美国fda顾问药品生产企业验证基础及实质培训(中英对照)

美国FDA顾问药品生产企业验证基础及实质培训中英对照FUNDAMENTALSANDESSENTIALSOFVALIDATION验证基础及实质MICHAELANISFELD（DR麦克安斯菲尔得）GLOBEPHARMCONSULTING1COPYRIGHTGLOBEPHARM,2005课程安排COURSESCHEDULEINTRODUCTIONREGULATORYENVIRONMENT介绍法规环境VALIDATIONBASICS验证基础知识VALIDATIONMASTERPLANS验证主文件PROCESSVALIDATION工艺验证UTILITIESVALIDATION公用系统验证CLEANINGVALIDATION清洁验证COMPUTERVALIDATION计算机系统验证ANALYTICALMETHODVALIDATION分析方法验证CASESTUDY案例研究2COPYRIGHTGLOBEPHARM,2005HOUSEKEEPINGCOURSENOTES课程注意MASTERLISTSURVEYSAREYOULOSTENGLISHAMERICANMOBILEPHONEBEEPERSPAGERSRESTROOMSFIREDRILLBREAKSANDENDINGMESSAGESFROMOFFICEAIRPORT3COPYRIGHTGLOBEPHARM,2005培训期间DURINGTHISTRAININGSESSIONIF如果1IGOTOOFAST我讲的太快2IUSESTRANGEWORDS我使用陌生词语3IGETTOOTECHNICAL我讲的太专业PLEASEINTERRUPTANDASKTHEREISNOSUCHTHINGASASILLYQUESTION请随时打断我，并提问。4COPYRIGHTGLOBEPHARM,2005请大家自我介绍WHOAREYOUTELLUSYOURNAME告诉我你的名字TELLUSYOURCOMPANY告诉我你的公司TELLUSYOURJOB你的职务TELLUSTHEPRODUCTSYOURCOMPANYMAKES你公司生产的产品TELLUSYOUREXPERIENCEWITHVALIDATION有关验证的经验TELLUSWHATSPECIFICALLYYOUCAMETOLEARN你想了解的内容5COPYRIGHTGLOBEPHARM,2005DR麦克H安斯菲尔得MICHAELHANISFELDINDUSTRIALPHARMACIST执业约师INDUSTRIALPHARMACYFACULTYUNIVERSITYOFILLINOIS毕业于伊利诺伊州州立大学药学系HASTRAINEDFDAANDMCAINSPECTORS培训过FDAMCA检查官PERFORMAUDITSONBEHALFOFUNAGENCIESANDGOVERNMENTS代表联合国政府部门进行审计PERFORMS2535FULLSCALEAUDITSANNUALLY每年进行2535个审计HASAUDITEDIN32COUNTRIES对32个国家的医药企业进行过审计GUIDESCLIENTSTHROUGHFDA,MCA,TGA,HPFBIANDOTHERINSPECTIONS帮助客户通过FDA,MCA,TGA,HPFBI及其他官方机构的现场检查6COPYRIGHTGLOBEPHARM,20057COPYRIGHTGLOBEPHARM,2005验证VALIDATIONDEFINITION非常VERY定义辛苦ARDUOUS周期长LENGTHY棘手INVOLVEDAND详细的DETAILEDATTEMPTTO试图要TEST测试所有事务EVERYTHING8COPYRIGHTGLOBEPHARM,2005验证原理及要素FUNDAMENTALSANDESSENTIALSOFVALIDATIONSREGULATORYENVIRONMENT法规环境9COPYRIGHTGLOBEPHARM,2005质量QUALITY“ACOMPREHENSIVESYSTEM,DESIGNED,DOCUMENTED,IMPLEMENTEDANDCONTROLLED,FURNISHEDWITHPERSONNEL,EQUIPMENTANDRESOURCES,TOPROVIDEASSURANCETHATPRODUCTSWILLBECONSISTENTLYFITFOR,ANDAPPROPRIATETO,THEINTENDEDUSE”一个全面的质量体系，包含了设计，文件，执行，控制，以及提供足够的人员、仪器、资源，为了确保产品能持续达到既定目标。10COPYRIGHTGLOBEPHARM,2005工艺验证PROCESSVALIDATIONFDA“ESTABLISHING,THROUGHDOCUMENTEDEVIDENCE,AHIGHDEGREEOFASSURANCETHATASPECIFICPROCESSWILLCONSISTENTLYPRODUCEAPRODUCTTHATMEETSITSPREDETERMINEDSPECIFICATIONSANDQUALITYCHARACTERISTICS”通过文档记录，建立一个高水平的保证，既在特定的工艺下能生产出符合既定标准的产品。FDAPROPOSEDCGMPRULES21CFR2113B24,MAY199611COPYRIGHTGLOBEPHARM,2005验证目的VALIDATIONOBJECTIVEASSURANCEOFCONSISTENCY确保连续性3CONSISTENCYISGREAT连续性很重要INCONSISTENCY,ORPOORCONSISTENCY,ISTERRIBLE不连续或连续性不好是很糟糕的12COPYRIGHTGLOBEPHARM,2005概念性定义CONCEPTUALDEFINITIONINSTRUMENTSEQUIPMENTPROCESSESAREAREISVALIDATEDCALIBRATEDQUALIFIED工艺被验证仪器被校验设备被确认13COPYRIGHTGLOBEPHARM,2005验证不是VALIDATIONISNOTVALIDATIONISNOTDEVELOPINGTHEPROCESS验证不是工艺研发VALIDATIONISNOTANEXPERIMENT验证不是试验VALIDATIONISNOTPROCESSOPTIMIZATION验证不是工艺优化VALIDATIONISNOTAPROCESSCAPABILITYSTUDY验证不是生产能力研究VALIDATIONISNOT“WORSTCASETESTING”验证不是最坏条件测试VALIDATIONISNOTWRITINGTHESOP验证不是写SOPVALIDATIONISNOTREINVENTINGTHEWHEEL验证不是彻底重来做VALIDATIONISNOTAVOYAGEOFDISCOVERY验证不是探索记录验证应该是令人很郁闷的14COPYRIGHTGLOBEPHARM,2005验证VALIDATIONPIC“ACTIONOFPROVING,INACCORDANCEWITHTHEPRINCIPLESOFGMP,THATANYPROCEDURE,PROCESS,EQUIPMENT,MATERIAL,ORSYSTEMACTUALLYLEADSTOEXPECTEDRESULTS”符合GMP原则的校对，既所有程序、工艺过程、设备、物料、系统实际上导致预期的结果。PHARMACEUTICALINSPECTIONCONVENTIONGMPS,199115COPYRIGHTGLOBEPHARM,2005验证VALIDATIONPICPIC521“VALIDATIONSTUDIESSHOULDREINFORCEGMPANDBECONDUCTEDINACCORDANCETODEFINEDPROCEDURESRESULTSANDCONCLUSIONSSHOULDBERECORDED”PIC521验证研究应强化GMP，应遵照既定程序执行。所有结果结论应进行记录。PIC522“WHENANYNEWMANUFACTURINGFORMULAORMETHODOFPREPARATIONISADOPTED,STEPSSHOULDBETAKENTODEMONSTRATESUITABILITYFORROUTINEPROCESSING”PIC522当新生产配方或制备方法被采用时，应采取措施表明常规操作的适用性。PHARMACEUTICALINSPECTIONCONVENTIONGMPS,199116COPYRIGHTGLOBEPHARM,2005验证VALIDATIONPICPIC523“SIGNIFICANTAMENDMENTSTOTHEMANUFACTURINGPROCESS,INCLUDINGANYCHANGESINEQUIPMENTORMATERIALSWHICHMAYAFFECTPRODUCTQUALITYAND/ORTHEREPRODUCIBILITYOFTHEPROCESSSHOULDBEVALIDATED”PIC523生产过程中的显著变更应进行验证。这些变更包括所有可能影响产品质量或影响工艺过程重复性的设备和物料方面的任何变更。PIC524“PROCESSESANDPROCEDURESSHOULDUNDERGOPERIODICCRITICALREVALIDATIONTOENSURETHATTHEYREMAINCAPABLEOFACHIEVINGTHEINTENDEDRESULTS”PIC524工艺过程和程序应进行周期性临界再验证，以确保这些过程和程序能保持完成既定的结果的能力。PHARMACEUTICALINSPECTIONCONVENTIONGMPS,199117COPYRIGHTGLOBEPHARM,2005FDA关于验证的要求FDAREGULATORYREQUIREMENTSFORVALIDATION21CFR21110SAMPLINGANDTESTING取样测试“ESTABLISHCONTROLPROCEDURESTOMONITORTHEOUTPUTANDTOVALIDATETHEPERFORMANCEOFTHOSEMANUFACTURINGPROCESSESTHATMAYBERESPONSIBLEFORCAUSINGVARIABILITYINTHECHARACTERISTICSOFINPROCESSMATERIALANDDRUGPRODUCT”建立控制程序，以监控产品和验证关键生产工艺过程，既可能导致中间体及成品性质的变动的生产过程。21CFR21168BAUTOMATICELECTRONICEQUIPMENT自动电子设备“AWRITTENRECORDOFTHECOMPUTERPROGRAMSHALLBEMAINTAINEDALONGWITHAPPROPRIATEVALIDATIONDATA”记录和验证数据应该进行保存及维护。18COPYRIGHTGLOBEPHARM,2005FDA关于验证的要求FDAREGULATORYREQUIREMENTSFORVALIDATION21CFR21184D2TESTINGOFCOMPONENTS测试原辅料“THEMANUFACTURERSHALLESTABLISHTHERELIABILITYOFTHESUPPLIERSANALYSESTHROUGHAPPROPRIATEVALIDATIONOFTHESUPPLIERSTESTRESULTS生产商通过对供应商分析测试结果的适当验证，来建立对供应商的分析结果可信性评价。21CFR211165ETESTINGRELEASEOFPRODUCTS测试放行产品“THEACCURACY,SENSITIVITY,SPECIFICITYANDREPRODUCIBILITYOFTESTMETHODSEMPLOYEDBYTHEFIRMSHALLBEESTABLISHEDANDDOCUMENTEDSUCHVALIDATIONANDDOCUMENTATION”生产商使用的成品测试方法的准确性、灵敏度、专署性和重复性应当被建立和文档化。如验证和文件。19COPYRIGHTGLOBEPHARM,2005工艺验证PROCESSVALIDATIONFDA21CFR211220ATHEMANUFACTURERSHALLVALIDATEALLDRUGPRODUCTMANUFACTURINGPROCESSESINCLUDING,BUTNOTLIMITEDTO,COMPUTERIZEDSYSTEMSTHATMONITORAND/ORCONTROLTHEMANUFACTURINGPROCESSTHEMANUFACTURINGPROCESSINCLUDESALLMANUFACTURINGSTEPSINTHECREATIONOFTHEFINISHEDPRODUCTINCLUDING,BUTNOTLIMITEDTOCLEANING,WEIGHING,MEASURING,MIXING,BLENDING,COMPRESSING,FILLING,PACKAGINGANDLABELING生产商应对所有产品的生产过程进行验证，包括，但不局限于，监控或控制生产过程的计算机处理系统验证。生产过程应该包括所有接触最终产品的过程，包括，单不局限于清洗、称量、测量、混合、混批、压缩、填充、包装及贴签。20COPYRIGHTGLOBEPHARM,2005工艺验证PROCESSVALIDATIONFDA21CFR211220BVALIDATIONPROTOCOLSTHATIDENTIFYTHEPRODUCTANDPRODUCTSPECIFICATIONSANDSPECIFYTHEPROCEDURESANDACCEPTANCECRITERIAFORTHETESTSTOBECONDUCTEDANDTHEDATATOBECOLLECTEDDURINGPROCESSVALIDATIONSHALLBEDEVELOPEDANDAPPROVED识别产品、产品标准、写明工艺过程及所要进行的测试以及可接受的标准，注明工艺验证过程中需要收集的数据的验证方案应该被建立和批准。THEPROTOCOLSHALLSPECIFYASUFFICIENTNUMBEROFREPLICATEPROCESSRUNSTODEMONSTRATEREPRODUCIBILITYOFTHEPROCESSANDPROVIDEANACCURATEMEASUREOFVARIABILITYAMONGSUCCESSIVERUNS验证方案中应规定需要足够数量的批次，以证明生产工艺的可重复性，以及准确评估连续批次之间的变化。VALIDATIONDOCUMENTATIONSHALLINCLUDEEVIDENCEOFMATERIALSUITABILITYANDTHEPERFORMANCEANDRELIABILITYOFEQUIPMENTANDSYSTEMS验证文件中应包括物料适用性的证据，和设备、体系性能和可信度的证据。21COPYRIGHTGLOBEPHARM,2005工艺验证PROCESSVALIDATIONFDA21CFR211220CTHEMANUFACTURERSHALLDESIGNORSELECTEQUIPMENTANDPROCESSESTOENSUREPRODUCTSPECIFICATIONSARECONSISTENTLYACHIEVEDTHEMANUFACTURERSDETERMINATIONOFEQUIPMENTSUITABILITYSHALLINCLUDETESTINGTOVERIFYTHATTHEEQUIPMENTISCAPABLEOFOPERATINGSATISFACTORILYWITHINTHEOPERATINGLIMITSREQUIREDBYTHEPROCESS生产商应该设计或选择合适的设备、工艺过程，以确保能持续生产出达到既定标准的产品。生产商关于设备使用性的决定，应当包括测试设备以确认在生产过程中所需的操作限度下能够进行满意的操作。PROCESSSUITABILITYSHALLINCLUDEDOCUMENTEDRIGOROUSTESTINGTODEMONSTRATETHEEFFECTIVENESSANDREPRODUCIBILITYOFTHEPROCESSPARTSOFTHEPROCESSTHATMAYCAUSEVARIABILITYOROTHERWISEAFFECTTHEPRODUCTSHALLBETESTED工艺过程的适用性应包括文档化的严格测试，以证明生产工艺的有效性和可重复性。应对可能影响产品质量的部分工艺过程进行测试。22COPYRIGHTGLOBEPHARM,2005工艺验证PROCESSVALIDATIONFDA21CFR211220DTHERESHALLBEAQUALITYASSURANCESYSTEMINPLACEWHICHREQUIRESREVALIDATIONWHENEVERTHEREARECHANGESINPACKAGING,COMPONENTCHARACTERISTICS,FORMULATION,EQUIPMENT,ORPROCESSES,INCLUDINGREPROCESSINGTHATCOULDAFFECTPRODUCTEFFECTIVENESSORPRODUCTCHARACTERISTICS,ANDWHENEVERCHANGESAREOBSERVEDINPRODUCTCHARACTERISTICS应当建立质量保障体系，无论何时，当包装、原辅料性质、配方、设备、或工艺过程（包括可能影响产品效价或产品性质的再加工）发生变更时；无论何时发现产品性质发生变化时，确保进行再验证。23COPYRIGHTGLOBEPHARM,2005分析方法验证METHODVALIDATIONFDA21CFR211222THEACCURACY,SENSITIVITY,SPECIFICITY,ANDREPRODUCIBILITYOFTESTMETHODSUSEDBYAMANUFACTURERSHALLBEVALIDATEDANDDOCUMENTEDSUCHVALIDATIONSHALLBEACCOMPLISHEDINACCORDANCEWITH21CFR211194A2生产商应对所使用的分析方法的精密度、灵敏性、专属性及重复性要进行验证以及文档化。分析方法验证应参考21CFR211194A2。24COPYRIGHTGLOBEPHARM,2005验证VALIDATIONSOUTHAFRICA9INMANUFACTURINGNOTWOOBJECTSAREEVERMADEEXACTLYALIKEFIVEFACTORSCONTRIBUTETOVARIATIONINHERENTPROCESSMETHODS,RAWMATERIALS,ENVIRONMENT,HUMANELEMENT,TESTINGMETHODS912在生产中，没有2个产品是能够完全一致地生产出来的。5个因素导致可变性生产工艺，原辅料，环境，人为因素，测试方法。9WHENALLASSIGNABLECAUSESOFVARIATIONAREELIMINATED,ANDONLYCHANCECAUSESREMAIN,THEPROCESSISVALIDATED913当所有影响因素被消除，生产工艺是验证过的。9SPCMAYBEUSEDTODEMONSTRATETHATAPROCESSHASBEENVALIDATED914SPC可用来证明生产工艺是验证过的。9APROCESSINASTATEOFCONTROLCONTRIBUTESTOPRODUCTIVITYANDPROFITABILITYBYREDUCINGWASTEINCREASINGTHEYIELDOFSALABLEPRODUCTANDREDUCINGTHECOSTOFINSPECTIONANDTESTACTIVITIES915处于控制状态的生产过程可以有助于减少浪费，提高收率，降低检查以及测试的成本。SOURCESOUTHAFRICAGMPS,199525COPYRIGHTGLOBEPHARM,2005验证阶段VALIDATIONPHASESCOVERSALLACTIVITIESIN包括所有活动DEVELOPMENTFORMULATION研发阶段PILOTBATCHESSCALEUPSTUDIES中试放大生产TECHTRANSFERTOCOMMERCIALSCALE转移到工业化规模EQUIPMENTQUALIFICATIONSIQ,OQSTAGE设备确认IQ,OQMASTERPRODUCTIONDOCUMENTS1工艺规程文件PROCESSCAPABILITYSTUDIES生产能力研究SOURCECANADIANVALIDATIONGUIDELINES,2000HCSCGCCA/HPBDGPS/THERAPEUT26COPYRIGHTGLOBEPHARM,2005验证阶段VALIDATIONPHASESCOVERSALLACTIVITIESIN包括所有活动PROCESSVALIDATIONPV工艺验证VERIFICATIONTHATALLCRITICALPARAMETERSAREVALIDANDCANBEREPRODUCEDEVENIN“WORSTCASE”STAGECONDITIONS2确认所有的关键工艺参数是有效的，能在最苛刻条件下重复生产的。CANADIANVALIDATIONGUIDELINES,200027COPYRIGHTGLOBEPHARM,2005验证阶段VALIDATIONPHASESCOVERSALLACTIVITIESIN包括所有活动VALIDATIONMAINTENANCE验证维护REVIEWOFPROCESSRELATEDDOCUMENTS回顾与工艺有关的所有文件REVIEWOFVALIDATIONAUDITREPORTS回顾验证审计报告DEVIATIONS偏差CHANGES变更STAGEFAILURES失败MODIFICATIONS修改3REVIEWTHATSOPSHAVEBEENVALIDATED回顾已经验证的SOPS。EFFECTIVENESSOFCHANGECONTROL评估变更结果REVALIDATION/REVALIDATIONNEED再验证/评定是否需要再验证CANADIANVALIDATIONGUIDELINES,200028COPYRIGHTGLOBEPHARM,2005文档化DOCUMENTEDWRITTEN起草BYAKNOWLEDGEABLEANDTRAINEDPERSON由经过培训的、有相应知识的人起草REVIEWED审核BYSOMEONEEQUALLYPROFICIENT由精通的人审核APPROVED批准ATANAPPROPRIATELEVELOFMANAGEMENT由适当的管理人员批准RETAINED保存KEPTONFILEANDAVAILABLEFORREFERENCE文件归档保存。29COPYRIGHTGLOBEPHARM,2005FDA座右铭FDAMAXIMSIFITISNOTDOCUMENTED,ITISARUMOR如果没有文档化，那就是谣言IFITSDOCUMENTED,BUTNOTSIGNEDITSGRAFFITI如果文档化了，但没有签名，那就是乱写INGODWETRUSTALLOTHERSPROVIDEDATA30COPYRIGHTGLOBEPHARM,2005问题QUESTIONS31COPYRIGHTGLOBEPHARM,2005FUNDAMENTALSANDESSENTIALSOFVALIDATIONVALIDATIONBASICS验证基础知识32COPYRIGHTGLOBEPHARM,2005验证策略VALIDATIONSTRATEGIESPROSPECTIVEVALIDATION前性验证CONCURRENTVALIDATION同步验证RETROSPECTIVEVALIDATION回顾性验证DEVELOPMENTVALIDATION研发验证33COPYRIGHTGLOBEPHARM,2005研发验证DEVELOPMENTVALIDATIONASERIESOFDOCUMENTEDEVIDENCESDEMONSTRATINGTHATTHEDEVELOPMENTPROCESSFOLLOWEDADEVELOPMENTPLAN,ANDTHATEACHPHASEOFTHEDEVELOPMENTPLANWASFORMALLYREVIEWEDANDAPPROVEDATSUITABLEMILESTONES一系列的文件证明研发过程是基于研发计划进行的，以及每一阶段研发计划是经过审核和批准的。NOTETHEENDRESULTOFDEVELOPMENTVALIDATIONISTYPICALLYATECHNOLOGYTRANSFERDOCUMENT,FORMALLYREVIEWEDANDAPPROVEDBYRESEARCHDEVELOPMENTPERSONNELANDFORMALLYACCEPTEDBYFACILITIESMANUFACTURING,ENGINEERINGANDQUALITYPERSONNEL注意研发验证的最终结果是技术转移文件，要经过RD人员审核和批准，生产、工程和质量人员的接受。34COPYRIGHTGLOBEPHARM,2005技术转移文件TECHNOLOGYTRANSFERDOCUMENTTECHNOLOGYTRANSFERDOCUMENTTTDSIGNIFIESTHEENDOFPRODUCTORPROCESSDEVELOPMENTACTIVITIES,ANDINCLUDES技术转移文件TTD意味着产品或工艺研发的结束，包括BILLSOFMATERIALS物料列表DEVELOPMENTPLANRATIONALE研发计划基本原理ACTIVESEXCIPIENTSCRITICALPARAMETERLISTINGSPECIFICATIONS标准关键参数列表TESTMETHODS测试方法BATCHCOMPARISONS批对照RAWMATERIALS原料FORMULATIONBATCHES制剂批INPROCESS中间控制STABILITYBATCHES稳定性批FINISHEDPRODUCT成品CLINICAL/BIOBATCHES临床试验批EQUIPMENTRECOMMENDATIONSSCALEUPBATCHES放大批建议使用的设备VALIDATIONBATCHES验证批大批PRODUCTMETHODS工艺过程STABILITYREPORTS稳定性报告35COPYRIGHTGLOBEPHARM,2005关键参数列表CRITICALPARAMETERLISTINGTTDTHEVALIDATIONTEAMSSTARTINGPOINT起始点IDENTIFIESVALIDATIONACTIVITIES确认验证内容SEQUENCESVALIDATIONACTIVITIES验证次序PRIORITIZESVALIDATIONACTIVITIES验证优先顺序36COPYRIGHTGLOBEPHARM,2005技术转移TECHNOLOGYTRANSFERTRANSFERPHASE1第一阶段DEVELOPMENTMEETSWITHPRODUCTION/QC/QAEXPLAINSTECHNOLOGY研发与生产部门/QC/QA开会，说明技术资料TRANSFERPHASE2DEVELOPMENTDEMONSTRATESTECHNOLOGYENSURESPRODUCTION/QCUNDERSTANDS研发讲解技术资料，确保生产部门/QC理解TRANSFERPHASE3PRODUCTION/QCAPPLYTECHNOLOGY生产部门/QC接受技术资料DEVELOPMENTMONITORASSUREADEQUATESKILLLEVELSDEMONSTRATED37COPYRIGHTGLOBEPHARM,2005TTD活动顺序TTDSEQUENCEOFACTIVITY1INPUTACTIVITYOUTPUTPLANNINGPURCHASINGVENDORSCHEDULINGAGREEDSCALEUPCAMPAIGNSCHEDULINGREGULATORYCOMPLIANCESTRATEGYNUMBEROFBATCHES,SCALEUPVALIDATIONARTWORKBATCHSIZESRAWMATERIALSBATCHESORDERED准备放大生产计划安排DEVELOPMENTSPECIFICATIONS,METHODSPREPARATIONPQPROTOCOLSCLEANINGDOCUMENTATIONVALIDATIONCOMPLIANCEFORVALIDATIONPROTOCOLSBATCHPRODUCTIONQUALITYMANUFACTURERECORDSMANUFACTURE/CLEANINGSOPSFORPLANT/EQUIPMENT准备生产PERSONNELTRAININGQCSPECIFICATIONSANDMETHODSQACOMPLIANCEAUDITDEVELOPMENTTECHNICAL/ENGINEERINGMANUFACTURINGSCALEUPOFFINISHEDPRODUCTPRODUCTIONCOMPLIANCEVALIDATION生产COMPLETEDBATCHDOCUMENTATIONQACOMPLETEDPQCOMPLETEDCLEANINGSTUDY38COPYRIGHTGLOBEPHARM,2005TTD活动顺序TTDSEQUENCEOFACTIVITY2INPUTACTIVITYOUTPUTSPECIFICATIONSMETHODSSCALEUPFINISHEDAPPROVEDFINISHEDPRODUCTBATCHESOFFINISHEDPRODUCTPQPACKAGINGCOASOOSREPORTSPRODUCTCRITERIATESTING成品测试COMPLETEDBATCHDOCUMENTATIONSCALEUPCHANGESADDITIONALSCALEUPINCIDENTREPORTSVALIDATIONAPPROVALORCOMPLIANCEREPORTSQA/QCTEST同意放大PRODUCTTRANSFERRESULTSPOSTAPPROVALSTABILITYPRODUCTTRANSFERSIGNOFFSTTDCOMPLETIONTTD完成39COPYRIGHTGLOBEPHARM,2005TTD接受TTDACCEPTANCEONLYACCEPTEDBYPRODUCTIONQUALITYCONTROLIFMETHODOLOGYISSHOWNTOBEROBUSTPROCESSISOPTIMIZEDORISASBESTASITSGOINGTOGETFORNOWATLEASTONEBATCHHASBEENRUNONPRODUCTIONQCEQUIPMENTTTDNEEDSTOBEFORMALLYACCEPTEDBYPRODUCTION,QUALITYCONTROL,ENGINEERINGANDQUALITYASSURANCETTDACCEPTANCEISFORMALENDTODEVELOPMENTACTIVITIES40COPYRIGHTGLOBEPHARM,2005技术转移TECHNOLOGYTRANSFERFORMALTECHNOLOGYTRANSFERISAVITALELEMENTINSPEEDYANDEFFICIENTPRODUCTSTARTUP正式的技术转移是否能快速、有效地生产中至关重要地一步。41COPYRIGHTGLOBEPHARM,2005预验证PROSPECTIVEVALIDATION“VALIDATIONOFAPROCESS,PROCEDURE,ETC,BEFOREPRODUCTIONBEGINSISAPARTOFORDERLYPRODUCTORPROCESSDEVELOPMENT”预验证是生产前验证工艺、过程等，是生产或工艺研发的一部分。AUSTRALIANCODEOFGMP,199342COPYRIGHTGLOBEPHARM,2005预验证PROSPECTIVEVALIDATION“ESTABLISHINGDOCUMENTEDEVIDENCETHATAPROCESSORSYSTEMWILLDOWHATITPURPORTSTODOBASEDONAPREPLANNEDPROTOCOL”建立文件体系，工艺或系统会按照预先制定的方案中要求的去做。FDAGUIDELINESONPROCESSVALIDATION,198743COPYRIGHTGLOBEPHARM,2005预验证PROSPECTIVEVALIDATION“ESTABLISHINGDOCUMENTEDEVIDENCETHATAPROCESSORSYSTEMWILLDOWHATITPURPORTSTODOBASEDONAPREPLANNEDPROTOCOL”FDAGUIDELINESONPROCESSVALIDATION,1987NOTECONSIDEREDTOBECOMPLETEWHENAMINIMUMOF3SUCCESSIVEEXPERIMENTALRUNSARESHOWNTOMEETPREDETERMINEDSPECIFICATIONS注意至少3个连续批次的产品能满足预先设定的标准，则认为完成了预验证。44COPYRIGHTGLOBEPHARM,2005为什么WHY33BLINDMICE3MUSKETEERS3STOOGES3WISEMEN3LITTLEPIGS3KINGS3STRIKESANDYOUAREOUT3COINSINAFOUNTAIN3POINTSONAGRAPHETCETCMINIMUMOF3RUNS45COPYRIGHTGLOBEPHARM,2005HOWMANYVALIDATIONRUNS/FDAGOV/CDER/GUIDANCE/CGMPS/PRODUCTIONHTM46COPYRIGHTGLOBEPHARM,2005CPG7132C08OFMAR12,2004FORGET347COPYRIGHTGLOBEPHARM,2005CPG7132C08PROCESSVALIDATIONREQUIREMENTSFORDRUGPRODUCTSANDACTIVEPHARMACEUTICALINGREDIENTSAVALIDATEDMANUFACTURINGPROCESSHASAHIGHLEVELOFSCIENTIFICASSURANCETHATITWILLRELIABLYPRODUCEACCEPTABLEPRODUCT一个经过验证的工艺应具有高度的科学的保证，确保能可靠的生产出可接受的产品。THEPROOFOFVALIDATIONISOBTAINEDTHROUGHRATIONALEXPERIMENTALDESIGNANDTHEEVALUATIONOFDATA,PREFERABLYBEGINNINGFROMTHEPROCESSDEVELOPMENTPHASEANDCONTINUINGTHROUGHCOMMERCIALPRODUCTIONPHASE验证的证据来自于合理的设计以及对数据的评估，最好从工艺研发阶段开始持续到工业生产阶段。BEFORECOMMERCIALDISTRIBUTIONBEGINS,AMANUFACTURERISEXPECTEDTOHAVEACCUMULATEDENOUGHDATAANDKNOWLEDGEABOUTTHECOMMERCIALPRODUCTIONPROCESSTOSUPPORTPOSTAPPROVALPRODUCTDISTRIBUTION商业销售前，生产商被要求积累关于改产品工业生产的足够的数据和知识，以便支持批准后的产品销售。CONFORMANCEBATCHESSOMETIMESREFERREDTOAS“VALIDATION”BATCHESAND“DEMONSTRATION”BATCHESAREPREPAREDTODEMONSTRATETHATUNDERNORMALCONDITIONSANDDEFINEDRANGESOFOPERATINGPARAMETERS,THECOMMERCIALSCALEPROCESSAPPEARSTOMAKEACCEPTABLEPRODUCT验证批次的生产用以证实在正常条件下和设定的操作参数范围内，商业规模的生产能够制造出合格的产品。PRIORTOTHEMANUFACTUREOFCONFORMANCEBATCHESTHEMANUFACTURERSHOULDHAVEIDENTIFIEDANDCONTROLLEDALLCRITICALSOURCESOFVARIABILITY在工业生产之前，生产商应鉴别和控制所有关键的可变性来源。48COPYRIGHTGLOBEPHARM,2005CPG7132C08PROCESSVALIDATIONREQUIREMENTSFORDRUGPRODUCTSANDACTIVEPHARMACEUTICALINGREDIENTSCONFORMANCEBATCHES验证批NEWDRUGAPPLICATIONSMAYBEAPPROVEDPRIORTOCOMPLETIONOFTHEINITIALCONFORMANCEBATCHPHASEOFPROCESSVALIDATION新药申请在完成首批的工艺验证前可能被批准。COMPLETIONOFINITIALCONFORMANCEBATCH完成首批工艺验证FORSOMEPRODUCTS,THECOMPLETIONOFTHEINITIALCONFORMANCEBATCHPHASEOFPROCESSVALIDATIONBEFORETHEDISTRIBUTIONOFANYONEBATCHWOULDREQUIRETHEMANUFACTUREOFUNNEEDEDBATCHESEGCERTAINORPHANDRUGS,WHICHWOULDNOTBEINTHEINTERESTOFPUBLICHEALTH对一些产品来说，在销售任何一批不需要再生产的批次（如罕用药）前完成完成首批工艺验证，不是为了公共健康。INADDITIONTHECOMPLETIONOFMULTIPLEBATCHESBEFOREFIRSTDISTRIBUTIONMAYALSOBEIMPRACTICALFORAPRODUCTWITHAVERYSHORTSHELFLIFEORONETHATISINTENDEDFORLIMITEDUSEEGRADIOPHARMACEUTICALSTHEREFORETHENEEDTOMANUFACTUREMULTIPLECONFORMANCEBATCHESINADVANCEOFINITIALPRODUCTDISTRIBUTIONMAYNOTBENEEDEDINSUCHCASESPRODUCTDISTRIBUTIONMAYHAVEOCCURREDCONCURRENTLYWITHRELEASEOFTHECONFORMANCEBATCH另外，对于效期很短的药物或限制使用的药物（如放射性药物），在首批商业销售前完成多批生产验证是很不实际的。因此，在销售前完成多批工艺验证是没有必要的。这种情况下，商业销售会与工艺验证同步进行。49COPYRIGHTGLOBEPHARM,2005CPG7132C08PROCESSVALIDATIONREQUIREMENTSFORDRUGPRODUCTSANDACTIVEPHARMACEUTICALINGREDIENTSTHEFDASEVALUATIONOFAFIRMSDECISIONTORELEASEBATCHESCONCURRENTWITHTHEMANUFACTUREOFTHEINITIALCONFORMANCEBATCHSHOULDINCLUDEREVIEWOFFDA会评估生产商关于销售产品伴随首批工艺验证的决定ATHEFIRMSBASISFORJUSTIFYINGTHEDISTRIBUTIONOFINDIVIDUALBATCHESPRIORTOCOMPLETIONOFTHEINITIALCONFORMANCEBATCHES生产商在完成首批工艺验证前销售生产批的依据BTHEFIRMSPROTOCOL/PLANANDAVAILABLEDATATOVERIFYTHATTHEREAREADEQUATEBATCHCONTROLSANDTESTINGPRIORTORELEASEFORDISTRIBUTIONOFEACHBATCH,ANDPROVISIONOFADEQUATEANDTIMELYASSESSMENTOFTHEPROCESSVALIDITYONCEALLINITIALCONFORMANCEBATCHESHAVEBEENMANUFACTURED,AND公司的方案/计划以及可得到的数据用以证明这些批次是经过适当的控制，每批产品在放行前经过测试，一旦首次的工艺验证完成后，能对工艺有效性提供足够的、及时的评估。CTHEFIRMSPROGRAMFORMONITORINGDISTRIBUTEDBATCHESANDPROVISIONSFORARAPIDRESPONSETOINFORMATIONSUGGESTINGTHEPROCESSISNOTUNDERCONTROLEGSUBSEQUENTBATCHFAILURES,PRODUCTIONPROBLEMSRELATEDTOPROCESSDESIGNOREQUIPMENTPERFORMANCE公司50COPYRIGHTGLOBEPHARM,2005设备确认EQUIPMENTQUALIFICATION“THEPROCESSOFDETERMININGTHATADEVICE,APPARATUS,ORPIECEOFMANUFACTURINGORCONTROLEQUIPMENTMEETSALLDESIGNANDPERFORMANCESPECIFICATIONSINCLUDINGBOUNDARY,WORSTCASE,ANDPOWERFAILURECONDITIONS”设备确认是确定装置、仪器，或生产的一部分或控制设备符合所有设计和性能标准的过程，包括“临界点”、“最坏情况”和“动力失灵”的情况。“EQUIPMENTQUALIFICATIONISANECESSARYPRELIMINARYTOPROCESSVALIDATION”设备确认是在工艺验证之前的必需的准备阶段。AUSTRALIANCODEOFGMP,199351COPYRIGHTGLOBEPHARM,2005最坏情况WORSTCASEWORSTCASE最坏情况ACONDITIONORSETOFCONDITIONSENCOMPASSINGUPPERANDLOWERPROCESSINGLIMITSAND