洁净空调系统验证 HVAC validation

洁净空调系统验证ValidationofHVACSystem-Macroprocess-主题•国内外有关法规和指南RegulationandGuidance•HVAC系统的要点KeypointsofHVACsystem•验证内容QualificationContent法规和指南RegulationandGuidance•(SFDA)GoodManufacturingPractice,revisedin1998(SFDA)1998年版GMP•EuropeanCommission.TheRulesGoverningMedicinalProductintheEuropeanUnion,Vol.IV,GoodManufacturingPractices.Medicinalproductsforhumanandveterinaryuse.欧盟药品法规第4卷GMP（人用和兽用药品）•Annex1totheEUGuidetoGoodManufacturingPractice,ManufactureOfSterileMedicinalProducts.2003Edition.欧盟GMP的附录1-无菌药品的生产，2003版•Annex15totheEUGuidetoGoodManufacturingPractice“ValidationandQualification”欧盟GMP的附录15-验证和确认法规和指南RegulationandGuidance•(FDA)Title21,CodeofFederalRegulations,Part210,CurrentGoodManufacturingPracticeinManufacturing,Processing,Packing,orHoldingofDrugs;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)Title21,CodeofFederalRegulations,Part211,CurrentGoodManufacturingPracticeforFinishedPharmaceuticals.(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)Title21,CodeofFederalRegulations,Part11,ElectronicRecords;ElectronicSignature.(FDA）联邦法规第21篇第11部分，电子记录和电子签名•(FDA)GuidelineonSterileDrugProductsProducedbyAsepticProcessing,September2004(FDA）无菌工艺的无菌药品生产的指南，2004年9月法规和指南RegulationandGuidanceISPEPharmaceuticalEngineeringGuides:ISPE制药工程指南：Volume1:BulkPharmaceuticalChemicalFacilities卷一：化学原料药厂房Volume2:OralSolidDosageForms卷二：口服固体制剂Volume3:SterileManufacturingFacilities卷三：无菌生产厂房Volume5:CommissioningandQualification卷五：调试和确认Volume6:Biopharmaceutics卷六：生物制药法规和指南RegulationandGuidanceISO14644CleanRoomStandardISO14644洁净室标准Part1:Classificationofaircleanliness第一部份：空气洁净度分类Part2:Specificationsfortestingandmonitoring第二部分：测试和监视的标准Part3:TestMethods第三部分：测试方法Part4:Design,ConstructionandStart-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：FDAcGMP211.42(b)Anysuchbuildingshallhaveadequatespacefortheorderlyplacementofequipmentandmaterialstopreventmixupsbetweendifferentcomponents,drugproductcontainers,closures,labeling,in-processmaterials,ordrugproducts,andtopreventcontamination.211.63Equipmentusedinthemanufacture,processing,packing,orholdingofadrugproductshallbeofappropriatedesign,adequatesize,andsuitablylocatedtofacilitateoperationsforitsintendeduseandforitscleaningandmaintenance.国内外GMP法规和指南的异同点•欧美有一系列具体GMP实施或检查指南如：FDA有”GuidanceforIndustry”和“GuidetoInspection”,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“GuidanceforIndustry,SterileDrugProductsProducedbyAsepticProcessing-CurrentGoodManufacturingPractice,September2004“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6inches（15.2cm)，并接近操作面）各个洁净等级的颗粒浓度：100级（3,520个/m3at＞0.5μm)10000级（352,000个/m3at＞0.5μm）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.90mm,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.GOODENGINEERINGPRACTICEHVAC系统的要点法规要求以美国cGMP(21CFRPart210-211)为例211.42(a)Anybuildingorbuildingsusedinthemanufacture,processing,packing,orholdingofadrugproductshallbeofsuitablesize,constructionandlocationtofacilitatecleaning,maintenance,andproperoperations.211.42(b)Anysuchbuildingshallhaveadequatespacefortheorderlyplacementofequipmentandmaterialstopreventmixupsbetweendifferentcomponents,drugproductcontainers,closures,labeling,in-processmaterials,ordrugproducts,andtopreventcontamination.Theflowofcomponents,drugproductcontainers,closures,labeling,in-processmaterials,anddrugproductsthroughthebuildingorbuildingsshallbedesignedtopreventcontamination.HVAC系统的要点211.46(b)Equipmentforadequatecontroloverairpressure,micro-organisms,dust,humidity,andtemperatureshallbeprovidedwhenappropriateforthemanufacture,processing,packing,orholdingofadrugproduct.211.46(c)Airfiltrationsystems,includingprefiltersandparticulatematterairfilters,shallbeusedwhenappropriateonairsuppliestoproductionareas.Ifairisrecirculatedtoproductionareas,measuresshallbetakentocontrolrecirculationofdustfromproduction.Inareaswhereaircontaminationoccursduringproduction,thereshallbeadequateexhaustsystemsorothersystemsadequatetocontrolcontaminants.211.46(d)Air-handlingsystemsforthemanufacture,processing,andpackingofpenicillinshallbecompletelyseparatefromthoseforotherdrugproductsforhumanuse.HVAC系统的要点Keypoints设计Design施工Construction调试Commissioning验证QualificationURS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WholeProcessManagementHVAC系统要点车间布局和人流物流LayoutandFlowsEUGMP洁净级别AirClassification•GradeA:Thelocalzoneforhighriskoperations,e.g.fillingzone,stopperbowls,openampoulesandvials,makingasepticconnections.•GradeB:Forasepticpreparationandfilling,thisisthebackgroundenvironmentforthegradeAzone.•GradeCandD:Cleanareasforcarryingoutlesscriticalstagesinthemanufactureofsterileproducts.EUGMP洁净级别GradeExamplesofoperationsforterminallysterilisedproducts.AFillingofproducts,whenunusuallyatriskCPreparationofsolutions,whenunusuallyatrisk.FillingofproductsDPreparationofsolutionsandcomponentsforsubsequentfillingGradeExamplesofoperationsforase