PDA TR42 蛋白产品工艺验证(中英文)

计算机化的实验室数据收集系统的验证和确认Validation and Qualification of Computerized Laboratory Data Acquisition SystemsPDA 技术报告No. 31Technical Report No. 31 PDA1. Objective 目的The purpose of this article is to provide guidance to laboratory scientists, technicians and managers responsible for the implementation, testing, control and usage of Laboratory Data Acquisition Systems (LDAS) used within a GMP, GLP, and GCP regulated environment.本文为实验室科学家、技术员以及管理者提供了在GMP, GLP和GCP 规范化环境下使用的LDAS的执行、测试、控制和用途方面的指南。

2. Scope 范围This article specifically addresses computerized LDAS within a regulated environment. This guidance is also applicable to systems considered critical to the operations of a company, department or function regardless of the system’s regulatory impact. The scope of this article excludes the typical Laboratory Information Management System (LIMS). The fundamental difference between a LIMS and an LDAS system is that the LDAS has a laboratory instrument as its primary focus, such as a computerized HPLC, whereas a LIMS, though instruments may be attached, has the management of data as its primary focus. The guiding key practices for testing and controlling an LDAS are similar to those for testing and controlling a LIMS;-1 the fundamental differences lie in the application of these key practices.本文仅涉及在规范化环境下的计算机化的LDAS。

Technical Report No.42Process Validation of Protein Manufacturing技术报告42号蛋白制造工艺验证PDA Journal of Pharmaceutical Science and Technology注射用药物协会杂志-制药科学与技术2005年9/10增刊59卷S-4 蛋白制造工艺验证工作组成员：Chris Bussineau, Ph.D., Chiron Corporation, Co-ChairRobert Seely, Ph.D., Amgen, Inc., Co-ChairGenevieve Lovitt, G.I. Lovitt& Associates, Project Manager/Technical EditorJames Fernandez, Fernandez and Associates, PDA LiaisonGreg Blank, Ph.D., Genentech, Inc.E.J. Brandreth, Favrille, Inc.Chris Bussineau, Ph.D., Chiron CorporationDoris Conrad, Consultant, GlaxoSmithKline BiologicalsRebecca A. Devine, Ph.D., Independent Regulatory ConsultantRobert J. Ferris, Ph.D., Chiron CorporationKoen de Heyder, GlaxoSmithKline BiologicalsRobert W. Juffras, M.S., Wyeth BioPharmaPeter Levy, Millennium Pharmaceuticals, Inc.Wolfgang List, Ph.D., Aventis BehringMorten Munk, CMC Biopharmaceuticals A/SBrian C. Neely, Don Hill and Associates, Inc.Stephen Notarnicola, Ph.D., Biogen IdecRhona O’Leary, Ph.D., Genentech, Inc.Harold van Deinse, Baxter Healthcare CorporationTable of Contents目录1 Introduction简介 (3)1.1 Purpose目的 (3)1.2 Scope范围 (3)2 Definitions定义 (4)3 Process Validation Prerequisites 工艺验证前提条件 (8)3.1 Introduction 简介 (8)3.2 Planning 计划制定 (9)3.3 Process Development 工艺开发 (10)3.3.1 Sequence of Activities Leading Up to Formal Process Validation 正式工艺验证的准备活动顺序 (11)3.3.2 Raw Materials 原材料 (12)3.3.3 Process Description 工艺描述 (13)3.3.4 Analytical Methods 分析方法 (13)3.3.5 Risk Assessment 风险评估 (15)3.3.6 Process Characterization 工艺特性 (15)3.3.7 Cell Line and Expression Construct Characterization 细胞系和表达载体特性 (20)3.3.8 Extractables from Product-contact Surfaces 产品接触面萃取物 (20)3.3.9 Development Documentation 开发文档 (21)3.4 Equipment and Facilities 设备设施 (21)3.5 Training 培训 (22)4 Process Validation 工艺验证 (22)4.1 Introduction 简介 (22)4.2 Process Validation Options 工艺验证选项 (22)4.3 Validation Approaches 验证方法 (23)4.3.1 Unit Operation Validation 单元操作验证 (23)4.3.2 Family and Matrix Validation 群体和矩阵验证 (24)4.4 Scale of Studies 规模研究 (24)4.5 Process Validation Studies 工艺验证研究 (25)4.5.1 Viral Clearance 病毒清除 (26)4.5.2 Impurity Clearance 杂质去除 (28)4.5.3 Process Consistency 工艺的一致性 (29)4.5.4 Process Intermediate Stability 工艺中间产物稳定性 (30)4.5.5 Process Solution Stability 工艺溶液稳定性 (31)4.5.6 Drug Substance Fill/Freeze/Thaw/Storage 药品配制/冻结/解冻/储存 (32)4.5.7 Mixing Studies 混合研究 (33)4.5.8 Chromatography Resin and Reusable Membrane Lifetime Validation 层析介质和膜包寿命验证 (34)5 Post-Validation Activities 再验证 (35)5.1 Change Control(58,59) 变更控制 (35)5.2 Ongoing Process Monitoring 持续工艺监测 (36)6 Documentation 文件 (38)6.1 Introduction 介绍 (38)6.2 Validation Protocols 验证方案 (38)6.3 Validation Reports 验证报告 (40)6.4 Compliance Program合规项目 (41)7 Appendices 附录 (41)7.1 Idealized Process Validation Workflow 理想工艺验证流程 (41)7.2 Process Description Example 工艺描述举例 (41)7.2.1 Cell Culture Process Description 细胞收获工艺描述 (44)7.2.2 Downstream Purification Process Flow 下游纯化工艺流程 (45)1 Introduction简介Significant advancement in the design and implementation of effective validation programs has been made since the 1987 Food and Drug Administration (FDA) Guideline on General Principles of Process Validation. (1) Open, candid discussions at conferences, many of which were dedicated specifically to process validation, and at other open forums have resulted in common practices.自1987年食品药品管理局提出工艺验证基本原理的指导方针一来，制定在设计和实施过程中都有效的验证程序已经取得了重大进展。

1. Introduction介绍1.1 Background背景In recent years, cleaning has achieved a position of increasing importance in the pharmaceutical industry. The current good manufacturing practices (CGMP) regulations recognize that cleaning is a critical issue to ensure product quality. Virtually every aspect of manufacturing involves cleaning, from the initial stages of bulk production to the final dosage form.近年来清洁作业逐渐在制药界占有重要的地位。

现行的GMP法规也指出清洁作业是保证产品质量的关键性工作。

自大宗原料的生产以迄最终剂型的制造作业，几乎每一个制造工序均含有清洁作业。

The CGMPs in the United States, Europe and other parts of the world have provided the pharmaceutical industry with general guidance for cleaning requirements. For example, in the U.S., section 211.67 of part 21 of the Code of Federal Regulations (CFR) states that "Equipment and utensils shall be cleaned, maintained, and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements." Section 211.182 of part 21 of the CFR identifies that cleaning procedures must be documented appropriately, and that a cleaning and use log should be established. In addition to CGMPs, various inspectional guideline documents published by the FDA contain expectations regarding cleaning in the pharmaceutical industry. Cleaning is also addressed in the PIC recommendations on cleaning validation and in the SFSTP Commission report "Validation desprocédés de nettoyage."美国、欧洲及全球其他地区均有制药界清洁作业的通则性指南。

PDA_TR28中英无菌原料药工艺模拟验证（2006年）无菌原料药（BPCs）的工艺模拟PDA第28份技术报告（2006年）This document provides guidance relative to the validation of aseptic processing activities associated with the production of sterile bulk pharmaceutical chemicals. It draws upon the concepts and principles developed in PDA's and PhRMA's prior publications on aseptic processing technology (1, 2, 3). This effort expands upon those documents to provide assistance for individuals and firms producing sterile bulk pharmaceutical chemicals. Our goal in this revision was to update the document to reflect 6 years of industry experience with it, as well as an acknowledgement of acceptance criteria limitations that were present in the first edition (4). We have also endeavored to address some of the issues raised by FDA in their review of the earlier edition.本文档提供了无菌原料药生产加工有关的验证指导。

对PDA发布的《工艺验证：一个生命周期方式》的解析发布时间：2013年5月16日——对PDA发布的《工艺验证：一个生命周期方式》的解析□徐禾丰编者按美国注射剂协会(PDA)于今年3月初在其官方网站上发布了题为《工艺验证：一个生命周期方式》的第60号技术报告(PDA60TR)。

这份技术报告是在美国食品药品管理局(FDA)于2011年1月发布的《工艺验证：一般原则与惯例》工业指南第一修订版的基础上，对产品生命周期内工艺验证整个过程的诠释。

如果说该修订版是为今后的工艺验证模式提出新要求的话，那么，PDA60TR就是为FDA新的工艺验证行业指南在业界实施画出了具体的路线图。

据了解，我国已经有部分医药企业开始按照FDA的《工艺验证：一般原则与惯例》第一修订版实施验证，但对一些实施细节并不是很清楚。

对此，本报特邀请业内专家对PDA60TR进行解析。

专家强调，对企业而言，关键是要真正认识到工艺验证对商业生产的意义，抓住工艺验证的关键点，转变工艺验证的观念，将老的工艺验证方式转换到生命周期的验证方式上来。

望专家的观点及其对PDA60TR的解析，能为我国有关企业的工艺验证提供助力。

PDA60TR中的核心理念是：“工艺验证不是一个一次性的活动，而是一个贯穿于整个产品生命周期，连接工艺开发与商业化生产工艺验证，并在日常商业化生产中维持的活动”。

我们在学习中发现，PDA60TR所讲的整个工艺验证过程还包括产品研发、质量风险管理、工艺管理、知识管理、工艺性能监控、技术转移等。

在PDA60TR发布之前，PDA还发布了很多与工艺验证有关的技术报告，但先前的技术报告都是针对具体的验证项目，而PDA60TR是基于质量体系对生命周期的工艺验证方式的展开。

另外，PDA60TR的正文部分有91页，这样的篇幅在PDA技术报告中是比较大的，这也从另外一个方面表现出工艺验证的复杂性。

PDA60TR不仅仅是制药行业官方与企业质量管理人员的必读资料，也是研发、管理、生产人员不可缺少的参考资料。

液体的除菌过滤PDA第26份技术报告（2008年修订本）制药科学与技术的PDA期刊增刊2008年第62卷，第S-5号1.0引言除菌过滤是从液体流中去除微生物*而对产品质量没有负面影响的过程。

（1-4）这份技术报告的目的是提供系统的方法，用于选择和验证液体除菌过滤应用的最适当过滤器。

PDA的第26份原始技术报告发表于1998年，标题为液体的除菌过滤，其中描述了一代制药科学家和工程师对除菌过滤的使用和验证。

由于过滤技术的加强以及制药行业近期产生了其他的法规要求，因而对原始报告进行了修改。

修订本涉及到了法规文件、标准以及科学出版物，其中包含更多的细节和支持性数据。

在20世纪60年代膜过滤器进入市场，当时认为0.45µm级别的膜为“除菌级”过滤器且成功应用于注射剂的除菌过滤。

使用serratia marcescens作为标准菌对这些过滤器进行确认，确认用于水质量测试的膜。

然而在1960年发布的论文中，美国FDA的Frances Bowman博士发现0.45µm的“除菌过滤的”培养基可受到一种生物的污染，在每平方厘米104-106以上的挑战水平下少量的这种生物可反复穿透0.45µm级别的膜。

（5）ASTM F838也由此产生，这是一种标准测试法，用于评估除菌级别的膜过滤器。

（6）在第6.4部分中对挑战生物进行了讨论。

1.1目的/ 适用范围工作组的主要目标是开发一份有关除菌过滤的科学的技术报告。

报告不会对区域的法规要求进行过多的描述，但是提供了最新的科学建议以供业内人士及制定除菌过滤政策的人员使用。

这份报告是一份指南性文件，其目的不是确立强制的除菌过滤标准。

报告中提出的概念与一些工艺有关，在这些工艺中除菌过滤器的性能是不可缺少的，而且这些概念不能通用于所有过滤工艺（例如，早期过滤或常规生物负载）。

这些概念包括但不限于细胞培养基、缓冲液、无菌工艺中的中间体暂存区、集中和最终无菌灌装。

PDA技术报告清单（官网2015年更新）1. Validation of Moist Heat Sterilization Processes: Cycle Design, Development, Qualification and Ongoing Control Revised 2007 (Published 1980)湿热灭菌工艺验证：循环设计、研发、确认和持续控制，修订20073. Validation of Dry Heat Processes Used for Depyrogenation and Sterilization Revised 2013 (Published 1981) 01003 43506 用于除热源和灭菌的干热工艺验证，修订20134. Design Concepts for the Validation of Water-for-Injection Systems 1983注射用水系统验证的设计概念，19835. Sterile Pharmaceutical Packaging: Compatibility and Stability 1984无菌制剂包装：相容性和稳定性，19847. Depyrogenation 1985除热源，19859. Review of Commercially Available Particulate Measurement Systems 1988商业可采购的颗粒物检测系统审核，198810. Parenteral Formulations of Proteins and Peptides: Stability and Stabilizers 1988蛋白质和多肽注射制剂：稳定性和稳定剂，198811. Sterilization of Parenterals by Gamma Radiation 1988静脉注射伽马辐射灭菌，198812. Siliconization of Parenteral Drug Packaging Components 1988静脉注射剂药品包装组分硅化处理，198813. Fundamentals of an Environmental Monitoring Program Revised 2014 (Published 1990)环境监测计划原则，修订201414. Validation of Column-Based Chromatography Processes for the Purification of Proteins Revised 2008 (Published 1992) 蛋白纯化用柱色谱工艺验证，修订200815. Validation of Tangential Flow Filtration in Biopharmaceutical Applications Revised 2009 (Published 1992) 生物制药用正切流过滤验证，修订200916. Effect of Gamma Irradiation on Elastomeric Closures 1992人造橡胶塞伽马辐射效应，199217. Current Practices in the Validation of Aseptic Processing -- 1992 1993无菌工艺验证现行规范，1992，199318. Report on the Validation of Computer-Related Systems 1995计算机相关系统验证报告，199519. Rapid/Automated ID Methods Survey 1990快速/自动ID方法调查，199020. Report on Survey of Current Industry Gowning Practices 1990行业现行更衣规范调查报告，199021. Bioburden Recovery Validation 1990生物负载回收率验证，199022. Process Simulation for Aseptically Filled Products Revised 2011 (Published 1996)无菌灌装药品工艺模拟，修订201123. Industry Survey on Current Sterile Filtration Practices 1996现行无菌过滤实践行业调查，199624. Current Practices in the Validation of Aseptic Processing – 1996 1996无菌工艺验证现行规范，199625. Blend Uniformity Analysis: Validation and In-Process Testing 1997混合均一性分析：验证和中控测试，199726. Sterilizing Filtration of Liquids Revised 2008 (Published 1998)液体无菌过滤，修订200827. Pharmaceutical Package Integrity 1998药品包装完整性，199828. Process Simulation Testing for Sterile Bulk Pharmaceutical Chemicals Revised 2006 (Published 1998)无菌散装药用化学物工艺模拟测试，修订200629. Points to Consider for Cleaning Validation Revised 2012 (Published 1998)清洁验证的考虑要点，修订201230. Parametric Release of Pharmaceuticals and Medical Device Products Terminally Sterilized by Moist Heat Revised 2012 (Published 1999)最终湿热灭菌的药物和医疗器械参数放行，修订201231. Validation and Qualification of Computerized Laboratory Data Acquisition Systems 1999计算机化实验室数据获取系统验证和确认，199932. Auditing of Suppliers Providing Computer Products and Services for Regulated Pharmaceutical Operations Revised 2004 (Published 1999)提供受法规管理的药物操作用计算机产品和服务的供应商审计，修订200433. Evaluation, Validation and Implementation of Alternative and Rapid Microbiological Methods Revised 2013 (Published 2000)替代性和快速微生物方法的评估、验证和实施，修订201334. Design and Validation of Isolate Systems for the Manufacturing and Testing of Health Care Products 2001 保健药品的生产和检测分离系统的设计和验证，200135. A Proposed Training Model for the Microbiological Function in the Pharmaceutical Industry 2001制药行业微生物功能培训模式建议，200136. Current Practices in the Validation of Aseptic Processing – 2001 2002无菌工艺验证的现行规范--2001，200238. Manufacturing Chromatography Systems Post-Approval Changes: (ChromPAC):Chemistry, Manufacturing and Controls Documentation 2006批准后生产用色谱系统：研发、生产和控制文件，200639. Guidance for Temperature-Controlled Medicinal Products: Maintaining the Quality of Temperature-Sensitive Medicinal Products through the Transportation Environment 2007 温度受控药物指南：通过运输环境来维护对温度敏感的药物的质量，200740. Sterilization Filtration of Gases 2005气体的无菌过滤，200541. Virus Filtration 2008病毒过滤，200842. Process Validation of Protein Manufacturing 2005蛋白质生产的工艺验证，200543. Identification and Classification of Nonconformities in Molded and Tubular Glass Containers for Pharmaceutical Manufacturing Revised 2013 (Published 2007)药物生产用模型制备和管式玻璃容器的识别和分类，修订201344. Quality Risk Management for Aseptic Processes 2008无菌工艺的质量风险管理，200845. Filtration of Liquids Using Cellulose-Based Depth Filters 2008使用纤维素基础深层过滤器的液体过滤，200846. Last Mile: Guidance for Good Distribution Practices for Pharmaceutical Products to the End User 2009最终里程：给最终用户的药物优良销售规范指南，200947. Preparation of Virus Spikes Used for Virus Clearance Studies 2010用于病毒清除研究的病毒加标样制备，201048. Moist Heat Sterilizer Systems: Design, Commissioning, Operation, Qualification and Maintenance 2010湿热灭菌系统：设计、调试、运行、确认和维护，201049. Points to Consider for Biotechnology Cleaning Validation 2010生物制品清洁验证考虑要点，201050. Alternative Methods for Mycoplasma Testing 2010支原体测试替代性方法，201051. Biological Indicators for Gas and Vapor-Phase Decontamination Processes: Specification, Manufacture, Control and Use2010气体和蒸汽相除污染工艺生物指示剂：质量标准、生产、控制和使用，201052. Guidance Good Distribution Practices for the Pharmaceutical Supply Chain 2011药品供应链优良销售规范指南，201153. Guidance for Industry: Stability Testing to Support Distribution of New Drug Products 2011行业指南：支持新药销售的稳定性测试，201154. Implementation of Quality Risk Management for Pharmaceutical and Biotechnology Manufacturing Operations 2012药品和生物制品生产操作的质量风险管理实施，201254-2. Implementation of Quality Risk Management for Pharmaceutical and Biotechnology Manufacturing Operation: Annex 1: Case Study Examples for Quality Risk Management in Packaging and Labeling 2013药品和生物制品生产操作的质量风险管理实施，附录1：包装和标识中的质量风险管理案例研究，201354-3. Implementation of Quality Risk Management for Pharmaceutical and Biotechnology Manufacturing Operations Annex 2: Case Studies in the Manufacturing of Pharmaceutical Drug Products 2013药品和生物制品生产操作的质量风险管理实施，附录2：药品生产中的质量风险管理案例研究，201354-4. Implementation of Quality Risk Management for Pharmaceutical and Biotechnology Manufacturing Operations Annex 3: Case Studies in the Manufacturing of Biotechnological Bulk Drug Substances 2015药品和生物制品生产操作的质量风险管理实施，附录3：生物散装药用物质生产中的质量风险管理案例研究，2013 55. Detection and Mitigation of 2,4,6-Tribromoanisole and 2,4,6-Trichloroanisole Taints and Odors in the Pharmaceutical and Consumer Healthcare Industries 2012药物和保健行业中2，4，6-三溴苯甲醚和2，4，6-三氯苯甲醚污染和气味的检测和移除，201256. Application of Phase-Appropriate Quality Systems and CGMP to the Development of Therapeutic Protein Drug Substance 2012治疗用蛋白质药用物质研发中与阶段相适当的质量体系和CGMP 应用，201257. Analytical Method Validation and Transfer for Biotechnology Products 2012生物制品的分析方法验证和转移，201258. Risk Management for Temperature-Controlled Distribution 2012温度受控销售风险管理，201259. Utilization of Statistical Methods for Production Monitoring 2012生产监测用统计学方法使用，201260. Process Validation: A Lifecycle Approach 2013工艺验证：生命周期方法，201361. Steam In Place 2013就地蒸汽，201362. Recommended Practices for Manual Aseptic Processes 2013人工无菌工艺规范建议，201363. Quality Requirements for the Extemporaneous Preparation of Clinical Trial 2013临床试验临时制备药物的质量要求，201364. Active Temperature-Controlled Systems: Qualification Guidance 2013在用温度控制系统：确认指南，201365. Technology Transfer 2014技术转移，201466. Application of Single-Use Systems in Pharmaceutical Manufacturing 2014药物生产中单次使用系统的应用，201467. Exclusion of Objectionable Microorganisms fromNonsterile Pharmaceuticals, Medical Devices, and Cosmetics 2014非无菌药物、医疗器械和化妆品中致病菌排除，201468. Risk-Based Approach for Prevention and Management of Drug Shortages 2014基于风险的药品存贮预防和管理，2014。

Technical Report No.42Process Validation of Protein Manufacturing技术报告42号蛋白制造工艺验证PDA Journal of Pharmaceutical Science and Technology注射用药物协会杂志-制药科学与技术2005年9/10增刊59卷S-4 蛋白制造工艺验证工作组成员：Chris Bussineau, Ph.D., Chiron Corporation, Co-ChairRobert Seely, Ph.D., Amgen, Inc., Co-ChairGenevieve Lovitt, G.I. Lovitt& Associates, Project Manager/Technical EditorJames Fernandez, Fernandez and Associates, PDA LiaisonGreg Blank, Ph.D., Genentech, Inc.E.J. Brandreth, Favrille, Inc.Chris Bussineau, Ph.D., Chiron CorporationDoris Conrad, Consultant, GlaxoSmithKline BiologicalsRebecca A. Devine, Ph.D., Independent Regulatory ConsultantRobert J. Ferris, Ph.D., Chiron CorporationKoen de Heyder, GlaxoSmithKline BiologicalsRobert W. Juffras, M.S., Wyeth BioPharmaPeter Levy, Millennium Pharmaceuticals, Inc.Wolfgang List, Ph.D., Aventis BehringMorten Munk, CMC Biopharmaceuticals A/SBrian C. Neely, Don Hill and Associates, Inc.Stephen Notarnicola, Ph.D., Biogen IdecRhona O’Leary, Ph.D., Genentech, Inc.Harold van Deinse, Baxter Healthcare CorporationTable of Contents目录1 Introduction简介 (3)1.1 Purpose目的 (3)1.2 Scope范围 (3)2 Definitions定义 (4)3 Process Validation Prerequisites 工艺验证前提条件 (8)3.1 Introduction 简介 (8)3.2 Planning 计划制定 (9)3.3 Process Development 工艺开发 (10)3.3.1 Sequence of Activities Leading Up to Formal Process Validation 正式工艺验证的准备活动顺序 (11)3.3.2 Raw Materials 原材料 (12)3.3.3 Process Description 工艺描述 (13)3.3.4 Analytical Methods 分析方法 (13)3.3.5 Risk Assessment 风险评估 (15)3.3.6 Process Characterization 工艺特性 (15)3.3.7 Cell Line and Expression Construct Characterization 细胞系和表达载体特性 (20)3.3.8 Extractables from Product-contact Surfaces 产品接触面萃取物 (20)3.3.9 Development Documentation 开发文档 (21)3.4 Equipment and Facilities 设备设施 (21)3.5 Training 培训 (22)4 Process Validation 工艺验证 (22)4.1 Introduction 简介 (22)4.2 Process Validation Options 工艺验证选项 (22)4.3 Validation Approaches 验证方法 (23)4.3.1 Unit Operation Validation 单元操作验证 (23)4.3.2 Family and Matrix Validation 群体和矩阵验证 (24)4.4 Scale of Studies 规模研究 (24)4.5 Process Validation Studies 工艺验证研究 (25)4.5.1 Viral Clearance 病毒清除 (26)4.5.2 Impurity Clearance 杂质去除 (28)4.5.3 Process Consistency 工艺的一致性 (29)4.5.4 Process Intermediate Stability 工艺中间产物稳定性 (30)4.5.5 Process Solution Stability 工艺溶液稳定性 (31)4.5.6 Drug Substance Fill/Freeze/Thaw/Storage 药品配制/冻结/解冻/储存 (32)4.5.7 Mixing Studies 混合研究 (33)4.5.8 Chromatography Resin and Reusable Membrane Lifetime Validation 层析介质和膜包寿命验证 (34)5 Post-Validation Activities 再验证 (35)5.1 Change Control(58,59) 变更控制 (35)5.2 Ongoing Process Monitoring 持续工艺监测 (36)6 Documentation 文件 (38)6.1 Introduction 介绍 (38)6.2 Validation Protocols 验证方案 (38)6.3 Validation Reports 验证报告 (40)6.4 Compliance Program合规项目 (41)7 Appendices 附录 (41)7.1 Idealized Process Validation Workflow 理想工艺验证流程 (41)7.2 Process Description Example 工艺描述举例 (41)7.2.1 Cell Culture Process Description 细胞收获工艺描述 (44)7.2.2 Downstream Purification Process Flow 下游纯化工艺流程 (45)1 Introduction简介Significant advancement in the design and implementation of effective validation programs has been made since the 1987 Food and Drug Administration (FDA) Guideline on General Principles of Process Validation. (1) Open, candid discussions at conferences, many of which were dedicated specifically to process validation, and at other open forums have resulted in common practices.自1987年食品药品管理局提出工艺验证基本原理的指导方针一来，制定在设计和实施过程中都有效的验证程序已经取得了重大进展。