公用系统检查

1、AIDE-MEMOIREINSPECTION OF UTILITIES备忘录公用系统检查TABLE OF CONTENTS目录1. Document History文件历史.12. Introduction 介绍.13. Purpose目的.14. Scope范围.15. Aide Memoire备忘录.26. Revision History修订历史.91. DOCUMENT HISTORY 文件历史Adoption by Committee获委员会采纳24 April 2002Entry into force实施1 July 20022. INTRODUCTION介绍2.1 Technol

2、ogical and technical progress have increased in the pharmaceutical industry in the last decades. Progress has not only been made in the area of production equipment, technology and quality control but also in the area of auxiliary systems such as HVAC and media systems.2.1 近十年来，制药行业的技术和技术进步已经增加。进步不仅

3、表现在生产设备、技术和质量控制方面，还在辅助系统如HVAC和介质系统等领域。2.2 PIC/S has paid due attention to these systems for the manufacture of medicinal products. In 2001, the annual PIC/S Seminar was devoted to the inspection of utilities used by the manufacturer of pharmaceuticals (Prague, Czech Republic).2.2 这些药品生产的这些系统已经引起的PIC

4、/S关注。2001年，年度PIC/S研讨会致力于药品生产的公用系统的检查（布拉格，捷克共和国）。3. PURPOSE 目的3.1 The purpose of this document is to provide guidance for GMP inspectors to use for training purposes and in preparation for inspections.3.1 该文件的目的是提供给GMP检查员用于培训目的和检查预期准备的指导。3.2 The Aide-Memoire is the direct result of the 2001 PIC/S Sem

5、inar and was drafted with the aim of facilitating the effective planning and conduct of GMP inspections of utilities. The Aide-Memoire should enable the inspector to make both an optimal use of the inspection time and an optimal evaluation of GMP compliance.3.2 该备忘是年度PIC/S研讨会的直接结果，并以促进公用系统的GMP检查有效规划

6、和管理为目的起草的。该备忘应能够使检查员既能完成检查时间的优化使用，又能得到GMP符合性的最佳评价。4. SCOPE 范围4.1 The following Aide-Memoire describes different areas which could be evaluated during the GMP inspection of HVAC systems, pharmaceutical water, steam and medicinal gases. However, the Aide-Memoire should be considered as a non-exhaustiv

7、e list of areas to be looked at during an inspection. 4.1 接下来的备忘描述了在对HVAV系统、制药用水、蒸汽和药用气体进行GMP检查期间可以进行评估的不同区域。但是，该备忘只能作为一个未全尽的清单来使用。4.2 At the time of issue, this document reflected the current state of the art. It is not intended to be a barrier to technical innovation or the pursuit of excellence.

8、The advice in this Aide-Memoire is not mandatory for industry. However, industry should consider PIC/S recommendations and aide-memoires as appropriate.4.2 在签发本文件时，该文件反映当前的理想状态。本文件无意阻碍技术革新或追求卓越。该备忘中的建议对制药行业来说并不是必须实施的。但是，制药行业应在适当时考虑PIC/S和备忘的建议。5. AIDE MEMOIRE备忘1.Area of operation/Items HVAC for medic

9、inal products操作区域/项目医药产品的HVAVNotes注意点Crucial questions关键问题Supporting documents支持性文件1.1Key design parameters关键设计参数n Need for separate systems需要独立的系统n Level of filtration (Filter specifications) 过滤级别（过滤器规格）How do you prevent cross contamination by air?如何防止空气交叉污染PIC/S GMP Guide 3.10, 3.14, 5.10, 5.11,

10、5.18, 5.20. Annex 1- 29-31, Annex2-9,10,14,15, Annex 15- 9,10PIC/SGMP指南3.10, 3.14, 5.10, 5.11, 5.18, 5.20.附录1-29-31,附录2 -9,10,14,15,附录15- 9,101.Area of operation/Items HVAC for medicinal products操作区域/项目医药产品的HVAVNotes注意点Crucial questions关键问题Supporting documents支持性文件n Recirculation or make up air 再循环或

11、补充空气n Location of filters过滤器位置n Position of inlet and air return, dust extractors 入口位置、回风和吸尘器n Temperature 温度n Humidity 湿度n Air changes 换气次数n Pressure differentials 压差n Design of ducting 管道设计n Easy and effective cleaning 简单有效的清洗n Alarm system 报警系统n Air flow direction- LAF and/or turbulent空气流动方向-LAF和

12、/或湍流ISO 14644-4: Clean rooms and associated controlled environments Part 4: Design and construction. ISO 14644-4：洁净室及相关受控环境-第4部分：设计和施工。International Organisation for Standardisation ISO, Geneva (April 2001) EN 1822: High efficiency particulate air filters (HEPA and ULPA): 国际标准化组织ISO，日内瓦（2001年4月）EN18

13、22：高效微粒空气过滤器（HEPA 和 ULPA）：Part 1 Requirements, testing, marking;部分1要求、测试、标记；Part 2 Aerosol production, measuring equipment, particle counting statistics; 部分2气溶胶生产、测量设备；Part 3 Testing the planar filter medium; 部分3平面过滤介质测试；Part 4 Testing the filter element for leaks (scan method); 部分4滤芯泄露测试（扫描法）；Part

14、5 Testing the efficiency of the filter element.部分5滤芯效率测试；1.Area of operation/Items HVAC for medicinal products操作区域/项目医药产品的HVAVNotes注意点Crucial questions关键问题Supporting documents支持性文件European Committee for Standardisation, Brussels (parts 1-3 were ratified in March 1998, parts 4-5 in August 2000). 欧洲标准

15、化委员会，布鲁塞尔(部分1-3是1998年3月批准的，部分4-5 是2000年8月)。EN 779: Particle air filters for general ventilation Requirements, testing, marking. EN 779：微粒空气过滤器一般通风需求、测试、标记。European Committee for Standardisation, Brussels (July 1993).欧洲标准化委员会，布鲁塞尔(1993年7月)。1.2Qualification of HVAC systemsHVAC系统的验证n DQ, IQ, OQ a PQ n

16、Average speed and uniformity of airflow平均速度和气流均一性n Pressure differentials 压差n Air changes 换气次数n Integrity and tightness of terminal installed final filters末端安装过滤器的完整性和气密性How have you implemented recommendations and correct deviations mentioned in qualification reports? 如何实现验证报告中提到的整改计划和偏差纠正？Guide -

17、4.26, 5.21, 5.22, 5.24, 5.37, Annex 1-30, Annex 15 2-18. 指南-4.26, 5.21, 5.22, 5.24, 5.37,附录1-30，附录15-2-18.EN ISO 14644-1: Clean rooms and associated controlled environments Part 1: Classification of air cleanliness. ISO 14644-1：洁净室及相关受控环境-部分1：空气洁净度等级划分。1.Area of operation/Items HVAC for medicinal pr

18、oducts操作区域/项目医药产品的HVAVNotes注意点Crucial questions关键问题Supporting documents支持性文件1.2n Number of particles粒子数n Recovery tests 自净测试n Air temperature 空气温度n Smoke tests 通烟测试n Requalification (parameters for requalification) 再验证（再验证参数）n Change control变更控制Who is responsible for evaluating if requalification is

19、 necessary?如果必须重新验证，谁来负责评估？What are the requirements for regular requalification?定期再验证的要求是什么？Show me your deviations and change control reports for HVAC?出示HVAC的偏差和变更控制报告？International Organisation for Standardisation ISO, Geneva and European Committee for Standardisation CEN, Brussels (May 1999).国际标

20、准化组织ISO，日内瓦和欧洲标准化委员会CEN，布鲁塞尔(1999年5月)。EN ISO 14644-2: Clean rooms and associated controlled environments Part 2: Specifications for testing and monitoring to prove continued compliance with ISO 14644-1. ISO 14644-2：洁净室及相关受控环境-部分2：为认证与ISO 14644-1 连续的相符性的测试和监测技术要求。International Organisation for Standa

21、rdisation ISO, Geneva and European Committee for Standardisation (September 2000).国际标准化组织ISO、日内瓦和欧洲标准化委员会(2000年9月)。1.Area of operation/Items HVAC for medicinal products操作区域/项目医药产品的HVAVNotes注意点Crucial questions关键问题Supporting documents支持性文件1.3Walk round tour Confront differences between design specifi

22、cations, drawings (in SMF) and reality, unplanned maintenance and change control and following items巡检比较设计规范、图纸(SMF)和现实的差异，计划外维护、变更控制和接下来的项目n Are rooms for the production of medicinal products equipped with HVAC in accordance with GMP requirements? 是否按照GMP的要求，为生产医药产品配备HVAC的房间?n Location of filters 过

23、滤器位置n Position of inlets and air return 空气进入和返回的位置n Dust extractors,吸尘器n Pressure differences (across filters, between production and adjacent rooms) 压力差（整个过滤器，生产与相邻房间之间）n Logbooks-maintenance and calibration 日志-维护和保养n Monitoring of other process parameters 其他工艺参数监控n HVAC alarm systems functionHVAC报

24、警系统功能How do you challenge your alarm systems? 如何挑战报警系统？Place and procedure for sampling? 采样地点和过程？Where and how do you weigh and refill starting materials?在哪里以及如何权衡和补充材料?Guide - 3.6, 3.7, 3.12, 4.27 Annex 1 -29, Annex 2-14指南 - 3.6, 3.7, 3.12, 4.27 附录1 -29, 附录 2-141.Area of operation/Items HVAC for me

25、dicinal products操作区域/项目医药产品的HVAVNotes注意点Crucial questions关键问题Supporting documents支持性文件1.4Monitoring of HVAC systems监控HVAC系统n Environmental monitoring (particles, micro organ, humidity, temperature)环境监测(粒子、微器官、湿度、温度)n Chemical residue testing 化学残留检测Guide 4.15, Annex 1 4-6, 1.5Maintenance and calibrat

26、ion of HVAC systemsHVAC系统的维护和校准n Maintenance program 维护方案n Calibration program校准方案n SOP´s n Records 记录n Breakdown/Emergency including challenges of alarm systems故障/紧急情况包括报警系统的挑战The interaction between unplanned maintenance and requalification计划外维护和重新验证的相互作用Guide 3.411.6Documentation for HVAC sy

27、stemsHVAC系统的文件n Technical data 技术数据n SOP, records-maintenance, calibration, validation, monitoring, deviations, change control SOP、记录-维护、校准、验证、监控、偏差、变更控制n Validation protocols and reports 验证计划n Asbuilt engine drawing竣工引擎图Guide 4.1, 4.26, 4.28, 4.292.Area of operation/Items Pharmaceutical water syste

28、m操作区域/制药项目水系统Notes注意点Crucial questions关键问题Supporting documents支持性文件2.1Key design parameters关键设计参数WFI n Weld quality 焊接质量n Passivation of pipeworks 管道工程的钝化处理n Vent filters 空气过滤器All kinds of pharmaceutical water 各种各样的制药用水n Suitability of construction materials建筑材料的适用性n Slope of pipeworks 管道工程的坡度n Reci

29、rculation at adequate velocity and temperature 在适当的速度和温度循环n Sanitary joints 卫生环节n Capacity x daily demand 产能x的日常需求n Valves 阀门n Draining /flushing 排水/冲洗n Samplings ports采样端What are the design features that prevent entrainment? 防止夹带的设计特点是什么？Who owns the system?谁有这个系统？Guide 3.10 FDA- Guide to Inspectio

30、n of Highly Purified Water Systems Annex 1-35 Annex 15 9,10指南3.10 FDA-高纯水系统的检查指导附录 1-35 附录15 9,102.2Qualification验证DQ, IQ, OQ, PQ AND COMPUTER VALIDATION IF NEEDEDDQ, IQ, OQ, PQ和如果需要计算机验证All qualification completed?所有验证已完成？3.3.4, 3.38, 5.22, 5.24 Annex 15 2-18.2.Area of operation/Items Pharmaceutica

31、l water system操作区域/制药项目水系统Notes注意点Crucial questions关键问题Supporting documents支持性文件2.2n Drawing, with all sampling points 所有取样点的图纸n Setting operation and cleaning parameters-I. Stage 安装操作和清洗参数-I阶段n CONSISTENTLY PRODUCING WATER OF DESIRED QUALITY连续生产所需质量的水For existing systems, show me deviation and chan

32、ge control reports? 对于现有系统，出示偏差和变更控制报告？Does staff understand what, how and why the work is performed? 员工是否了解如何以及为什么执行工作吗?What do signatures mean?签名意味着什么？2.3Walk round inspection 巡检Is water for injection produced and used according to requirements of Note for Guidance on Quality of Water for Pharmace

33、utical Purposes and Ph Eur? 是否根据Ph. Eur用于指导制药用水质量记录的要求生产和使用注射用水？n Water quality grade and purposes of its use水质量等级和其使用的目的n feed water 锅炉水n pre- treatment 前处理n distillation sight glass 蒸馏观察镜n storage tank-filter, break valve, Q-spray ball 存储槽过滤器、截止阀、Q-喷雾球n distribution loop-temp, conductivity, TOC 水温

34、循环分布、电导率、TOCHow is the system kept in a validated state? 系统如何保持在一个验证的状态？Let me have a look in the sight glass! 看看观察镜Show me records of alarms that have occurred!出示已经发生的警报记录Ph. Eur. current edition CPMP - Note for Guidance on Quality of Water for Pharmaceutical Purposes Annex 1 35Ph. Eur. 现行版本 CPMP 用

35、于指导制药用水质量的记录附录 1 352.Area of operation/Items Pharmaceutical water system操作区域/制药项目水系统Notes注意点Crucial questions关键问题Supporting documents支持性文件2.3Confront differences between drawings and reality, unplanned maintenance and change control. 面对图纸与现实之间的差异，计划外维护和变更控制。Follow the system from pre-treatment to us

36、er points: in each part, check leaks, sampling points (access), who does what, start up and shutdown, cleaning / disinfection /sterilisation), quantities produced.从预处理系统到使用点：在每个部分，检查泄漏、采样点（进入）、谁做什么、启动和关闭、清洁/消毒/灭菌、生产数量。n heat exchanger-integrity 热交换器完整性n user points-number, design and location 用户点次量、

37、设计和位置n control system-alarms, record of action, set points and demonstration 控制系统-报警、行动的记录、设置点和演示n monitoring print outs 监控打印n DISINFECTION? HOT WATER? STEAM? CONTINUOUS RECIRCULATION?消毒？热水？蒸汽？连续循环？2.4Quality control testing质量控制测试n PROGRAMME, INCLUDING TEST METHODS 计划，包括测试方法2.Area of operation/Items

38、 Pharmaceutical water system操作区域/制药项目水系统Notes注意点Crucial questions关键问题Supporting documents支持性文件2.4n SCHEDULE? 计划表n SAMPLING, WHO TAKES SAMPLES, RAINING, VOLUME SAMPLED, HANDLING OF SAMPLES 取样、谁取走样品、下雨、取样体积、样品的处理n Limits (micro, chemical, endotoxin) 限制（基本的、化工、内毒素）n Out of spec. results (OOS) 超标的结果（OOS

39、）n Trending of results 结果的趋势n Check that all points are sampled over time, accessibility to sampling points随着时间的推移，所有点都被取样，无障碍取样点How do you perform sampling (handling, volume, done by, all points covered)? 如何执行取样（处理、体积、所有点覆盖）？What are alert, action limits? 警报是什么，行动限制吗？Source water testing?源水测试？Ph. E

40、ur. Current edition CPMP Note for Guidance on Quality of Water for Pharmaceutical Purposes Guide 3.43, 4.15, 4.22, 6.7Ph. Eur. 现行版本 CPMP 用于指导制药用水质量的记录3.43, 4.15, 4.22, 6.72.5Monitoring监控n Temperature 温度n Speed 速度n Vent filters空气过滤器n DI column regeneration DI柱平衡n pH n UV light (PW)紫外线n Conductivity 电

41、导率n Leakage 渗漏n TOC总有机碳By whom and how are corrective actions made?由谁并如何完成纠正措施？Guide 4.15 Annex 1 442.Area of operation/Items Pharmaceutical water system操作区域/制药项目水系统Notes注意点Crucial questions关键问题Supporting documents支持性文件2.6Maintenance and calibration of water systems水系统的维护和校准n Maintenance program 维护计

42、划n Calibration programme校准计划n SOP´s n Records 记录n Breakdown/Emergency including challenges of alarm systems故障/紧急情况包括报警系统的挑战The interaction between unplanned maintenance and requalification计划外维护和再验证之间的相互作用Guide 3.412.7Documentation文件n Drawing up to date (SMF?) 最新图纸（SMF）n OOS evaluation OOS评价n De

43、viation reports 偏差报告n Change control reports变更控制报告n Operation of the system 系统的操作n Cleaning / sanitation / sterilisation 清洁/卫生/灭菌n Logbook monitoring parameters- see 1.6, incidents, filter changes, shut down periods, cleaning/sanitation, maintenance日志监控参数见1.6，事件、过滤器的变化、关闭时间、清洁/卫生、维护Guide 5.38 Guide

44、4.1, 4.26,4.28, 4.293.Area of operation/Items Pharmaceutical steam system操作区域/制药项目蒸汽系统Notes注意点Crucial questions关键问题Supporting documents支持性文件3.1Key design parameters关键设计参数n entrainment prevention夹带预防n cross contamination factory/ clean steam 交叉污染工厂/清洁蒸汽n non condensable gases reduction 不凝结的气体减少n slop

45、e of pipeworks 管道工程的坡度n no dead legs 无死角Guide 3.10 Annex 15 9-103.2Qualification验证DQ, IQ, OQ, PQ AND COMPUTER VALIDATION IF NEEDED THE SCOPE OF VALIDATIONDQ, IQ, OQ, PQ和如果需要计算机验证验证范围All qualification completed? 所有验证已完成？For existing systems, show me deviation and change control reports对于现有系统，出示偏差和变更控

46、制报告？3.3.4, 3.38, 5.22, 5.24 Annex 15- 2-183.3Walk round tour What kind of steam is used for manufacture of pharmaceutical products factory, clean steam generator)? 巡检什么样的蒸汽用于医药产品的生产工厂，清洁蒸汽发生器）？n FEED WATER-TYPE, LEVEL, TEMPERATURE 锅炉水水型、级别、温度n Sample points- location, number, access 采样点位置、数量、留样n Sys

47、tem for removal of air loop空气循环清除系统3.Area of operation/Items Pharmaceutical steam system操作区域/制药项目蒸汽系统Notes注意点Crucial questions关键问题Supporting documents支持性文件3.3What kind of source water is used for production of steam? 什么样的源水用于生产蒸汽？Confront differences between drawings and reality, unplanned maintenan

48、ce and change control. 面对图纸与现实之间的差异，计划外维护和变更控制。Follow the system in logical order. Pay attention to leaks, sampling points (access), who does what, start up and shutdown, cleaning / disinfection / sterilisation), quantities produced.遵循系统逻辑顺序。注意泄漏、采样点（留样）、谁做什么、启动和关闭、清洁/消毒/灭菌）、生产数量。3.Area of operation

49、/Items Pharmaceutical steam system操作区域/制药项目蒸汽系统Notes注意点Crucial questions关键问题Supporting documents支持性文件3.4Monitoring监控n control of entrainment 夹带控制n level control of feed water 锅炉水的控制级别n pressure control inside still 内部压力控制n temperature 温度n filters 过滤器n blown down frequency刮倒频率n emergency shutdown and

50、 start up紧急关闭和启动Guide 4.153.5Quality control testing质量控制测试n methods (contains non condensable gases and additives) 方法（包含不凝结的气体和添加剂）n limits 范围n sampling 取样n OOS results OOS结果n Trending results 结果趋势Guide 3.43, 4.15, 4.22, 6.7 Annex 1- 683.6Maintenance and calibration of the system系统的维护和校准n Maintenanc

51、e program 维护计划n Calibration programme校准计划n SOP´s n Records 记录n Breakdown/Emergencyincluding challenges of alarm systems故障/紧急情况包括报警系统的挑战The interaction between unplanned maintenance and requalification计划外维护和再验证之间的相互作用Guide 3.413.7Documentation文件n Drawing up to date (SMF?) 最新图纸（SMF）n OOS evaluati

52、on OOS评价n Deviation reports 偏差报告n Change control reports 变更控制报告Guide 4.1, 4.26, 4.28, 4.293.Area of operation/Items Pharmaceutical steam system操作区域/制药项目蒸汽系统Notes注意点Crucial questions关键问题Supporting documents支持性文件3.7n Operation of the system 系统的操作n Cleaning / sanitation / sterilisation 清洁/卫生/灭菌n Logboo

53、k - monitoring parameters - see 1.6, incidents, filter changes, shut down periods, cleaning / sanitation, maintenance日志监控参数见1.6，事件、过滤器的变化、关闭时间、清洁/卫生、维护4.Area of operation/Items Pharmaceutical gases操作区域/制药项目气体Notes注意点Crucial questions关键问题Supporting documents支持性文件4.1Key design parameters关键设计参数n air inlet-source, contamination risks n filters (pre final) n suitability of materials n welding n prevention of contamination