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PHARMACEUTICALINSPECTIONCONVENTIONPHARMACEUTICALINSPECTIONCO-OPERATIONSCHEME1July2004PI007-2PI007-21July2004RECOMMENDATIONONTHEVALIDATIONOFASEPTICPROCESSES©PIC/SJuly2004Reproductionprohibitedforcommercialpurposes.Reproductionforinternaluseisauthorised,providedthatthesourceisacknowledged.Editor:PIC/SSecretariatP.O.Box5695CH-1211Geneva11e-mail:daniel.brunner@picscheme.orgwebsite:http://www.picscheme.org1July2004-i-PI007-2TABLEOFCONTENTSPage1.DOCUMENTHISTORY................................................................................12.INTRODUCTION...........................................................................................12.1Purpose...........................................................................................................12.2Scope..............................................................................................................12.3Generalinformation.........................................................................................13.DEFINITIONS................................................................................................24.PROCESSSIMULATIONTESTPROCEDURES.......................................44.1GeneralComments........................................................................................44.2LiquidProducts...............................................................................................44.3InjectablePowderProducts............................................................................54.4SuspensionProducts.....................................................................................54.5FreezeDried(Lyophilised)Products..............................................................54.6Semi-SolidProducts(e.g.sterileointments)..................................................64.7ClinicalTrialsMaterialsandSmallBatchSizeProducts...............................64.8BiologicalandBiotechnologyProducts..........................................................64.9SterileBulkPharmaceuticals..........................................................................65.PROCESSSIMULATIONTESTCONDITIONS..........................................75.1TestPerformance...........................................................................................75.2SelectionofGrowthMedium...........................................................................75.3IncubationConditions......................................................................................85.4ReadingoftheTest.........................................................................................85.5TestFrequency...............................................................................................86.INTERPRETATIONOFDATA......................................................................97.ENVIRONMENTALANDPERSONNELMONITORING...........................117.1AirBorneMicrobialandNon-ViableParticleMonitoring................................117.2Non-viablemonitoring...................................................................................117.3MicrobialMonitoring.......................................................................................117.4InterventionMonitoring..................................................................................128.STAFFTRAINING........................................................................................12PagePI007-2-ii-1July20049.IMPORTANTFACTORSINVALIDATIONOFASEPTICMANUFACTURING.....................................................................................139.1Container/ClosureIntegrityTesting..............................................................139.2Container/ClosureSterilisation.....................................................................139.3EquipmentCleaningandSterilisation...........................................................139.4Disinfection...................................................................................................149.5FilterValidation..............................................................................................149.6VentFilters....................................................................................................159.7EquipmentMaintenanceandTesting...........................................................159.8BlowFillSeal/FormFillSeal.........................................................................159.9SterilityTest..................................................................................................1610.REVISIONHISTORY...................................................................................16_______________1July2004Page1of16PI007-21.DOCUMENTHISTORYAdoptionbythePIC/SCommittee7September1999EntryintoforceofversionPR1/991January2000EntryintoforceofversionPI007-11September20012.INTRODUCTION2.1Purpose2.1.1Theaimofthisdocumentistoprovideguidancetothecurrentpracticeinthisfieldbygivingrecommendationsforthevalidationofasepticprocesses.Inparticular,thedocumentshouldprovideguidanceforGMPinspectorsbothfortrainingpurposesandinpreparationforinspectionsofcompanypremises.2.2Scope2.2.1Thisdocumentappliestoallmanufacturersinvolvedinasepticprocessingoffinisheddosageforms(humanandveterinary)aswellasmanufacturersofsterilelabelledbulkdrugsubstances(activepharmaceuticalingredients).2.2.2Atthetimeofissuethisdocumentreflectedthecurrentstateoftheart.Itisnotintendedtobeabarriertotechnicalinnovationorthepursuitofexcellence.Theadviceinthisrecommendationisnotmandatoryforindustry.However,industryshouldconsiderthisrecommendationasappropriate.2.3Generalinformation2.3.1ThebasicprinciplesandapplicationofprocessvalidationaredescribedinAnnex15totheEU/PIC/SGuidetoGMPandarefurtherelaboratedinPIC/SDocumentPI006(RecommendationsonValidationMasterPlan,InstallationandOperationalQualification,Non-SterileProcessValidation,CleaningValidation)andapplyalsotoasepticprocessing.AnnexItotheEU/PIC/SGuidetoGMPprovidesthebasicrequirementsforthemanufactureofsterileproductsincludingthoseasepticallyprocessed.TheAnnexincludesrequirements,standardsandrecommendations,forexample,formonitoringoftheenvironmentandofpersonnel.2.3.2Validationofasepticprocessesreliesuponprospective,concurrentandretrospectivevalidationaswellasre-validation.2.3.3ProspectivestudieswouldincludeinstallationandoperationalqualificationforaneworrenovatedfacilityaswellasproductsimulationstudiesandaprospectiveprocessvalidationwiththeoriginalproductaccordingtoPIC/SDocumentPI006.PI007-2Page2of161July20042.3.4Concurrentvalidationincludesaprocessvalidationwiththesamerequirementsasforprospectivestudies,butperformedduringroutineproductiononqualifiedequipment.2.3.5Retrospectivevalidationusesthedataofearliermanufactures,butisnotarecommendedtechniqueforasepticprocesses.2.3.6Re-validationincludes:ØRegularperformanceofprocesssimulationstudiesØMonitoringofenvironment,disinfectionprocedures,equipmentcleaningandsterilisation(includingcontainersandclosures)ØRoutinemaintenanceandre-qualificationofequipment,e.g.autoclaves,ovens,HVAC(heating,ventilationandairconditioning)systems,watersystems,etc.ØRegularintegritytestingofproductfilters,containers,closuresandventfiltersØRe-validationafterchanges2.3.7Itisthesumtotalofallvalidationdatathatprovidesthenecessarylevelofassuranceforasepticallyproducedproducts.2.3.8Processsimulationstudies(mediafills)aresimulatingthewholeprocessinordertoevaluatethesterilityconfidenceoftheprocess.Processsimulationstudiesincludeformulation(compounding),filtrationandfillingwithsuitablemedia.Simulationsaremadetoensurethattheregularprocessforcommercialbatchesrepeatedlyandreliablyproducesthefinishedproductoftherequiredquality.However,eachprocesssimulationtrialisuniqueandsoitisnotpossibletoextrapolatetheseresultsdirectlytoactualproductioncontaminationrates.2.3.9Themethodsforsimulatinganasepticprocessvaryaccordingtotheprocessusedforthevarioustypesofproducts,i.e.liquid,semi-liquidandsoliddosageforms.2.3.10IntheseRecommendationstheterm“should”indicatesrequirementsthatareexpectedtoapplyunlessshowntobeinapplicableorreplacedbyanalternativedemonstratedtoprovideatleastanequivalentlevelofqualityassurance.3.DEFINITIONSActionlevel:Establishedcriteria,e.g.microbialorparticulatelevels,requiringimmediatefollow-upandcorrectiveactionifexceeded.Alertlimits(environmentalmonitoring):Establishedmicrobialorparticulatelevelsgivingearlywarningofpotentialdriftfromnormaloperatingconditionswhicharenotnecessarilygroundsfordefinitivecorrectiveactionbutwhichrequirefollow-upinvestigation.1July2004Page3of16PI007-2Alertlimits(mediafill):Establishedlevelsornumbersofpositivemediafilledunits,thecauseofwhichshouldbeinvestigated,butwhicharenotnecessarilygroundsfordefinitivecorrectiveaction.Asepticfilling:Operationwherebytheproductissterilisedseparately,thenfilledandpackagedusingsterilisedcontainersandclosuresincriticalprocessingzones.Bioburden:Totalnumberofviablemicroorganismsonorinpharmaceuticalproductpriortosterilisation.Compounding:Aprocesswhereinbulkdrugsubstanceiscombinedwithanotherbulkdrugsubstanceand/oroneormoreexcipientstoproduceadrugproduct.Environmentalmonitoringprogramme:Defineddocumentedprogrammewhichdescribestheroutineparticulateandmicrobiologicalmonitoringofprocessingandmanufacturingareas,andincludesacorrectiveactionplanwhenactionlevelsareexceeded.Growthpromotiontest:Testperformedtodemonstratethatmediawillsupportmicrobialgrowth.Highefficiencyparticulateair(HEPA)filter:Retentivematrixdesignedtoremoveadefinedpercentageofparticulatematterofadefinedsize.HVAC:Heating,ventilationandairconditioningIntegritytest:Testtodeterminethefunctionalperformanceofafiltersystem.Mediafills:Methodofevaluatinganasepticprocessusingamicrobialgrowthmedium.(Mediafillsareunderstoodtobesynonymoustosimulatedproductfills,brothtrials,brothfillsetc.).Samplingfrequency:Establishedperiodforcollectingsamples.Shift:Scheduledperiodsofworkorproduction,usuallylessthan12hoursinlength,staffedbyalternatinggroupsofworkers.Sterile:Freeofanyviableorganisms.(Inpractice,nosuchabsolutestatementregardingtheabsenceofmicroorganismscanbeproven,seesterilisation.)Sterilisation:Validatedprocessusedtorenderaproductfreeofviableorganisms.Note:Inasterilisationprocess,thenatureofmicrobiologicaldeathofreductionisdescribedbyanexponentialfunction.Therefore,thenumberofmicroorganismswhichsurviveasterilisationprocesscanbeexpressedintermsofprobability.Whiletheprobabilitymaybereducedtoaverylownumber,itcanneverbereducedtozero.Sterilityassurancelevel(SAL):Probabilitythatabatchofproductissterile.(SALisexpressedas10-n).PI007-2Page4of161July2004Sterilitytest:Testperformedtodetermineifviablemicroorganismsarepresent.Ventfilter:Non-sheddingporousmaterialcapableofremovingviableandnon-viableparticlesfromgasespassinginandoutofaclosedvessel.4.PROCESSSIMULATIONTESTPROCEDURES4.1GeneralComments4.1.1Themediafillshouldemulatetheregularproductfillsituationintermsofequipment,processes,personnelinvolvedandtimetakenforfillingaswellasforholding.4.1.2Wherefillingtakesplaceoverextendedperiods,i.e.longerthan24hours,theprocesssimulationtestshouldextendoverthewholeofthestandardfillingperiod.Inordertopreventexcessivelyhighnumbersofunitsbeingfilleditisusuallyacceptabletojustrunthemachineforareasonabletime,ifthevalidityofthesimulationisnotdiminishedbythisprocedure.4.1.3Itshouldbeconsideredthatinertgaseswillpreventthegrowthofaerobicmicroorganisms.Thereforeforprocesssimulationssterilefilteredairshouldbeusedinsteadofinertgases,alsoforbreakingavacuum.Whereanaerobesaredetectedintheenvironmentalmonitoringorsterilitytesting,theuseofaninertgasshouldbeconsideredforaprocesssimulation,asinertgasissupportingthegrowthofanaerobes.4.1.4Beforeenumeratingthedifferentprocesssimulationtestproceduressomepreliminaryexplanationsarenecessaryforthepreparationofliquidmediaasitisusedforthemajorityoftheprocesssimulationtests.Wherealiquidnutrientmediumisuseditshouldbepreparedinasimilarmannertotheproduct.ThemediumshouldbedissolvedinWaterforInjectioninastandardmanufacturingvessel.Ifheatisrequiredtodissolveitthenonlyminimalheatshouldbeused.ThepHofthemediumshouldbemeasuredand,ifnecessary,adjustedtobringitintotherequiredrange.Themediumshouldbeasepticallyfilteredintoanasepticholdingvesselusingthenormalproductionfilterandprocessingprocedure.Injustifiedcasesitmaybealsoacceptabletosterilisethemedia.Allasepticholdingvesselsshouldbecoveredbyaprocesssimulationtestonaregularbasisunlessavalidated,pressureholdorvacuumholdtestisroutinelyperformed.4.1.5Thefollowingchapterillustratesthetestproceduresforthevarioussimulationtestsforasepticallyproducedsolutions,lyophiles,suspensions,ointmentsandpowdersandsummarisestheconsiderationstobemade.4.2LiquidProducts4.2.1VialProducts4.2.1.1Theliquidgrowthmediumforthesimulationtestispreparedasaboveandkeptinasterileholdingvesselforthemaximumpermittedholdingtimebeforestartingthesimulationtest.Ifthebulksolutionisstoredunderrefrigeratedconditionsduringtheholdingtimethenthisshouldalsobeperformedforthemedium.Vialsandclosuresshouldbepreparedasinregularproduction.1July2004Page5of16PI007-24.2.2SterileProductsinPlasticContainers4.2.2.1Earandeyedropsaretypicallymarketedinplasticcontainers.Containers,inserts,closuresandwhereapplicableoversealsarewashedandsterilisedasinregularproduction.Insteadofsterilisationwithheat,irradiationorethyleneoxideareused.4.2.2.2Whilstclearplasticcontainersarefrequentlyusedforprocesssimulationtrials,theplasticisusuallyslightlyopaqueandthushindersidentificationofcontaminatedunitsthatshowonlyaslighthaze.Insuchcaseexaminationundernaturalorroomlightingwouldnotsuffice.Whereopaquecontainersareusedforprocesssimulationtrialsthewholecontentsshouldberemovedforexamination.4.2.3AmpouleProducts4.2.3.1Openorclosedampouletypesmaybeused.Theyshouldbesterilisedbydryheatandafterwardsusedinthesimulationtestaspertheregularproductionrun.4.2.3.2Ampoulesshouldbepreparedasinregularproduction.4.3InjectablePowderProducts4.3.1Therearetwopossibilitiesforsimulationofthisprocess.Eitherbyfillingasterilisedliquidgrowthmediumintothesterilecontaineroraddingapowder(inertorgrowthmedium)beforeorafterasterilediluent(WFIorgrowthmedium).Inertmaterialscommonlyusedinclude:polyethyleneglycol8000andcarboxymethylcellulose.Thesematerialsareusuallysterilisedbyirradiation.4.4SuspensionProducts4.4.1Thisprocedureiscomparabletothefillingofliquidproducts,exceptfortheprocessstepofmaintainingsuspensionoftheingredients.Thestirringorrecirculationshouldbepartofthesimulation.Ifasepticadditionsaremadetothebulksolutiontheseshouldbesimulatedbytheuseofinertsterileliquids/powders.4.5FreezeDried(Lyophilised)Products4.5.1Crystallisationofthemediumshouldbepreventedbecauseitmayreducethelikelihoodofrecoveryoforganisms.4.5.2Twosimulationmethodsarecommonlyused.Inthefirstoneadilutemediumissubjecttoacyclethatremoveswateruntiladeterminedmediumstrengthisobtained,butisnotsubjecttofreezing.Thesecondmethodusesfullstrengthmediumandrequiresonlyapartialvacuumbedrawnwhilstthechambershouldbekeptatambienttemperature.Thereisariskthatthemediummayboiloverandcontaminatethechamberunlessconditionsaretightlycontrolled.Theabsenceofboilingunderthedefinedcycleconditionsshouldbeconfirmed.PI007-2Page6of161July20044.6Semi-SolidProducts(e.g.sterileointments)4.6.1Forthissimulationtesttheliquidgrowthmediumisthickenedtotheappropriateviscosity,usedasintheroutineproductionprocedure.Suitablethickeningagentsareagarandcarboxymethylcellulose.Otheragentswouldneedtobevalidatedwithregardtolackoftheirbacteriostaticandfungistaticproperties.Metalandplasticointmenttubespreventtheexaminationofthemediumin-situ.Usuallythewholecontentofthetubeshouldbeexaminedandthisisusuallyachievedbysqueezingthecontentsintoaplate(petridish),andafterwhirlingitisexaminedforturbidityandfungalcoloniesunderdefinedlightconditionsorbyperformingasterilitytest.Ifproperlyvalidated,analternativemethodfordetectionofcontaminationofsemi-solidproductscouldbetheuseofmediawhichchangescolourinthepresenceofcontamination.4.7ClinicalTrialsMaterialsandSmallBatchSizeProducts4.7.1Asprocessesforsmallerquantities(lessthan3000units)donotallowaninterpretationaccordingtochapter5oftheseRecommendations,anypresenceofmicrobialcontaminationshouldberegardedasanalertlimit.Monitoringandtestconditions,likeincubationormediaselectionremainthesameasforcommercialproductionruns.4.7.2Thesizeofmediafillsforsmallbatchsizeproductsshouldatleastequalthenumberofcontainersfilledforthecommercialproduct.4.8BiologicalandBiotechnologyProducts4.8.1Themanufactureoftheseproductsvary,suchthatthereisnotonesingleprocess.Itmaybemorepracticaltovalidatethevarioussegmentsoftheprocessindividually.Thefrequencyoftherevalidationshouldrelatetotheoneofregular,commercialproduction.4.9SterileBulkPharmaceuticals4.9.1Wheneverpossibleagrowthmediumshouldbeusedandtheprocessshouldbesimulatedascloselyaspossibletothenormalrouteofmanufacturingthesterilebulkdrugsubstance.4.9.2Theasepticmanufactureofasterilebulkdrugsubstancesisadifficultprocess,whichmayhavenumerousindividualsegmentsthatneedtobevalidated.Thepossibilityofmicrobialingressintothesystemhastobeconsideredaftereachstepoftheroutineproduction.4.9.3Thevalidationmayincludesegments,wheretheuseofgrowthmediaisnotfeasible.1July2004Page7of16PI007-25.PROCESSSIMULATIONTESTCONDITIONS5.1TestPerformance5.1.1Theprocesssimulationtestshouldfollowascloselyaspossibletheroutineasepticmanufacturingprocessandincludeallcriticalsubsequentmanufacturingsteps.Allequipmentshouldremainthesamewhereverpracticableasfortheroutineprocess.Appropriatecombinationsofcontainersizeandopeningaswellasspeedoftheprocessinglineshouldbeused(preferablyattheextremes).5.1.2Theprocesssimulationtestshouldrepresenta“worstcase”situationandincludeallmanipulationsandinterventionslikelytoberepresentedduringashift.5.1.3Worstcaseconditionsareoftenthoughttobethelargestcontainerwiththewidestmouthasitisexposedlongertotheenvironment.However,thereareexceptionstothisandoneofthemissmallampoulesrunatthehighestspeedastheampoulesmaybeunstableandcausefrequentjamsthusnecessitatingfrequentoperatorintervention.5.1.4Thefillvolumeofthecontainersshouldbesufficienttoenablecontactofallthecontainer-closuresealsurfaceswhenthecontainerisinvertedandalsosufficienttoallowthedetectionofmicrobialgrowth.5.1.5Ifbatchessmallerthan3000unitsareproduced,theminimumnumberofcontainersusedfortheprocesssimulationshouldbeequaltothatofthecommercialbatchsize.5.1.6Simulationtestsshouldbeperformedondifferentdaysandhoursduringtheweekandnotonlyatthebeginningofaworkday.5.1.7Ifthesameprocessisconductedinaseparatecleanroom,thisshouldalsobevalidated.5.1.8Inordertofindthepossiblesourceofcontaminationitmaybeagoodadvisetovideotapetheasepticfillandalsonumbertheindividualvialsorsegregatevialsinchronologicalorderduringincubation.5.2SelectionofGrowthMedium5.2.1Thecriteriafortheselectionofgrowthmediuminclude:lowselectivity,clarity,mediumconcentrationandfilterability.5.2.2Abilitytosupportgrowthofawiderangeofmicroorganisms:Themediumshouldhavealowselectivityi.e.becapableofsupportinggrowthofawiderangeofmicroorganismssuchasBacillussubtilis,Staphylococcusaureus,Candidaalbicans,AspergillusnigerandClostridiumsporogenes(e.g.SoybeanCaseinDigest).5.2.3Theselectionofthemediumhastobebasedalsoontheinhouseflora(e.g.isolatesfrommonitoringetc.).PI007-2Page8of161July20045.2.4Growthpromotiontestsshoulddemonstratethatthemediumsupportsrecoveryandgrowthoflownumbersofmicroorganisms,i.e.10-100CFU/unitorless.5.2.5Growthpromotiontestingofthemediausedinsimulationstudiesshouldbecarriedoutoncompletionoftheincubationperiodtodemonstratetheabilityofthemediatosustaingrowthifcontaminationispresent.Growthshouldbedemonstratedwithin5daysatthesameincubationtemperatureasusedduringthesimulationtestperformance.5.2.6Clarity:Themediumshouldbecleartoallowforeaseinobservingturbidity.5.2.7MediumConcentration:Recommendationsofthesuppliershouldbefollowedunlessalternativeconcentrationsarevalidatedtodeliverequalresults.5.2.8Filterability:Ifafilterisusedintheasepticmanufacturingprocess,themediumshouldbecapableofbeingfilteredthroughthesamegradeasusedinproduction.5.3IncubationConditions5.3.1Itisgenerallyacceptedtoincubateat20-25°Cforaminimumof14