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1、洁净空调系统验证,Validation of HVAC System,-Macroprocess-,主题,国内外有关法规和指南 Regulation and GuidanceHVAC系统的要点 Key points of HVAC system验证内容 Qualification Content,法规和指南 Regulation and Guidance,(SFDA)Good Manufacturing Practice,revised in 1998(SFDA)1998年版GMP European Commission.The Rules Governing Medicinal Produc
2、t in the European Union,Vol.IV,Good Manufacturing Practices.Medicinal products for human and veterinary use.欧盟药品法规第4卷GMP（人用和兽用药品）Annex 1 to the EU Guide to Good Manufacturing Practice,Manufacture Of Sterile Medicinal Products.2003 Edition.欧盟GMP的附录1-无菌药品的生产，2003版Annex 15 to the EU Guide to Good Manuf
3、acturing Practice“Validation and Qualification”欧盟GMP的附录15-验证和确认,法规和指南 Regulation and Guidance,(FDA)Title 21,Code of Federal Regulations,Part 210,Current Good Manufacturing Practice in Manufacturing,Processing,Packing,or Holding of Drugs;General.(FDA)联邦法规第21篇第210部分，有关药品生产、加工、包装和贮存的CGMP总则(FDA)Title 21
4、,Code of Federal Regulations,Part 211,Current Good Manufacturing Practice for Finished Pharmaceuticals.(FDA)联邦法规第21篇第211部分，成品药的现行生产质量管理规范(FDA)Title 21,Code of Federal Regulations,Part 11,Electronic Records;Electronic Signature.(FDA）联邦法规第21篇第11部分，电子记录和电子签名(FDA)Guideline on Sterile Drug Products Produ
5、ced by Aseptic Processing,September 2004(FDA）无菌工艺的无菌药品生产的指南，2004年9月,法规和指南 Regulation and Guidance,ISPE Pharmaceutical Engineering Guides:ISPE制药工程指南：Volume 1:Bulk Pharmaceutical Chemical Facilities卷一：化学原料药厂房Volume 2:Oral Solid Dosage Forms卷二：口服固体制剂Volume 3:Sterile Manufacturing Facilities卷三：无菌生产厂房Vol
6、ume 5:Commissioning and Qualification卷五：调试和确认Volume 6:Biopharmaceutics卷六：生物制药,法规和指南 Regulation and Guidance,ISO 14644 Clean Room StandardISO 14644洁净室标准Part 1:Classification of air cleanliness第一部份：空气洁净度分类Part 2:Specifications for testing and monitoring第二部分：测试和监视的标准Part 3:Test Methods第三部分：测试方法Part 4:D
7、esign,Construction and Start-up第四部分：设计、施工和启动,国内外GMP法规和指南的异同点,GMP条款都是原则性的如：FDA cGMP 211.42(b)Any such building shall have adequate space for the orderly placement of equipment and materials to prevent mixups between different components,drug product containers,closures,labeling,in-process materials,o
8、r drug products,and to prevent contamination.211.63 Equipment used in the manufacture,processing,packing,or holding of a drug product shall be of appropriate design,adequate size,and suitably located to facilitate operations for its intended use and for its cleaning and maintenance.,国内外GMP法规和指南的异同点,
9、欧美有一系列具体GMP实施或检查指南 如：FDA有”Guidance for Industry”和“Guide to Inspection”,有“水系统”、“口服制剂”、“无菌工艺制剂”、“原料药”、“冻干制剂”、“清洗制剂”、“无菌原料药”等等方面的指南。欧盟EMEA也有一系列指南作为GMP总则的附件，如Annex1“无菌制剂”，Annex2“生物制品”，Annex15“验证和确认”，Annex18“原料药GMP”。另外EMEA之下的CHMP也发布了一系列的指南。,国内外GMP法规和指南的异同点,指南会给出一些具体的标准如：FDA的“Guidance for Industry,Sterile
10、 Drug Products Produced by Aseptic Processing-Current Good Manufacturing Practice,September 2004“要求：HEPA过滤器完整性测试：泄漏率0.01%层流罩空气流速：0.45+/-20%(距离过滤器表面6 inches（15.2 cm)，并接近操作面）各个洁净等级的颗粒浓度：100级（3,520个/m3 at 0.5m)10000级（352,000个/m3 at 0.5m）各个洁净等级的微生物限度（以沉降菌为例）：100级（1cfu,diam.90mm,4hours)10000级（5cfu,diam.9
11、0mm,4hours),国内外GMP法规和指南的异同点,ISPE工程指南最具操作性如厂房布局,墙板和地面材料,空调系统标准,换气次数,压差,温湿度,制水设备,水系统循环系统要求,管道材料和抛光要求,工程文件要求,验证要求等等.,GOOD ENGINEERING PRACTICE,HVAC系统的要点,法规要求以美国cGMP(21CFR Part 210-211)为例 211.42(a)Any building or buildings used in the manufacture,processing,packing,or holding of a drug product shall be
12、of suitable size,construction and location to facilitate cleaning,maintenance,and proper operations.211.42(b)Any such building shall have adequate space for the orderly placement of equipment and materials to prevent mixups between different components,drug product containers,closures,labeling,in-pr
13、ocess materials,or drug products,and to prevent contamination.The flow of components,drug product containers,closures,labeling,in-process materials,and drug products through the building or buildings shall be designed to prevent contamination.,HVAC系统的要点,211.46(b)Equipment for adequate control over a
14、ir pressure,micro-organisms,dust,humidity,and temperature shall be provided when appropriate for the manufacture,processing,packing,or holding of a drug product.211.46(c)Air filtration systems,including prefilters and particulate matter air filters,shall be used when appropriate on air supplies to p
15、roduction areas.If air is recirculated to production areas,measures shall be taken to control recirculation of dust from production.In areas where air contamination occurs during production,there shall be adequate exhaust systems or other systems adequate to control contaminants.211.46(d)Air-handlin
16、g systems for the manufacture,processing,and packing of penicillin shall be completely separate from those for other drug products for human use.,HVAC系统的要点 Key points,设计Design,施工Construction,调试Commissioning,验证Qualification,URS,设计标准,施工文件,变更控制,设计文件控制,调试报告,URS,竣工资料,URS,验证报告,验证方案,全过程管理Whole Process Mana
17、gement,HVAC系统要点,车间布局和人流物流Layout and Flows,EU GMP 洁净级别 Air Classification,Grade A:The local zone for high risk operations,e.g.filling zone,stopper bowls,open ampoules and vials,making aseptic connections.Grade B:For aseptic preparation and filling,this is the background environment for the grade A zo
18、ne.Grade C and D:Clean areas for carrying out less critical stages in the manufacture of sterile products.,EU GMP 洁净级别,HVAC系统的要点,青霉素类产品车间的要求中国GMP第二十条 生产青霉素类等高致敏性药品必须使用独立的厂房与设施，分装室应保持相对负压，排至室外的废气应经净化处理并符合要求，排风口应远离其它空气净化系统的进风口；生产-内酰胺结构类药品必须使用专用设备和独立的空气净化系统，并与其它药品生产区域严格分开。(欧盟、美国、WHO和ICH的GMP都有类似的规定),HVA
19、C系统的要点,避孕药品、激素类、抗肿瘤类化学药品、放射性药品中国GMP 第二十一条 避孕药品的生产厂房应与其它药品生产厂房分开，并装有独立的专用的空气净化系统。生产激素类、抗肿瘤类化学药品应避免与其它药品使用同一设备和空气净化系统。放射性药品的生产、包装和储存应使用专用的、安全的设备，生产区排出的空气不应循环使用，排气中应避免含有放射性微粒，符合国家关于辐射防护的要求与规定。,HVAC系统的要点,生物制品中国GMP第二十二条 生产用菌毒种与非生产用菌毒种、生产用细胞与非生产用细胞、强毒与弱毒、死毒与活毒、脱毒前与脱毒后的制品和活疫苗与灭活疫苗、人血液制品、预防制品等的加工或灌装不得同时在同一生
20、产厂房内进行，其贮存要严格分开。不同种类的活疫苗的处理及灌装应彼此分开。强毒微生物及芽胞菌制品的区域与相邻区域应保持相对负压，并有独立的空气净化系统。,HVAC系统的要点 Key points,几个主要的设计参数 Design Criteria洁净度 Air Classification换气次数 Air Change压差 Room Differential Pressure温湿度范围 Temperature and Humidity,洁净度Air Classification,中国98版GMP,洁净度Air Classification,欧盟GMP（2008.11.25 Rev),洁净度Air
21、 Classification,FDA,洁净度Air Classification,ISO14644,换气次数 Air Change,1.中国GMP没有规定，参考中国洁净室设计标准（GB50073-2001)2.EU GMP Annex1:the number of air changes should be related to the size of the room and the equipment and personnel present in the room.3.参考FDA 指南（Sterile Drug Products produced by Aseptic process
22、ing-Current Good Manufacturing Practice)：For Class 100,000(ISO 8)supporting rooms,airflow sufficient to achieve at least 20 air changes per hour is typically acceptable.Significantly higher air change rates are normally needed for Class 10,000 and Class 100 areas.,NA:不适用 ND:未明确,压差 Room Pressure,中国GM
23、P:空气洁净度等级不同的相邻房间之间的静压差应大于5帕，洁净室(区)与室外大气的静压差应大于10 帕FDA:不同洁净等级房间相差12.5Pa欧盟GMP：1015Pa,压力分布图,温湿度范围 Temperature and Humidity,HVAC系统的要点,自控系统Control System控制参数Control Parameters温度Temperature（主动控制，连续记录）相对湿度Humidity（主动控制，连续记录）压差Differential Pressure（主动或被动控制，建议连续记录）粒子数Particle count（被动控制，建议关键区域连续记录）控制功能 Contr
24、ol Function校准 Calibration,HVAC系统的验证,V模型,设计确认（DQ),DQ要点设计文件的确认 Design Documents Verification房间布局和HVAC系统图的确认 Room Layout and HVAC P&ID房间参数的确认（风量、温湿度、压差等）Room Parameters Verification(Air volume,temp./hum.Pressure)设备和组件的确认 Components Verification仪器仪表的确认 Instruments Verification系统风管和风口布置图的确认 Ducts and HEP
25、A filters Layout空调控制功能的确认 Control Function Verification偏差报告 Deviation,HVAC的设计文件 Design Documents,需要有以下文件(Recommended Design documents)：设计说明 Design Specification房间平面图 Room Layout洁净区划分图 Air classification layout人流物流图 Personnel/materials flowsHVAC系统区域划分图 HVAC Zone Layout房间压力分布图Room Pressure LayoutHVAC系
26、统流程图 P&ID of HVAC system风管布置图（送、回、排风）Ducts Layout设备和仪表清单 Components and Instruments list风量平衡计算表 Calculation of air volume balance空气处理计算表（机组冷热负荷计算）Calculation of thermal/cooling load,安装确认(IQ),IQ要点文件的确认 Documents Verification风管安装的确认 Ducts Installation Verification系统图和布局图的确认 P&ID and Layout Verificatio
27、n设备安装的确认 Components Verification关键仪表和校准的确认 Critical Instruments Verification高效过滤器布置的确认 HEPA filters layout verification公用设施的确认 Utilities Verification偏差报告 Deviation Report,运行确认（OQ),OQ要点验证仪器校准的确认 Validation Instruments Verification高效过滤器完整性检查（DOP测试）HEPA Filter Integrity Testing房间风量和换气次数测试 Air Volume an
28、d Air Change Testing房间压差测试Room Differential Pressure Testing房间温湿度测试Temperature/Humidity Testing气流流型测试Air Direction Testing自净时间测试 Recovery time Testing洁净度测试（静态）Cleanliness Testing(static)偏差报告 Deviation Report,DOP测试,PAO aerosol（10-30g/l),标准：泄漏率小于0.01%,DOP测试,风量测试和换气次数计算,风量平衡和压差调试成功后进行记录风机频率、阀门位置等等换气次数=
29、房间总送风量/房间体积,层流风速测试,离送风面约15-30cm处进行测试取样数量为该层流装置送风面的面积的10倍的平方根，但不小于4个，每个过滤器或FFU出口必须有一个测试点取样点按送风面平均分布,标准：0.45m/s20%,压差测试,所有房间的门要关闭标准：中国：洁净区对外10Pa 不同级别5Pa欧盟:10-15Pa美国：12.5Pa,验证标准依据设计的压差标准,房间温湿度测试,测点选择高度应离地面0.8m，距设备周围0.8m以外处，并应避开出、回风口处标准：根据设计标准,气流流型测试,摄像机拍摄烟雾流动方向层流：单向平行移动,自净时间,欧盟GMP:15-20min“动态”“静态”不适用于层
30、流ISO14644-3,自净时间,洁净度测试,取样点数 Sampling Point NumberISO14644：面积的平方根，不少于2个取样量100级：不小于1m310000级、100000级：理论上要取得20个大颗粒（5m)所以，对于10000级，需要用流量28.3L/min的测试仪95%UCL,性能确认（PQ),PQ要点验证仪器校准的确认 Validation Instruments Calibration Verification系统标准操作程序（SOP）的确认 SOP verification验证取样计划 Sampling Plan洁净房间洁净度的测试（动态条件下）Cleanliness Testing(Dynamic)房间压差的测试 Room Differential Pressure Testing房间温湿度的测试 Temperature and Humidity Testing房间微生物的测试 Microbiology Testing,PQ取样计划和确认周期,周期Period：一个月 One monthPQ取样计划(供参考）Sampling Plan(only for reference),期待与您的合作！Looking forward to cooperating with you!,
