歐盟《滅菌指南》2019（中英文對(duì)照版）

EMA《藥品、活性物質(zhì)、輔料和內(nèi)包材滅菌指南》-2019版分享給大家！4.Generalrequirements一般要求Theguidelineconcernsspecificrequirementsrelatedtosterility,sterilisationprocessesandasepticprocessingofsterileproductsandproductcomponents.本指南包含與滅菌、滅菌工藝以及無(wú)菌產(chǎn)品和產(chǎn)品組份的無(wú)菌工藝相關(guān)的具體要求。Requirementsforthemanufactureofsterilemedicinalproductsandsterilecomponents無(wú)菌藥品和無(wú)菌組分生產(chǎn)的要求Thechoiceofsterilisationmethodorasepticprocessingshouldbejustified,seesection4.3Selectionofsterilisationmethod.滅菌方法或無(wú)菌工藝的選擇應(yīng)合理，見第4.3節(jié)滅菌方法的選擇。AllsterilisationprocessesshouldbecarriedoutaccordingtotheinstructionsofthePh.Eur.unlessjustified.除非經(jīng)過論證，否則所有滅菌工藝都應(yīng)按照Ph.Eur.的規(guī)定進(jìn)行。Allsterilisationproceduresforthefinishedproduct,activesubstance,theexcipient(s)orthecontainersandthenameandaddressofthesterilisationsiteshouldbestated.Adescriptionofthesterilisationmethodand/orasepticprocessing,includingin-processcontrolsandvalidationdatashouldbeprovided.應(yīng)說明所有成品、活性物質(zhì)、輔料或容器的滅菌工藝，以及滅菌地點(diǎn)的名稱和地址。應(yīng)提供滅菌方法和/或無(wú)菌工藝的說明，包括中控和驗(yàn)證數(shù)據(jù)。Whenparametricreleaseofsterilityisproposed,theGuidelineonrealtimereleasetesting(formerlyGuidelineonparametricrelease),EMA/CHMP/QWP/811210∕2009-Rev1(humanproductsonly),theGuidelineonParametricrelease,EMEA/CVMP/QWP/339588/2005(veterinaryproductsonly)andthetextofPh.Eur.Chapter5.1.1shouldbetakenintoaccount.光提出無(wú)菌參數(shù)放行時(shí)，應(yīng)考慮EMA/CHMP/QWP/811210∕2009-Rev1《實(shí)時(shí)放行檢驗(yàn)指南(僅適用于人用產(chǎn)品)》(原《參數(shù)放行指南》)、EMEA/CVMP/QWP/339588/2005《參數(shù)放行指南(僅適用于獸藥產(chǎn)品)》和Ph.Eur.5.1.1章節(jié)的要求。Thebioburdencontrolcriteriashouldbespecifiedpriortoallsterilisationprocesses.Highbioburdenacceptancecriteriashouldnotbejustifiedbythecapacityofthesterilisationprocessoranybioburdenreducingstepbeforesterilisation.Acceptancecriteriaforbioburdenarediscussedundertherelevantsub-sectionsof4.1below.應(yīng)明確滅菌前的生物負(fù)荷控制標(biāo)準(zhǔn)。高生物負(fù)荷接受標(biāo)準(zhǔn)不應(yīng)依賴滅菌工藝的能力或滅菌前的任何生物清除步驟。以下章節(jié)4.1的相關(guān)小節(jié)討論了生物負(fù)荷的接受標(biāo)準(zhǔn)。Thelevelsofbacterialendotoxinsinthefinishedproductcanbeimpactedbythebioburdenandbacterialendotoxinsinthecomponents(i.e.activesubstance,excipientsandcontainers),andbymicrobiologicalcontaminantsintroducedduringmanufacture.Toensureanacceptablelevelofbacterialendotoxinsinthefinishedproduct,thelevelofmicrobiologicalcontaminantsofthecomponentsshouldbeminimal.Acceptancecriteria

forbioburdenand,whererelevant,bacterialendotoxinsincomponentsandbulksolutionsshouldbespecified.成品中細(xì)菌內(nèi)毒素的水平可能會(huì)受到組件（即活性物質(zhì)、輔料和容器）中生物負(fù)荷和細(xì)菌內(nèi)毒素的影響，也會(huì)受到生產(chǎn)過程中引入的微生物污染物的影響。為確保成品中細(xì)菌內(nèi)毒素的可接受水平，各組件的微生物污染物水平應(yīng)最低“應(yīng)規(guī)定組件和待灌裝溶液的生物負(fù)荷和細(xì)菌內(nèi)毒素（如適用）的接受標(biāo)準(zhǔn)。Allfiltersusedinthemanufactureofthefinishedproductthatcomeincontactwiththefinishedproduct,orwithanycomponent（substanceorintermediateproduct）incorporatedinthefinishedproductshouldbedescribedandtheinformationstatedinTable3,section4.1.5shouldbeprovidedinthequalitydossier.TheinformationshouldbeinlinewiththerequirementsstatedinEudralexGMPAnnex1.ForATMPs,theGuidelinesonGoodManufacturingPracticespecifictoAdvancedTherapyMedicinalProductsshouldbefollowed.應(yīng)描述所有與成品接觸或與成品中任何組分（活性成分或中間產(chǎn)品）接觸的用于成品生產(chǎn)的過濾器，并在其質(zhì)量檔案中提供章節(jié)4.1.5表3中要求的信息。這些資料應(yīng)符合EudralexGMP附錄1的要求°對(duì)于ATMP,應(yīng)遵循《ATMP良好生產(chǎn)規(guī)范指南》。Ifasecondarycontainer（e.g.secondarypouchforinfusionbagsorblistersintendedtokeeptheoutsideofthecontainersterile）isusedtoprovideaspecificprotectiontothemedicinalproduct,thepackagingprocessshouldbedescribed,includingariskassessment,sinceitmayaffectthesterilityofthefinishedproduct;forexample,trappingmoisturebetweentheprimaryandsecondarycontainers.Informationshouldbeprovidedastowhenthepackagingstepisperformed（beforeoraftersterilisation）andanyaseptictechniquesemployed.Theproposedprocessesshouldbejustifiedfromamicrobiologicalperspective.Iftheuseofasecondarycontainermeansadditionalsterilisationofthefinishedproductisperformed,thisshouldbejustifiedwithregardtosterilityassuranceandanypotentialimpactonfinishedproductquality.如果使用二級(jí)容器（例如用于保持輸液袋或泡罩外部無(wú)菌的外袋）為醫(yī)藥產(chǎn)品提供特定保護(hù)，則應(yīng)說明包裝過程，包括風(fēng)險(xiǎn)評(píng)估，因?yàn)樗赡軙?huì)影響成品的無(wú)菌性;例如，在內(nèi)包裝容器和二級(jí)容器之間殘留水分。應(yīng)提供關(guān)于何時(shí)（滅菌前或滅菌后）進(jìn)行包裝步驟以及所采用的任何無(wú)菌技術(shù)的信息。工藝應(yīng)從微生物的角度加以證明。如果使用二級(jí)容器意味著需要對(duì)成品進(jìn)行額外的滅萌，則應(yīng)在無(wú)南保證和對(duì)成品質(zhì)量的任何潛在影響方面進(jìn)行論證。Documentationregardingsterilisationandasepticprocessingtobeincludedinthequalitydossierispresentedbelow.Thedocumentationcould,forpracticalreasons,bepresentedinconnectionwiththeitemwhichistobesterilisedifareferencetothelocationofthedocumentsisprovidedinsection3.2.P.3.3orinPart2B.Thedocumentsmaybeprovidedforhumanproductsinsections3.2.S.2Manufacture,3.2.P.2Pharmaceuticaldevelopment,3.2.P.3Manufacture,3.2.P.4Controlofexcipients,or3.2.P.7Containerclosuresystem,orforveterinaryproductsinPart2A.4Developmentpharmaceutics,Part2B.1Manufacturingmethod,Part2C.1Activesubstance,Part2C.2ExcipientsorPart2C.3Containerclosuresystems.Thedocumentationshouldbeprovidedforallsitesperformingsterilisationorasepticprocessing,regardlessofwhethertheprocessesareperformedin-houseoroutsourced.需包含在質(zhì)量檔案中的關(guān)于滅菌和無(wú)菌工藝的文件羅列如下。出于實(shí)際原因，如果P.3.3節(jié)或第2b部分提到文件的位置，則文件可和待滅菌的物品放在-起。這些文件

可在人用藥品的3.2.S.2生產(chǎn)、3.2.P.2藥品研發(fā)、3.2.P.3生產(chǎn)、3.2.P.4輔料控制，或P.7容器封閉系統(tǒng)中提供；或獸藥第2部分A.4藥品研發(fā)，第2部分B.1生產(chǎn)方法,第2部分C.1活性物質(zhì)，第2部分C.2輔料或第2部分C.3容器封閉系統(tǒng)中提供。所有進(jìn)行滅菌或無(wú)菌工藝的場(chǎng)所都應(yīng)提供文件，無(wú)論操作是本廠執(zhí)行或是外包。Processparameterssuchasprocessingandholdingtimesareassessedandagreedduringtheevaluationofthequalitydossier.ThesemaybefurtherreviewedduringGMPinspections,whichmayresultinchangestotheregistereddossierbeingrequired.在質(zhì)髭檔案的評(píng)估過程中，會(huì)對(duì)工藝參數(shù)，例如工藝和保留時(shí)間進(jìn)行評(píng)估和商定°這些可能會(huì)在GMP檢查期間進(jìn)一步審查，并可能導(dǎo)致需要變更注冊(cè)檔案資料。4.1.1.Steamsterilisation蒸汽滅菌AllsteamsterilisationprocessesrequireaminimumlethalityofF0≥8minutesandaminimumprocessholdtemperatureof110oC.所有蒸汽滅菌工藝都要求最低殺滅力為f0N8分鐘，最低工藝溫度為11(Γc°SterilisationprocessesofdifferentlevelsoflethalityarepresentedinTable1,alongwiththedocumentationtobeincludedinthequalitydossier.Theprocessesinthetablearepresentedwithdecreasinglethalitywhenreadfromtoptobottom,thusthefirstfeasibleprocessshouldbeselected.表1列出了不同水平的殺滅力的滅菌過程，以及需要列入質(zhì)量檔案的文件。表中的工藝從上到下殺死力逐漸降低，因此應(yīng)優(yōu)先選擇上-個(gè)可行的工藝。ForsterilisationusingareferenceconditionofthePh.Eur.5.1.1(≥121oC,≥15mininallunits)validationdataforthesterilisationcycleisnotrequiredtobesubmittedinthequalitydossier.對(duì)于使用ph.eur.5.1.1的參考條件進(jìn)行滅菌?(所有位置≥121oct≥15分鐘)，則無(wú)需在質(zhì)量檔案中提交滅菌周期的驗(yàn)證數(shù)據(jù)。Ifusedasanadditionalcontroltomeasuretheprocesslethality,F0,shouldbestated,togetherwiththelowesttemperaturemeasuredbythetemperaturesensorstodetermineF0.如果使用fθ作為監(jiān)測(cè)工藝殺滅力的額外控制，則應(yīng)說明fθ,并由溫度傳感器測(cè)得的最低溫度來(lái)確定fθ.Steamsterilisationperformedwithfinishedproducttemperaturebelow115oCduringtheholdingphaseisanexceptionalcaseandshouldbescientificallyjustifiedandsupportedbyadditionaldataasdescribedinTable1.Iftemperaturesbelow1100Careincluded(duringheat-upandcool-down)inthedeterminationofF0,thisshouldbejustified.成品溫度低F115P的蒸汽滅菌保持階段是?種特殊情況，應(yīng)進(jìn)行論證,并有表1所述的其他數(shù)據(jù)的支持。如果fθ的測(cè)定中包括低于110oc的溫度(在加熱和冷卻過程中)，則應(yīng)進(jìn)行論證。InformationregardingtheF0conceptandmicrobialreductionisprovidedinPh.Eur.5.1.5ApplicationoftheF0concepttosteamsterilisationofaqueouspreparations.關(guān)于fθ概念和微生物降低的信息載于ph.eur.5.1.5fθ概念在水制劑蒸汽滅菌中的應(yīng)用。Thebioburdenlimitshouldbeinlinewithanypre-sterilisationbioburdenreductionprocesscapability(e.g.filtration).Foraqueoussolutions,thelimitsstatedinTable1are

acceptableforactivesubstancesanddrugproductformulationswithoutfurtherjustification.Othertestingregimesandlimitstocontrolbioburdenatthedefinedlevelshouldbejustified.生物負(fù)荷限度應(yīng)與任何預(yù)滅菌生物負(fù)荷降低工藝能力（如過濾）一致。在沒有特殊說的情況卜《對(duì)于水溶液，表1所述的限度對(duì)于活性物質(zhì)和藥物產(chǎn)品制劑是可以接受的。其他控制生物負(fù)荷在既定水平的測(cè)試方法和限度應(yīng)進(jìn)行論證。MoistheatprocesseswithanF0<8minmaybesuitableasapost-asepticprocessingterminalheattreatmentforformulationsthatcannotwithstandacompleteterminalsterilisationcycle.SuchprocessesmayfurtherensureaSALofsterilefiltered（orotherwisesterilised）bulkcomponents,whichhavebeenasepticallyfilled.Post-asepticprocessingterminalheattreatmentsarealsopresentedinTable1.fθ<8分鐘的濕熱處理工藝可作為無(wú)菌處理后的終端熱處理，適用于無(wú)法承受完整的終端滅菌程序的情況。此類工藝可進(jìn)一步確保無(wú)菌過濾（或以其他方式滅菌）的散裝組件經(jīng)無(wú)菌分裝后的SAL。無(wú)菌處理后終端熱處理也見表LItisemphasisedthatthisadditionalpost-asepticprocessingterminalheattreatmentshouldnotcompensateforpoorasepticmanufacturingpractice.Thesamerequirementsfortheasepticpartoftheprocessapplyasforfinishedproductsmanufacturedwithoutsuchanadditionalpost-asepticprocessingterminalheattreatment.需要強(qiáng)調(diào)的是，這種額外的無(wú)菌加工終端熱處理不應(yīng)作為不良無(wú)菌生產(chǎn)操作的補(bǔ)償。這與沒有額外無(wú)菌加工終端熱處理在無(wú)菌工藝部分的要求是?樣的。ValidationdatatobeprovidedinthequalitydossierforallsteamsterilisationprocessesthatdonotfulfiltherequirementsofPh.Eur.5.1.1standardprocess（requiredinformation7inTable1）:對(duì)于不符合ph.eur.標(biāo)準(zhǔn)工藝要求的所有蒸汽滅菌工藝，需在質(zhì)量檔案中提供的驗(yàn)證數(shù)據(jù)（表1中所需信息7）:Loadmappingofthechamberandloadmappingdistributionoftheitemsinthechamber（includingtheslowesttoheatlocations）;summaryorconfirmationofperformance.腔體的裝載布置和腔體中物品的裝載熱分布（包括加熱最慢的位置）；性能確認(rèn)總結(jié)。PhysicalandbiologicalcycleeffectconfirmationsummaryofatleastthreesterilisationrunsdemonstratinganSAL≤10-6,asdescribedinPh.Eur.5.1.1ensuring:至少三次滅菌程序的物理和生物效果確認(rèn)總結(jié)，顯示SAL≤10-6,如ph.Eur第5.1.1章節(jié)的要求：Demonstrationthatthesterilisationloadinthesteriliserchamberachievesthespecifiedcycleparameters,includingtime,temperature,pressureandF0,ifapplicable;顯示滅菌腔室中的滅菌負(fù)荷達(dá)到規(guī)定的循環(huán)參數(shù)，包括時(shí)間、溫度、壓力和fθ（如適用）;Acceptabletemperaturedifferencesbetweentemperaturesensorsintheload;裝載中溫度傳感器之間可接受的溫差；AcceptableF0variabilitywithintheload;負(fù)載內(nèi)可接受的fθ波動(dòng)；Relationshipbetweenphysicalandbiologicalvalidation.物理驗(yàn)證和生物驗(yàn)證之間的關(guān)系。Forthebiologicalvalidation,abiologicalindicatorasdescribedinPh.Eur.chapterBiologicalindicatorsandrelatedmicrobialpreparationsusedinthemanufactureofsterileproductswithaD121-valueof≥1.5minutesshouldbeused.對(duì)于生物驗(yàn)證，應(yīng)使用Ph.Eur.5.1.2章節(jié)“用于無(wú)菌產(chǎn)品生產(chǎn)的生物指示劑和相關(guān)微生物制品無(wú)菌產(chǎn)品的相關(guān)微生物制劑"中規(guī)定的D12ΓC>1.5分鐘的生物指示劑cTheSALshouldbedetermined,itsmicrobiologicalbasisshouldbejustifiedanddetailsofcalculationsprovidedinthequalitydossier.PreferablyitshouldbecalculatedfromthemaximumbioburdenpercontainerandtheD-valueofthebiologicalindicatorusedinthevalidation.應(yīng)確定SAL,其微生物基礎(chǔ)應(yīng)合理，并在質(zhì)量檔案中提供計(jì)算細(xì)節(jié)。最好是根據(jù)每個(gè)容器的最大生物負(fù)荷和驗(yàn)證中使用的生物指示劑的D值計(jì)算。Additionalvalidationdatatobeprovidedinthequalitydossierforlowenergysteamprocessesorwhereabio-indicatorwithaD121-valueof<1.5minutesisusedinthevalidationofthesterilisationprocess(requiredinformation8inTable1):在低殺滅率蒸汽滅菌工藝的質(zhì)量檔案中提供的補(bǔ)充驗(yàn)證數(shù)據(jù)，或在滅菌過程的驗(yàn)證中使用D121值<1.5分鐘的生物指示劑的情況下需提供的補(bǔ)充驗(yàn)證數(shù)據(jù)(表1中所需信息8):Thefollowingadditionaldatashouldbeprovided:應(yīng)提供以卜補(bǔ)充數(shù)據(jù)：Ajustificationforthestartpointofthesterilisationphase,thatisthetemperaturewhenthetemperaturesensorsrecordtheF0fromthestarttoendoftheprocess;論證滅菌階段的起點(diǎn)，即滅菌開始至結(jié)束溫度探頭用于記京fθ的溫度；BiologicalindicatorswithsuitableresistanceattheactualtemperaturerangeasdescribedinPh.Eur.5.1.2shouldbeincludedinthevalidationtodemonstratesensitivitytotheprocess.驗(yàn)證應(yīng)包括在Ph.Eur,第5.1.2章中所述的實(shí)際溫度范圍內(nèi)具有適當(dāng)阻力的生物指示劑,以證明對(duì)工藝的敏感性。Moredetailedvalidationdataisrequestedtoensurethattheproposedsterilisationprocessissuitableforlowtemperatureprocessesandforprocessesusingbiologicalindicatorsoflowheatresistancebecause:需要更詳細(xì)的驗(yàn)證數(shù)據(jù)，以確保建議的滅菌工藝適用于低溫工藝和使用低耐熱性生物指示劑的工藝，因?yàn)椋篢hechangeinlethaleffectinrelationtotheprocesstemperaturemaynotbeloglinearatlowersterilisationtemperatures.在較低的滅菌溫度下，殺滅效率與工藝溫度的變化可能不是對(duì)數(shù)線性的。TheSALdemonstratedinthevalidationofasterilisationprocessisdependentontheheatresistanceofthebiologicalindicatorusedinthevalidationoftheprocess.WhenabiologicalindicatoroflowD-valueisusedinthevalidationofthesterilisationprocess,theSALdemonstratedbecomesnumericallyhigher,butdoesnotprovideashighasafetymarginaswhereamoreresistantbiologicalindicatorisused.TheSALshouldalwaysbeestablishedinrelationtoaD-valuethatishigherthanthatofthenormalbioburdenatroutineproduction.在滅菌工藝的驗(yàn)證中顯示的SAL取決于在驗(yàn)證過程中使用的生物指示劑的耐熱性。當(dāng)在滅菌過程的驗(yàn)證中使用低D值的生物指示劑時(shí)，所顯示的SAL會(huì)變得更高，但不能提供與使用更耐熱的生物指示劑那樣高的安全系數(shù)。SAL應(yīng)該始終與D值相關(guān)，D值高于常規(guī)生產(chǎn)中的正常生物負(fù)荷。Dryheatsterilisation干熱滅菌

Timeandtemperatureofthesterilisationcycleandabioburdenlimitshouldalwaysbestated.通常應(yīng)說明滅菌周期的時(shí)間和溫度以及生物負(fù)荷限度“ForsterilisationusingareferenceconditionofthePh.Eur.5.1.1（aminimumof160oCforatleast2h）,thevalidationdataforthesterilisationcycleisnotrequiredtobesubmittedinthequalitydossier.Forsterilisationcycleswithtimeand/ortemperaturelowerthanthereferenceconditionsofthePh.Eur.,physicalandbiologicalvalidationofthesterilisationcycleshouldbeprovidedtodemonstrateanSALof≤10-6,asdescribedinPh.Eur.5.1.1.TheSALofsuchasterilisationprocessshouldbecalculatedfromthemaximumbioburdenpercontainer.對(duì)于使用ph.eur.5.1.1的參考條件（2160C至少2小時(shí)）進(jìn)行滅菌，滅菌周期的驗(yàn)證數(shù)據(jù)不需要在質(zhì)量檔案中提交。對(duì)于時(shí)間和溫度低于藥典參考條件的火菌周期，應(yīng)提供滅菌周期的物理和生物驗(yàn)證，以證明SAL≤10-6o這種滅菌工藝的SAL應(yīng)根據(jù)繇個(gè)容器的最大生物負(fù)荷計(jì)算。Whererequired,sufficientvalidationdatashouldbesubmittedtodemonstratethatanSALof≤10-6isobtainedforallcontainers.Thedatasubmittedshouldincludeatleast,butisnotlimitedto:必要時(shí)，應(yīng)提交足夠的驗(yàn)證數(shù)據(jù)，以證明所有容器都能獲得＜10-6的sa∣o提交的數(shù)據(jù)至少應(yīng)包括但不限于：腔體負(fù)載分布和箱體中物品負(fù)載的分布（包括最慢加熱位置）--性能的總結(jié)或確認(rèn)；Physicalandbiologicalcycleeffectconfirmationsummaryofatleastthreesterilisationrunsensuring:至少3次的物理和生物性能確認(rèn)總結(jié)，以確保：Demonstrationthatthesterilisationloadinthesteriliserchamberachievesthespecifiedcycleparameters,includingtime,temperature,and,lethality;證實(shí)滅菌器腔體中的滅南負(fù)載達(dá)到規(guī)定的循環(huán)參數(shù)，包括時(shí)間、溫度、殺滅力等；負(fù)載中溫度傳感器之間可接受的溫差；Acceptablelethalityvariabilitywithintheload;負(fù)載內(nèi)殺滅率的可接受波動(dòng)范圍；物理和生物驗(yàn)證之間的關(guān)系。Forthebiologicalvalidation,abiologicalindicatorasdescribedinPh.Eur.chaptershouldbeused.對(duì)于生物驗(yàn)證，應(yīng)使用5.1.2所述的生物指示劑。Amaximumbioburdenlimitof100CFU/100gor100CFU/100mlwouldbeacceptableforparenteralfinishedproductformulationswithoutfurtherjustification.Foractivesubstancesandfinishedproductsthatarenotusedforparenteraladministration,amaximumtotalbioburdenlimitof10CFU/gor10CFU/mlisacceptablewithoutfurtherriskbasedjustification.Othertestingregimesandlimitstocontrolbioburdenatthedefinedlevelshouldbejustified.Ajustifiedbioburdenlimitshouldalsobeestablishedforemptycontainers.對(duì)于腸外成品配方，在沒有進(jìn)?步說明的情況下，最大生物負(fù)荷限制為100cfu/100g或100cfu∕100亳升是可以接受的。對(duì)于不用于腸外給藥的活性物質(zhì)和成品，最大總生物量限制為10cfu/g或10cfu/ml是可以接受的，沒有進(jìn)?步基于風(fēng)險(xiǎn)說明。其他用以控制生

物負(fù)荷在規(guī)定水平內(nèi)的方法和限度應(yīng)進(jìn)行論證“對(duì)于空的容器.也應(yīng)建立合理的生物負(fù)荷限度。Dryheatattemperaturesofgreaterthan220oCforavalidatedtimeisfrequentlyusedforbothsterilisationanddepyrogenationofglasswareandotherheat-resistantcontainermaterialse.g.aluminiumcrimps.Inthiscase,demonstrationofa3logreductioninheat-resistantendotoxinscanbeusedasvalidationcriteria.在溫度大于2201的情況R在經(jīng)過驗(yàn)證的時(shí)間內(nèi)進(jìn)行干熱，通常用于玻璃器皿和其他耐熱容器材料的滅菌和去熱原。在這種情況卜，可將耐熱內(nèi)毒素下降3個(gè)log作為驗(yàn)證標(biāo)準(zhǔn)。Ionizationradiationsterilisation電離輻射滅菌Forthismethodofsterilisation,thereferenceabsorbeddoseis≥25kGy.OtherdosesmaybeusedtoachieveanSAL≤106,ifjustifiedandvalidated.對(duì)于這種火菌方法，參考吸收?JM≥25kGy,,如經(jīng)論證和驗(yàn)證，也可-以使用其他劑后以達(dá)到sal≤10-6oDataasrequestedinNoteforGuidance"TheuseofIonizationRadiationintheManufactureforMedicinalProducts,,andincompliancewithPh.Eur.chapter5.1.1shouldbeprovided.Relevantguidanceinestablishingtheradiationdoseotherthan25kGyisavailableinISOstandard11137.應(yīng)提供指南《藥品生產(chǎn)中使用電離輻射》中要求的數(shù)據(jù)，并符合ph.eur5.1.1章的要求oISO標(biāo)準(zhǔn)11137提供了確定25kgy以外的輻射劑枷勺相關(guān)指導(dǎo).WhereanyrequirementsinISO11137areincontradictiontorequirementsstatedinanyNoteforGuidanceissuedbytheEMAorPh.Eur.monograph,therequirementsofthePh.Eur.andtheNoteforguidanceapply.如果ISO11137中的任何要求與ema或ph.eur.專論發(fā)布的任何指導(dǎo)說明中的要求相抵觸，則應(yīng)使用ph.eur.和指南的要求.Gassterilisation氣體滅菌4.1.4.1Generalconsiderations-般考慮Generally,gassterilisationisonlyacceptableifnoothermethodofsterilisationispossible.Gassterilisationprovidessterilisationofthesurfaceofmaterials.Itismainlyemployedforsterilisingpackagingmaterialsandequipment,andhasthereforeonlybeenincludedinthedecisiontreeforcontainers.Toensureadequatesterility,sufficientpenetrationbygasandmoistureisessential.Thisshouldbefollowedbyapurgingprocesstoensurethatanyresiduesofgasorrelatedtransformationby-productsarebelowconcentrationsthatcouldgiverisetotoxiceffectsduringuseofthefinishedproduct.Theeffectivenessofthepurgingprocessshouldbedemonstrated.?般來(lái)說，只有在沒有其他滅菌方法的情況下，氣體滅菌才是可以接受的。氣體滅菌可對(duì)材料表面進(jìn)行滅菌。它主要用于對(duì)包裝材料和設(shè)備進(jìn)行滅菌，因此只包括在容器的決策樹中。為r確保足夠的無(wú)菌性，氣體和水分的充分滲透是必不可少的。氣體滅菌結(jié)束后應(yīng)采取消除工藝，以確保氣體或相關(guān)轉(zhuǎn)化副產(chǎn)品的任何殘留物低于可能導(dǎo)致成品使用過程中產(chǎn)生毒性影響的濃度。應(yīng)證明清除過程的有效性。

Gassterilisationofporouscompounds,suchasdrypowders,isnotacceptableunlessothermethodsofsterilisationarenotfeasibleanditsuseisscientificallyjustified.Priortothegassterilisation,theactivesubstanceorexcipientshouldbesterilefilteredandcrystallisedunderasepticconditionstominimisebioburdenandentrapmentofmicroorganismswithinthecrystals.Convincingevidenceshouldbeprovideddemonstratingthatthematerialtobesterilisedisnotsusceptibletocompressionpreventinggasandmoisturepenetrationduringsterilisation.對(duì)多孔化合物(如干粉體)進(jìn)行氣體滅菌是不可接受的，除非其他滅菌方法不可行且使用該方法經(jīng)科學(xué)論證。在氣體滅菌之前，活性物質(zhì)或輔料應(yīng)在無(wú)菌條件卜-進(jìn)行無(wú)菌過濾和結(jié)晶，以最大限度地減少微生物在晶體中的吸收和包裹。應(yīng)提供令人信服的證據(jù)，證明待滅菌的材料在滅菌過程中不易擠壓，防止氣體和水分滲透。Adescriptionoftheapparatus,quantitativedataongas(es)tobeused,thebioburdenpriortosterilisation,thetimeofexposuretothegas,thetemperatureandhumiditypriortoandduringeachstepofthesterilisationcycle,and,ifapplicable,theconditionsfortheremovalofanytoxicgasresiduesshouldbeprovided.Humidityusedforthepreconditioningand/orconditioningofthematerialtobesterilisedshallbegeneratedbycleansteam.Theseconditionsshouldbemonitoredbyappropriatein-processcontrolswithjustifiedacceptancecriteria.TheprocessshouldbedevelopedandvalidatedincompliancewithPh.Eur.5.1.1and5.1.2.Ariskassessmentwithregardstoresidualtoxicimpuritiesshouldbeconductedandacontrolstrategyshouldbeprovidedwhereapplicable.TherequirementsshouldbeinaccordancewiththerequirementsofICHM7"Assessmentand∞ntrolofDNAreactive(mutagenic)impuritiesinpharmaceuticalstolimitpotentialcarcinogenicrisk*'.Eveniftherelevantproductisoutsidethescopeofthatguideline,itslimitsforhighlytoxicimpuritiescouldbeapplied.應(yīng)提供設(shè)備說明、要使用的氣體的定量數(shù)據(jù)、滅菌前的生物負(fù)荷、接觸氣體的時(shí)間、滅菌周期每-步開始前和期間的溫度和濕度，以及，適當(dāng)時(shí),清除任何有毒氣體殘留的條件。用于對(duì)待滅菌材料進(jìn)行預(yù)處理和/或調(diào)節(jié)的濕度應(yīng)通過消潔蒸汽產(chǎn)生。這些條件應(yīng)通過適當(dāng)?shù)倪^程控制和合理的接受標(biāo)準(zhǔn)進(jìn)行監(jiān)測(cè)。應(yīng)按照ph.eur.5.1.1和5.1.2制定和驗(yàn)證這?程序。應(yīng)對(duì)殘留有毒雜質(zhì)進(jìn)行風(fēng)險(xiǎn)評(píng)估，并酌情提供控制戰(zhàn)略。這些要求應(yīng)符合ichm7"評(píng)估和控制藥品中的dna反應(yīng)性(誘變)雜質(zhì)以限制潛在致癌風(fēng)險(xiǎn)”。即使相關(guān)產(chǎn)品超出J'該準(zhǔn)則的適用范圍，也可以使用其對(duì)劇毒雜質(zhì)的限度。ResultsoftheprocessvalidationshoulddemonstrateanSALof≤10-6.工藝驗(yàn)證的結(jié)果應(yīng)證明sal≤10-6°Theeffectivenessoftheprocessshouldberoutinelycheckedforeverybatchconfirmingthattheprocessparametersandbiologicalindicatorsareallwithintheiracceptancecriteriaandbysterilitytesting.Parametricreleaseisnotacceptableforgassterilisation(accordingtoPh.Eur.chapter5.1.1).應(yīng)檢查每?批工藝的有效性，確認(rèn)工藝參數(shù)和生物指示劑都在其接受標(biāo)準(zhǔn)范圍內(nèi)，并通過無(wú)菌測(cè)試。參數(shù)放行對(duì)于氣體滅菌是不可接受的(根據(jù)5.1.1頁(yè))。Ethyleneoxidesterilisation環(huán)氧乙烷滅菌Ethyleneoxide(ETO)sterilisationprocessesshouldbedevelopedandvalidatedincompliancewithPh.Eur.5.1.1and5.1.2.RelevantguidanceinestablishingthesterilisationprocesscycleparametersandvalidationisavailableinISOstandard11135.

應(yīng)按照ph.eur5.1.1和5.1.2開發(fā)和驗(yàn)證環(huán)氧乙烷(eto)滅菌工藝“iso標(biāo)準(zhǔn)11135提供了在確定滅菌工藝循環(huán)參數(shù)和驗(yàn)證方面的相關(guān)指導(dǎo)。ETOisagaswhichishighlytoxic.ETOsterilisationisgenerallyonlyacceptableifnoothermethodofsterilisationispossible.Theriskassessmentshouldconsidertheresidualknowngenotoxicimpurities(suchasETOandhalogenatedethylenehydrines).ThisshouldbeevaluatedinaccordancewiththerequirementsofICHM7"AssessmentandcontrolofDNAreactive(mutagenic)impuritiesinpharmaceuticalstolimitpotentialcarcinogenicrisk",unlesstherelevantproductisoutsidethescopeofthatguideline.ForproductsoutsidethescopeofICHM7,theapplicantshouldapplylimitsforhighlytoxicimpuritiesinaccordancewithICHM7,ortheacceptancecriteriastatedinTable2,whicheverismostappropriate.eto是一種劇毒氣體。eto滅菌通常只有在沒有其他滅菌方法的情況卜-才口I■接受。風(fēng)險(xiǎn)評(píng)估應(yīng)考慮己知的殘留遺傳毒性雜質(zhì)(如eto和鹵化乙二氫)。應(yīng)根據(jù)ichm7"評(píng)估和控制藥品中的dna反應(yīng)性(誘變)雜質(zhì)以限制潛在致癌風(fēng)險(xiǎn)”的要求對(duì)此進(jìn)行評(píng)估，除非相關(guān)產(chǎn)品不在該指南的范圍之內(nèi)。對(duì)于ichm7范圍以外的產(chǎn)品，申請(qǐng)人應(yīng)根據(jù)ichm7或表2中規(guī)定的接受標(biāo)準(zhǔn)對(duì)劇毒雜質(zhì)實(shí)施限制，以最適當(dāng)者為準(zhǔn)。Foremptycontainersintendedtobefilledwithaqueousproducts,(e.g.prefilledsyringes),theneedtojustifytheuseofETOinthesterilisationofthecontainerpriortofillingcanbewaived,asthedegradationkineticsofETOinanaqueousmediumhavebeensufficientlydemonstrated.However,thelevelsoftoxicresidues(ETOandhalogenatedethylenehydrines)inthefinishedproductneedtofulfiltherequirementsofICHM7,orthelimitsstatedinTable2below,asapplicable.對(duì)于打算裝滿水性產(chǎn)品的空容器(例如預(yù)填充注射器)，可以免除對(duì)灌裝前使用ETO對(duì)容器滅菌的論證，因?yàn)镋TO在水介質(zhì)中的降解動(dòng)力學(xué)已經(jīng)充分證明。但是，成品中毒性殘留物(ETO和鹵化乙基氫)的含量需要滿足ichm7的要求，或者適當(dāng)時(shí)，滿足下文表2所述的限度。Table2LimitsfortoxicgasresiduesfromethylenesterilisationwheretheICHM7limitsdonotapply在不適用ichm7限度的情況下，乙烯滅菌產(chǎn)生的有毒氣體殘留限值Material物料EthyleneOxide環(huán)狙乙燒Ethylenechlorhydrin(oranyotherhalogenatedethylenehydrine)戒)1他鹵化乙烯Rawmaterials族科〔μg∕g50μg∕gFinishedproduct(whenusedonthefinishedproduct)成品1μg∕g50μg∕gContainer(basedonsimulateduse)容馨1μg∕ml50μg∕mlSterilefiltration除菌過濾Theintegrityofthesterilisedfiltershouldbeverifiedbytestingbeforeuseunlessspecificallyjustifiedandvalidated,andshouldbeverifiedbyonlinetestingimmediately

afteruse.Nominalporesizesof0.22morlessareacceptablewithoutfurtherjustification,inaccordancewithPh.Eur.除非有明確的證明和驗(yàn)證，除菌過濾器的完整性應(yīng)在使用前通過測(cè)試進(jìn)行確認(rèn)，并應(yīng)在使用后立即通過在線測(cè)試進(jìn)行確認(rèn)。根據(jù)ph.eur.,在沒有進(jìn)一步理由的情況下，可以接受0.22μm或以卜的公稱孔徑。Forroutinecommercialmanufacturing,bioburdentestingshouldbeperformedonthebulksolutionimmediatelybeforesterilefiltration.對(duì)于日常的商業(yè)生產(chǎn)，應(yīng)在除菌過濾前立即對(duì)溶液進(jìn)行生物負(fù)荷測(cè)試。Inmostsituations,alimitofNMT10CFU/100ml(TAMC)wouldbeacceptableforbioburdentesting.Ifapre-filterisaddedasaprecautiononlyandnotbecausetheunfilteredbulksolutionhasahigherbioburden,thislimitisapplicablealsobeforethepre-filterandisstronglyrecommendedfromaGMPpointofview.Abioburdenlimitofhigherthan10CFU/100mlbeforepre-filtrationmaybeacceptableifthisisduetostartingmaterialknowntohaveinherentmicrobialcontamination.Insuchcases,itshouldbedemonstratedthatthefirstfilteriscapableofachievingabioburdenofNMT10CFU/100mlpriortothelastfiltration.Bioburdenshouldbetestedinabulksampleof100mlinordertoensurethesensitivityofthemethod.Othertestingregimestocontrolbioburdenatthedefinedlevelshouldbejustified.在大多數(shù)情況下，生物負(fù)荷測(cè)試可以接受＜10cfu∕100ml(?需氧菌計(jì)數(shù))的限度。如果添加預(yù)過濾器僅為預(yù)防措施，而不是因?yàn)榇^濾溶液生物負(fù)荷過高，則此限度也適用于預(yù)過濾器之前，并且從GMP角度考慮也是強(qiáng)烈建議如此。如果由于起始材料己知具有固有微生物污染，任預(yù)過濾前生物負(fù)荷限度高于10cfu∕100ml可能是可以接受的。在這種情況下，應(yīng)證明第-個(gè)過濾器能夠達(dá)到在后一個(gè)過濾器之前達(dá)到≤10cfu∕100ml的生物負(fù)荷。生物負(fù)荷應(yīng)該在100?升的溶液中進(jìn)行測(cè)試，以確保該方法的敏感性。其他用以控制生物負(fù)荷在規(guī)定水平的測(cè)試方法應(yīng)進(jìn)行論證。Themaximumtimebetweenthestartofbulksolutionpreparationandsterilefiltrationshouldbestated,minimisedandappropriatelysupportedbydata.Filtrationtimeslongerthan24hoursshouldbejustified.應(yīng)說明和最大限度減少?gòu)娜芤号渲频匠^濾之間的最長(zhǎng)時(shí)間間隔，并有數(shù)據(jù)支持。過濾時(shí)間超過24小時(shí)應(yīng)進(jìn)行論證αIfasterilefilteredbulksolutionisnotfilledintothefinalproductcontainerswithin24hours,thesterilefiltrationshould,unlessjustified,berepeatedimmediatelybeforefilling.Anadditionalbioburdentestshouldbeperformedbeforeanyfurtherbioburdenreductionstepaftertheholdingtime.Theholdingtimeshouldbeadequatelyjustified.如果無(wú)菌過濾溶液未在24小時(shí)內(nèi)灌入最終產(chǎn)品容器，除非經(jīng)論證，否則應(yīng)立即重新進(jìn)行無(wú)菌過濾才能灌裝。-旦超出保持時(shí)間，任任何進(jìn)-步減少生物負(fù)荷的步驟之前，應(yīng)進(jìn)行額外的生物負(fù)荷檢驗(yàn)。保持時(shí)間應(yīng)進(jìn)行充分論證。Asepticprocessing無(wú)菌工藝Asepticprocessingisnotconsideredtobeasterilisationprocessbutconcernstheusageoftechnologiestoprocesssterilecomponentsavoidingadditionofmicrobiologicalcontaminants,e.g.useofanisolatororRestrictedAccessBarrierSystem(RABS).無(wú)菌處理不被認(rèn)為是滅菌過程，但涉及使用無(wú)菌部件進(jìn)行加工的技術(shù)，需要避免引入微生物污染，例如使用隔離器或受限進(jìn)入屏障系統(tǒng)(rabs)。

Forasepticprocessing,informationonthebulkholdingtimebeforefillingandonthefillingtimeshouldbestatedandappropriatelysupportedbydata.Thetimesshouldbeminimised.Thegroundsforholdingandfillingtimeslongerthan24hoursshouldbejustifiedandsupportedbyariskassessment.Itshouldbeverifiedthattheresultsofthemediasimulationssupporttheproposedholdingandprocessingtimes.TheactualresultsofmediasimulationsfallwithinthefieldofGMPandneednotbepresentedroutinely,butmayberequestedbythecompetentauthoritiesincertaincircumstancessincesuchdataareimportanttojustifyproposedholdingandfillingtimes.對(duì)于無(wú)菌處理，應(yīng)說明灌裝前的保持時(shí)間和灌裝時(shí)長(zhǎng)的信息，并有適當(dāng)?shù)臄?shù)據(jù)支持＜，時(shí)間應(yīng)盡鬲減少。保持時(shí)間和灌裝時(shí)長(zhǎng)超過24小時(shí)的理由應(yīng)得到風(fēng)險(xiǎn)評(píng)估的論證和支持“應(yīng)當(dāng)核實(shí)的是，培養(yǎng)基模擬灌裝的結(jié)果支持了擬議的保持時(shí)間和處理（灌裝）時(shí)長(zhǎng)。培養(yǎng)基模擬灌裝的實(shí)際結(jié)果屬于GMP領(lǐng)域，不需要例行提出，但在某些情況F,主管當(dāng)局可能會(huì)提出要求，因?yàn)檫@類數(shù)據(jù)對(duì)于證明擬議的保持時(shí)間和灌裝時(shí)長(zhǎng)的合理性是很重要的。Sterilecontainersshouldbeusedforasepticallytreatedactivesubstances,excipientsandfinishedproducts.經(jīng)無(wú)菌處理的活性物質(zhì)、輔料和成品應(yīng)使用無(wú)菌容器。Whereblow-fill-sealtechnologyisusedforasepticallytreatedproducts,asummaryofthevalidationdatashouldbeprovidedtoconfirmthatthecontainerproducedissterile.Thevalidationshould,usingabiologicalindicatorwithasuitableresistance,demonstrateaSALof≤10-6forthesurfaceofthecontainer.Thebioburdenofthematerials）usedforthemanufactureoftheblow-fill-sealcontainershouldbecontrolled.Thelimitshouldbejustifiedinrelationtothelethalityofthevalidatedblow-fill-sealprocess.Thebioburdenlimitshouldalsoincludeasafetymarginasaforanypossiblebioburdenenclosedwithinthematerial.當(dāng)吹-灌■封技術(shù)用于在無(wú)菌處理產(chǎn)品時(shí)，應(yīng)提供驗(yàn)證數(shù)據(jù)總結(jié)，以確認(rèn)所生產(chǎn)的容器是無(wú)菌的c驗(yàn)證應(yīng)使用具有適當(dāng)耐受性的生物指示劑，證明容器表面的SAL≤10-6o應(yīng)控制用于制造吹-灌-封容器的材料的生物負(fù)荷。生物負(fù)荷的限度應(yīng)結(jié)合吹-灌-封工藝的殺滅力進(jìn)行論證。生物負(fù)荷限度還應(yīng)包括安全系數(shù)，以防止材料中包含的任何可能的生物負(fù)荷。ThemajorityofATMPscannotbeterminallysterilised.Insuchcases,themanufacturingprocessshouldbeconductedaseptically.FurtherdetailsonasepticmanufacturingforATMPscanbefoundintheGuidelinesonGoodManufacturingPracticeforAdvancedTherapyMedicinalProducts.大多數(shù)ATMP不能進(jìn)行最終滅菌。在這種情況下，生產(chǎn)過程應(yīng)無(wú)菌。有關(guān)ATMP無(wú)菌生產(chǎn)的更多詳細(xì)信息，請(qǐng)參見《先進(jìn)治療藥品良好生產(chǎn)規(guī)范指南》。Goodmanufacturingpra