工艺验证通用原则指南.doc

The AlliancePharm(US ), Inc. 美国洲际药业有限公司美国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 PRINCIPLESOF PROCESS VALIDATION美国洲际药业有限公司网址：电子邮件：ellenAlliancePGUIDELINE ON GENERAL PRINCIPLESOF PROCESS VALIDATION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, andCenter for Devices and Radiological HealthFood and Drug AdministrationMaintained by: Division of Manufacturing and Product Quality (HFD-320)Office of ComplianceCenter for Drug Evaluation and ResearchFood and Drug Administration5600 Fishers LaneRockville, Maryland 20857Reprinted February, 1993byThe Division of Field InvestigationsOffice of Regional OperationsOffice of Regulatory AffairsU.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 products 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 todays 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 products 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 con