ISPE Guide 清洁验证生命周期应用方法和控制(1-6章).docx

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1、ISPEGUIDE:Cleaning Validation Lifecycle -Applications, Methods, and Controls清洁验证生命周期，应用，方法，和控制Disclaimer:免责声明：The ISPE Guide: Cleaning Validation Lifecycle- Applications, Methods, and Controls provides detailec practical guidance to help pharmaceutical companies meet global requlatory cleaning valid

2、atior expectations. This Guide is solely created and owned by ISPE. It is not a regulation, standard or regulatory guideline document. ISPE cannot ensure and does not warrant that a system managed in accordance with this Guide will be acceptable to regulatory authorities. Further, this Guide does no

3、t replace the need for hiring professional engineers or techniciansISPE 指南：清洗验证生命周期，应用，方法，和控制提供了详细的实用指导，以帮助制药企业满足全球监 管清洗验证的要求。本指南完全由 ISPE 创建和拥有。它不是法规、标准或法规指南文件。 ISPE 不能保 证，也不能保证，按照本指南管理的系统可以被监管部门接受。此外，本指南并不取代雇用专业工程师 或技术人员的需要。Limitation of Liability责任限制In no event shall /SPE or any of its affiliates,

4、 or the officers, directors, employees, members, or agents of each of them, or the authors, be liable for any damages of any kind, including without limitation any special, incidental, indirect, or consequential damages. whether or not advised of the possibility of such damages. and on any theory of

5、 liability whatsoever, arising out of or in connection with the use of this information在任何情况下， ISPE 或其任何关联公司，或其管理人员、董事、员工、成员或代理人，或作者，均不应 对任何类型的任何损害负责，包括但不限于任何特殊的、偶然的、间接的或间接的损害。是否告知发生此种损害的可能性。以及因使用本信息而产生的或与之有关的任何责任理论。Copyright ISPE 2020.All rights reserved版权所有 ISPE 2020保留所有权利。All rights reserved. No

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7、All trademarks used are acknowledged. ISBN 978-1-9469,6431-1所有使用的商标均得到承认。 ISBN 978-1-9469,6431-1Preface前言Regulatory agencies expect the development and validation of a compliant cleaning program. This critical activity ensures that the risks of contamination, product carryover, and cross-contaminati

8、on are controlled, minimized, and monitored to safeguard patient safety and product quality.监管机构期望开发和验证一个合规的清洗程序。这一关键活动确保污染、产品转移和交叉污染的风险得 到控制、最小化和监控，以保障患者安全和产品质量。This ISPE Guide: Cleaning Validation Lifecycle - Applications; Methods, and Controls describes the application of the process lifecycle mo

9、del to cleaning. This will aid organizations in developing and adopting scientifically sound approaches, resulting in a robust cleaning validation program.本ISPE 指南：清洗验证生命周期，应用，方法，和控制描述了过程生命周期模型在清洗中的应用。这将帮 助组织发展和采用科学合理的方法，从而产生一个完善的清洁验证程序 。An integral part of an effective cleaning program is using ris

10、k-based approaches in the design and management of the validation process; accordingly, this ISPE Guide is aligned with the principles described in the ISPE Baseline Guide: Volume 7-Risk-Based Manufacture of Pharmaceutical Products Risk-MaPP(Second Edition).有效的清洗程序的一个组成部分是在验证过程的设计和管理中使用基于风险的方法；因此，本

11、ISPE 指南与ISPE Baseline指南：基于风险的第7卷药品制造Risk-MaPP (第二版)中所述的原则保持一致。This ISPE Guide: Cleaning Validation Lifecycle -Applications, Methods, and Controls promotes the use of health-based exposure limits(HBEL) and offers guidance and examples for developing and/or transitioning to the determination of cleani

12、ng specifications using HBEL.本 ISPE 指南：清洗验证生命周期-应用、方法和控制促进基于健康的暴露极限(HBEL) 的使用，并为使用HBEL 制定和/或过渡到确定清洗规范提供指导和示例。Created by a team of industry experts with global experience, this ISPE Guide is intended as a reference for the cleaning lifecycle model as well as a practical guide for applying the theory

13、and concepts to help create compliant and effective cleaning programs.该 ISPE 指南由具有全球经验的行业专家团队创建，旨在作为清洁生命周期模型的参考，以及应用理论和概念帮助创建符合要求和有效的清洁方案的实用指南。Acknowledgements鸣谢The Guide was produced by a Task Team led by Jose Caraballo (Bayer U.S., USA) and Joseph Payne (Tergyus Pharma (formerly with Alcami Corp.)

14、, USA).该指南是由Jose Caraballo(美国拜耳公司)和 Joseph Payne(美国 Tergus Pharma 公司(原 Alcami Corp.) 领导的一个任务小组编写的。Core Team核心团队The following individuals took lead roles in the preparation, writing, and review of this Guide:以下人员在本指南的准备、撰写和审查中发挥了主导作用：Jose CaraballoPfizer Ltd.USALiz DallisonForsyth Pharmaceutical Cons

15、ultingUnitedRich ForsythBluehatch Consultancy Ltd.KingdomTrefor JonesSTERIS CorpUSABeth Kroeger-FahnestockElectrol Specialties Co.USASam LebowitzOakes Group GlobalTurkey/USACatherine OakesNovo NordiskUSAFred OhsiekTergus Pharma (formerly with Alcami Corp.)USAJoseph PayneVTI Life Sciences, Inc.USA/As

16、iaDavid W.Vincent, MPH, PhDUSABayer U.S.United KingdomOther Contributors其他贡献者The Core Team wish to thank the following individuals for their valuable contribution to the document.核心小组感谢下列人士对该文件所作的宝贵贡献。Janet FreerPfizer Ltd.(retired)JapanHiroaki MatsumotoAsahi Kasei Finechem Co.USA.Rizwan Sharnez, Ph

17、DLtd. Cleaning ValidationUnited KingdomSarah RobertsSolutions Pfizer R&DTurkeyFikret UsluGlatt Turkey (ExU Turkey)United KingdomRegulatory Input and Review监管意见和审核Particular-thanks go to the following for their review and comments on this Guide:特别感谢以下人士对本指南的审阅和评论：Norman Gray, Senior GMDP Inspector,IE

18、&S, Medicines and Healthcare products Regulatory Agency (MHRA), United Kingdom英国药品及医疗保健产品监管局 (MHRA)IE&S 的高级 GMDP 检查员 Norman Gray,Graeme Mckilligan, Lead Senior GMDP Inspeclor, IE&S, Medicines and Healthcare products Regulatory Agency (MHRA), United Kingdom英国药品及医疗保健产品监管局 (MHRA)IE&S 的 GMDP 高级首席检查员Grae

19、me McKilliganSpecial Thanks特别感谢The Core Team would like to thank Stephanie A.Wilkins. PE (Pharma Consult Us, Inc., USA) for her efforts as ISPE Guidance Documents Committee (GDC) Mentor. Particular thanks to Rob Walker (Rob Walker GMP Consultancy Ltd, United Kingdom) for his assistance with initiati

20、ng this project.核心团队感谢斯蒂芬妮 威尔金斯。 PE (美国医药咨询公司)担任ISPE 指导文件委员会 (GDC) 导师的努力。 特别感谢Rob Walker (英国 Rob Walker GMP 咨询有限公司)在启动该项目方面的协助。The Leads would also like to thank ISPE for technical writing and editing support by Jeanne Perez (ISPE Guidance Documents Technical Writer/Editor) and production support by

21、 Lynda Goldbach (ISPE Guidance Documents Manager).潜在客户也要感谢 ISPE 由 Jeanne Perez(ISPE指导文档技术作家/编辑)提供的技术写作和编辑支持以及 Lynda Goldbach(ISPE 指导文档经理)的生产支持。The Team Leads would like to express their grateful thanks to the many individuals and companies from around the world who reviewed and provided comments dur

22、ing the preparation of this Guide; although they are too numerous to list here, their input is greatly appreciated Company affiliations are as of the final draft of the Guide.团队负责人在此感谢世界各地的许多个人和公司，他们在编写本指南时进行了审查并提出了意见；尽管他们 太多了，无法在这里列出，但是他们的投入深表感谢。公司隶属关系截至本指南的最终草案。Equipment cover photo courtesy of Fe

23、tte Compacting GmbH. Grabauer Str. 24, 21493 Schwarzenbek, www.fette- . Image rights remain the property of Fette Compacting GmbH.设备封面照片由 Fette Compacting GmbH 提供。 格拉鲍尔大街24,21493 Schwarzenbek, www.fette- 。 图像版权归Fette Compacting GmbH所有。1. Introduction简介Cleaning validation is a requirement of the biot

24、echnology, biological, pharmaceutical. diagnostics, medical device, nutraceutical, and in some cases cosmetic industries. Regulatory agencies expect the development and validation of a compliant cleaning program. This critical activrty ensures that the risks of contamination, product carryover, and

25、cross-contamination are controlled, minimized, and monitored to safeguard patient safety and product quality.清洁验证是生物技术、生物、制药、诊断、医疗设备、营养药品和化妆品行业的要求。监管机构期望开发和 验证一个合适的清洗程序。来保证产品在生产过程中的污染、交叉污染和产品残留的风险减低至最小，以保 障患者安全和产品质量An effective cleaning program shall be in place to provide documented evidence that c

26、leaning processes will reproducibly remove previous product or other residues on product contact equipment surfaces below scientifically set acceptable levels 1. Cleaning soiled surfaces allows the use of that equipment with other products or materials without undue risk of cross-contamination of th

27、ose products or materials.必须制定有效的清洁程序，以提供书面证据，证明清洁过程的有效性和重复性，有效性是指清洁过程可以将 设备表面的产品或其他残留物降低至经过科学计算而得到的可接受水平1,重复性是指通过规定的清洁方法 多次清洁后都能够将产品会其他残留物的浓度降低至可接受水平，清洁后的设备能够用于其他产品或原料的 生产，而不会对其他产品或原料造成风险。This ISPE Guide: Cleaning Validation Lifecycfe-Applications, Methods, and Controls aims to provide a comprehens

28、ive explanation and hands-on guidance for cleaning validation lifecycle. It describes the fundamental elements applicable to the pharmaceutical, biotechnology, and other life science-related industries. This ISPE Guide has been created as a consensus document by a team of industry experts after care

29、ful consideration of regulatory requirements, industry practices, and feedback received during peer review. Alternate approaches to the ones described here to meet regulatory requirements may be acceptable if scientifically justified and properly documented. A country, company. or facility may have

30、additional or unique requirements that could necessitate adaptation of the principles presented in this ISPE Guide on a case-by-case basis.本 ISPE 指南：清洁验证生命周期-应用程序，方法和控制旨在为清洁验证生命周期提供全面的解释和操作指南。它描述了适用于制药，生物技术和其他生命科学相关行业的基本要素。仔细考虑法规要求，行业惯例以 及同行评审期间收到的反馈后，此 ISPE 指南已由一组行业专家创建为共识文件。如果有科学依据并有适当 的文件证明，可以采用此

31、处描述的满足监管要求的替代方法。 一个国家，公司。或设施可能有其他或独特的 要求，可能需要根据具体情况对本ISPE 指南中提出的原则进行调整。1.1. Background背景The main purpose of cleaning validation is to prove the effectiveness and reproducibility of the cleaning process for a given piece of production equipment to prevent cross-conta1nination and adulteration of a Dr

32、ug Product (DP), substance, or biological product from other active ingredients, chemicals. and other unintended compounds or microbiological contamination. It also establishes criteria to reduce patient risk by producing a safe and effective product.清洁验证的主要目的是证明给定生产设备的清洁过程的有效性和可重复性，以防止药物产品 (DP), 物质

33、 或生物产品与其他活性成分，化学药品发生交叉污染和掺假。以及其他意外的化合物或微生物污染。 它还建 立了通过生产安全有效的产品来降低患者风险的标准。Cleaning validation is labor intensive, requiring resources from multiple areas. Functions involved in cleaning activities include:清洁验证是劳动密集型的，需要来自多个领域的资源。清洁活动涉及的功能包括： Research and Development (e.g., establishment of manufactu

34、ring processes and corresponding cleaning agents)研究与开发(例如，建立生产流程和相应的清洁剂) Process Development (e.g., establishment of cycle development studies, calculations)工艺开发(例如，建立周期开发研究，计算)Toxicology (to determine Health-Based Exposure Limits (HBELs) and provide Acceptable Daily Exposure (ADE)/ Permitted Daily

35、Exposure (PDE) information as needed)毒理学(确定健康风险敞口限制(HBELs) 和提供可接受的每日暴露(正面)/允许每日接触(PDE) 信息根据需要)Virology (when cleaning biologicals and equipment used for advanced therapies)病毒学(当清洁用生物制品、设备先进的疗法) Engineering(for equipment design and readiness)工程(设备设计和准备) Production (e.g., operating equipment, supporti

36、ng validation execution, troubleshooting failures)生产(例如，操作设备，支持验证执行故障排除故障) Validation(e.g., writing validation protocols, reports, and master plans, and/or executing validation protocols)验证(例如，编写验证方案、报告和主计划，和/或执行验证协议) Quality Conto(e.g., sampling, laboratory recovery studies, methods development. an

37、d validation studies)质量控制(如采样、实验室恢复研究中，方法的发展。和验证研究) Quality Assurance(e.g., ensure compliance with GMP regulations)质量保证(例如，确保遵守GMP 法规)Over the years regulated GxP industries have acknowledged that cleaning validation is an integral part of manufacturing operations and should be treated as a critical

38、 process. Applying a process lifecycle model to cleaning processes helps ensure the application of scientifically sound approaches, resulting in a robust cleaning validation program.多年来，受监管的 GxP 行业已经认识到，清洁验证是生产操作不可或缺的一部分，应将其视为关键过程。 将工艺生命周期模型应用于清洁过程有助于确保采用科学合理的方法，从而形成成熟的清洁验证程序。1.2. Purpose and Object

39、ives目的和目标1.2.1. Benefit好处This Guide prov ides a hands-on approach to support the pharmaceutical, biotechnology, and other life science industries in the development and establishment of compliant cleaning programs that will meet or exceed regulatory expectations This Guide is intended as a reference

40、 for the cleaning lifecycle model and a practical guide for applying the theory and concepts to product contact surfaces to help create compliant and practical cleaning programs.本指南提供了一种动手方法，以支持制药，生物技术和其他生命科学行业开发和建立符合标准的清洁程序， 这些程序将达到或超过监管要求。本指南旨在作为清洁生命周期模型和将理论和概念应用于产品接触表面的 实用指南，以帮助创建合规且实用的清洁程序。1.2.2

41、.Scope范围Application of phased appropriate GMPs for commercial and clinical manufacturing cleaning practices (validation or verification) is addressed in this Guide.本指南介绍了适用阶段的GMP 在商业和临床制造清洁实践(验证或验证)中的应用。As illustrated in Figure 1.1, this Guide is designed in three parts. Chapters 1 to 4 provide an o

42、verview, containing industry trends, regulatory references, cleaning risk management, and the cleaning validation lifecycle. The reader is then led through the validation lifecycle stages. Chapters 5 to 11 present in-depth information on pl anni n g the process, preparing and conducting validation,

43、and implementing and maintaining the validated processes. These chapters provide guidance for creating new programs as well as bringing legacy programs in line with current regulatory expectations. This information culminates into several examples and case studies (Appendices 1 to 8) to help increas

44、e the readers understanding of the application of these principles in the cleaning process.如图1.1所示，本指南分为三部分。 第1章至第4章提供概述，其中包含行业趋势，法规参考，清洁风险管 理以及清洁验证生命周期。然后，引导读者完成验证生命周期的各个阶段。第5章至第11 章提供了有关制 定流程，准备和进行验证以及实施和维护经过验证的流程的详细信息。这些章节为创建新程序以及使旧程序 与当前法规要求保持一致提供了指导。 该信息最终汇集为几个示例和案例研究(附录1至8),以帮助读者 了解这些原理在清洁过程中的

45、应用。Figure 1.1:Guide Structure图1.1:指南结构Chapter 3第3章Chapter 11第10章Appendix 4附件4Appendix 5附件5Appendix 6附件6Appendix 7附件7Appendix 8附件8Appendix 2附件2Appendix 3附件3Appendix 4附件4Appendix 5附件5Appendix 6附件6Appendix 7附件7Appendix 4附件4Appendix 5附件5Appendix1附件1Appendix 2附件2Appendix 8附件8Appendix 8附件8Chapter 9第9章Chap

46、ter 8第8章Chapter 2第2章Chapter 4第4章Chapter 7第7章Chapter 6第6章Chapter 5第5章Chapter 1第1章Chapter 10第11章The Guide discusses the following topics (see also Figure 1.2):本指南讨论以下主题(另请参见图1.2): Current regulation s and relevant standards现行法规和相关标准 Application of risk management in cleaning validation风险管理在清洁验证中的应用Des

47、cription of the cleaning validation lifecycle model清洁验证生命周期模型的描述 Cleaning methodologies清洁方法 Creation of cleaning validation acceptance criteria创建清洁验证验收标准Determination of visual inspection limits确定外观检查极限 Cleaning validation strategies清洁验证策略 Documentation for cleaning validation programs清洁验证程序的文档 Calculation and justification of residue limits残留限量的计算和证明 Validation of testing and sampling methods验证测试和抽样方法 Periodic review a