工艺验证通用原则指南

《美国FDA认证与申办指南》

权威资讯系列

《工艺验证的通用原则指南》GUIDELINE ON GENERAL PRINCIPLES OF PROCESS V ALIDATION

美国洲际药业有限公司

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GUIDELINE ON GENERAL PRINCIPLES

OF PROCESS V ALIDATION

工艺验证的通用原则指南

Prepared by: Center for Drug Evaluation and Research,

Center for Biologics Evaluation and Research, and

Center for Devices and Radiological Health

Food and Drug Administration

Maintained by: Division of Manufacturing and Product Quality (HFD-320)

Office of Compliance

Center for Drug Evaluation and Research

Food and Drug Administration

5600 Fishers Lane

Rockville, Maryland 20857

Reprinted February, 1993

by

The Division of Field Investigations

Office of Regional Operations

Office of Regulatory Affairs

U.S.Food and Drug Administration

TABLE OF CONTENTS目录

I. PURPOSE目的

II. SCOPE范围

III. INTRODUCTION简介

IV. GENERAL CONCEPTS 通用概念

V. CGMP REGULATIONS FOR FINISHED PHARMACEUTICALS 关于最终药品的CGMP法规VI. GMP REGULATION FOR MEDICAL DEVICES 关于医疗器械的CGMP法规

VII. PRELIMINARY CONSIDERATIONS 预先考虑

VIII. ELEMENTS OF PROCESS VALIDATION 工艺验证的原理

A. Prospective Validation 预确认

1. Equipment and Process 设备和工艺

a. Equipment : Installation Qualification 设备：安装确认

b. Process: Performance Qualification 工艺：性能确认

c. Product: Performance Qualification产品：性能确认

2. System to Assure Timely Revalidation 保证及时再验证的系统

3. Documentation 文件

B. Retrospective Process Validation回顾性工艺验证

IX. ACCEPTABILITY OF PRODUCT TESTING产品检验的可接受性

Guideline on General Principles of Process Validation

工艺验证通用原则指南

I. PURPOSE目的

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.

本指南概要描述了FDA认为人用药、兽用药、医疗器械的工艺验证所必须遵循的一般原则。II. SCOPE范围

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.

本指南是根据21 CFR 10.90章节出版的，适用于药品和医疗器械的生产。它所规定的通用适用性的原则和实践虽不是法律要求，但是是被FDA所接受的。为确保FDA会接受，你可以依靠本指南操作，也可依据不同的程序。当使用不同的程序时，你可以，但不是必须的，预先与FDA 讨论这件事情避免在付出金钱和努力后做出来的成果FDA并不接受。简言之，本指南列出了关于药品和医疗器械工艺验证的FDA可接受的原则和实践，在任何情况下，都应按照法律要求进行。

III. INTRODUCTION 简介

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 pharmaceuticals 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.

工艺验证是现行制剂药品生产质量管理规范规则（21 CFR210、211）以及医疗器械生产质量管理规范规则（21 CFR Part 820）的要求，因此适用于药品和医疗器械的制造。许多企业向FDA 征询详细的指南，说明FDA期望企业做什么才能保证符合工艺验证的要求。许多企业向FDA 询问关于FDA期望企业做什么才能保证符合工艺验证的要求的特别指南。本指南论述了工艺验证的原理和概念，是FDA认为是应该包括在验证程序中的内容。

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 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.

本文件描述的验证内容并不是包括所有的。FDA认为因为医疗产品（药品和医疗器械）、工艺和生产设施的多样性，在一个文件规定所有可适用的针对性验证要素是不可能的。本文件提供了几个具有通用性用途的范围较宽的概念，生产企业可以成功的利用其作为对具体工艺验证的指导。虽然工艺验证的具体要求随着医疗产品的性质（如，无菌与非无菌）和工艺的复杂程度而不同，本文件中所阐述的范围较宽的通用性概念还是具有普遍适用性的并且为构建综合性的工艺验证方法提供了合适的框架。

Definitions

定义

Installation qualification - Establishing confidence that process equipment and ancillary systems are capable of consistently operating within established limits and tolerances.

安装确认----确立对设备和辅助系统能够在规定的限度和公差范围内持续运行的信任感的过程。Process performance qualification - Establishing confidence that the process is effective and reproducible.

工艺性能确认--------确立工艺是有效并可重现的信任感的过程。

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.

产品性能确认---通过合适的检验确立用指定的工艺生产的成品符合所有的功能性和安全性要求的信任感的过程。

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.

预验证----在新产品销售之前，或在采用可能会影响产品特性的修订后的工艺生产的产品销售之前所进行的验证。

Retrospective validation - Validation of a process for a product already in distribution based upon accumulated production, testing and control data.

回顾性验证---依据累积的生产、检验和控制数据对已销售产品的工艺验证。

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.

验证---能够提供高保证度的特定的工艺能够持续的生产符合预定标准和质量属性的产品的文件化证据的过程。

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.

验证方案----一个书面的规定验证如何进行的计划，包括试验参数，生产特征，生产设备和构成可接受的试验结果的决定点。

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.

最差情况---一组包含工艺限度和环境上下限的情况，包括那些在标准操作规范限度内的，当与理想条件相比会对工艺和产品造成最大失败机会的情况。这些情况并不一定会导致产品或工艺失败。

IV. GENERAL CONCEPTS基本概念

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。

产品质量的保证源自于对部件和物料的质量选择、适当的产品和工艺设计、生产过程控制、生产过程和终产品的检验等一系列因素的仔细控制。由于当今医药产品的复杂性，从下面几个理由讲仅靠对最终产品的测试已不足以保证产品质量。许多成品检测灵敏度有限。

(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.

（1）有些情况下，需要用破坏性试验显示生产工艺是充分的，在另外一些情况下，成品检验不能揭示产品中所存在的会影响产品安全性和有效性的变化。

(2)The basic principles of quality assurance have as their goal the production of articles that are fit for their intended use. These principles may be stated as follows:

质量保证的基本原则是生产出符合预期用途的产品，这些原则规定如下：

(1) quality, safety, and effectiveness must be designed and built into the product;

产品的质量、安全、有效性是设计和制定出来。

(2) quality cannot be inspected or tested into the finished product; and

成品的质量不能检验出来

(3) each step of the manufacturing process must be controlled to maximize the probability that the finished product meets all quality and design specifications.

应该控制生产工艺的每一步才能最大可能的保证成品符合全部质量和设计标准。Process validation is a key element in assuring that these quality assurance goals are met。

工艺验证是确保这些质量保证目标能够实现的关键因素。

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.

通过精心的设计和对工艺及工艺控制的验证，生产企业对于连续生产批次的所有产品符合要求更有信心。成功的工艺验证可以减少对过程和终产品检验的依靠性。应注意到在大多数情况下，成品检验在保证质量保证符合要求方面，起着重要的作用，也就是说：验证和成品检验不是互相排斥的。FDA如此的定义工艺验证：工艺验证是一个文件化证据的过程，能够较高保证的特定的工艺能够持续的生产符合预定标准和质量属性的产品。

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. 生产企业准备一个书面的验证方案，规定了应执行的程序（和测试）以及要收集的数据，这点相当重要。收集数据的目的必须非常的清晰，数据必须反映实际情况且要仔细精确的收集。方案应该规定足够数量的重复的工艺流程以证明重现性和提供对连续流程的变量的正确的测定。对于这些参数的测试条件应该围绕工艺限度和环境的上限和下限，包括那些在标准操作规程规定的条件，与理想条件相比它们会对工艺和产品造成最大失败机会的情况。这些条件就是常说的“最差状态条件”（有时也叫“最适宜的挑战性”情况）。验证文件也包括物料适应性以及设备、系统性能与可靠性的证据。

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.

应该监测和记录关键的工艺变量。对监测中所收集到的数据进行分析能够确定每次运作中工艺参数的变异性，并能确定设备和工艺控制能否足够保证达到产品标准。

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.

成品和过程控制检验数据在工艺验证中是有价值的，特别是在质量属性和变异性能容易测量到的情况下。当成品检验（或过程检验）不能充分测量某种属性时，应该首先从生产中的每一系统的确认和不同系统的相互作用考虑来进行工艺验证。

V. CGMP REGULATIONS FOR FINISHED PHARMACEUTICALS

CGMP对于成品方面的法规要求

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.

在一般条款和专门条款上，制剂的CGMP法规（21 CFR210、211）都要求进行工艺验证。下面列出了这种要求一些例子，但不是包括所有的。

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."

在一般条款，在211.100章节，提出了工艺验证的要求――书面程序；偏差――规定（仅摘一部分）：“应制定以确保药品具有其应有或声称的性状，含量，品质和纯度的生产和控制的书面程序。

Several sections of the CGMP regulations state validation requirements in more specific terms. Excerpts from some of these sections are:

CGMP在几个章节更多的专门条款内规定了对验证的要求。现从几个章节摘录一部分：

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)

211.110章节，过程物料和药品的取样和检测：

应该建立监测产品和验证引起中间体和成品特性的变异性相关的生产工艺性能的控制程序。

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)

211.113章节，微生物污染的控制

应建立和遵守防止无菌药品受到微生物污染的适宜的书面程序。这类程序应包括对所有灭菌工艺的验证。

VI. GMP REGULATION FOR MEDICAL DEVICES

GMP关于医疗器械的法规要求

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..."

医疗器械GMP, 21 CFR 820 ，提出了对工艺验证的要求，820.5章节要求医疗器械制造商：应该建立并执行与特殊医疗器械的生产相适应的质量保证程序。

Section 820.3(n) defines quality assurance as:

820.3(n)章节定义了质量保证：

"...all activities necessary to verify confidence in the quality of the process used to manufacture a finished device."

用于查证生产成品医疗器械的工艺质量可信度的所有必需的活动。

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.

当用于特殊工艺时，在确立某工艺能持续生产出符合设计要求的质量特性的产品的信任度时，工艺验证是关键要素。

A generally stated requirement for process validation is contained in section 820.100:

820.100章节提出了对工艺验证一般性要求：

"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."

应该建立、执行、控制书面生产标准和工艺程序以保证医疗器符合最初的设计或设计中任何批准的变更。

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.

验证不仅在建立和实施工艺程序时是一个关键因素，在为保证符合质量标准确定需采取什么工艺控制措施时也是一样。

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."

820.100规定：应建立控制措施以保证器械、组成和包装的设计原理恰当的转变成已经批准的标准。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

验证是一个能确保器械和生产工艺的标准适宜于生产出符合经批准的设计参数的器械的关键控制措施。

VII. PRELIMINARY CONSIDERATIONS 初步考虑

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.

在设计和进行一个工艺验证研究时，生产商应该评估所有影响产品质量的因素。这些因素可能因不同的产品和生产技术而差异很大，可能包括，例如：成分规格、空气和水处理系统、环境控制、设备功能和工艺控制操作。没有一种单独的工艺验证方法能够适宜于所有的情况；然而，在大多数情况下必须采取下列质量活动。

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 performance characteristics. 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.

在研发阶段，应该仔细规定所设计产品的特性，如：物理、化学、电和性能特性。把产品特性转移至标准作为产品的描述和控制基础是非常重要的。开发过程中的变更记录能提供可追溯性，以便以后用于找到将来发生的问题的解决方法。

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 include performance, reliability and stability. Acceptable ranges or limits should be established for each characteristic to set up allowable variations. These ranges should be expressed in readily measurable terms.

产品的最终用途在产品（和成分）特性和标准研发中是一个决定因素。应该考虑影响安全性和有效性的产品所有相关方面，这些方面包括性能、可靠性和稳定性。为确定准许的变化范围，应为每个特性建立起接受范围和限度。这些范围应该以容易测量项目来表示。

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.

在最初研发和生产阶段，通过试验和在正确科学的基础上的挑战性试验确认可接受标准的正确性。

一旦标准证明是可接受的，任何的标准变更都应该按照书面的变更控制程序进行，这点是很重要的。

VIII. ELEMENTS OF PROCESS VALIDATION

工艺验证的要素

A. Prospective Validation 前验证

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.

前验证包括所有应该在一个完全的新产品被引入之前完成的，或当在生产工艺中进行了可能影响产品特性的变更时，如均一性和鉴别，应考虑的因素。下面是预验证的关键要素。

1. Equipment and Process 设备和工艺

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.

设备和工艺的设计和选择应确保产品持续达到标准要求。这应该由与产品质量保证相关的合适的小组共同参与完成，如：工程设计、生产操作，质量保证人员。

a. Equipment : Installation Qualification

设备：安装确认

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.

安装确认研究建立工艺设备和辅助系统有能力在确定的限度和公差内持续操作的信心。生产设备在设计或选择后，就应该进行评估和检验以确认能在工艺要求的操作限度内进行滿意的操作。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.

验证的这个阶段包括设备设计的检查，校正的确认、维护保养和调整要求，鉴别影响工艺和产品的关键设备特征。用从这些研究中获得的信息来建立包括设备校正，维护保养，监测和控制在内的书面程序。

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. Sound theoretical and practical engineering principles and considerations are a first step in the assessment.

在设备部件的适应性评估，仅仅依靠设备供应商的陈述或依靠生产其它产品的经验是不够的。正确的理论和实用的工程学原理和考虑是评估的第一步。

It is important that equipment qualification simulate actual production conditions, including those which are "worst case" situations.

模拟实际生产状态进行设备确认，包括“最差状态”，是重要的。

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.

试验和挑战应该重复足够的次数以保证可靠的和有意义的结果。在试验和挑战期间，应该达到所有的接受标准。如果试验和挑战显示设备不能在它的指标内运行，应该进行评估以鉴别失败的原因。应该采取纠正措施和附加的试验，以确认设备能在指标内运行。在各次设备运行之间和各次运行期间内观察到的设备流程的可变性可以用作一个基础，以此判断用于后面的工艺性能确认的总试验次数。

(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 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.

一旦建立和确认设备构型和性能，应该进行记录。安装确认应该包括相关的维护程序的审核、部件清单、设备每一部位的校正方法。目标是保证在进行维修的时候不影响修理后生产的物料特征。另外，应该研究修理后的清洁和校正以保证不会由于疏忽而生产出不合格的产品。在确认阶段，合理的计划能防止因使用了错误的替代部分的紧急维修而引起的混乱。

b. Process: Performance Qualification 工艺：性能确认

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.

性能确认的目的是提供严格的试验以证明工艺的有效性和再现性。在进行性能确认前，工艺标准已经建立并通过实验室或其它的试验证明可以接受，设备在安装确认适应性的基础上判为可接受。

Each process should be defined and described with sufficient specificity so that employees understand what is required. 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.

每一工艺应该定义并充分的特征性进行描述以保证员工能理解要求是什么，影响产品质量的工艺工序应该进行挑战性试验。挑战工艺并评估它的适当性，挑战条件应该摸拟在实际生产中能遇到的情况，包括“最差状态”条件，这一点是很重要的。挑战性试验应该重复足够的次数以保证结果是有意义的和是一致的。

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.

每一特殊的生产工艺应该被充分的确认和验证。在没有充分的挑战，依靠感觉认为产品、工艺、设备是相类的，这是内在的危险。

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.

产品：性能确认

本指南的目的，产品的性能确认活动仅仅应用于医疗器械。这些步骤应该作为生产前的质量保证活动进行评估。

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.

在得出结论之前，工艺被成功的确认，必须证明该工艺没有对最终产品造成不良影响。若可能，产品的性能确认试验应该包括模拟实际使用状态下的性能检验。产品性能确认试验应该使用相同类型的生产设备、方法和程序生产的产品。否则，被确认的产品就不能代表实际生产的产品，也不能证明生产工艺能生产出符合既定的标准和质量属性的产品。

After actual production units have successfully passed product performance qualification, a formal technical review should be conducted and should include:

在实际的产品成功的通过了产品性能确认之后，应该进行正式的技术评论并包括：

o Comparison of the approved product specifications and the actual qualified product.

批准后的产品标准和实际确认的产品进行比较。

o Determination of the validity of test methods used to determine compliance with the approved specifications.

对用于判断批准后标准的分析方法的有效性进行判定。

o Determination of the adequacy of the specification change control program.

判定标准变更控制程序的充分性。

2. System to Assure Timely Revalidation

保证及时再验证的系统

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.

在可能影响产品有效性或产品特性的包装、配方、设备、工艺，只要在这些方面发生了变更，和产品特性发生了变更，应该有一个质量保证系统要求进行再验证。而且，如原辅料供应商发生了变更，生产商也应该对原辅料特性方面的潜在的不良差异进行周密的考虑，对原辅料不良差异进行判断，标明需要进行工艺的再验证。

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.

检测启动再验证的变更种类的方法之一是使用试验和分析方法，这些试验和分析方法能测量可能改变的特性。这些试验和分析方法通常得出明确的结果，这些结果超出了起码的合格/失败基础，从而判断产品和工艺标准的变更，判断工艺是否在渐渐的超出控制范围。

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 evalidation is warranted.

质量保证程序应该规定在什么情况下需要再验证。这些应该依据在最初挑战性验证观测到的设备、工艺、产品性能来确定。应指派一个负责评估产品、工艺、设备和人员变更的人员判定是否或什么时间需要进行再验证。

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.

再验证的范围应依据变更的种类和对先前已经确认的产品的不同方面的影响。最初开始的一个工艺仅仅因为一个详情发生了变化，是没有必要进行再验证的。但是，认真评估变更的种类以判断可能发生的连锁反应和应从那些部分考虑需要再验证，这是很重要的。

3. Documentation 文件

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.

文件规定了验证程序，文件应该适当的保存。用于常规生产的工艺的批准和放行应该依据对所有验证文件的审核，包括设备确认数据、工艺性能确认数据，保证工艺相容性的产品/包装检验数据。

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.

对于日常生产，充分记录生产细节（如：时间、温度、使用的设备）和发生的变化是重要的。维护记录对于一个特殊生产批的不合格调查是有用的。验证数据（和特殊的试验数据）也可以确定在产品和设备特性的预期变化。

B. Retrospective Process Validation回顾性工艺验证

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.

在有些情况下，一个产品在没有经过充分的上市前工艺验证就进行了销售。在这种情况下，可以通过检查累积的产品试验数据和生产过程记录来确定工艺的充分性，从而进行工艺验证是可能的。

Retrospective validation can also be useful to augment initial premarket prospective validation for new products or changed processes. In such cases, preliminary prospective validation 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.

回顾性验证也用于新产品或改变工艺后的最初试销前的前验证。在这类情况下，验证必须能够保证产品是可以上市的。当收集了很多批的数据，这些数据就用于建立对工艺适当性的可信度。相反，这些数据也可能显示工艺可信度下降并需要采取纠正措施。

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.

如果方法和结果是充分明确的，检验数据是有用的。如果检验结果仅仅表示合格/失败，评估工艺仅仅依靠批产品符合标准，这是不充分的。特别的检验结果，统计分析并判断数据能发生什么样的预期变化。描述操作工艺特性的记录应该保留，如：时间、温度、湿度和设备设置等。如果检验数据是用于判断符合标准，确认检验方法论保证检验结果是客观的和准确的，这一点是重要的。

IX. ACCEPTABILITY OF PRODUCT TESTING 产品测试的可接受性

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.