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 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.
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copyright 1995 by Jason Kaye and Craig Brozefsky
药品微生物检验替代方法验证指导原则 本指导原则是为所采用的试验方法能否替代药典规定的方法用于药品微生物的检验提供指导。 随着微生物学的迅速发展，制药领域不断引入了一些新的微生物检验技术，大体可分为三类：（1)基于微生物生长信息的检验技术，如生物发光技术、电化学技术、比浊法等；(2)直接测定被测介质中活微生物的检验技术，如固相细胞技术法、流式细胞计数法等；（3)基于微生物细胞所含有特定组成成分的分析技术，如脂肪酸测定技术、核酸扩增技术、基因指纹分析技术等。这些方法与传统检查方法比较，或简便快速，或具有实时或近实时监控的潜力，使生产早期采取纠正措施及监控和指导优良生产成为可能，同时新技术的使用也促进了生产成本降低及检验水平的提高。 在控制药品微生物质量中，微生物实验室出于各种原因如成本、生产量、快速简便及提高药品质量等需要而采用非药典规定的检验方法（即替代方法）时，应进行替代方法的验证，确认其应用效果优于或等同于药典的方法。 微生物检验的类型及验证参数 药品微生物检验方法主要分两种类型：定性试验和定量试验。定性试验就是测定样品中是否存在活的微生物，如无菌检查及控制菌检査。定量试验就是测定样品中存在的微生物数量，如菌落计数试验。 由于生物试验的特殊性，如微生物检验方法中的抽样误差、稀释误差、操作误差、培养误差和计数误差都会对检验结果造成影响，因此，药品质量标准分析方法验证指导原则（附录XIX A)不完全适宜于微生物替代方法的验证。药品微生物检验替代方法的验证参数见表1。 表1 不同微生物检验类型验证参数 注： 尽管替代方法的验证参数与药品质量标准分析方法验证参数有相似之处，但是其具体的内容是依据微生物检验特点而设立的。替代方法验证的实验结果需进行统计分析，当替代方法属于定性检验时，一般采用非参数的统计技术；当替代方法属于定量检验时，需要采用参数统计技术。 进行微生物替代方法的验证时，若替代方法只是针对药典方法中的某一环节进行技术修改，此时，需要验证的对象仅是该项替代技术而不是整个检验方法。如无菌试验若改为使用含培养基的过滤器，然后通过适宜的技术确认活的微生物存在，那么，验证时仅需验证所用的微生物回收系统而不是整个无菌试验方法。 替代方法验证的一般要求 在开展替代方法对样品检验的适用性验证前，有必要对替代方法有一个全面的了解。首先，所选用的替代方法应具备必要的方法适用性证据，表明在不含样品的情况下，替代方法
1．目的：新产品研制成功后，通过生产证实新工艺的可靠性和重视性，并通过工艺验证以确定起始原料及成品的纯度，均一性，可靠性，为新药大规模生产提供依据。 2．范围：新产品、新技术。 3．职责：质量部、工程部、生产部、采供部、验证小组负责人、验证小组成员。 4．内容： 4.1公司只对获得新药证书和生产批准文号的新产品或者引进的新技术产品进行工艺验证。并对质量分析方法进行验证。 4.2新产品及新技术必须经生产车间中试，对产品工艺进行预验证合格后才能进行产品的工艺验证。 4.3新产品工艺验证步骤： 4.3.1依据国家药品监督管理局批准认可的质量标准，对其中“制法”部分进行审批，并起草工艺操作规程。
4.3.2依据工艺规程中工艺流程选择先进合格的制药设备。 4.3.3必要时可对工艺生产用设备的运行参数进行更改修正，以满足工艺要求的需要。 4.3.4对已确定的设备安装到位后，可编制设备验证方案，对设备进行预确认，安装确认，运行确认，性能确认，撰写验证报告，经QA经理审批通过，方可开始工艺验证。 4.3.5编制工艺验证方案（参照验证编制管理规程）经QA审核；验证委员会批准，验证办公室组织验证小组实施。 4.3.6进行工艺验证的人员必须是各部门有技术资质的人员胜任，并经过严格技术培训才可上岗。 4.3.7验证工艺经过三次试生产获得成功后，即可进一步完善工艺规程及标准操作规程（SOP）。 4.3.8验证工艺经过三次试生产，对不能达到原质量标准要求时，查明原因后即可更换设备，修正工艺规程或更换不称职的操作人员，直到完成验证工艺工作。 4.4 QA验证合格后，验证办公室即可发放验证合格证书。 4.5经验证符合可知的工艺规程通过公司所有技术人员认可，技术交底后，可进行正式生产。验证状态维持6-12个月后进行回顾性验证，以确定生产工艺的稳定性。 4.6验证工艺结束，验证工艺全部资料都应登记归档。
无菌工艺模拟试验指南（无菌制剂） （征求意见稿） 国家食品药品监督管理总局 食品药品审核查验中心
二〇一六年十月 目录 1.目的 (1) 2.定义 (1) 3.范围 (1) 4.原则 (2) 5.无菌制剂生产工艺及模拟范围 (2) 6.模拟试验方案的设计及实施过程要求 (3) 6.1. 无菌工艺模拟试验的前提条件 (3) 6.2.基于风险的方案设计 (4) 6.3.模拟介质的选择与评价 (4) 6.4.灌装数量及模拟持续时间 (8) 6.5.容器装量 (9) 6.6. 模拟试验方法的选择 (9) 6.7. 最差条件的选择 (10) 6.8.干预 (12) 6.9.容器规格 (13) 6.10.培养与观察 (14) 6.11. 计数与数量平衡 (15) 6.12. 环境（包括人员）监控 (15) 6.13. 人员因素 (16) 6.14. 不同剂型应考虑的特殊因素 (16) 6.15. 方案的实施 (19) 7.可接受标准与结果评价 (20)
8.污染调查及纠正措施 (21) 9.模拟试验的周期与再验证 (21) 10.无菌工艺模拟试验的局限性 (212) 11.术语 (23) 12. 参考文献 (24)
无菌工艺模拟试验指南（无菌制剂） 1.目的 为指导和规范无菌制剂生产企业开展无菌工艺模拟试验，充分评价无菌制剂产品生产过程的无菌保障水平，确保无菌制剂的安全性，依据《药品生产质量管理规范》（2010版）及附录，制定本指南。 2.定义 本指南所述的无菌工艺模拟试验，是指采用适当的培养基或其他介质，模拟制剂生产中无菌操作的全过程，评价该工艺无菌保障水平的一系列活动。 3.范围 3.1.本指南涵盖了无菌工艺模拟试验的基本要求、不同工艺模式的相应要求、试验的基本流程等内容，适用于无菌制剂的无菌工艺验证。 3.2.本指南所述条款是在现有无菌工艺技术基础上提出的相 关要求，旨在规范企业开展无菌工艺模拟试验活动。在科学的基础上，鼓励新技术、新设备的引入，进一步提高无菌制剂的无菌保障水平。 4.原则 在对无菌生产工艺充分认知和生产经验累积的基础上，应结合工艺、设备、人员和环境等要素定期开展无菌工艺模拟试验，
工艺验证管理规程 一、目的：制定工艺验证制度，使工艺验证过程程序化、规范化。 二、适用范围：适用于公司制剂工艺验证的实施。 三、职责： 生产管理部：负责新工艺及工艺验证方案的起草。 生产车间：负责工艺验证方案的组织实施。 验证办公室：负责组织与协调验证的日常工作。 质量保证部QC：负责验证方案中检验方法的审核，准确及时完成相关的检验任务，作好记录，并对检验结果的准确性负责。 质量保证部长：负责验证方案及报告的审核。 验证负责人：负责验证方案及报告的批准。 四、内容： 4.1目的 通过工艺验证的有效实施，证实某一工艺过程确实能始终如一地生产出符合预定规格及质量标准的产品。为工艺规程的修订提供依据。 4.2验证小组成员： 生产技术部部长、车间主任、质量保证部部长、QA质监员、QC主管、QC质检员。 4.3验证的前提条件： 4.3.1检验方法及仪器已经验证 4.3.2设备及公用工程系统已经验证 4.3.3已起草工艺规程 4.3.4新产品、新工艺的验证，应至少完成一个批号的试生产，在试生产过程中没有出现过数据“漂移”现象。
4.4验证步骤 4.4.1制订验证计划 4.4.1.1由验证办公室起草验证计划。 4.4.2准备验证方案 4.4.2.1验证方案的内容原则上包括： ·概述：简要说明验证产品信息，如处方、工艺规程、生产历史等，同时应说明验证目的及验证方法。 ·产品涉及的生产质量管理文件 ·工艺流程图 ·主要原、辅料：包括主要原、辅料名称、规格、生产厂家及质量标准。 ·主要生产设备：包括设备名称、规格型号、生产厂家。 ·日常生产控制：依据工艺规程说明在正常生产过程中例行的控制。 ·验证内容确定：说明验证的内容，验证条件的设计（允许的最差条件）及确认的依据及原因。 4.4.3验证方法： 4.4.3.1验证项目：依据产品不同和工艺方法不同制定不同的验证项目及验证参数。 4.4.3.2目的：说明各项验证的目的。 4.4.3.3取样：详细说明验证过程中的取样方法、取样数量及样品名、必要是以图示表示，以便操作人员实施。 4.4.3.4检验方法：详细说明检验方法，必要时说明检验依据。 4.4.3.5接受标准：接受标准一般可采用两种方法确定： ·如果验证项目在日常生产工艺过程中有控制，并有标准，即以此标准为接受标准。 ·如果验证项目在日常生产过程中无控制标准，接受标准由生产车间依据经验及工艺过程要求自己确定，但必须合适。 4.5验证实施： 工艺验证过程依据已经批准的验证方案早先，原则上须在工艺过程、工艺参数等不变的条件下工艺验证连续进行三批欠。如果验证过程中出现偏差，执行《偏差处理制度》，由验证小组决定是否有效及是否需要增加验证批次等。 4.6验证报告：
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
I. INTRODUCTION This guidance provides recommendations to applicants on submitting analytical procedures, validation data, and samples to support the documentation of the identity, strength, quality, purity, and potency of drug substances and drug products. 1. 绪论 本指南旨在为申请者提供建议，以帮助其提交分析方法，方法验证资料和样品用于支持原料药和制剂的认定，剂量，质量，纯度和效力方面的文件。 This guidance is intended to assist applicants in assembling information, submitting samples, and presenting data to support analytical methodologies. The recommendations apply to drug substances and drug products covered in new drug applications (NDAs), abbreviated new drug applications (ANDAs), biologics license applications (BLAs), product license applications (PLAs), and supplements to these applications. 本指南旨在帮助申请者收集资料，递交样品并资料以支持分析方法。这些建议适用于NDA，ANDA，BLA，PLA及其它们的补充中所涉及的原料药和制剂。 The principles also apply to drug substances and drug products covered in Type II drug master files (DMFs). If a different approach is chosen, the applicant is encouraged to discuss the matter in advance with the center with product jurisdiction to prevent the expenditure of resources on preparing a submission that may later be determined to be unacceptable. 这些原则同样适用于二类DMF所涉及的原料药和制剂。如果使用了其它方法，鼓励申请者事先和FDA药品评审中心的官员进行讨论，以免出现这种情况，那就是花了人力物力所准备起来的递交资料后来发现是不可用的。 The principles of methods validation described in this guidance apply to all types of analytical procedures. However, the specific recommendations in this guidance may not be applicable to certain unique analytical procedures for products such as biological, biotechnological, botanical, or radiopharmaceutical drugs. 本指南中所述的分析方法验证的原则适用于各种类型的分析方法。但是，本指南中特定的建议可能不适用于有些产品所用的特殊分析方法，如生物药，生物技术药，植物药或放射性药物等。 For example, many bioassays are based on animal challenge models, 39 immunogenicity assessments, or other immunoassays that have unique features that should be considered when submitting analytical procedure and methods validation information. 比如说，许多生物分析是建立在动物挑战模式，免疫原性评估或其它有着独特特性的免疫分析基础上的，在递交分析方法和分析方法验证资料时需考虑这些独特的性质。Furthermore, specific recommendations for biological and immunochemical tests that may be necessary for characterization and quality control of many drug substances and drug products are beyond the scope of this guidance document. 而且，许多原料药和制剂的界定和质量控制所需的生物和免疫化学检测并不在本指南的范围之内。 Although this guidance does not specifically address the submission of analytical procedures and validation data for raw materials, intermediates, excipients, container closure components, and other materials used in the production of drug
工艺验证评审办法 1．主题内容与适用范围 1．1 本标准规定了工艺验证评审程序、评审内容及标准。 1．2 适用范围 本标准适用于在生产准备完成后所进行的工艺验证评审管理。 2．工艺验证评审程序 2．1 由技术部牵头，组织公司有关部门及人员进行评审 2．2 对评审不合格内容，组织人员立即整改，整改完成后，再次组织评审。所有评审项评审合格后，方可转入正常生产。 3．工艺验证评审的主要内容 3.1 工艺设计 工艺设计应经过工艺设计质量评审，且有相关记录。 3.2 产品工艺质量 3.2.1 产品经工艺调试，应符合产品图样要求及相关的技术标准。 3.2.2 调试的合格样件应经过全面的检测。且检测合格并保留有相关检测记录。 3．3 工艺文件的验收 3.3.1 工艺文件应正确、完整、统一、清晰。其编制、审批、更改等符合公司相关的文件管理规定。3.3.2 工艺文件内容完整，工艺参数及工艺方法明确。且经过调试后验证正确。 3.3.3 工艺文件经调试验证需进行修改的已修改完毕并已按规定下发。 3.3.4 现场工艺文件为现行有效版本，操作者易于得到。 3．4 设备与工艺装备的要求 3．4．1 工艺规定的设备与工装应配齐。
3．4．2 工艺规定的量具、检具等检测器具应配齐，且所有的检测器具均经过检测，为合格检测器具。3．4．3 设备与工装型号、规格符合工艺提出的要求，更改部分经过工艺认可。 3．4．4 设备与工装经过调试验证，其精度与技术状态能满足生产合格零件的需要。 3．4．5 设备与工装按工艺规定的节拍调试验证后，其生产能力能满足预定的生产纲领要求，且安全措施可靠。 3.5 对操作者要求 3．5．1 基本知识要求 ①必须经过岗位培训，并考核合格，获得上岗许可证，确保达到工序对操作者的技术要求。 ②熟记本岗位零件号、零件名称、设备工装技术参数等工艺内容，掌握相关工艺要求、操作要点、检测方法等。能清楚叙述工艺文件内容及质量要求 3．5．2 基本技能要求 ①能按照工艺文件要求进行生产操作，严格过程控制的有关要求，坚持按图纸、按工艺、按 标准生产。 ②能对设备进行维护、保养 ③能使用检具进行质量特性自检 ④能对工艺参数进行调整和监控 ⑤能使用各类管理工具，包括各种记录和自检标识 3．6 对材料、半成品、制成品的工艺要求 3．6．1 各种规格的原材料、辅料要符合工艺规定。 3．6．2 所使用原材料、半成品均经过检验，为合格品。 3．6．2 材料、半成品、制成品均应按规定摆放，标识正确、清楚，且有专门的工位器具及运输器具进行存放与转运。 3.7 对环境的要求 3.7.1 现场干静，整洁，符合产品特性要求 3.7.2 工作现场实行定置管理，物流合理、通畅
如何做好工艺验证工作呢一个人或者说一个部门能不能做好验证工作在论坛经常会看到一个验证主管去完成公司全部的验证文件（方案及报告），这样的验证能否做好待下去大家讨论！ 验证是一项跨部门的工作，与多个部门有关，需要相关部门的密切合作。故此对于验证工作大家一定要有团队概念，这是做好验证工作的必要条件（注：对于全公司验证交个一个人或者一个部门来完成的，自己在尽力去做的同时，要和你的领导沟通让更多的相关人员参与进来）。要做好验证这点很重要。 下面从几个方面来阐述我们对做好工艺验证应有的认识： 1.首先做好验证计划 这个计划是从下到上来做的，也就是说每个车间要每年将本单位要做的工艺验证按照生产计划及车间具体情况列出自己的计划，交质量部验证主管统一平衡，起草出公司的工艺验证总计划，这里注意时间节点及可能出现的变更，尽可能列出切实可行的年度总计划，交生产及质量负责人批准下发至各有关部门，质量部负责验证跟踪的人员按总计划列出每月需要完成的项目，及时的跟踪完成情况，做好各方面的沟通协调（注意，质量部验证主管不是起草方案和报告的人员，是审核和协调）； 2. 关于职责分配 虽然在验证管理或者验证主计划内会有规定，但是那些一般对于具体的验证实施不会具体到参与验证的人员，在起草验证方案和审核时要注意，涉及具体工作一定要落实到具体的人，并且还要培训到位，让每一份验证方案涉及到的相关人员明确自己职责，
提前做好准备工作，以便验证顺利进行。养成习惯，形成流程，可以使验证按计划有效性的执行。 3.工艺验证实施前需要完成的项目： 这个在你的公司文件中会有明确的规定。 ⑴关键质量属性和关键工艺参数已确定；与验证相关文件要确认是否现行版本（包括工艺规程、各工序SOP，所有记录（批生产记录，批检验记录、清洁记录，设备运行记录等）、质量标准，检验操作规程）； ⑵厂房设施、系统和设备的验证或确认（包括计量器具的校准或检定，检验仪器的确认及产品分析方法验证或确认）已完成； ⑶参与工艺验证执行的所有人员的培训已经完成（无菌制剂要完成人员进入无菌区的更衣确认），验证负责人负责组织工艺验证的培训，起草人负责对方案进行培训； ⑷工艺验证中所用物料，包装材检验合格并放行（如：操作间和设备及现场环境满足工艺要求；公用系统满足工艺要求（工艺用水，空气、氮气及净化系统检测结果合格）4.工艺验证的方案（报告）的起草 工艺验证方案起草人要对产品工艺有足够的认识，研发转移至生产的产品的工艺验证由研发工艺开发人员及生产单位工艺员共同起草（涉及变更的也有双方共同起草）；日常生产产品的工艺验证由生产生产单位工艺负责人起草； 5.验证的实施 工艺验证按批准的验证方案逐项落实，生产车间负责人做好工作计划的人员分配，工艺员及QA做好验证过程数据收集的记录整理分析，跟踪中间体控制情况，做好验证过程的变更及偏差处理。 6.验证报告的起草：
201507 FDA行业指南：分析方法验证（中英文）（下） VII. STATISTICAL ANALYSIS AND MODELS 统计学分析和模型 A. Statistics 统计学 Statistical analysis of validation data can be used to evaluate validation characteristics against predetermined acceptance criteria. All statistical procedures and parameters used in the analysis of the data should be based on sound principles and appropriate for the intended evaluation. Several statistical methods are useful for assessing validation characteristics, for example, an analysis of variance (ANOVA) to assess regression analysis R (correlation coefficient) and R squared (coefficient of determination) or linear regression to measure linearity. Many statistical methods used for assessing validation characteristics rely on population normality, and it is important to determine whether or not to reject this assumption. There are many techniques, such as histograms, normality tests, and probability plots that can be used to evaluate the observed distribution. It may be appropriate to transform the data to better fit the normal distribution or apply distribution-free (nonparametric) approaches when the observed data are
一、准确度 准确度系指采用该方法测定的结果与真实值或参考值接近的程度，一般用回收率（％)表示。准确度应在规定的范围内测定。 1.化学药含量测定方法的准确度 原料药采用对照品进行测定，或用本法所得结果与已知准确度的另一个方法测定的结果进行比较。制剂可在处方量空白辅料中，加入已知量被测物对照品进行测定。如不能得到制剂辅料的全部组分，可向待测制剂中加人已知量的被测物对照品进行测定，或用所建立方法的测定结果与已知准确度的另一种方法测定结果进行比较。准确度也可由所测定的精密度、线性和专属性推算出来。 2.化学药杂质定量测定的准确度 可向原料药或制剂处方量空白辅料中加人已知量杂质进行测定。如不能得到杂质或降解产物对照品，可用所建立方法测定的结果与另一成熟的方法进行比较，如药典标准方法或经过验证的方法。在不能测得杂质或降解产物的校正因子或不能测得对主成分的相对校正因子的情况下，可用不加校正因子的主成分自身对照法计算杂质含量。应明确表明单个杂质和杂质总量相当于主成分的重量比（％) 或面积比（％ )。 3.中药化学成分测定方法的准确度 可用对照品进行加样回收率测定，即向已知被测成分含量的供试品中再精密加人一定量的被测成分对照品，依法测定。用实测值与供试品中含有量之差，除以加入对照品量计算回收率。在加样回收试验中须注意对照品的加人量与供试品中被测成分含有量之和必须在标准曲线线性范围之内；加入对照品的量要适当，过小则引起较大的相对误差，过大则干扰成分相对减少，真实性差。 回收率：％= (C - A ) /S X 100% 式中：A为供试品所含被测成分量；B 为加入对照品量； C 为实测值。 4.校正因子的准确度 对色谱方法而言，绝对（或定量）校正因子是指单位面积的色谱峰代表的待测物质的量。待测定物质与所选定的参照物质的绝对校正因子之比，即为相对校正因子。相对校正因子计算法常应用于化学药有关物质的测定、中药材及其复方制剂中多指标成分的测定。校正因子的表示方法很多，本指导原则中的校正因
工艺验证方案 本公司产品XXXXX是非无菌原料药产品，为保证生产工艺在实际生产中的有效性和可靠性，故对其进行工艺验证，本工艺验证采用同步验证的方式。本生产工艺的验证是由质量管理部负责组织，生产技术部、设备工程部、生产车间及QC检验室有关人员参与实施。 本工艺验证方案参考了ICH Q7A的生产工艺验证的指导原则。 验证小组成员 方案制订 方案审核 方案批准
目录 1. 基本情况 (4) 1.1. 概述 (4) 1.2. 生产工艺 (4) 1.2.1. 生产工艺流程图 (4) 1.2.2. 生产工艺的详细描述 (4) 1.2.3. 关键工艺步骤和参数 (4) 2. 验证目的 (5) 3. 验证前提 (5) 3.1. 工艺环境包括公用系统情况 (5) 3.2. 工艺设备情况 (5) 3.3. 所用原辅料和包装材料情况 (5) 3.4. 所用文件的准备情况 (6) 3.5. 人员情况 (6) 4. 验证方案 (6) 4.1. 验证计划 (6) 4.2. 第一步反应（生产XXXXX粗品）的验证（应包括所有重点 考察的生产关键参数、结晶、离心、干燥） (6) 4.2.1第一步反应（生产XXXXX粗品）关键工艺参数验证 (6) 4.2.2第一步反应收率情况验证 (7) 4.2.3第一步反应中间体的质量情况验证 (7) 4.3. 粗品精制工序的验证 (8) 4.3.1溶解脱色验证 (8) 4.3.2 结晶工序验证 (8) 4.3.3 分离工序验证 (9) 4.3.4 干燥工序验证 (10) 4.3.5小批成品收率情况验证 (10) 4.3.6小批成品的质量情况验证 (11) 4.4批混合工艺的验证 (11) 4.4.1批混合工序关键工艺参数验证 (11) 4.4.2批混合效果的验证 (11) 4.5最终成品的质量情况验证 (12)
验证文件 XXXXXX有限公司 2013年XX月6.验证报告起草、审核与批准 6.1验证报告起草 6.2 再验证报告审核 6.3 再验证报告批准
目录 1. 验证概述 2. 验证目的 3. 验证范围 4. 再验证依据标准 5. 机构与职责 5.1 验证机构 5.2 验证职责 6. 验证方式 7. 验证准备 7.1 设备设施准备7.2 仪器试剂准备
7.3 原辅物料准备 7.4 文件与培训 8. 验证时间与计划 9. 验证实施 9.1 产品的工艺流程图9.2产品的工艺验证： 9.2.1称量备料 9.2.1.1目的 9.2.1.2文件 9.2.1.3检查项目及结果9.2.2 配制 9.2.2.1 目的
9.2.2.2 文件 9.2.2.3 评估项目 9.2.2.4 评估方法 9.2.2.5 取样方法 9.2.2.6配制试验数据 9.2.3 灌装封尾 9.2.3.1 目的 9.2.3.2文件 9.2.3.3评估项目 9.2.3.4评估方法 9.2.3.5灌装封尾检查数据9.2.4 成品抽样检验
9.2.4.1 目的 9.2.4.2 文件 9.2.4.3 评估项目 9.2.4.4 评估方法 9.2.4.5产品检验报告复印件 10. 偏差与处理. 11. 结果与分析 11.1 验证数据汇总 11.2 存在问题与措施 11.3 风险与预防 12. 验证结论 12.1 验证结论
12.2 验证评价与建议 13. 验证周期 14. 附件 15.参考或引用文件 1.概述： 复方醋酸地塞米松乳膏为我司生产多年的乳膏剂品种，自2009GMP再认证以来，乳膏剂生产线生产所用关键设备、生产工艺及工艺参数没有改变，为了验证在正常的生产条件和GMP文件管理体系下能生产出符合预定的规格及质量标准的产品，根据验证管理文件的要求，我们对复方醋酸地塞米松乳膏的生产工艺进行再验证。 2.目的： 在现行的GMP文件管理体系下，生产三批复方醋酸地塞米松乳膏进行工艺再验证: （1）确认关键工序质量监控点是否符合质量要求； （2）确认该产品质量是否符合预定成品的标准。
工艺验证规程 1 适用范围 本标准适用于本公司所有产品工艺验证。 2 工艺验证的目的 通过工艺验证的有效实施，考察某一工艺过程是否能始终如一地生产出符合预定规格及质 量标准的产品。为工艺规程定稿提供依据。 3 职责 生产车间:负责工艺验证方案的起草及验证的组织实施。 综合部:负责协助新工艺验证方案的起草。 QA现场监控员:协助验证方案的组织实施。 质量部QC:负责按计划完成工艺验证方案中相关检验任务，确保检验结论正确可靠。 QA验证管理员:负责验证工作的管理，协助工艺验证方案的起草，组织协调验证工作， 并总结验证结果，起草验证报告。 质量部经理:负责工艺验证方案及报告的审核。 质量总监:负责工艺验证方案及报告的批准。 4 内容 4.1 验证小组成员 综合部工艺研究人员、生产部技术人员、QC主管、QC检验员、生产部技术管理人员、 QA验证管理员。
4.2 验证步骤 4.2.1 制订验证计划 4.2.1.1 由验证小组成员(通常是验证管理员)首先起草该项目的验证总计划，然后将 验证总计划交给验证小组讨论和审批后分发至各责任部门。 4.2.1.2 验证总计划包括: , 简介:简要说明验证对象信息、验证目的和拟采用的验证方法。 , 验证小组成员。 , 验证工作日程安排表(包括各验证项目的实施部门、责任人、实施日期及完成日期)。 4.2.2 准备验证方案: 4.2.2.1 验证方案的内容原则上包括: ——适用范围 , 概述:简要说明验证产品信息，如处方、工艺规程、生产历史等，同时说明验证目 的及验证方法。 , 产品及生产质量管理文件。 , 工艺流程图:依据工艺规程绘制简要工艺流程图，为制定验证内容提供依据。 , 主要原材料:包括主要原材料名称、规格、生产厂家及质量标准。 , 主要生产设备:包括设备名称、规格型号、生产厂家。 , 日常生产控制:依据工艺规程说明在正常生产过程中例行的控制。 , 验证内容确定:说明验证的内容，验证条件的设计(模拟实际生产状态和允许的最差条件)及确认的依据及原因。 4.2.2.2 验证方法:
FDA工艺验证指南新旧版透彻比较解读 【整理者提醒】 1-左侧文本为2011年1月最新修订版本，右侧文本为2008年11月草案版本。 2-蓝色文本为修订后文本或者新增加文本。 3-下划线文本是比旧版本增加的部分内容。 4-删除线文本表示该部分存在于旧版本中，在新版本中删除。 5-注释前面加【注释】2字注明。 6-Zhulikou431关于FDA2008年11月草案彻底解读版本可以在丁香园论坛搜索到，欢迎下载阅读、讨论。 7-不得用于商业用途，转载请注明丁香园信息。 8-增加了新旧版本的中文译文。 9-欢迎各位朋友提出宝贵建议，联系邮箱zhulikou431@https://www.doczj.com/doc/018609604.html,. Guidance for Industry Process Validation: General Principles and Practices Final Version January 2011 Draft 2008 I. INTRODUCTION I. INTRODUCTION 简介
This guidance outlines the general principles and approaches that FDA considers appropriate elements of process validation for the manufacture of human and animal drug and biological products, including active pharmaceutical ingredients (APIs or drug substances), collectively referred to in this guidance as drugs or products. This guidance incorporates principles and approaches that all manufacturers can use to validate manufacturing processes. 本指南概括了一般的原则与方法，这些原则与方法是FDA 认为进行工艺验证的恰当要素，这些工艺被用于生产人用药、动物用药以及生物制品，包括活性药物成分(API 或药用物质)，在本指南中以上统称为药品或产品。本指南整合了一般的原则和方法，所有的生产企业都可以将这些原则和方法应用于生产工艺的验证。 This guidance outlines the general principles and approaches that FDA considers to be appropriate elements of process validation for the manufacture of human and animal drug and biological products, including active pharmaceutical ingredients (API or drug substance), collectively referred to in this guidance as drugs or products. This guidance incorporates principles and approaches that all manufacturers can use in validating a manufacturing process. 本指南概括了一般的原则与方法，这些原则与方法是FDA 认为进行工艺验证的恰当要素，这些工艺被用于生产人用药、动物用药以及生物制品，包括活性药物成分(API 或药用物质)，在本指南中以上统称为药品或产品。本指南整合了一般的原则和方法，所有的生产企业都可以将这些原则和方法应用于生产工艺的验证。 This guidance aligns process validation activities with a product lifecycle concept and with existing FDA guidance, including the FDA/International Conference on Harmonisation (ICH) guidances for industry, Q8(R2) Pharmaceutical Development, Q9 Quality Risk Management, and Q10 Pharmaceutical Quality System.2 Although this guidance does not repeat the concepts and principles explained in those guidances, FDA encourages the use of modern pharmaceutical development concepts, quality risk man- agement, and quality systems at all stages of the manufacturing process lifecycle. 本指南将工艺验证活动与产品生命周期概念以及现有FDA 相关指南进行了协调；这些存在的FDA指南包括FDA/ICH指南，Q8(R2)药品研发指南、Q9质量风险管理指南和Q10制药质量体系指南。尽管本指南没有重复上述指南解释的概念和This guidance aligns process validation activities with the product lifecycle concept and with existing FDA guidance.2 2 See the FDA/International Conference on Harmonisation (ICH) guidances for industry: Q8 Pharmaceutical Development, Q9 Quality Risk Management, and when finalized, Q10 Pharmaceutical Quality System (a notice of availability for the May 2007 ICH draft guidance, Q10 Pharmaceutical Quality System, published in the Federal Register on July 13, 2007 (72 FR 38604)). We update guidance documents periodically. To make sure you have the most recent version of a guidance, check the CDER guidance page at https://www.doczj.com/doc/018609604.html,/cder/guidance/index.htm, the CBER guidance page at
美国FDA分析方法验证指南中英文对照 美国FDA分析方法验证指南中英文对 照 I. INTRODUCTION This guidance provides recommendations to applicants on submitting analytical procedures, validation data, and samples to support the documentation of the identity, strength, quality, purity, and potency of drug substances and drug products. 1. 绪论 本指南旨在为申请者提供建议，以帮助其提交分析方法，方法验证资料和样品用 于支持原料药和制剂的认定，剂量，质量，纯度和效力方面的文件。 This guidance is intended to assist applicants in assembling information, submitting samples, and presenting data to support analytical methodologies. The recommendations apply to drug substances and drug products covered in new drug applications (NDAs), abbreviated new drug applications (ANDAs), biologics license applications (BLAs), product license applications (PLAs), and supplements to these applications. 本指南旨在帮助申请者收集资料，递交样品并资料以支持分析方法。这些建议适 用于NDA，ANDA，BLA，PLA及其它们的补充中所涉及的原料药和制剂。 The principles also apply to drug substances and drug products covered in Type II drug master files (DMFs). If a different approach is chosen, the applicant is encouraged to discuss the matter in advance with