1、AIDE-MEMOIREINSPECTION OF UTILITIES備忘錄公用系統檢查TABLE OF CONTENTS目錄1. Document History文件歷史.12. Introduction 介紹.13. Purpose目的.14. Scope范圍.15. Aide Memoire備忘錄.26. Revision History修訂歷史.91. DOCUMENT HISTORY 文件歷史Adoption by Committee獲委員會采納24 April 2002Entry into force實施1 July 20022. INTRODUCTION介紹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 近十年來，制藥行業的技術和技術進步已經增加。進步不僅

3、表現在生產設備、技術和質量控制方面，還在輔助系統如HVAC和介質系統等領域。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 這些藥品生產的這些系統已經引起的PIC

4、/S關注。2001年，年度PIC/S研討會致力于藥品生產的公用系統的檢查（布拉格，捷克共和國）。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 該文件的目的是提供給GMP檢查員用于培訓目的和檢查預期準備的指導。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 該備忘是年度PIC/S研討會的直接結果，并以促進公用系統的GMP檢查有效規劃

6、和管理為目的起草的。該備忘應能夠使檢查員既能完成檢查時間的優化使用，又能得到GMP符合性的最佳評價。4. SCOPE 范圍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 接下來的備忘描述了在對HVAV系統、制藥用水、蒸汽和藥用氣體進行GMP檢查期間可以進行評估的不同區域。但是，該備忘只能作為一個未全盡的清單來使用。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 在簽發本文件時，該文件反映當前的理想狀態。本文件無意阻礙技術革新或追求卓越。該備忘中的建議對制藥行業來說并不是必須實施的。但是，制藥行業應在適當時考慮PIC/S和備忘的建議。5. AIDE MEMOIRE備忘1.Area of operation/Items HVAC for medic

9、inal products操作區域/項目醫藥產品的HVAVNotes注意點Crucial questions關鍵問題Supporting documents支持性文件1.1Key design parameters關鍵設計參數n Need for separate systems需要獨立的系統n Level of filtration (Filter specifications) 過濾級別（過濾器規格）How do you prevent cross contamination by air?如何防止空氣交叉污染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.附錄1-29-31,附錄2 -9,10,14,15,附錄15- 9,101.Area of operation/Items HVAC for medicinal products操作區域/項目醫藥產品的HVAVNotes注意點Crucial questions關鍵問題Supporting documents支持性文件n Recirculation or make up air 再循環或

11、補充空氣n Location of filters過濾器位置n Position of inlet and air return, dust extractors 入口位置、回風和吸塵器n Temperature 溫度n Humidity 濕度n Air changes 換氣次數n Pressure differentials 壓差n Design of ducting 管道設計n Easy and effective cleaning 簡單有效的清洗n Alarm system 報警系統n Air flow direction- LAF and/or turbulent空氣流動方向-LAF和

12、/或湍流ISO 14644-4: Clean rooms and associated controlled environments Part 4: Design and construction. ISO 14644-4：潔凈室及相關受控環境-第4部分：設計和施工。International Organisation for Standardisation ISO, Geneva (April 2001) EN 1822: High efficiency particulate air filters (HEPA and ULPA): 國際標準化組織ISO，日內瓦（2001年4月）EN18

13、22：高效微粒空氣過濾器（HEPA 和 ULPA）：Part 1 Requirements, testing, marking;部分1要求、測試、標記；Part 2 Aerosol production, measuring equipment, particle counting statistics; 部分2氣溶膠生產、測量設備；Part 3 Testing the planar filter medium; 部分3平面過濾介質測試；Part 4 Testing the filter element for leaks (scan method); 部分4濾芯泄露測試（掃描法）；Part

14、5 Testing the efficiency of the filter element.部分5濾芯效率測試；1.Area of operation/Items HVAC for medicinal products操作區域/項目醫藥產品的HVAVNotes注意點Crucial questions關鍵問題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). 歐洲標準

15、化委員會，布魯塞爾(部分1-3是1998年3月批準的，部分4-5 是2000年8月)。EN 779: Particle air filters for general ventilation Requirements, testing, marking. EN 779：微粒空氣過濾器一般通風需求、測試、標記。European Committee for Standardisation, Brussels (July 1993).歐洲標準化委員會，布魯塞爾(1993年7月)。1.2Qualification of HVAC systemsHVAC系統的驗證n DQ, IQ, OQ a PQ n

16、Average speed and uniformity of airflow平均速度和氣流均一性n Pressure differentials 壓差n Air changes 換氣次數n Integrity and tightness of terminal installed final filters末端安裝過濾器的完整性和氣密性How have you implemented recommendations and correct deviations mentioned in qualification reports? 如何實現驗證報告中提到的整改計劃和偏差糾正？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,附錄1-30，附錄15-2-18.EN ISO 14644-1: Clean rooms and associated controlled environments Part 1: Classification of air cleanliness. ISO 14644-1：潔凈室及相關受控環境-部分1：空氣潔凈度等級劃分。1.Area of operation/Items HVAC for medicinal pr

18、oducts操作區域/項目醫藥產品的HVAVNotes注意點Crucial questions關鍵問題Supporting documents支持性文件1.2n Number of particles粒子數n Recovery tests 自凈測試n Air temperature 空氣溫度n Smoke tests 通煙測試n Requalification (parameters for requalification) 再驗證（再驗證參數）n Change control變更控制Who is responsible for evaluating if requalification is

19、 necessary?如果必須重新驗證，誰來負責評估？What are the requirements for regular requalification?定期再驗證的要求是什么？Show me your deviations and change control reports for HVAC?出示HVAC的偏差和變更控制報告？International Organisation for Standardisation ISO, Geneva and European Committee for Standardisation CEN, Brussels (May 1999).國際標

20、準化組織ISO，日內瓦和歐洲標準化委員會CEN，布魯塞爾(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：潔凈室及相關受控環境-部分2：為認證與ISO 14644-1 連續的相符性的測試和監測技術要求。International Organisation for Standa

21、rdisation ISO, Geneva and European Committee for Standardisation (September 2000).國際標準化組織ISO、日內瓦和歐洲標準化委員會(2000年9月)。1.Area of operation/Items HVAC for medicinal products操作區域/項目醫藥產品的HVAVNotes注意點Crucial questions關鍵問題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巡檢比較設計規范、圖紙(SMF)和現實的差異，計劃外維護、變更控制和接下來的項目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，為生產醫藥產品配備HVAC的房間?n Location of filters 過

23、濾器位置n Position of inlets and air return 空氣進入和返回的位置n Dust extractors,吸塵器n Pressure differences (across filters, between production and adjacent rooms) 壓力差（整個過濾器，生產與相鄰房間之間）n Logbooks-maintenance and calibration 日志-維護和保養n Monitoring of other process parameters 其他工藝參數監控n HVAC alarm systems functionHVAC報

24、警系統功能How do you challenge your alarm systems? 如何挑戰報警系統？Place and procedure for sampling? 采樣地點和過程？Where and how do you weigh and refill starting materials?在哪里以及如何權衡和補充材料?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 附錄1 -29, 附錄 2-141.Area of operation/Items HVAC for me

25、dicinal products操作區域/項目醫藥產品的HVAVNotes注意點Crucial questions關鍵問題Supporting documents支持性文件1.4Monitoring of HVAC systems監控HVAC系統n Environmental monitoring (particles, micro organ, humidity, temperature)環境監測(粒子、微器官、濕度、溫度)n Chemical residue testing 化學殘留檢測Guide 4.15, Annex 1 4-6, 1.5Maintenance and calibrat

26、ion of HVAC systemsHVAC系統的維護和校準n Maintenance program 維護方案n Calibration program校準方案n SOP´s n Records 記錄n Breakdown/Emergency including challenges of alarm systems故障/緊急情況包括報警系統的挑戰The interaction between unplanned maintenance and requalification計劃外維護和重新驗證的相互作用Guide 3.411.6Documentation for HVAC sy

27、stemsHVAC系統的文件n Technical data 技術數據n SOP, records-maintenance, calibration, validation, monitoring, deviations, change control SOP、記錄-維護、校準、驗證、監控、偏差、變更控制n Validation protocols and reports 驗證計劃n Asbuilt engine drawing竣工引擎圖Guide 4.1, 4.26, 4.28, 4.292.Area of operation/Items Pharmaceutical water syste

28、m操作區域/制藥項目水系統Notes注意點Crucial questions關鍵問題Supporting documents支持性文件2.1Key design parameters關鍵設計參數WFI n Weld quality 焊接質量n Passivation of pipeworks 管道工程的鈍化處理n Vent filters 空氣過濾器All kinds of pharmaceutical water 各種各樣的制藥用水n Suitability of construction materials建筑材料的適用性n Slope of pipeworks 管道工程的坡度n Reci

29、rculation at adequate velocity and temperature 在適當的速度和溫度循環n Sanitary joints 衛生環節n Capacity x daily demand 產能x的日常需求n Valves 閥門n Draining /flushing 排水/沖洗n Samplings ports采樣端What are the design features that prevent entrainment? 防止夾帶的設計特點是什么？Who owns the system?誰有這個系統？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-高純水系統的檢查指導附錄 1-35 附錄15 9,102.2Qualification驗證DQ, IQ, OQ, PQ AND COMPUTER VALIDATION IF NEEDEDDQ, IQ, OQ, PQ和如果需要計算機驗證All qualification completed?所有驗證已完成？3.3.4, 3.38, 5.22, 5.24 Annex 15 2-18.2.Area of operation/Items Pharmaceutica

31、l water system操作區域/制藥項目水系統Notes注意點Crucial questions關鍵問題Supporting documents支持性文件2.2n Drawing, with all sampling points 所有取樣點的圖紙n Setting operation and cleaning parameters-I. Stage 安裝操作和清洗參數-I階段n CONSISTENTLY PRODUCING WATER OF DESIRED QUALITY連續生產所需質量的水For existing systems, show me deviation and chan

32、ge control reports? 對于現有系統，出示偏差和變更控制報告？Does staff understand what, how and why the work is performed? 員工是否了解如何以及為什么執行工作嗎?What do signatures mean?簽名意味著什么？2.3Walk round inspection 巡檢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? 是否根據Ph. Eur用于指導制藥用水質量記錄的要求生產和使用注射用水？n Water quality grade and purposes of its use水質量等級和其使用的目的n feed water 鍋爐水n pre- treatment 前處理n distillation sight glass 蒸餾觀察鏡n storage tank-filter, break valve, Q-spray ball 存儲槽過濾器、截止閥、Q-噴霧球n distribution loop-temp, conductivity, TOC 水溫

34、循環分布、電導率、TOCHow is the system kept in a validated state? 系統如何保持在一個驗證的狀態？Let me have a look in the sight glass! 看看觀察鏡Show me records of alarms that have occurred!出示已經發生的警報記錄Ph. Eur. current edition CPMP - Note for Guidance on Quality of Water for Pharmaceutical Purposes Annex 1 35Ph. Eur. 現行版本 CPMP 用

35、于指導制藥用水質量的記錄附錄 1 352.Area of operation/Items Pharmaceutical water system操作區域/制藥項目水系統Notes注意點Crucial questions關鍵問題Supporting documents支持性文件2.3Confront differences between drawings and reality, unplanned maintenance and change control. 面對圖紙與現實之間的差異，計劃外維護和變更控制。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.從預處理系統到使用點：在每個部分，檢查泄漏、采樣點（進入）、誰做什么、啟動和關閉、清潔/消毒/滅菌、生產數量。n heat exchanger-integrity 熱交換器完整性n user points-number, design and location 用戶點次量、

37、設計和位置n control system-alarms, record of action, set points and demonstration 控制系統-報警、行動的記錄、設置點和演示n monitoring print outs 監控打印n DISINFECTION? HOT WATER? STEAM? CONTINUOUS RECIRCULATION?消毒？熱水？蒸汽？連續循環？2.4Quality control testing質量控制測試n PROGRAMME, INCLUDING TEST METHODS 計劃，包括測試方法2.Area of operation/Items

38、 Pharmaceutical water system操作區域/制藥項目水系統Notes注意點Crucial questions關鍵問題Supporting documents支持性文件2.4n SCHEDULE? 計劃表n SAMPLING, WHO TAKES SAMPLES, RAINING, VOLUME SAMPLED, HANDLING OF SAMPLES 取樣、誰取走樣品、下雨、取樣體積、樣品的處理n Limits (micro, chemical, endotoxin) 限制（基本的、化工、內毒素）n Out of spec. results (OOS) 超標的結果（OOS

39、）n Trending of results 結果的趨勢n Check that all points are sampled over time, accessibility to sampling points隨著時間的推移，所有點都被取樣，無障礙取樣點How do you perform sampling (handling, volume, done by, all points covered)? 如何執行取樣（處理、體積、所有點覆蓋）？What are alert, action limits? 警報是什么，行動限制嗎？Source water testing?源水測試？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. 現行版本 CPMP 用于指導制藥用水質量的記錄3.43, 4.15, 4.22, 6.72.5Monitoring監控n Temperature 溫度n Speed 速度n Vent filters空氣過濾器n DI column regeneration DI柱平衡n pH n UV light (PW)紫外線n Conductivity 電

41、導率n Leakage 滲漏n TOC總有機碳By whom and how are corrective actions made?由誰并如何完成糾正措施？Guide 4.15 Annex 1 442.Area of operation/Items Pharmaceutical water system操作區域/制藥項目水系統Notes注意點Crucial questions關鍵問題Supporting documents支持性文件2.6Maintenance and calibration of water systems水系統的維護和校準n Maintenance program 維護計

42、劃n Calibration programme校準計劃n SOP´s n Records 記錄n Breakdown/Emergency including challenges of alarm systems故障/緊急情況包括報警系統的挑戰The interaction between unplanned maintenance and requalification計劃外維護和再驗證之間的相互作用Guide 3.412.7Documentation文件n Drawing up to date (SMF?) 最新圖紙（SMF）n OOS evaluation OOS評價n De

43、viation reports 偏差報告n Change control reports變更控制報告n Operation of the system 系統的操作n Cleaning / sanitation / sterilisation 清潔/衛生/滅菌n Logbook monitoring parameters- see 1.6, incidents, filter changes, shut down periods, cleaning/sanitation, maintenance日志監控參數見1.6，事件、過濾器的變化、關閉時間、清潔/衛生、維護Guide 5.38 Guide

44、4.1, 4.26,4.28, 4.293.Area of operation/Items Pharmaceutical steam system操作區域/制藥項目蒸汽系統Notes注意點Crucial questions關鍵問題Supporting documents支持性文件3.1Key design parameters關鍵設計參數n entrainment prevention夾帶預防n cross contamination factory/ clean steam 交叉污染工廠/清潔蒸汽n non condensable gases reduction 不凝結的氣體減少n slop

45、e of pipeworks 管道工程的坡度n no dead legs 無死角Guide 3.10 Annex 15 9-103.2Qualification驗證DQ, IQ, OQ, PQ AND COMPUTER VALIDATION IF NEEDED THE SCOPE OF VALIDATIONDQ, IQ, OQ, PQ和如果需要計算機驗證驗證范圍All qualification completed? 所有驗證已完成？For existing systems, show me deviation and change control reports對于現有系統，出示偏差和變更控

46、制報告？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)? 巡檢什么樣的蒸汽用于醫藥產品的生產工廠，清潔蒸汽發生器）？n FEED WATER-TYPE, LEVEL, TEMPERATURE 鍋爐水水型、級別、溫度n Sample points- location, number, access 采樣點位置、數量、留樣n Sys

47、tem for removal of air loop空氣循環清除系統3.Area of operation/Items Pharmaceutical steam system操作區域/制藥項目蒸汽系統Notes注意點Crucial questions關鍵問題Supporting documents支持性文件3.3What kind of source water is used for production of steam? 什么樣的源水用于生產蒸汽？Confront differences between drawings and reality, unplanned maintenan

48、ce and change control. 面對圖紙與現實之間的差異，計劃外維護和變更控制。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.遵循系統邏輯順序。注意泄漏、采樣點（留樣）、誰做什么、啟動和關閉、清潔/消毒/滅菌）、生產數量。3.Area of operation

49、/Items Pharmaceutical steam system操作區域/制藥項目蒸汽系統Notes注意點Crucial questions關鍵問題Supporting documents支持性文件3.4Monitoring監控n control of entrainment 夾帶控制n level control of feed water 鍋爐水的控制級別n pressure control inside still 內部壓力控制n temperature 溫度n filters 過濾器n blown down frequency刮倒頻率n emergency shutdown and

50、 start up緊急關閉和啟動Guide 4.153.5Quality control testing質量控制測試n methods (contains non condensable gases and additives) 方法（包含不凝結的氣體和添加劑）n limits 范圍n sampling 取樣n OOS results OOS結果n Trending results 結果趨勢Guide 3.43, 4.15, 4.22, 6.7 Annex 1- 683.6Maintenance and calibration of the system系統的維護和校準n Maintenanc

51、e program 維護計劃n Calibration programme校準計劃n SOP´s n Records 記錄n Breakdown/Emergencyincluding challenges of alarm systems故障/緊急情況包括報警系統的挑戰The interaction between unplanned maintenance and requalification計劃外維護和再驗證之間的相互作用Guide 3.413.7Documentation文件n Drawing up to date (SMF?) 最新圖紙（SMF）n OOS evaluati

52、on OOS評價n Deviation reports 偏差報告n Change control reports 變更控制報告Guide 4.1, 4.26, 4.28, 4.293.Area of operation/Items Pharmaceutical steam system操作區域/制藥項目蒸汽系統Notes注意點Crucial questions關鍵問題Supporting documents支持性文件3.7n Operation of the system 系統的操作n Cleaning / sanitation / sterilisation 清潔/衛生/滅菌n Logboo

53、k - monitoring parameters - see 1.6, incidents, filter changes, shut down periods, cleaning / sanitation, maintenance日志監控參數見1.6，事件、過濾器的變化、關閉時間、清潔/衛生、維護4.Area of operation/Items Pharmaceutical gases操作區域/制藥項目氣體Notes注意點Crucial questions關鍵問題Supporting documents支持性文件4.1Key design parameters關鍵設計參數n air inlet-source, contamination risks n filters (pre final) n suitability of materials n welding n prevention of contamination