy of the process.
Conversely, such data may indicate a
declining confidence in the
process and a commensurate need for
corrective changes.
Test data may be useful only if the
methods and results are
adequately specific. As with
prospective validation, it may be
insufficient to assess the process
solely on the basis of lot by
lot conformance to specifications if
test results are merely
expressed in terms of pass/fail.
Specific results, on the other
hand, can be statistically analyzed and
a determination can be made
of what variance in data can be
expected. It is important to
maintain records which describe the
operating characteristics of
the process, e.g., time, temperature,
humidity, and equipment
settings.11 Whenever test data
are used to demonstrate
conformance to specifications, it is
important that the test
methodology be qualified to assure that
test results are objective
and accurate.
11 For example, sterilizer time and temperature data
collected on
recording equipment found to be
accurate and precise could
establish that process parameters had
been reliably delivered to
previously processed loads. A
retrospective qualification of the
equipment could be performed to
demonstrate that the recorded data
represented conditions that were
uniform throughout the chamber and
that product load configurations,
personnel practices, initial
temperature, and other variables had
been adequately controlled
during the earlier runs.
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IX. ACCEPTABILITY OF PRODUCT TESTING
In some cases, a drug product or
medical device may be manufactured
individually or on a one-time
basis. The concept of prospective or
retrospective validation as it relates
to those situations may have
limited applicability, and data
obtained during the manufacturing
and assembly process may be used in
conjunction with product
testing to demonstrate that the instant
run yielded a finished
product meeting all of its
specifications and quality
characteristics. Such evaluation
of data and product testing would
be expected to be much more extensive
than the usual situation
where more reliance would be placed on
prospective validation.