欧盟对灭菌技术的要求

欧盟对灭菌技术的要求SterilisationTechnology–

EURegulatoryExperiencesthecompliancegroupStanO’NeillCPAPE2011年会Agenda内容Background背景TypicalProcessdescription典型工艺的描述Virtualinspection–typicalissues我们来作一次虚拟的检查–看常见的问题Miscellaneous其它Background背景ExperienceinindustryinRegAffairsandQA(asQP)priortoIMB在进爱尔兰药品管理局前，有制药、法规与QA(QP)的经验10YearsIMB,experienceinmosttechnologies,EMEAIWG,andtraining.爱尔兰药品管理局10年，有多种技术、EMEAIWG以及培训方面的经验Nowa“virtualinspector”现在是“事实上的检查员”Soletsdoa“virtualinspection”好，我们来做当一回“检查员”Butletstalkaboutthesolutions/strategies/positions;notjusttheproblems.我们先来讨论战略位置/策略/解决方案，而不只是讨论问题Typicalprocess典型工艺Rawmaterialsampling原料取样Materialsdispensed物料配制Rawmaterialsmixed原料混合Bulkproductfiltered已过滤的药液Productfilled已灌装产品Bulkproductstored药液储存Unitssealed密封产品Unitsstoppered已加塞产品Unitsinspected已检查品Qualitycontrol质量控制Sealedunitsterminallysterilised密封产品最终灭菌Colourcodingsystem彩色编码系统Processingsteps操作步骤Aseptic无菌操作TerminallySterilized最终灭菌Problem问题Solution解决方案Ancillarysteps辅助步骤ProcessingstepsAsepticTerminallySterilizedProblemSolutionAncillarystepsRawmaterialsamplingIdentitytestingofeachcontainerofAPIandexcipientsValidatedNIRacceptableoneachcontainerwithMAidentitytestoncompositeClassificationandgarbingforsamplingareaGradeC(equivalentactivitytocompounding).Nooutdoorclothing.MaterialsdispensedClassificationandgarbingfordispensingareaGradeC(equivalentactivitytocompounding).Nooutdoorclothing.Sampling&identification加工步骤无菌操作最终灭菌问题解决方案辅助操作原料取样对每个容器的原料药与辅料进行鉴别实验可用经验证的近红外，在生产现场对组份作每个容器的鉴别试验取样区级别与着装C级区(与配制活动同级)，不穿室外衣服物料称量配料区级别与着装C级区(与配制活动同级)，不穿室外衣服原料鉴别ProcessingstepsAsepticTerminallySterilisedProblemSolutionAncillarystepsRawmaterialsmixedBulkproductfilteredWeepingsealbetweencleanandnon-cleansideofmixingshaftUnderstandingthesystem,ensuringweepingfluidisWFI.Pre-use,poststerilizationintegritytestThetestshouldbeperformed,asconfirmedbytheEMEA.Numeroustechnicalsolutionsarepossible.TandPnotindependentofcontrolsystemsConsiderintroductionofindependentmonitoringsystem.Ataminimum,apressuregaugeperiodicallychecked.SterilizationofequipmentusingSIPT&Pmonitoring原料混合过滤的半成品搅拌轴清洁和不清洁间的密封要淋洗搞清楚系统，保证用注射用水淋洗使用前，灭菌后，作完整性测试正如EMEA确认的那样，应进行测试，可采用多种技术方案温度与压力不独立于控制系统考虑引入独立的监测系统，至少定期检查压力表使用在线灭菌的灭菌设备加工步骤无菌最终灭菌问题解决方案辅助步骤搅拌密封清洁、过滤器、监测系统BulkproductstoredHoldingtimeexceededOftenamis-undestandingthatthereisanabsolutelimit.Longertimescanbevalidated,(takingintoaccountMAfiling).ProcessingstepsAsepticTerminallySterilisedProblemSolutionAncillarystepsHoldingtime半成品储存存放时间超标经常出现误解，认为限度是绝对的。时间长一些可经过验证(考虑上市场许可的要求)加工步骤无菌操作最终灭菌问题解决方案辅助步骤存放时间ProcessingstepsAsepticTerminallySterilizedProblemSolutionAncillarystepsProductfilledAutoclavevalidationforporousloadsUseofairdetectorsinautoclaves,useofHTM2010validationcriteria,useof5pulsestomeetequilibrationtimecriteriaAsepticprocessingSterilizationofancillarysuppliese.g.pens,paperWheresteamsterilizationnotpossible,considergammairradiationSterilizationofcomponentsbyethyleneoxide-"torturouspath"VentplasticbagswithatyvexstripOperatorbehaviourPractiseobservationofsetupandobservationofgarbinginanon-familiarenvironment(e.g.Board.Room)wheresuitablefacilitiesnotavailable.Tunnelvalidation,lackofobjectivecriteriaConsideruseofobjectivecriteriasuchasFHVentplasticbags产品灌装多孔装载蒸汽灭菌的验证在灭菌柜采用空气探测器，采用HTM2010标准，用5个脉冲使平衡时间达到标准无菌工艺辅助材料，如笔，纸的灭菌在不可能蒸汽灭菌时，考虑射线辐照灭菌部件用环氧乙烷灭菌--“折磨人的路径"塑料袋口用tyvex条操作人员的行为在无合适设备时，在不熟悉的环境(如会议室)中，安排调试和着装，观察人员的行为隧道灭菌器验证无客观标准考虑使用客观标准如FH加工步骤无菌操作最终灭菌问题解决方案辅助步骤纸笔灭菌及人员行为UnitsstopperedFreezedrying;pressurenotmonitoredduringsterilisationofchamberDesignindependentpressuremonitoringintosterilisationcycle.Freezedrying;nosystemtoassessforshelfcoolantleakage,potentiallyenteringunitsUsepressureholdtesttocheckshelfintegrity.Maynecessitatevapourpressurecalculationsforcoolant.2ndchoice-declarechembertobesanitisedratherthansterilised2ndchoice-checkcoolantlevelsinbetweenbatchesSterilisationofstoppersusingstopperprocessorConsideredtobeSIPratherthanautoclaving,solowersterilityassuranceDesigntakingaccountofsomeaspectsofautoclavesandautoclavevalidationcriteria.ProcessingstepsAsepticTerminallySterilizedProblemSolutionAncillarystepspressurenotmonitored已加塞瓶/单元冻干：冻干腔室/箱灭菌过程中没监测压力在灭菌程序设计中,增加独立的压力监测冻干：无系统来评估冷媒的泄露,有可能进入瓶/单元中使用压力保持试验对系统检漏，有必要计算冷媒的蒸汽压第2种办法-声明腔室是消毒处理的，不是灭菌的第2种办法-在批与批之间检查冷媒的水平用塞处理机灭菌胶塞考虑在线灭菌而不是高压灭菌,由此降低了无菌保证水平设计中考虑蒸汽灭菌的相关因素及蒸汽灭菌程序验证的标准加工步骤无菌操作最终灭菌问题解决方案辅助步骤冻干Unitssealedcapping!wheretobegin!GradeAairsupply.Viablemonitoringofarea.Raisedstopperdetectionsystemmeasuring"thegap"FMEAforparametricreleaseincompleteorinaccurateFMEAspreparedonlybyexperts.Considerusingfreshpairofeyes.DoublecheckcrucialelementssuchastrainingUnitssteamsterilisedProcessingstepsAsepticTerminallySterilizedProblemSolutionAncillarystepsCapping已密封单元轧盖!在此开始!A级送风，测浮游菌。胶塞监测系统，以检查“缝隙、凸起及错位”FMEA对参数放行不完全或不准确FMEA仅由专家编写，考虑用新的眼光来审视，重点审视培训这类关键要素作蒸汽灭菌轧盖加工步骤无菌操作最终灭菌问题解决方案辅助步骤UnitsinspectedValidationofautomatedinspectionsystemscomplicatedvshumansUnderstandlimitationsofhumaninspectione.g.90%detectabilitycutoffpointForsemi-automatedequipment,noluxreadingsinaccordancewithPh.EurDefendpositionbasedondifferenttypeofequipment,differentlightsource,noblack/whitebackground,inabilitytoplaceluxometerinameaningfullocationQualitycontrolSterilitytestmedianotinaccordancewithsuppliersinstructions(overcookedissue)Validateliquidloadsfor121degCfor15mins,orobtainconfirmationfromsupplierfrommediathatnotanissue.ProcessingstepsAsepticTerminallySterilizedProblemSolutionAncillarystepsautomatedinspectionsystems检查单元验证自动检测系统，比人工法复杂理解人工检查的局限性，如90%的可检出率对于半自动设备，不需要符合欧洲药典照度的要求根据不同设备设放置位置，不同光源，无黑/白色背景，不能在一个有意义的位置放照度计质量控制无菌检查培养基不按供应商说明处理(煮得过久的问题)对121℃x15分钟灭菌的液体装载做验证，或从培养基供应商确认无问题加工步骤无菌操作最终灭菌问题解决方案辅助步骤自动检查系统Miscellaneous其它TransferbarforALULsystemsnotsterilisabl