Performance Qualification (PQ) Protocol性能確認(PQ)方案Equipment NO.設(shè)備編號：EU-SB-S-07NO.編號：PQP-EU-UT-002Project Name項目名稱Manufacture Name制造商名稱Index目錄1.Introduction介紹52.Purpose目的73.Scope范圍83.1Scope范圍內(nèi)83.2Exclusion of Scope范圍外94.Responsibilities職責94.1Austar Responsibilities奧星職責94.2HGPF Responsibilities哈藥總廠職責95.Abbreviations縮略語116.Regulation and Guidance法規(guī)和指南137.References參考文件148.System Description系統(tǒng)/設(shè)備描述198.1System Use系統(tǒng)用途198.2Operation and Design Features運行和設(shè)計特點229.Validation Strategy驗證策略259.1Performance Qualification Flow性能確認流程259.2PQ sampling plan性能確認取樣計劃2510.Documentation Control Specification文件管理規(guī)范3911.Test List測試項目列表4312.Performance Qualification Tests性能確認測試4512.1Prerequisites Verification先決條件確認4512.2Personnel Verification人員確認4712.3SOP Verification SOP確認4812.4Training Verification培訓確認5112.5Testing Instrument Calibration Verification測試用儀器儀表校準確認5312.6System Operation Parameters Verification系統(tǒng)運行參數(shù)確認5512.7Sanitization Verification消毒確認5612.8The Water quality for pre-treatment System Verification預(yù)處理水質(zhì)認5912.9PW Quality Verification純化水質(zhì)量確認6113.Deviation Handling偏差處理6614.Change Handling變更處理6615.Summary of PQ性能確認總結(jié)6616.List of Attachment測試報告附件68Test Report 1 測試報告170Test Report 2 測試報告274Test Report 3 測試報告376Test Report 4 測試報告479Test Report 5 測試報告581Test Report 6 測試報告683Test Report 7 測試報告786Test Report 8 測試報告888Test Report 9 測試報告9911. Introduction介紹Harbin Pharmaceutical Group General Pharmaceutical Factory (hereinafter called HGPF) is establishing a new production building in accordance with the Chinese GMP and EU GMP requirements. Shanghai Austar is responsible for detailed design and construction of new Purified Water Generation Storage and Distribution System in this plant, and it is used for providing water for production of sterile powder for injection on second floor and QC lab on forth floor. This system is designed for circulating 24hours, and sterilized by pasteurization for one hour each time. It has emptying ability and 33 points of use. A set of 3.5m3/h purified water generator is installed in water generation room, and the generated PW is stored in a 6m3 vertical storage tank. Control system can monitor critical parameter of conductivity on line. It has the functions of automatic alarm and automatic discharging of water out of specification. When the generation stopped, volume of purified water in the system can still be use for about 1 day.哈藥集團制藥總廠（以下簡稱哈藥總廠）正在新建一個滿足中國GMP和歐盟GMP的生產(chǎn)樓。該車間新建純化水制備、儲存和分配系統(tǒng)由上海奧星制藥裝備有限公司負責詳細設(shè)計和施工，主要用于二樓無菌粉針的生產(chǎn)和四樓化驗室用水。該系統(tǒng)設(shè)計為24小時循環(huán)系統(tǒng)，采用1小時巴氏消毒，并保證有排空能力，該系統(tǒng)共有33個使用點。純化水制備機制備速度為3.5m3/h，制備的純化水貯存在一個容積6m3的立式儲罐內(nèi)。控制系統(tǒng)對純化水的關(guān)鍵參數(shù)如電導率能夠進行在線監(jiān)控，有自動報警和超標自動排放功能。當供水停止時，儲存和分配系統(tǒng)中的儲水大概可供正常使用1天的時間。The Purified water Generation System (System Number: EU-UT-001) and Purified water Storage and Distribution System (System Number: EU-UT-002) is system is determined to be direct impact system according to system impact assessment method. See SIAR-EU-2011-00.該純化水制備系統(tǒng)（系統(tǒng)編號EU-UT-001）和純化水儲存和分配系統(tǒng)（系統(tǒng)編號EU-UT-002）根據(jù)系統(tǒng)影響評估的方法確定為直接影響系統(tǒng)，見SIAR-EU-2011-00。Before Performance Qualification of Purified water System is performed, Installation Qualification and Operation Qualification should have been completed. Installation Qualification of Purified water Generation System (Document No.: IQR-EU-UT-001, Version: 0). Installation Qualification of Purified water Storage and Distribution System (Document No.: IQR-EU-UT-002, Version: 0). Operational Qualification of Purified water Generation System (Document No.: OQR-EU-UT-001, Version: 0). Operational Qualification of Purified water Storage and Distribution System (Document No.: OQR-EU-UT-002, Version: 0).該純化水系統(tǒng)的性能確認前，安裝確認和運行確認應(yīng)該已經(jīng)已經(jīng)完成。純化水制備系統(tǒng)安裝確認報告（報告名稱：IQR-EU-UT-001，版本:0）；純化水儲存和分配系統(tǒng)安裝確認報告（報告名稱：IQR-EU-UT-002，版本:0）；純化水制備系統(tǒng)運行確認報告（報告名稱：OQR-EU-UT-001，版本:0）；純化水儲存和分配系統(tǒng)運行確認報告（報告名稱: OQR-EU-UT-002，版本:0）。2. Purpose目的This Performance Qualification is prospective validation of new Purified Water System of EU Powder for Injection Plant.本性能確認為EU粉針車間純化水儲存和分配系統(tǒng)新建后前驗證。The purpose of this Performance Qualification Protocol is to provide documented evidence to verify that Purified Water System, used in new EU Powder for Injection Plant of HGPF can consistently produce qualified purified water in compliance with requirements specified in Chinese Pharmacopoeia 2010 , and to determine the applicability of SOP for purified water System and continuous stability of system operation. 本性能確認方案的目的是提供文件證據(jù)證明哈藥總廠新建EU粉針車間內(nèi)純化水系統(tǒng)能持續(xù)產(chǎn)出符合中國藥典CP 2010版的相關(guān)規(guī)定和要求的純化水，并確定純化水系統(tǒng)SOP的適用性和系統(tǒng)設(shè)備運行的持續(xù)穩(wěn)定性。Performance test shall be performed under real production condition, and verification data shall be collected and recorded in attached test report. PQ is the last step of formal test and providing documented evidence for system (for which PQ is required in qualification requirement matrix) with correct performance before formal operation. When the final PQ report is approved, this system can be used for normal production operation or process validation.性能測試應(yīng)在真實生產(chǎn)條件下進行，應(yīng)收集確認數(shù)據(jù)并記錄在附件的測試報告上。PQ是正式測試的最后步驟，以及確認需求矩陣中識別為進行PQ測試的系統(tǒng)正式運行前正確性能的文件證據(jù)。當最終PQ報告批準后，系統(tǒng)可用于正常生產(chǎn)操作或用于工藝驗證。3. Scope范圍 3.1 Scope范圍內(nèi)The scope of this Performance Qualification includes the Purified Water Generation System (System Number: EU-UT-001) and Purified Water Storage and Distribution System (System Number: EU-UT-002). It will be performed in the method of three phases. Sampling plan of Phase 1 and Phase 2 and sanitization qualification of Phase 1, Phase 2 and Phase 3 the three phases are described in details in this Protocol.本性能確認的范圍為哈藥總廠EU粉針車間純化水制備系統(tǒng)（系統(tǒng)編號EU-UT-001）和純化水儲存和分配系統(tǒng)（系統(tǒng)編號EU-UT-002）。該純化水系統(tǒng)將按照三階段法進行，本方案詳細描述了性能確認階段1和階段2的取樣計劃和階段1、階段2、階段3，三個階段消毒確認。3.2 Exclusion of Scope范圍外The followings are not included in this Performance Qualification Protocol:下述內(nèi)容未包含在本性能確認方案中： The Phase 3 Performance Qualification shall take samples as per the routine monitoring plan of HGPF EU Powder for Injection Plant, and the sampling plan of Phase 3 is not listed in this Protocol.該純化水系統(tǒng)的階段3的性能確認主要按照哈藥總廠EU粉針車間日常監(jiān)測計劃計劃進行取樣，本方案沒有詳細制定階段3的取樣計劃。4. Responsibilities職責4.1 Austar Responsibilities奧星職責 Protocol compilation方案的編寫。4.2 HGPF Responsibilities哈藥總廠職責 Review and approval of this protocol before execution執(zhí)行前審核和批準本方案。 Execution of this protocol執(zhí)行本方案。 Assuring the satisfaction of any prerequisites before execution保證在執(zhí)行前所有的先決條件得到滿足。 Assuring the operation of utilities保證公用系統(tǒng)的運行。 Critical and non-critical measurement, recording and calibration of control instrument關(guān)鍵和非關(guān)鍵的測量、記錄和控制儀表的校準。 Deviation report compilation偏差報告編寫。 Test data analysis測試數(shù)據(jù)的分析。 Final report compilation最終報告編寫。 Review and approve report審核和批準報告。5. Abbreviations縮略語The abbreviations which will be used in this protocol are listed in the following form.在下面的表格中規(guī)定了本方案中使用的縮略語。Abbreviations縮略語Definition定義CPChinese Pharmacopoeia中國藥典DQDesign Qualification設(shè)計確認EUEuropean Union歐洲聯(lián)盟GMPGood Manufacturing Practice 藥品生產(chǎn)質(zhì)量管理規(guī)范GAMPGood Automated Manufacturing Practice良好自動化生產(chǎn)實踐指南IQInstallation Qualification安裝確認ISPEInternational Society for Pharmaceutical Engineering國際制藥工程協(xié)會N/ANon Applicable不適用OQOperational Qualification 運行確認P&IDPiping and Instrumentation Diagram儀表和管路圖PQPerformance Qualification 性能確認SFDAState Food and Drug Administration國家食品藥品管理局SIASystem Impact Assessment系統(tǒng)影響評估SOPStandard Operating Procedure標準操作程序PWPurified Water純化水WFIWater for Injection注射用水6. Regulation and Guidance法規(guī)和指南To write this protocol the following regulation and guidance have been used為編寫本方案，參考了以下法規(guī)和指南：l Chinese Pharmacopoeia (CP) 2010 Edition, January 2010 國家藥典委員會，中國，中國藥典（CP）2010年版，2010年01月l State Food and Drug Administration (SFDA), China, Good Manufacturing Practice (2010 Revision), March, 2011國家食品藥品監(jiān)督管理局（SFDA ），中國，藥品生產(chǎn)質(zhì)量管理規(guī)范（2010年修訂），2011年03月l Guidance of Good Manufacturing Practice for Drug,China,2011藥品GMP指南 ，中國，2011l EudraLex - Volume 4, Good manufacturing practice (GMP) Guidelines, Annex 15: Qualification and Validation , September 2001歐盟藥事法規(guī) 第四卷 藥品生產(chǎn)質(zhì)量管理規(guī)范，附錄15 驗證與確認，2001年9月l EudraLex Volume 4 EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, November, 2008EudraLex 第四卷歐盟藥品生產(chǎn)質(zhì)量管理規(guī)范指南 醫(yī)藥產(chǎn)品人用及獸用，2008年11月l ISPE Baseline Guide Volume 5 Commissioning and Qualification, First Edition 2001ISPE指南第5卷“調(diào)試和確認” 2001年第一版l (ISPE)Pharmaceutical Engineering Guides for New and Renovated facilities, Volume 4: Water and steam systems，2011 the second edition(ISPE)新建和改造的工廠醫(yī)藥工程指南，第4卷-水和蒸汽系統(tǒng)，2011年第二版l ISPE-GPG：Commissioning and Qualification of Pharmaceutical Water and Steam SystemsISPE-GPG:制藥用水和蒸汽的調(diào)試與確認指南7. References參考文件 To write this protocol the following reference documents have been used:為編寫本方案，參考了以下文件： Document Name文件名稱Document No.文件編號Version Number版本Effective Date生效日期Validation Master Plan驗證主計劃VMP-EU-2011-00SIA of EU Powder for Injection PlantEU粉針車間SIASIA-EU-2011-00P&ID Drawing for PW Generation System純化水制備系統(tǒng)P&ID圖SAP09013W251-P&IDP&ID Drawing for PW Storage and Distribution System純化水儲存和分配系統(tǒng)P&ID圖C1022-D51231PW Points of Use Drawing純化水系統(tǒng)用點圖C1022-D51232PW and PW Sampling and Analysis Operating Procedure of EU Powder for Injection PlantEU車間純化水和純化水取樣送檢操作程序PW Description Test Procedure純化水性狀檢測程序PW PH Test Procedure純化水pH值檢測程序PW Nitrate Test Procedure純化水硝酸鹽檢測程序PW Nitrite Test Procedure純化水亞硝酸鹽檢測程序PW Ammonia Content Test Procedure純化水氨含量檢測程序PW Conductivity Test Procedure純化水電導率檢測程序PW TOC Test Procedure純化水總有機碳檢檢測程序PW Nonvolatile Matter Test Procedure純化水不揮發(fā)物檢測程序PW Heavy Metal Content Test Procedure純化水重金屬含量檢測程序PW and PW Microbial Limit Test Procedure純化水和純化水微生物限制檢測程序8. System Description系統(tǒng)/設(shè)備描述8.1 System Use系統(tǒng)用途The system is the new PW Generation and Storage and Distribution System in EU Powder for Injection Plant of HGPF. A set of 3.5m3/h purified water generator is installed in water generation room on second floor, and the generated PW is stored in a 6m3 vertical storage tank. Liquid level is controlled by level switch. If the level is higher than set value, the switch will close the inlet valve automatically. If the level is lower than the set value, the inlet valve will be opened to supplement water. The system has only one branch used for entire production building. One set of circulation pump transfers the water from storage tank, then pass through SKID and to the use points via loop. At last the water will return to the storage tank via SKID and a spray ball. The system operates at a normal temperature and it has 33 points of use. There are 30 POUs for cleaning use, 1 for pure steam generator water supply, 1 for Purified Water Generation water supply, one for air conditioning and wet,The main compositions of system are as follows: 本系統(tǒng)為哈藥總廠EU粉針車間新建純化水制備、儲存和分配系統(tǒng)。在車間二層制水間安裝有一套3.5m3/h純化水制備機，制備的純化水貯存在一個容積6m3的立式儲罐內(nèi)，儲罐設(shè)置了液位開關(guān)來控制液位，當儲罐高于設(shè)定值時，該開關(guān)將自動關(guān)閉進水閥，當儲罐內(nèi)液位降低到設(shè)定點時，進水閥自動打開進行補水。系統(tǒng)只有一個支路，供整個生產(chǎn)樓使用。一臺循環(huán)泵從儲罐中取水，先經(jīng)過SKID，然后通過環(huán)路去往各使用點，最后通過SKID和1個噴淋球回到儲罐中，該系統(tǒng)保持常溫運行，共有33個使用點。其中有30個供衛(wèi)生清洗使用，1個用于純蒸汽發(fā)生器供水，1個用于多效蒸餾水機供水，1個用于空調(diào)加濕。 No. 序號Room 房間Use 用途PW01NR-W201二樓水制備間純蒸汽發(fā)生器PW02NR-W201二樓水制備間多效蒸餾水機PW03CR-D205二樓氣閘（洗瓶）水池PW04CR-D207二樓更衣間（洗衣）水池PW05CR-D206二樓洗衣干衣間水池PW06CR-D206二樓洗衣干衣間洗脫烘一體機PW07CR-D208二樓脫鞋脫衣間（分裝女）水池PW08CR-D209二樓脫鞋脫衣間（分裝男）水池PW09CR-D211二樓外清間1水池PW10CR-D212二樓更衣間（清洗區(qū)傳遞）水池PW11CR-D213二樓脫鞋脫衣間（清洗）水池PW12 CR-C212二樓清洗間1水池PW13CR-C209二樓滅菌間（軋蓋）器具清洗機PW14一樓脫鞋脫衣區(qū)（取樣）水池PW15一樓外清間（取樣）水池PW16CR-D214二樓脫鞋脫衣間（消毒液）水池PW17CR-C227二樓消毒液配制間水池PW18CR-D215二樓防爆門斗（物流）甩頭PW19CR-D216二樓脫鞋脫衣間（軋蓋）水池PW20CR-D217二樓更衣間（外清3）水池PW21CR-C208二樓清洗間3水池PW22CR-D218二樓外清間3水池PW23三樓空調(diào)間空調(diào)加濕PW24CR-D202二樓清洗間2水池PW25CR-D204二樓更衣間（洗瓶）水池PW26四樓脫鞋脫衣區(qū)水池PW27四樓清洗間水池PW28四樓洗滌室2水池PW29四樓更衣間水池PW30四樓脫鞋脫衣區(qū)水池PW31四樓廢液間水池PW32四樓洗滌室水池PW33四樓理化室水池PW34二樓水制備間 總出水點PW35二樓水制備間 總回水點8.2 Operation and Design Features運行和設(shè)計特點The PW distribution system is designed for circulating 24 hours at normal temperature, and storage tank has installed pressure gauge, level sensor, temperature sensor and respirator. PW generation system can supply water automatically for level variations. The generation system start to work when water level of the tank is below 30%. When water level of the tank is up to 80%, it stopped. Rotary spray ball is installed on the water return inlet of storage tank to avoid cleaning deadlegs within the tank.該純化水分配系統(tǒng)設(shè)計為24小時常溫循環(huán)運行，純化水儲罐上安裝有壓力表、液位傳感器、溫度傳感器和呼吸器，純化水制備系統(tǒng)可根據(jù)液位的變化自動給儲罐補水。當儲罐液位低于30%，制備系統(tǒng)開始工作，當儲罐液位高于80%，制備系統(tǒng)停止供水。儲罐回水口安裝有旋轉(zhuǎn)噴淋球避免儲罐內(nèi)出現(xiàn)清洗死角。Pressure gauge is installed after the circulation pump to monitor the supplied water pressure. Pressure gauge, temperature sensor, conductivity and flow meter are installed on the loop. Circulation pump is interlocked with the flow meter for return water, so the return water flow rate can be frequency-controlled automatically and maintained above 1m/s. Liquid level, conductivity, flow volume, temperature are monitored by PLC and HMI with appropriate alarming. The data can be printed and downloaded on computer.循環(huán)泵后安裝有壓力表監(jiān)測供水壓力，回路安裝有壓力表、溫度傳感器、電導率、流量計。循環(huán)泵與回水流量計連鎖控制，可自動變頻以維持回水流速大于1m/s。儲罐液位、電導率、流量、溫度參數(shù)均是由PLC和HMI進行監(jiān)控并設(shè)置有適當?shù)膱缶瑪?shù)據(jù)可打印并用電腦下載。The PW Distribution System adopts pasteurization, and UV lamp installed on return water pipe can inhibit the growth of microorganism. The entire system is installed with assurance of drainage.分配系統(tǒng)可以通過一個自動控制的程序進行巴氏消毒，回水管路安裝有UV燈可抑制微生物的滋生。整個系統(tǒng)的安裝被保證具有排水能力。System instruments which can be monitored via PLC of PW Generation and Distribution System and alarming can be generated, include: 純化水制備和分配系統(tǒng)通過可編程控制器（PLC）進行監(jiān)控并可生成報警的系統(tǒng)儀表包括：l Storage tank level and temperature儲罐液位和溫度l PW return water temperature純化水回水溫度l PW return water conductivity純化水回水電導率l PW return water flow rate純化水回水流量l PW return water TOC 純化水回水TOCPW tank and distribution pipeline pressure can be indicated only on site, but can not be monitored via PLC純化水儲罐和分配管網(wǎng)壓力只能現(xiàn)場指示，不能進行可編程控制器（PLC）監(jiān)控。Critical operation parameters of PW Storage and Distribution System can be stored and printed, such as conductivity and operation temperature純化水儲存和分配系統(tǒng)的關(guān)鍵運行參數(shù)電導率、運行溫度可進行存儲并打印。9. Validation Strategy驗證策略9.1 Performance Qualification Flow性能確認流程9.1.1. IQ、OQ Review: Review the IQ and OQ of this sytem before PQ beginning. PQ can begin after IQ and OQ completed successfully.IQ、OQ 審核 :在開始性能確認前審核該系統(tǒng)的安裝和運行確認，成功完成后才能開始性能確認。9.1.2. Standard Operating Procedure (SOP) and training document verification: before PQ execution, System Operation and Maintenance Procedure shall be available. Revew the application of SOP and update it in time during PQ execution.標準操作流程（SOP）和培訓文件確認 ：在性能確認前應(yīng)具備至少為草稿版的系統(tǒng)運行維護操作規(guī)程，在性能確認期間審核系統(tǒng)SOP的適用性，如需要及時更新。9.1.3. Calibration review: to verify that all the test equipments have been calibrated and within due date.校驗審核 ：確認所有測試設(shè)備都經(jīng)過校驗。9.1.4. System performance and water quality verification: to verify the operation of PW system is conforming to the requirements, and it can consistently produce PW conforming to the relevant requirements specified in CP2010.系統(tǒng)性能和水質(zhì)確認 ： 確定純化水系統(tǒng)的操作符合規(guī)定，能持續(xù)生產(chǎn)符合CP 2010對純化水的要求。9.1.5. Sampling plan of Phase 1 and phase 2 see 9.2 Performance Sampling Plan.純化水系統(tǒng)的性能確認將為階段1、階段2階段進行。見9.2性能取樣計劃。9.1.6. Record the critical online operation parameters of PW System once a day during PQ Phase 1 and 2, so as to verify the system is running consistently without any faults.在性能確認階段1、階段2期間每天記錄一次純化水制備、儲存和分配系統(tǒng)的關(guān)鍵在線運行參數(shù)，確認系統(tǒng)持續(xù)運行而不能出現(xiàn)故障。9.2 PQ sampling plan性能確認取樣計劃PW system PQ is performed in three phases:純化水系統(tǒng)性能確認將分為三個階段進行：Phase 1: it is an intensive sampling period of three weeks (21 days). The purpose is to verify the new PW system can consistently produce and supply PW conforming to the requirements. During Phase 1, the system shall be running continuously without any faults or performance deviations. Phase 1 sampling plan is listed in Table 1, including:階段1：階段1是一個為期三周（21天）的密集取樣期，目的是證明新建的純化水系統(tǒng)能夠持續(xù)生產(chǎn)和分配符合要求的純化水，在此期間，系統(tǒng)需要持續(xù)運行而不能出現(xiàn)故障或性能偏差。階段1取樣計劃在表1中詳細列出，包括： Testing the feed water once a quarter in three phases working period for PW system PQ. 在PQ取樣三階段內(nèi)，每季度測試一次供水。 Testing the SDI of waterproducded by multimedia, testing the free chlorine of waterproducded by the active carbon filter and testing the hardness of waterproducded by softer once weekly over a three weeks at sampling point to assess the efficacy of the multimedia, active carbon filter and softening units. 在多介質(zhì)過濾器取樣點測試產(chǎn)水的SDI，在活性炭取樣點測試產(chǎn)水的余氯，在軟化器取樣點測試產(chǎn)水的硬度，在連續(xù)三周取樣時，每周測試一次。從而評估供水處的多介質(zhì)過濾器、活性炭和軟化單元的效率。 Sampling at outlet of PW Generation everyday.在純化水機產(chǎn)水口處每天進行取樣。 Total feed water outlet (V845.7.11) and total return water outlet (V8545.9.11) of PW Storage and Distribution Loop shall be sampled everyday.純化水儲存和分配環(huán)路總供水口（V845.7.11）和總回水口（V845.9.11）每天進行取樣。 Each PW user point shall be sampled everyday.純化水每個使用點每天進行取樣。After two weeks testing, a summary of test results will be produced. If the test results comform to the requirements and the identified deviations are closed, PW can be used for process validation and/or other equipment qualification.完成二周的測試之后，對測試結(jié)果進行總結(jié)。如果測試結(jié)果符合要求并且已經(jīng)解決所發(fā)現(xiàn)的偏差情況，系統(tǒng)產(chǎn)品可供進行工藝驗證或其它設(shè)備的驗證使用。9.2.1. Phase 2: the purpose is to verify system can consistently produce and distribute qualified PW if the system operates as per the corresponding SOP. Sampling period is same with the one of Phase 1, as consistently sampling three weeks 21 days. During this period, system needs to consiste