制藥用水和蒸汽系統(tǒng)指南

1、A GUIDE FOR NEW FACILITIES 為新型設施準備的指南VOLUME 4: WATER AND STEAM GUIDE卷4：水和蒸汽系統(tǒng)的指導原則EXECUTIVE SUMMARY執(zhí)行概況 DECEMBER 20002000年12月 A DOCUMENT DEVELOPED IN PARTNERSHIP WITH FDA 本文件由下列單位與FDA合作編寫25 / 25文檔可自由編輯打印ISPE PHARMACEUTICAL ENGINEERING GUIDE/ISPE制藥工程指南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.長年以來，制藥行業(yè)在購進的大量新設施方面的支出一直持續(xù)增長。造成這些支出的部分原因是法規(guī)符合力度的要求的無常。驗證是得到重點關注的方面之一，特別是與自動化系統(tǒng)、回溯驗證源效用的趨勢、建筑和HVAC有關的內容。一致且得到廣泛接受的法規(guī)要求的欠缺造就了突出的情況：對技術先進的設施的追求導致成本的劇增、交貨與訂貨之間所需時間的延長、以及，在某些情況下，可導致新產品上市的延期。 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，制藥行業(yè)的技術代表與國際制藥工程協(xié)會（ISPE）和美國食品與藥品監(jiān)督管理局（FDA）召開了討論會。討論的結果是從1994年11月起，ISPE開始致力于10本設施工程學指南的編寫，這10本指南也就是現(xiàn)在為大家所熟知的Baseline®制藥工程指南。199

8、6年6月出版的指南的第一卷的內容是關于批量藥用化學品（BPC）的，第2本，“口服固體制劑”出版于1998年2月；第3本，“無菌生產設施”出版于1999年2月。本指南是這個系列的第4卷，介紹的是制藥用水和蒸汽系統(tǒng)的內容。每本指南都由ISPE編寫，其版權歸ISPE獨家擁有。FDA對這本指南和本系列之前出版的指南的編寫都給予了寶貴意見，這些意見很多都已經整合入本系列叢書中。 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.與BPC指南、OSD和無菌指南相同，這本水和蒸汽系統(tǒng)指南也得到了ISPE的藥品咨詢委員會的贊助；該委員會的成員由企業(yè)自身的制藥工程高中級資深管理人員、FDA和ISPE管理高層組成。指導委員會為調試和合格確認指南的編寫提供整體規(guī)劃、方向的定位和技術指導；該委員會主要由參與BPC指

11、南編寫的人員組成。水和蒸汽系統(tǒng)指南的編寫工作組的成員為這本書的編寫和發(fā)展花費了大量私人時間。 Editors Disclaimer: /編輯的聲明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.本指南旨在給藥品生產者提供符合美國食品與藥品監(jiān)督管理局（FDA）要求的新設施的設計和構造方面的協(xié)助。國際制藥工程協(xié)會（ISPE）并不為按照本指南要求建造的工廠通過FDA的檢查提供擔保和保證。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. 本文件的版權歸ISPE所有。任何人不得在沒有得到ISPE的授權信的情況下復制本文件的全部或部分內容。ACKNOWLEDGEMENTS /感謝CHAPTER WRITERS AND REVIEWERS /各章的編寫人和審查人The following individuals took lead roles in the preparation of this document:以下人士在本

14、文件的編寫過程中發(fā)揮了帶頭作用：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審查員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 /緒論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和其他注冊機構在醫(yī)藥行業(yè)的水和蒸汽系統(tǒng)的設計、構造、驗證（調試和合格確認）給生產者、工程專業(yè)人員和設備供應商提供了重要的商機。求這些設施不僅要達到現(xiàn)行的藥品生產管理規(guī)范的要求，而且也要順應其他管理條例、法律和規(guī)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.法規(guī)要求的形形色色的解釋，以及過度保守的設計方法，導致引進這些在線系統(tǒng)在花費上的極大差別。因此，本指南試圖在允許靈活和創(chuàng)新的前提下，給出一種實用且一致的解釋。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.在得到各個領域和學科的行業(yè)代表的反饋和FDA的意見的情況下，ISPE編寫了這本指南。本書反映了ISPE在水和蒸汽的新型系統(tǒng)的工程方面的當前觀點。 It is recognized that industry stand

29、ards evolve, and this document reflects the understanding of them as of the publication date.考慮到行業(yè)指南的不斷變化與更新，需要指出的是，本指南反映的是截止出版日的行業(yè)標準和對這些標準的理解。1.2 SCOPE OF THIS GUIDE /指南的范圍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.本指南適用于水和蒸汽的新型系統(tǒng)的設計、建造和操作，但這并不是一本標準或詳細的設計指南。包括調試和合格

31、確認活動的水和蒸汽系統(tǒng)的驗證不是本指南深入討論的問題；這些問題是調試和合格確認Baseline®指南的闡述內容。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.這本指南的重點是工程問題，其目的在于準備低本高效的水和蒸汽系統(tǒng)。指南中也提到了不屬于

33、工程問題的內容（如微生物），這是為了強調這些問題的重要性和這些問題對水和蒸汽系統(tǒng)設計的影響。當然，沒有詳細闡述這些不屬于工程問題的內容；在要求給出技術內容的地方，必須咨詢QA部門和技術專家。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.本指南主要為銷往美國市場的符合法規(guī)要求的設施、設備和器械而編寫，它使用的是美國標準和參考文獻。將來的版本可能會整合歐洲和其它非美國地區(qū)的標準和參考文獻。 1.3 SOME APPLICABLE FDA CURRENT REGULATIONS AND GUIDES FOR PHARMACEUTICAL WATER SYSTEMS /可用于制藥用水系統(tǒng)的一些現(xiàn)行FDA法規(guī)和指南l Food and Drug and Cosmetic Act 食品、藥品和化妝品法案l The United States Pharmacopoeia XXIV

35、 美國藥典XXIV l Title 21 CFR, Part 21121 CFR的211部l FDA Guide To Inspections of High Purity Water Systems高純水系統(tǒng)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.定義水

36、的質量和配置水的傳輸系統(tǒng)的方法b) Critical process parameters.關鍵工藝參數 c) Good Engineering Practices.優(yōu)良工程規(guī)范 d) Design Options設計方案a) Methodology for defining the required quality and configuring a water delivery system: 定義質量和配置水的傳輸系統(tǒng)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.從法規(guī)、技術和財政方面來看，新型制藥用水和蒸汽系統(tǒng)中最關鍵的步驟可能就是水的標準或對蒸汽質量的要求。這些標準對系統(tǒng)的周期成本的影響，要比任何后續(xù)的審計決議對周期成本的影響要大得多。此外，這個受管制的行業(yè)必須考慮到不合格和水系統(tǒng)故

39、障對成本投入的影響。因此，設計者應在這個過程的早期向質量部門和技術專家咨詢意見，做到這一點是很有必要的。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.一旦確定了對工藝用水和/或蒸汽的要求，

41、就應給出系統(tǒng)的設計方案。這本指南介紹了可選的基線水和蒸汽系統(tǒng)的標準部件和它們的優(yōu)點和缺點。和成本、飲用水化學性質、產品水質、化學物的處理、耗水量、能量消耗、有維護要求的外部設施和化學物/微生物/內毒素的去除效果有關的基線標準部件應是合格的。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.指南將闡述的重點放在如何在飲用水的質量的基礎上確定系統(tǒng)的設計、前處理和后期處理系統(tǒng)的設計、貯存和分配系統(tǒng)的設計以及操作/維護章程上。 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.通過改善系統(tǒng)性能和可靠性，這本指南試圖給出提高企業(yè)的制藥用水和蒸汽質量的連續(xù)性的建議。它也給使用者介紹了其他的基礎系統(tǒng)的標準部件，這些系統(tǒng)可保證得到的水或蒸汽質量的可靠性和連續(xù)性。 b) Critical process parameters /關鍵工藝參數 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.關鍵工藝參數指那些能直接作用于產品質量的參數。例如，考慮到不能對微生物的質量實施實時的直接監(jiān)測，所以通常認為微生物生長的控制參數是關鍵的。這些參數可能包括溫度、UV密度、臭氧濃度、正壓下的循環(huán)系統(tǒng)等。就能生產藥典標準的水系統(tǒng)而言，關鍵參數的種類和要求可參閱官方專論。 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. 關鍵儀器是用來測量關鍵質量屬性的儀器。第2章中對這個概念進行了討論；接下來的章節(jié)的討論中，“關鍵儀器”作為基礎概念而使用。 c) Good Engineering Practice (GEP) /優(yōu)良工程規(guī)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認為生產設施中的所有系統(tǒng)，不管是水系統(tǒng)、蒸汽系統(tǒng)、電梯、過程反應器、安全閥，還是廁所，都需要某種形式的調試和/或合格確認。幾乎所有系統(tǒng)都要求歸檔、考察和現(xiàn)

50、場測試。針對這方面的實踐活動，優(yōu)良工程規(guī)范提出了建議，它建議生產者應在策劃、設計、建造、調試/合格確認階段的初期與所有的項目執(zhí)行單位（工程師、操作員、質量保證部門和其他單位）聯(lián)系，從而保證這些系統(tǒng)都只歸檔一次。d) Design Options /設計方案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.這本指南還強調指出只要能滿足這個系統(tǒng)的所有要求，可用多種方式設計水系統(tǒng)。它鼓勵采用經過深思熟慮的、經過策劃的方法來進行設計，設計的過程中要參考包括質量保證部門在內的不同領域的機構的意見。1.5 GUIDE STRUCTURE /指南的結構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.這本指南的結構如下圖1-1所示。這些章節(jié)的組織方式能為建立合乎邏輯的決策過程提供幫助，從而確定合乎要求的水的類型和合乎需要的系統(tǒng)設計。Figure 1-1 Pharmaceutical Water and Steam Baseline® Guide Structure圖 1-1 制藥用水和蒸汽Baseline®指南的結

53、構圖Chapter 8Storage and Distribution Systems第八章 貯存和分配系統(tǒng)Chapter 4Pretreatment Options第四章 前處理方案 Chapter 11Appendix第十一章 附錄Chapter 10Commissioning and Qualification第十章 調試和合格確認Chapter 9Instrumentation & Control第九章 儀器和控制Chapter 7Pharmaceutical Steam第七章制藥用蒸汽Chapter 6Final Treatment Options:Water for Inj

54、ection(WFI)第六章 終處理方案：注射用水（WFI）Chapter 5Final Treatment Options: Non-Compendial & Compendial Purified Water第五章 終處理方案：非藥典級和藥典級純化水Chapter 3Water Options and System Planning第三章 水的選擇和系統(tǒng)策劃Chapter 2Key Design Philosophies第二章主要設計原理Chapter 1Introduction第一章緒論2. KEY DESIGN PHILOSOPHIES /主要設計原理2.1 INTRODUCT

55、ION /緒論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.制藥用水不僅是藥品生產中使用最廣泛的成分，它也在設備/系統(tǒng)清潔過程中擔任主要角色。因此，生產制藥用水的系統(tǒng)是每家工廠的關鍵組成部分。之所以要生產制藥級的水，是為了減少或消除潛在的污染源。這本指南討論了這個問題，以及工程師們設計水系統(tǒng)的方式，并介紹了能

57、給控制這些危險提供保證的方式。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.不論是從法規(guī)要求的觀點來看，抑或是從財政的觀點來看，制藥用水和蒸汽的質量的重要

58、性都很突出。對該系統(tǒng)的周期成本影響最大的是制藥用水和蒸汽的標準。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.必須證明所有的制藥用水（非法定標準和美國藥典（USP）專論做出規(guī)定的水）的生產具備連續(xù)性，且都得到的水的水質合格。確定非無菌制劑生產中使用的制藥用水和蒸汽系統(tǒng)的微生物控制標準時，首先要掌握產品的使用方法和生產工藝。Manufacturers need to define th