制药用水和蒸汽系统指南

1、A GUIDE FOR NEW FACILITIES 为新型设施准备的指南VOLUME 4: WATER AND STEAM GUIDE卷4：水和蒸汽系统的指导原则EXECUTIVE SUMMARY执行概况 DECEMBER 20002000年12月 A DOCUMENT DEVELOPED IN PARTNERSHIP WITH FDA 本文件由下列单位与FDA合作编写25 / 25文档可自由编辑打印ISPE PHARMACEUTICAL ENGINEERING GUIDE/ISPE制药工程指南FOREWORD /序For many years, the pharmaceutical ind

2、ustry has experienced increases in the cost of new facilities. These increases in cost have been driven in part by uncertainty about the requirements for regulatory compliance. Some significant areas of concern are validation, particularly related to automation systems, and the trend to validate bac

3、k to source utilities. The absence of a consistent and widely accepted interpretation of some regulatory requirements has led to one-upmanship. This practice of building increasingly technically advanced facilities has led to increased cost, longer lead times and, in some cases, delays in bringing n

4、ew products to market.长年以来，制药行业在购进的大量新设施方面的支出一直持续增长。造成这些支出的部分原因是法规符合力度的要求的无常。验证是得到重点关注的方面之一，特别是与自动化系统、回溯验证源效用的趋势、建筑和HVAC有关的内容。一致且得到广泛接受的法规要求的欠缺造就了突出的情况：对技术先进的设施的追求导致成本的剧增、交货与订货之间所需时间的延长、以及，在某些情况下，可导致新产品上市的延期。 In May 1994, engineering representatives from the pharmaceutical industry engaged in a disc

5、ussion with the International Society for Pharmaceutical Engineering (ISPE) and the Food and Drug Administration (FDA). As a result of that discussion in November 1994, ISPE began work on 10 facility engineering Guides, now known as the Baseline® Pharmaceutical Engineering Guides. The first, “B

6、ulk Pharmaceutical Chemicals,” was published in June 1996. The second, “Oral Solid Dosage Forms,” was published in February 1998. The third, “Sterile Manufacturing Facilities,” was published in February 1999. This is the fourth such Guide, covering Pharmaceutical Water and Steam Systems. Each Engine

7、ering Guide was created by, and is owned solely by ISPE. FDA provided comments on this and previous Guides, and many of their suggestions have been incorporated.1994年5月，制药行业的技术代表与国际制药工程协会（ISPE）和美国食品与药品监督管理局（FDA）召开了讨论会。讨论的结果是从1994年11月起，ISPE开始致力于10本设施工程学指南的编写，这10本指南也就是现在为大家所熟知的Baseline®制药工程指南。199

8、6年6月出版的指南的第一卷的内容是关于批量药用化学品（BPC）的，第2本，“口服固体制剂”出版于1998年2月；第3本，“无菌生产设施”出版于1999年2月。本指南是这个系列的第4卷，介绍的是制药用水和蒸汽系统的内容。每本指南都由ISPE编写，其版权归ISPE独家拥有。FDA对这本指南和本系列之前出版的指南的编写都给予了宝贵意见，这些意见很多都已经整合入本系列丛书中。 As with the BPC Guide, OSD and Sterile Guide, the Water and Steam Guide has been sponsored by ISPEs Pharmaceutical

9、 Advisory Council, made up of senior pharmaceutical engineering executives from owner companies, and ISPE senior management. Overall planning, direction and technical guidance in the preparation of the Water and Steam Guide was provided by a Steering Committee most of whom were involved in the BPC G

10、uide. The Water and Steam Guide itself was produced by a Task Team of individuals who expended a great deal of their own time in its preparation and development.与BPC指南、OSD和无菌指南相同，这本水和蒸汽系统指南也得到了ISPE的药品咨询委员会的赞助；该委员会的成员由企业自身的制药工程高中级资深管理人员、FDA和ISPE管理高层组成。指导委员会为调试和合格确认指南的编写提供整体规划、方向的定位和技术指导；该委员会主要由参与BPC指

11、南编写的人员组成。水和蒸汽系统指南的编写工作组的成员为这本书的编写和发展花费了大量私人时间。 Editors Disclaimer: /编辑的声明This Guide is meant to assist pharmaceutical manufacturers in the design and construction of new and renovated facilities that are required to comply with the requirements of the Food and Drug Administration (FDA). The Internat

12、ional Society for Pharmaceutical Engineering (ISPE) cannot ensure, and does not warrant, that a facility built in accordance with this Guide will be acceptable to FDA.本指南旨在给药品生产者提供符合美国食品与药品监督管理局（FDA）要求的新设施的设计和构造方面的协助。国际制药工程协会（ISPE）并不为按照本指南要求建造的工厂通过FDA的检查提供担保和保证。This document is owned by ISPE. No rep

13、roduction of the whole or any part of this document is to be made without the written authority of ISPE. 本文件的版权归ISPE所有。任何人不得在没有得到ISPE的授权信的情况下复制本文件的全部或部分内容。ACKNOWLEDGEMENTS /感谢CHAPTER WRITERS AND REVIEWERS /各章的编写人和审查人The following individuals took lead roles in the preparation of this document:以下人士在本

14、文件的编写过程中发挥了带头作用：Gerald L. Geisler, Bristol-Myers Squibb Co. was Team Leader for the Pharmaceutical Water and Steam Guide. Moe Elmorsi , Boehringer Ingelheim, acted s the Guide mentor. Guides Steering Committee Chair Paul Lorenzo, (Retired)/ Paul DEramo, Johnson & Johnson The Core Team on the Pha

15、rmaceutical Water and Steam Guide comprised: Gerald L. Geisler, Bristol-Myers Squibb Co. Robert Myers, Kvaerner Jeff Biskup, Clark, Richardson & Biskup Bob Bader, Kinetics The Chapter Credits are as follows: Gerald Geisler, Bristol-Myers Squibb Co. Chapter 1: Introduction Brian Owens, H2O Pure,

16、Inc. Gerald Geisler, Bristol-Myers Squibb Co. Chapter 2: Key Design Philosophies Brian Owens, Water Pure, Inc. Jeffrey Biskup, Clark, Richardson & Chapter 3: Water Options and Programming Biskup Maria Capote, Source Tech James C. Cox, Merck & Co. Gerald L. Geisler, Bristol-Myers Squibb Co. R

17、yan Schroeder, Clark, Richardson & Biskup Sidney Brookes, DuPont Merck Pharmaceuticals Chapter 4: Source Feed Water Quality and Pretreatment ISPE BASELINE GUIDE WATER AND STEAM EXECUTIVE SUMMARY DECEMBER 2000 Michael Partow, Pfizer Inc. Andrew Zaske, Osmonics Gary Zoccalante, U. S. Filter Chapte

18、r 5: Final Treatment Non-Compendial and Compendial Purified Water Sharif Disi, Meco Brian Owens, H2O Pure, Inc. Chapter 6: Final Treatment Compendial WFI Brian Owens, H2O Pure, Inc. Bob Bader, Kinetics Chapter 7: Pharmaceutical Steam Robert Myers, Kvaerner Gary Gray, East Group Bob Bader, Kinetics R

19、andolph Brozek, Pfizer, Inc. James Cox, Merck & Co Paul Skinner, Clark, Richardson & Biskup Gerald Geisler, Bristol-Myers Squibb Co. Chapter 8: Storage and Distribution Systems John Linder, CE & IC Debra Nahas, Eli Lilly & Co. Chapter 9: Instrumentation and Control John Fadool, Glaxo

20、 Wellcome Robert Myers, Kvaerner Manfred Septinus, Roche Carolina, Inc. Phil DeSantis, Fluor Daniel Chapter 10: Commissioning & Validation Dominick Smith, Regeneron Phil Desantis, Fluor Daniel Chapters 11 and 12: Appendices Sidney Brooks, DuPont Merk Pharmaceuticals James C. Cox, Merck & Co.

21、 Sharif Disi, Meco Brian Owens, Water Pure, Inc. Michael Partow, Pfizer Paul Skinner, Clark, Richardson & Biskup Gary P Zoccalante, U. S. Filter Pat H. Banes, Oakley Services Co. The above Guide Task Team worked on one or more chapters and volunteered countless hours to attend meetings, and revi

22、ew the many drafts, which were prepared over an eighteen-month period.The following members of the Pharmaceutical Water and Steam Systems Task Team also worked on one or more of the chapters and reviewed drafts:Georgia Keresty, Ph.D., Bristol-Myers Squibb Paula Soteropoulis, Genzyme Corp. Alex Konop

23、ka, Eli Lilly & Co. John Trentacosti, Johnson & Johnson Carl Roe, Abbott Labs FDA Reviewers /FDA审查员We would like to thank the following FDA review team for their input to this Guide: l Sharon Smith (Deputy Commissioner for External Affairs) Holston l Joseph Phillips (Deputy Regional Food and

24、 Drug Director, Mid-Atlantic Region) l Tracy Roberts (CDER, Office of Compliance) l Robert (Atlanta National Expert) Coleman l Richard (CDER, Office of Compliance) Friedman l Nancy Rolli (Investigator, Drug Specialist, New Brunswick, NJ Inspection Post) 1. INTRODUCTION /绪论1.1 BACKGROUND /背景The desig

25、n, construction, and validation (commissioning and qualification) of water and steam systems for the pharmaceutical industry represent key opportunities for manufacturers, engineering professionals, and equipment suppliers. These systems are required to meet current Good Manufacturing Practice cGMP

26、regulations while remaining in compliance with all other governing codes, laws, and regulations.FDA和其他注册机构在医药行业的水和蒸汽系统的设计、构造、验证（调试和合格确认）给生产者、工程专业人员和设备供应商提供了重要的商机。求这些设施不仅要达到现行的药品生产管理规范的要求，而且也要顺应其他管理条例、法律和规范。 The cost of bringing these systems on line is highly variable, owing to interpretation of reg

27、ulatory requirements and overly conservative design approaches. This Guide is intended to offer a practical, consistent interpretation, while still allowing flexibility and innovation.法规要求的形形色色的解释，以及过度保守的设计方法，导致引进这些在线系统在花费上的极大差别。因此，本指南试图在允许灵活和创新的前提下，给出一种实用且一致的解释。This Guide was prepared by ISPE, with

28、 feedback from industry representatives from all areas and disciplines, and comments provided by FDA. It reflects ISPEs current thinking related to engineering of new water and steam systems.在得到各个领域和学科的行业代表的反馈和FDA的意见的情况下，ISPE编写了这本指南。本书反映了ISPE在水和蒸汽的新型系统的工程方面的当前观点。 It is recognized that industry stand

29、ards evolve, and this document reflects the understanding of them as of the publication date.考虑到行业指南的不断变化与更新，需要指出的是，本指南反映的是截止出版日的行业标准和对这些标准的理解。1.2 SCOPE OF THIS GUIDE /指南的范围This Guide is intended for the design, construction, and operation of new water and steam systems. It is neither a standard nor

30、 a detailed design guide. The validation of water and steam systems, which comprises commissioning and qualification activities, will not be discussed in-depth in this Guide, but is covered in the Commissioning and Qualification Baseline® Guide.本指南适用于水和蒸汽的新型系统的设计、建造和操作，但这并不是一本标准或详细的设计指南。包括调试和合格

31、确认活动的水和蒸汽系统的验证不是本指南深入讨论的问题；这些问题是调试和合格确认Baseline®指南的阐述内容。The purpose of this Guide is to focus on engineering issues, and provide cost effective water and steam systems. Where non-engineering issues (e.g., microbiological topics) are covered, the information is included to stress the importance

32、of such topics and the impact they have on water and steam system design. Such non-engineering topics, therefore, are not covered comprehensively, and specific advice from QA departments and technical experts must be sought where technical input is required.这本指南的重点是工程问题，其目的在于准备低本高效的水和蒸汽系统。指南中也提到了不属于

33、工程问题的内容（如微生物），这是为了强调这些问题的重要性和这些问题对水和蒸汽系统设计的影响。当然，没有详细阐述这些不属于工程问题的内容；在要求给出技术内容的地方，必须咨询QA部门和技术专家。This Guide is intended primarily for regulatory compliance for the domestic United States (US) market, and follows US standards and references. European and other non-US standards and references may be inc

34、orporated in future revisions.本指南主要为销往美国市场的符合法规要求的设施、设备和器械而编写，它使用的是美国标准和参考文献。将来的版本可能会整合欧洲和其它非美国地区的标准和参考文献。 1.3 SOME APPLICABLE FDA CURRENT REGULATIONS AND GUIDES FOR PHARMACEUTICAL WATER SYSTEMS /可用于制药用水系统的一些现行FDA法规和指南l Food and Drug and Cosmetic Act 食品、药品和化妆品法案l The United States Pharmacopoeia XXIV

35、 美国药典XXIV l Title 21 CFR, Part 21121 CFR的211部l FDA Guide To Inspections of High Purity Water Systems高纯水系统的FDA考察指南 1.4 KEY CONCEPTS/重要概念 The following key concepts covered in this Guide are:本指南涉及的重要概念如下：a) Methodology for defining the required water quality and configuring a water delivery system.定义水

36、的质量和配置水的传输系统的方法b) Critical process parameters.关键工艺参数 c) Good Engineering Practices.优良工程规范 d) Design Options设计方案a) Methodology for defining the required quality and configuring a water delivery system: 定义质量和配置水的传输系统的方法 Perhaps the most critical step in a new pharmaceutical water or steam system, from

37、 a regulatory as well as technical and financial standpoint, is the specification of water or steam quality required. The specification established is likely to have a larger impact on lifecycle costs of the system than any of the subsequent design decisions. In addition, regulated industries must c

38、onsider the costs of noncompliance and water system failures. Therefore, it is essential for the designer to seek advice from the Quality unit and technical experts early in the process.从法规、技术和财政方面来看，新型制药用水和蒸汽系统中最关键的步骤可能就是水的标准或对蒸汽质量的要求。这些标准对系统的周期成本的影响，要比任何后续的审计决议对周期成本的影响要大得多。此外，这个受管制的行业必须考虑到不合格和水系统故

39、障对成本投入的影响。因此，设计者应在这个过程的早期向质量部门和技术专家咨询意见，做到这一点是很有必要的。Once process water and/or steam requirements are determined, system design options need to be addressed. This Guide presents alternative baseline water and steam system building blocks and associated advantages and disadvantages of each. These base

40、line building blocks are qualified relative to such things as capital costs; feed water chemistry; product water quality; chemical handling; water consumption; energy consumption; outside service costs maintenance requirements; and chemical/microbial/endotoxin removal performance.一旦确定了对工艺用水和/或蒸汽的要求，

41、就应给出系统的设计方案。这本指南介绍了可选的基线水和蒸汽系统的标准部件和它们的优点和缺点。和成本、饮用水化学性质、产品水质、化学物的处理、耗水量、能量消耗、有维护要求的外部设施和化学物/微生物/内毒素的去除效果有关的基线标准部件应是合格的。Guide emphasis is on how the system design should be determined based on the quality of feed water; the design of the pretreatment and final treatment system; the storage and distr

42、ibution system design; and operation/maintenance procedures.指南将阐述的重点放在如何在饮用水的质量的基础上确定系统的设计、前处理和后期处理系统的设计、贮存和分配系统的设计以及操作/维护章程上。 The Guide aims to improve consistency of pharmaceutical water and steam quality throughout the industry, as a result of system performance and reliability improvements. It a

43、lso provides the user with alternative basic system building blocks to permit reliable and consistent generation of the required water or steam quality.通过改善系统性能和可靠性，这本指南试图给出提高企业的制药用水和蒸汽质量的连续性的建议。它也给使用者介绍了其他的基础系统的标准部件，这些系统可保证得到的水或蒸汽质量的可靠性和连续性。 b) Critical process parameters /关键工艺参数 Critical parameter

44、s are defined as those parameters that directly affect the product quality. For example, since microbial quality cannot be directly monitored in real time, the parameters relied upon to control microbial growth are normally considered critical. These may include temperature; UV intensity; ozone conc

45、entration; circulating systems under positive pressure; etc. In regard to chemical purity, the quality attributes themselves (properties of water produced), may be monitored at or after each process step, and the proper performance of that operation confirmed directly. For a system producing compend

46、ial water, properties mandated in the official monograph obviously constitute critical parameters.关键工艺参数指那些能直接作用于产品质量的参数。例如，考虑到不能对微生物的质量实施实时的直接监测，所以通常认为微生物生长的控制参数是关键的。这些参数可能包括温度、UV密度、臭氧浓度、正压下的循环系统等。就能生产药典标准的水系统而言，关键参数的种类和要求可参阅官方专论。 Critical instruments are those instruments that measure critical qua

47、lity attributes. This concept is discussed in Chapter 2 and used as a basis for subsequent chapter discussions where appropriate. 关键仪器是用来测量关键质量属性的仪器。第2章中对这个概念进行了讨论；接下来的章节的讨论中，“关键仪器”作为基础概念而使用。 c) Good Engineering Practice (GEP) /优良工程规范（GEP）GEP recognizes that all systems in a facility, whether they a

48、re water systems, steam systems, elevators, process reactors, safety valves, or rest rooms, require some form of commissioning and/or qualification. Nearly all systems require documentation, inspection, and field testing. Good Engineering Practice capitalizes upon this practice suggesting that manuf

49、acturers engage all stakeholders (engineers, operators, Quality Assurance, and others) very early in the planning, design, construction, commissioning/qualification phases to ensure that systems are documented only once.GEP认为生产设施中的所有系统，不管是水系统、蒸汽系统、电梯、过程反应器、安全阀，还是厕所，都需要某种形式的调试和/或合格确认。几乎所有系统都要求归档、考察和现

50、场测试。针对这方面的实践活动，优良工程规范提出了建议，它建议生产者应在策划、设计、建造、调试/合格确认阶段的初期与所有的项目执行单位（工程师、操作员、质量保证部门和其他单位）联系，从而保证这些系统都只归档一次。d) Design Options /设计方案The Guide emphasizes that a water system can be designed in many different ways, yet meet the overall requirements of the system. It encourages a well-thought-out, planned

51、approach to the design with input from many areas of the organization including Quality Assurance.这本指南还强调指出只要能满足这个系统的所有要求，可用多种方式设计水系统。它鼓励采用经过深思熟虑的、经过策划的方法来进行设计，设计的过程中要参考包括质量保证部门在内的不同领域的机构的意见。1.5 GUIDE STRUCTURE /指南的结构The structure of the Guide is shown in Figure 1-1 below. The chapters have been org

52、anized to assist in a logical decision process to determine the type of water required and the system design needed to provide it.这本指南的结构如下图1-1所示。这些章节的组织方式能为建立合乎逻辑的决策过程提供帮助，从而确定合乎要求的水的类型和合乎需要的系统设计。Figure 1-1 Pharmaceutical Water and Steam Baseline® Guide Structure图 1-1 制药用水和蒸汽Baseline®指南的结

53、构图Chapter 8Storage and Distribution Systems第八章 贮存和分配系统Chapter 4Pretreatment Options第四章 前处理方案 Chapter 11Appendix第十一章 附录Chapter 10Commissioning and Qualification第十章 调试和合格确认Chapter 9Instrumentation & Control第九章 仪器和控制Chapter 7Pharmaceutical Steam第七章制药用蒸汽Chapter 6Final Treatment Options:Water for Inj

54、ection(WFI)第六章 终处理方案：注射用水（WFI）Chapter 5Final Treatment Options: Non-Compendial & Compendial Purified Water第五章 终处理方案：非药典级和药典级纯化水Chapter 3Water Options and System Planning第三章 水的选择和系统策划Chapter 2Key Design Philosophies第二章主要设计原理Chapter 1Introduction第一章绪论2. KEY DESIGN PHILOSOPHIES /主要设计原理2.1 INTRODUCT

55、ION /绪论Pharmaceutical water is the most widely used ingredient in drug manufacturing and the main component in equipment/system cleaning. Therefore, systems for the production of pharmaceutical water constitute a key component in every manufacturing facility. The nature of producing pharmaceutical w

56、aters is to minimize or eliminate potential sources of contamination. This Guide considers this and the means by which engineers can design out, or ensure control of the risk.制药用水不仅是药品生产中使用最广泛的成分，它也在设备/系统清洁过程中担任主要角色。因此，生产制药用水的系统是每家工厂的关键组成部分。之所以要生产制药级的水，是为了减少或消除潜在的污染源。这本指南讨论了这个问题，以及工程师们设计水系统的方式，并介绍了能

57、给控制这些危险提供保证的方式。The quality of Pharmaceutical Water and Steam is not only critical from a regulatory point of view, but also from a financial point of view. The Pharmaceutical Water and Steam specification has the largest impact on lifecycle costs of the system.不论是从法规要求的观点来看，抑或是从财政的观点来看，制药用水和蒸汽的质量的重要

58、性都很突出。对该系统的周期成本影响最大的是制药用水和蒸汽的标准。It must be demonstrated that all pharmaceutical waters (non-compendial and United States Pharmacopoeia (USP) monograph compendial waters) can be produced consistently to specification. Establishing the level of microbial control needed in a pharmaceutical water and steam system used in the manufacture of a non-sterile product requires an understanding of both the use of the product and the manufacturing process.必须证明所有的制药用水（非法定标准和美国药典（USP）专论做出规定的水）的生产具备连续性，且都得到的水的水质合格。确定非无菌制剂生产中使用的制药用水和蒸汽系统的微生物控制标准时，首先要掌握产品的使用方法和生产工艺。Manufacturers need to define th