纯化水系统性能确认（PQ）方案

1、harbin pharmaceutical group co., ltd. general pharm. factory哈药集团制药总厂performance qualification (pq) protocol性能确认(pq)方案equipment no.设备编号：eu-sb-s-07no.编号：pqp-eu-ut-002project name项目名称manufacture name制造商名称index目录1.introduction介绍52.purpose目的73.scope范围83.1scope范围内83.2exclusion of scope范围外94.responsibiliti

2、es职责94.1austar responsibilities奥星职责94.2hgpf responsibilities哈药总厂职责95.abbreviations缩略语116.regulation and guidance法规和指南137.references参考文件148.system description系统/设备描述198.1system use系统用途198.2operation and design features运行和设计特点229.validation strategy验证策略259.1performance qualification flow性能确认流程259.2pq

3、sampling plan性能确认取样计划2510.documentation control specification文件管理规范3911.test list测试项目列表4312.performance qualification tests性能确认测试4512.1prerequisites verification先决条件确认4512.2personnel verification人员确认4712.3sop verification sop确认4812.4training verification培训确认5112.5testing instrument calibration verif

4、ication测试用仪器仪表校准确认5312.6system operation parameters verification系统运行参数确认5512.7sanitization verification消毒确认5612.8the water quality for pre-treatment system verification预处理水质认5912.9pw quality verification纯化水质量确认6113.deviation handling偏差处理6614.change handling变更处理6615.summary of pq性能确认总结6616.list of at

5、tachment测试报告附件68test report 1 测试报告170test report 2 测试报告274test report 3 测试报告376test report 4 测试报告479test report 5 测试报告581test report 6 测试报告683test report 7 测试报告786test report 8 测试报告888test report 9 测试报告9911. introduction介绍harbin pharmaceutical group general pharmaceutical factory (hereinafter called

6、 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 prod

7、uction 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 ge

8、neration 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

9、in the system can still be use for about 1 day.哈药集团制药总厂（以下简称哈药总厂）正在新建一个满足中国gmp和欧盟gmp的生产楼。该车间新建纯化水制备、储存和分配系统由上海奥星制药装备有限公司负责详细设计和施工，主要用于二楼无菌粉针的生产和四楼化验室用水。该系统设计为24小时循环系统，采用1小时巴氏消毒，并保证有排空能力，该系统共有33个使用点。纯化水制备机制备速度为3.5m3/h，制备的纯化水贮存在一个容积6m3的立式储罐内。控制系统对纯化水的关键参数如电导率能够进行在线监控，有自动报警和超标自动排放功能。当供水停止时，储存和分配系统中的储水大

10、概可供正常使用1天的时间。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.该纯化水制备系统（系统编号eu-ut-001）和纯化水储

11、存和分配系统（系统编号eu-ut-002）根据系统影响评估的方法确定为直接影响系统，见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-u

12、t-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

13、 distribution system (document no.: oqr-eu-ut-002, version: 0).该纯化水系统的性能确认前，安装确认和运行确认应该已经已经完成。纯化水制备系统安装确认报告（报告名称：iqr-eu-ut-001，版本:0）；纯化水储存和分配系统安装确认报告（报告名称：iqr-eu-ut-002，版本:0）；纯化水制备系统运行确认报告（报告名称：oqr-eu-ut-001，版本:0）；纯化水储存和分配系统运行确认报告（报告名称: oqr-eu-ut-002，版本:0）。2. purpose目的this performance qualification

14、is prospective validation of new purified water system of eu powder for injection plant.本性能确认为eu粉针车间纯化水储存和分配系统新建后前验证。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 co

15、nsistently 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. 本性能确认方案的目的是提供文件证据证明哈药总厂新建eu粉针车间内纯化水系统能持续产出符合中国药典cp 2010版的相关规定和要求的纯化水

16、，并确定纯化水系统sop的适用性和系统设备运行的持续稳定性。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

17、 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.性能测试应在真实生产条件下进行，应收集确认数据并记录在附件的测试报告上。pq是正式测试的最后步骤，以及确认需求矩阵中识别为进行pq测试的系统正式运行前正确性能的文件证据。当最终pq报告批准后，系统可用于正常生产操作或用于工艺验

18、证。3. scope范围 3.1 scope范围内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 an

19、d phase 2 and sanitization qualification of phase 1, phase 2 and phase 3 the three phases are described in details in this protocol.本性能确认的范围为哈药总厂eu粉针车间纯化水制备系统（系统编号eu-ut-001）和纯化水储存和分配系统（系统编号eu-ut-002）。该纯化水系统将按照三阶段法进行，本方案详细描述了性能确认阶段1和阶段2的取样计划和阶段1、阶段2、阶段3，三个阶段消毒确认。3.2 exclusion of scope范围外the following

20、s are not included in this performance qualification protocol:下述内容未包含在本性能确认方案中： 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.该纯化水系统的阶段3的性能确认主要按照哈药总厂eu

21、粉针车间日常监测计划计划进行取样，本方案没有详细制定阶段3的取样计划。4. responsibilities职责4.1 austar responsibilities奥星职责 protocol compilation方案的编写。4.2 hgpf responsibilities哈药总厂职责 review and approval of this protocol before execution执行前审核和批准本方案。 execution of this protocol执行本方案。 assuring the satisfaction of any prerequisites before e

22、xecution保证在执行前所有的先决条件得到满足。 assuring the operation of utilities保证公用系统的运行。 critical and non-critical measurement, recording and calibration of control instrument关键和非关键的测量、记录和控制仪表的校准。 deviation report compilation偏差报告编写。 test data analysis测试数据的分析。 final report compilation最终报告编写。 review and approve repor

23、t审核和批准报告。5. abbreviations缩略语the abbreviations which will be used in this protocol are listed in the following form.在下面的表格中规定了本方案中使用的缩略语。abbreviations缩略语definition定义cpchinese pharmacopoeia中国药典dqdesign qualification设计确认eueuropean union欧洲联盟gmpgood manufacturing practice 药品生产质量管理规范gampgood automated man

24、ufacturing practice良好自动化生产实践指南iqinstallation qualification安装确认ispeinternational society for pharmaceutical engineering国际制药工程协会n/anon applicable不适用oqoperational qualification 运行确认p&idpiping and instrumentation diagram仪表和管路图pqperformance qualification 性能确认sfdastate food and drug administration国家食品药品管理

25、局siasystem impact assessment系统影响评估sopstandard operating procedure标准操作程序pwpurified water纯化水wfiwater for injection注射用水6. regulation and guidance法规和指南to write this protocol the following regulation and guidance have been used为编写本方案，参考了以下法规和指南：l chinese pharmacopoeia (cp) 2010 edition, january 2010 国家药典

26、委员会，中国，中国药典（cp）2010年版，2010年01月l state food and drug administration (sfda), china, good manufacturing practice (2010 revision), march, 2011国家食品药品监督管理局（sfda ），中国，药品生产质量管理规范（2010年修订），2011年03月l guidance of good manufacturing practice for drug,china,2011药品gmp指南 ，中国，2011l eudralex - volume 4, good manufac

27、turing practice (gmp) guidelines, annex 15: qualification and validation , september 2001欧盟药事法规 第四卷 药品生产质量管理规范，附录15 验证与确认，2001年9月l eudralex volume 4 eu guidelines to good manufacturing practice medicinal products for human and veterinary use, november, 2008eudralex 第四卷欧盟药品生产质量管理规范指南 医药产品人用及兽用，2008年1

28、1月l ispe baseline guide volume 5 commissioning and qualification, first edition 2001ispe指南第5卷“调试和确认” 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)新建和改造的工厂医药工程指南，第4卷-水和蒸汽系统，2011年第二版l ispe-gpg：commiss

29、ioning and qualification of pharmaceutical water and steam systemsispe-gpg:制药用水和蒸汽的调试与确认指南7. references参考文件 to write this protocol the following reference documents have been used:为编写本方案，参考了以下文件： document name文件名称document no.文件编号version number版本effective date生效日期validation master plan验证主计划vmp-eu-201

30、1-00sia of eu powder for injection planteu粉针车间siasia-eu-2011-00p&id drawing for pw generation system纯化水制备系统p&id图sap09013w251-p&idp&id drawing for pw storage and distribution system纯化水储存和分配系统p&id图c1022-d51231pw points of use drawing纯化水系统用点图c1022-d51232pw and pw sampling and analysis operating procedu

31、re of eu powder for injection planteu车间纯化水和纯化水取样送检操作程序pw description test procedure纯化水性状检测程序pw ph test procedure纯化水ph值检测程序pw nitrate test procedure纯化水硝酸盐检测程序pw nitrite test procedure纯化水亚硝酸盐检测程序pw ammonia content test procedure纯化水氨含量检测程序pw conductivity test procedure纯化水电导率检测程序pw toc test procedure纯化水

32、总有机碳检检测程序pw nonvolatile matter test procedure纯化水不挥发物检测程序pw heavy metal content test procedure纯化水重金属含量检测程序pw and pw microbial limit test procedure纯化水和纯化水微生物限制检测程序8. system description系统/设备描述8.1 system use系统用途the system is the new pw generation and storage and distribution system in eu powder for inje

33、ction 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 valv

34、e 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.

35、 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 a

36、nd wet,the main compositions of system are as follows: 本系统为哈药总厂eu粉针车间新建纯化水制备、储存和分配系统。在车间二层制水间安装有一套3.5m3/h纯化水制备机，制备的纯化水贮存在一个容积6m3的立式储罐内，储罐设置了液位开关来控制液位，当储罐高于设定值时，该开关将自动关闭进水阀，当储罐内液位降低到设定点时，进水阀自动打开进行补水。系统只有一个支路，供整个生产楼使用。一台循环泵从储罐中取水，先经过skid，然后通过环路去往各使用点，最后通过skid和1个喷淋球回到储罐中，该系统保持常温运行，共有33个使用点。其中有30个供卫生清洗使

37、用，1个用于纯蒸汽发生器供水，1个用于多效蒸馏水机供水，1个用于空调加湿。 no. 序号room 房间use 用途pw01nr-w201二楼水制备间纯蒸汽发生器pw02nr-w201二楼水制备间多效蒸馏水机pw03cr-d205二楼气闸（洗瓶）水池pw04cr-d207二楼更衣间（洗衣）水池pw05cr-d206二楼洗衣干衣间水池pw06cr-d206二楼洗衣干衣间洗脱烘一体机pw07cr-d208二楼脱鞋脱衣间（分装女）水池pw08cr-d209二楼脱鞋脱衣间（分装男）水池pw09cr-d211二楼外清间1水池pw10cr-d212二楼更衣间（清洗区传递）水池pw11cr-d213二楼脱鞋脱

38、衣间（清洗）水池pw12 cr-c212二楼清洗间1水池pw13cr-c209二楼灭菌间（轧盖）器具清洗机pw14一楼脱鞋脱衣区（取样）水池pw15一楼外清间（取样）水池pw16cr-d214二楼脱鞋脱衣间（消毒液）水池pw17cr-c227二楼消毒液配制间水池pw18cr-d215二楼防爆门斗（物流）甩头pw19cr-d216二楼脱鞋脱衣间（轧盖）水池pw20cr-d217二楼更衣间（外清3）水池pw21cr-c208二楼清洗间3水池pw22cr-d218二楼外清间3水池pw23三楼空调间空调加湿pw24cr-d202二楼清洗间2水池pw25cr-d204二楼更衣间（洗瓶）水池pw26四楼脱

39、鞋脱衣区水池pw27四楼清洗间水池pw28四楼洗涤室2水池pw29四楼更衣间水池pw30四楼脱鞋脱衣区水池pw31四楼废液间水池pw32四楼洗涤室水池pw33四楼理化室水池pw34二楼水制备间 总出水点pw35二楼水制备间 总回水点8.2 operation and design features运行和设计特点the pw distribution system is designed for circulating 24 hours at normal temperature, and storage tank has installed pressure gauge, level sens

40、or, 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 in

41、let of storage tank to avoid cleaning deadlegs within the tank.该纯化水分配系统设计为24小时常温循环运行，纯化水储罐上安装有压力表、液位传感器、温度传感器和呼吸器，纯化水制备系统可根据液位的变化自动给储罐补水。当储罐液位低于30%，制备系统开始工作，当储罐液位高于80%，制备系统停止供水。储罐回水口安装有旋转喷淋球避免储罐内出现清洗死角。pressure gauge is installed after the circulation pump to monitor the supplied water pressure. pre

42、ssure 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, te

43、mperature are monitored by plc and hmi with appropriate alarming. the data can be printed and downloaded on computer.循环泵后安装有压力表监测供水压力，回路安装有压力表、温度传感器、电导率、流量计。循环泵与回水流量计连锁控制，可自动变频以维持回水流速大于1m/s。储罐液位、电导率、流量、温度参数均是由plc和hmi进行监控并设置有适当的报警，数据可打印并用电脑下载。the pw distribution system adopts pasteurization, and uv l

44、amp installed on return water pipe can inhibit the growth of microorganism. the entire system is installed with assurance of drainage.分配系统可以通过一个自动控制的程序进行巴氏消毒，回水管路安装有uv灯可抑制微生物的滋生。整个系统的安装被保证具有排水能力。system instruments which can be monitored via plc of pw generation and distribution system and alarming c

45、an be generated, include: 纯化水制备和分配系统通过可编程控制器（plc）进行监控并可生成报警的系统仪表包括：l storage tank level and temperature储罐液位和温度l pw return water temperature纯化水回水温度l pw return water conductivity纯化水回水电导率l pw return water flow rate纯化水回水流量l pw return water toc 纯化水回水tocpw tank and distribution pipeline pressure can be in

46、dicated only on site, but can not be monitored via plc纯化水储罐和分配管网压力只能现场指示，不能进行可编程控制器（plc）监控。critical operation parameters of pw storage and distribution system can be stored and printed, such as conductivity and operation temperature纯化水储存和分配系统的关键运行参数电导率、运行温度可进行存储并打印。9. validation strategy验证策略9.1 perf

47、ormance qualification flow性能确认流程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 审核 :在开始性能确认前审核该系统的安装和运行确认，成功完成后才能开始性能确认。9.1.2. standard operating procedure (sop) and training document verification: before pq execu

48、tion, system operation and maintenance procedure shall be available. revew the application of sop and update it in time during pq execution.标准操作流程（sop）和培训文件确认 ：在性能确认前应具备至少为草稿版的系统运行维护操作规程，在性能确认期间审核系统sop的适用性，如需要及时更新。9.1.3. calibration review: to verify that all the test equipments have been calibrated

49、 and within due date.校验审核 ：确认所有测试设备都经过校验。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.系统性能和水质确认 ： 确定纯化水系统的操作符合规定，能持续生产符合

50、cp 2010对纯化水的要求。9.1.5. sampling plan of phase 1 and phase 2 see 9.2 performance sampling plan.纯化水系统的性能确认将为阶段1、阶段2阶段进行。见9.2性能取样计划。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 fault

51、s.在性能确认阶段1、阶段2期间每天记录一次纯化水制备、储存和分配系统的关键在线运行参数，确认系统持续运行而不能出现故障。9.2 pq sampling plan性能确认取样计划pw system pq is performed in three phases:纯化水系统性能确认将分为三个阶段进行：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 p

52、w 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:阶段1：阶段1是一个为期三周（21天）的密集取样期，目的是证明新建的纯化水系统能够持续生产和分配符合要求的纯化水，在此期间，系统需要持续运行而不能出现故障或性能偏差。阶段1取样计划在表1中详细列出，包括： testin

53、g the feed water once a quarter in three phases working period for pw system pq. 在pq取样三阶段内，每季度测试一次供水。 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

54、 weeks at sampling point to assess the efficacy of the multimedia, active carbon filter and softening units. 在多介质过滤器取样点测试产水的sdi，在活性炭取样点测试产水的余氯，在软化器取样点测试产水的硬度，在连续三周取样时，每周测试一次。从而评估供水处的多介质过滤器、活性炭和软化单元的效率。 sampling at outlet of pw generation everyday.在纯化水机产水口处每天进行取样。 total feed water outlet (v845.7.11)

55、and total return water outlet (v8545.9.11) of pw storage and distribution loop shall be sampled everyday.纯化水储存和分配环路总供水口（v845.7.11）和总回水口（v845.9.11）每天进行取样。 each pw user point shall be sampled everyday.纯化水每个使用点每天进行取样。after two weeks testing, a summary of test results will be produced. if the test resul

56、ts comform to the requirements and the identified deviations are closed, pw can be used for process validation and/or other equipment qualification.完成二周的测试之后，对测试结果进行总结。如果测试结果符合要求并且已经解决所发现的偏差情况，系统产品可供进行工艺验证或其它设备的验证使用。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 week