歐盟對(duì)滅菌技術(shù)的要求課件

歐盟對(duì)滅菌技術(shù)的要求SterilisationTechnology–

EURegulatoryExperiencesthecompliancegroupStanO’NeillCPAPE2011年會(huì)Agenda內(nèi)容Background背景TypicalProcessdescription典型工藝的描述Virtualinspection–typicalissues我們來作一次虛擬的檢查–看常見的問題Miscellaneous其它Background背景ExperienceinindustryinRegAffairsandQA(asQP)priortoIMB在進(jìn)愛爾蘭藥品管理局前，有制藥、法規(guī)與QA(QP)的經(jīng)驗(yàn)10YearsIMB,experienceinmosttechnologies,EMEAIWG,andtraining.愛爾蘭藥品管理局10年，有多種技術(shù)、EMEAIWG以及培訓(xùn)方面的經(jīng)驗(yàn)Nowa“virtualinspector”現(xiàn)在是“事實(shí)上的檢查員”Soletsdoa“virtualinspection”好，我們來做當(dāng)一回“檢查員”Butletstalkaboutthesolutions/strategies/positions;notjusttheproblems.我們先來討論戰(zhàn)略位置/策略/解決方案，而不只是討論問題Colourcodingsystem彩色編碼系統(tǒng)Processingsteps操作步驟Aseptic無菌操作TerminallySterilized最終滅菌Problem問題Solution解決方案Ancillarysteps輔助步驟ProcessingstepsAsepticTerminallySterilizedProblemSolutionAncillarystepsRawmaterialsamplingIdentitytestingofeachcontainerofAPIandexcipientsValidatedNIRacceptableoneachcontainerwithMAidentitytestoncompositeClassificationandgarbingforsamplingareaGradeC(equivalentactivitytocompounding).Nooutdoorclothing.MaterialsdispensedClassificationandgarbingfordispensingareaGradeC(equivalentactivitytocompounding).Nooutdoorclothing.Sampling&identification加工步驟無菌操作最終滅菌問題解決方案輔助操作原料取樣對(duì)每個(gè)容器的原料藥與輔料進(jìn)行鑒別實(shí)驗(yàn)可用經(jīng)驗(yàn)證的近紅外，在生產(chǎn)現(xiàn)場(chǎng)對(duì)組份作每個(gè)容器的鑒別試驗(yàn)取樣區(qū)級(jí)別與著裝C級(jí)區(qū)(與配制活動(dòng)同級(jí))，不穿室外衣服物料稱量配料區(qū)級(jí)別與著裝C級(jí)區(qū)(與配制活動(dòng)同級(jí))，不穿室外衣服原料鑒別ProcessingstepsAsepticTerminallySterilisedProblemSolutionAncillarystepsRawmaterialsmixedBulkproductfilteredWeepingsealbetweencleanandnon-cleansideofmixingshaftUnderstandingthesystem,ensuringweepingfluidisWFI.Pre-use,poststerilizationintegritytestThetestshouldbeperformed,asconfirmedbytheEMEA.Numeroustechnicalsolutionsarepossible.TandPnotindependentofcontrolsystemsConsiderintroductionofindependentmonitoringsystem.Ataminimum,apressuregaugeperiodicallychecked.SterilizationofequipmentusingSIPT&PmonitoringBulkproductstoredHoldingtimeexceededOftenamis-undestandingthatthereisanabsolutelimit.Longertimescanbevalidated,(takingintoaccountMAfiling).ProcessingstepsAsepticTerminallySterilisedProblemSolutionAncillarystepsHoldingtimeProcessingstepsAsepticTerminallySterilizedProblemSolutionAncillarystepsProductfilledAutoclavevalidationforporousloadsUseofairdetectorsinautoclaves,useofHTM2010validationcriteria,useof5pulsestomeetequilibrationtimecriteriaAsepticprocessingSterilizationofancillarysuppliese.g.pens,paperWheresteamsterilizationnotpossible,considergammairradiationSterilizationofcomponentsbyethyleneoxide-"torturouspath"VentplasticbagswithatyvexstripOperatorbehaviourPractiseobservationofsetupandobservationofgarbinginanon-familiarenvironment(e.g.Board.Room)wheresuitablefacilitiesnotavailable.Tunnelvalidation,lackofobjectivecriteriaConsideruseofobjectivecriteriasuchasFHVentplasticbagsUnitsstopperedFreezedrying;pressurenotmonitoredduringsterilisationofchamberDesignindependentpressuremonitoringintosterilisationcycle.Freezedrying;nosystemtoassessforshelfcoolantleakage,potentiallyenteringunitsUsepressureholdtesttocheckshelfintegrity.Maynecessitatevapourpressurecalculationsforcoolant.2ndchoice-declarechembertobesanitisedratherthansterilised2ndchoice-checkcoolantlevelsinbetweenbatchesSterilisationofstoppersusingstopperprocessorConsideredtobeSIPratherthanautoclaving,solowersterilityassuranceDesigntakingaccountofsomeaspectsofautoclavesandautoclavevalidationcriteria.ProcessingstepsAsepticTerminallySterilizedProblemSolutionAncillarystepspressurenotmonitored已加塞瓶/單元凍干：凍干腔室/箱滅菌過程中沒監(jiān)測(cè)壓力在滅菌程序設(shè)計(jì)中,增加獨(dú)立的壓力監(jiān)測(cè)凍干：無系統(tǒng)來評(píng)估冷媒的泄露,有可能進(jìn)入瓶/單元中使用壓力保持試驗(yàn)對(duì)系統(tǒng)檢漏，有必要計(jì)算冷媒的蒸汽壓第2種辦法-聲明腔室是消毒處理的，不是滅菌的第2種辦法-在批與批之間檢查冷媒的水平用塞處理機(jī)滅菌膠塞考慮在線滅菌而不是高壓滅菌,由此降低了無菌保證水平設(shè)計(jì)中考慮蒸汽滅菌的相關(guān)因素及蒸汽滅菌程序驗(yàn)證的標(biāo)準(zhǔn)加工步驟無菌操作最終滅菌問題解決方案輔助步驟凍干Unitssealedcapping!wheretobegin!GradeAairsupply.Viablemonitoringofarea.Raisedstopperdetectionsystemmeasuring"thegap"FMEAforparametricreleaseincompleteorinaccurateFMEAspreparedonlybyexperts.Considerusingfreshpairofeyes.DoublecheckcrucialelementssuchastrainingUnitssteamsterilisedProcessingstepsAsepticTerminallySterilizedProblemSolutionAncillarystepsCapping已密封單元軋蓋!在此開始!A級(jí)送風(fēng)，測(cè)浮游菌。膠塞監(jiān)測(cè)系統(tǒng)，以檢查“縫隙、凸起及錯(cuò)位”FMEA對(duì)參數(shù)放行不完全或不準(zhǔn)確FMEA僅由專家編寫，考慮用新的眼光來審視，重點(diǎn)審視培訓(xùn)這類關(guān)鍵要素作蒸汽滅菌軋蓋加工步驟無菌操作最終滅菌問題解決方案輔助步驟UnitsinspectedValidationofautomatedinspectionsystemscomplicatedvshumansUnderstandlimitationsofhumaninspectione.g.90%detectabilitycutoffpointForsemi-automatedequipment,noluxreadingsinaccordancewithPh.EurDefendpositionbasedondifferenttypeofequipment,differentlightsource,noblack/whitebackground,inabilitytoplaceluxometerinameaningfullocationQualitycontrolSterilitytestmedianotinaccordancewithsuppliersinstructions(overcookedissue)Validateliquidloadsfor121degCfor15mins,orobtainconfirmationfromsupplierfrommediathatnotanissue.ProcessingstepsAsepticTerminallySterilizedProblemSo