FDA美国食品药物管理局工艺验证指南英文版模板.doc

GUIDELINE
ON GENERAL PRINCIPLES OF
PROCESS VALIDATION

May, 1987

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

General Principles of Process Validation May 1987
GENERAL PRINCIPLES OF PROCESS VALIDATION

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 effectiveness2

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 facto