EUGMP附录1：无菌药品的生产-英文

PrincipleThemanufactureofsterileproductsissubjecttospecialrequirementsinordertominimizerisksofmicrobiologicalcontamination,andofparticulateandpyrogencontamination.Muchdependsontheskill,trainingandattitudesofthepersonnelinvolved.QualityAssuranceisparticularlyimportant,andthistypeofmanufacturemuststrictlyfollowcarefullyestablishedandvalidatedmethodsofpreparationandprocedure.Solerelianceforsterilityorotherqualityaspectsmustnotbeplacedonanyterminalprocessorfinishedproducttest.Note:Thisguidancedoesnotlaydowndetailedmethodsfordeterminingthemicrobiologicalandparticulatecleanlinessofair,surfacesetc.ReferenceshouldbemadetootherdocumentssuchastheEN/ISOStandards.GeneralThemanufactureofsterileproductsshouldbecarriedoutincleanareasentrytowhichshouldbethroughairlocksforpersonneland/orforequipmentandmaterials.Cleanareasshouldbemaintainedtoanappropriatecleanlinessstandardandsuppliedwithairwhichhaspassedthroughfiltersofanappropriateefficiency.Thevariousoperationsofcomponentpreparation,productpreparationandfillingshouldbecarriedoutinseparateareaswithinthecleanarea.Manufacturingoperationsaredividedintotwocategories;firstlythosewheretheproductisterminallysterilised,andsecondlythosewhichareconductedasepticallyatsomeorallstages.Cleanareasforthemanufactureofsterileproductsareclassifiedaccordingtotherequiredcharacteristicsoftheenvironment.Eachmanufacturingoperationrequiresanappropriateenvironmentalcleanlinesslevelintheoperationalstateinordertominimisetherisksofparticulateormicrobialcontaminationoftheproductormaterialsbeinghandled.Inordertomeet“inoperation”conditionstheseareasshouldbedesignedtoreachcertainspecifiedair-cleanlinesslevelsinthe“atrest”occupancystate.The“at-rest”stateistheconditionwheretheinstallationisinstalledandoperating,completewithproductionequipmentbutwithnooperatingpersonnelpresent.The“inoperation”stateistheconditionwheretheinstallationisfunctioninginthedefinedoperatingmodewiththespecifiednumberofpersonnelworking.The“inoperation”and“atrest”statesshouldbedefinedforeachcleanroomorsuiteofcleanrooms.Forthemanufactureofsterilemedicinalproducts4gradescanbedistinguished.GradeA:Thelocalzoneforhighriskoperations,e.g.fillingzone,stopperbowls,openampoulesandvials,makingasepticconnections.Normallysuchconditionsareprovidedbyalaminarairflowworkstation.Laminarairflowsystemsshouldprovideahomogeneousairspeedinarangeof0.36—0.54m/s(guidancevalue)attheworkingpositioninopencleanroomapplications.Themaintenanceoflaminarityshouldbedemonstratedandvalidated.Auni-directionalairflowandlowervelocitiesmaybeusedinclosedisolatorsandgloveboxes.GradeB:Forasepticpreparationandfilling,thisisthebackgroundenvironmentforthegradeAzone.GradeCandD:Cleanareasforcarryingoutlesscriticalstagesinthemanufactureofsterileproducts.CleanroomandcleanairdeviceclassificationCleanroomsandcleanairdevicesshouldbeclassifiedinaccordancewithENISO14644-1.Classificationshouldbeclearlydifferentiatedfromoperationalprocessenvironmentalmonitoring.Themaximumpermittedairborneparticleconcentrationforeachgradeisgiveninthefollowingtable.GradeMaximumpermittednumberofparticlesperm3equaltoorgreaterthanthetabulatedsizeAtrestInoperation>0.5^m>5.0^m>0.5^m>5.0^mA352020352020B3520293520002900C3520002900352000029000D352000029000NotdefinedNotdefinedForclassificationpurposesinGradeAzones,aminimumsamplevolumeof1mshouldbetakenpersamplelocation.ForGradeAtheairborneparticleclassificationisISO4.8dictatedbythelimitforparticles>5.0^m.ForGradeB(atrest)theairborneparticleclassificationisISO5forbothconsideredparticlesizes..ForGradeC(atrest&inoperation)theairborneparticleclassificationisISO7andISO8respectively.ForGradeD(atrest)theairborneparticleclassificationisISO8.ForclassificationpurposesEN/ISO14644-1methodologydefinesboththeminimumnumberofsamplelocationsandthesamplesizebasedontheclasslimitofthelargestconsideredparticlesizeandthemethodofevaluationofthedatacollected.Portableparticlecounterswithashortlengthofsampletubingshouldbeusedforclassificationpurposesbecauseoftherelativelyhigherrateofprecipitationofparticles>5.0^minremotesamplingsystemswithlonglengthsoftubing.Isokineticsampleheadsshallbeusedinunidirectionalairflowsystems.“Inoperation”classificationmaybedemonstratedduringnormaloperations,simulatedoperationsorduringmediafillsasworst-casesimulationisrequiredforthis.ENISO14644-2providesinformationontestingtodemonstratecontinuedcompliancewiththeassignedcleanlinessclassifications.CleanroomandcleanairdevicemonitoringCleanroomsandcleanairdevicesshouldberoutinelymonitoredinoperationandthemonitoringlocationsbasedonaformalriskanalysisstudyandtheresultsobtainedduringtheclassificationofroomsand/orcleanairdevices.ForGradeAzones,particlemonitoringshouldbeundertakenforthefulldurationofcriticalprocessing,includingequipmentassembly,exceptwherejustifiedbycontaminantsintheprocessthatwoulddamagetheparticlecounterorpresentahazard,e.g.liveorganismsandradiologicalhazards.Insuchcasesmonitoringduringroutineequipmentsetupoperationsshouldbeundertakenpriortoexposuretotherisk.Monitoringduringsimulatedoperationsshouldalsobeperformed.TheGradeAzoneshouldbemonitoredatsuchafrequencyandwithsuitablesamplesizethatallinterventions,transienteventsandanysystemdeteriorationwouldbecapturedandalarmstriggeredifalertlimitsareexceeded.Itisacceptedthatitmaynotalwaysbepossibletodemonstratelowlevelsof>5.0^mparticlesatthepointoffillwhenfillingisinprogress,duetothegenerationofparticlesordropletsfromtheproductitself.ItisrecommendedthatasimilarsystembeusedforGradeBzonesalthoughthesamplefrequencymaybedecreased.TheimportanceoftheparticlemonitoringsystemshouldbedeterminedbytheeffectivenessofthesegregationbetweentheadjacentGradeAandBzones.TheGradeBzoneshouldbemonitoredatsuchafrequencyandwithsuitablesamplesizethatchangesinlevelsofcontaminationandanysystemdeteriorationwouldbecapturedandalarmstriggeredifalertlimitsareexceeded.Airborneparticlemonitoringsystemsmayconsistofindependentparticlecounters;anetworkofsequentiallyaccessedsamplingpointsconnectedbymanifoldtoasingleparticlecounter;oracombinationofthetwo.Thesystemselectedmustbeappropriatefortheparticlesizeconsidered.Whereremotesamplingsystemsareused,thelengthoftubingandtheradiiofanybendsinthetubingmustbeconsideredinthecontextofparticlelossesinthetubing.Theselectionofthemonitoringsystemshouldtakeaccountofanyriskpresentedbythematerialsusedinthemanufacturingoperation,forexamplethoseinvolvingliveorganismsorradiopharmaceuticals.Thesamplesizestakenformonitoringpurposesusingautomatedsystemswillusuallybeafunctionofthesamplingrateofthesystemused.Itisnotnecessaryforthesamplevolumetobethesameasthatusedforformalclassificationofcleanroomsandcleanairdevices.InGradeAandBzones,themonitoringofthe>5.0^mparticleconcentrationcounttakesonaparticularsignificanceasitisanimportantdiagnostictoolforearlydetectionoffailure.Theoccasionalindicationof>5.0^mparticlecountsmaybefalsecountsduetoelectronicnoise,straylight,coincidence,etc.Howeverconsecutiveorregularcountingoflowlevelsisanindicatorofapossiblecontaminationeventandshouldbeinvestigated.SucheventsmayindicateearlyfailureoftheHVACsystem,fillingequipmentfailureormayalsobediagnosticofpoorpracticesduringmachineset-upandroutineoperation.Theparticlelimitsgiveninthetableforthe“atrest”stateshouldbeachievedafterashort“cleanup”periodof15-20minutes(guidancevalue)inanunmannedstateaftercompletionofoperations.ThemonitoringofGradeCandDareasinoperationshouldbeperformedinaccordancewiththeprinciplesofqualityriskmanagement.Therequirementsandalert/actionlimitswilldependonthenatureoftheoperationscarriedout,buttherecommended“cleanupperiod”shouldbeattained.Othercharacteristicssuchastemperatureandrelativehumiditydependontheproductandnatureoftheoperationscarriedout.Theseparametersshouldnotinterferewiththedefinedcleanlinessstandard.Examplesofoperationstobecarriedoutinthevariousgradesaregiveninthetablebelow(seealsoparagraphs28to35):GradeExamplesofoperationsforterminallysterilisedproducts.(seeparagraphs28-30)AFillingofproducts,whenunusuallyatriskCPreparationofsolutions,whenunusuallyatrisk.FillingofproductsDPreparationofsolutionsandcomponentsforsubsequentfillingGradeExamplesofoperationsforasepticpreparations.(seeparagraphs.31-35)AAsepticpreparationandfilling.CPreparationofsolutionstobefiltered.DHandlingofcomponentsafterwashing.Whereasepticoperationsareperformedmonitoringshouldbefrequentusingmethodssuchassettleplates,volumetricairandsurfacesampling(e.g.swabsandcontactplates).Samplingmethodsusedinoperationshouldnotinterferewithzoneprotection.Resultsfrommonitoringshouldbeconsideredwhenreviewingbatchdocumentationforfinishedproductrelease.Surfacesandpersonnelshouldbemonitoredaftercriticaloperations.Additionalmicrobiologicalmonitoringisalsorequiredoutsideproductionoperations,e.g.aftervalidationofsystems,cleaningandsanitisation.19.Recommendedlimitsformicrobiologicalmonitoringofcleanareasduringoperation:GradeRecommendedlimitsformicrobialcontamination(a)airsamplecfu/m3settleplates(diameter90mm)cfu/4hours(b)contactplates(diameter55mm)cfu/plategloveprint5fingerscfu/gloveA<1<1<1<1B10555C1005025D20010050Notes(a)Theseareaveragevalues.(b)Individualsettleplatesmaybeexposedforlessthan4hours.Appropriatealertandactionlimitsshouldbesetfortheresultsofparticulateandmicrobiologicalmonitoring.Iftheselimitsareexceededoperatingproceduresshouldprescribecorrectiveaction.IsolatortechnologyTheutilisationofisolatortechnologytominimizehumaninterventionsinprocessingareasmayresultinasignificantdecreaseintheriskofmicrobiologicalcontaminationofasepticallymanufacturedproductsfromtheenvironment.Therearemanypossibledesignsofisolatorsandtransferdevices.Theisolatorandthebackgroundenvironmentshouldbedesignedsothattherequiredairqualityfortherespectivezonescanberealised.Isolatorsareconstructedofvariousmaterialsmoreorlesspronetopunctureandleakage.Transferdevicesmayvaryfromasingledoortodoubledoordesignstofullysealedsystemsincorporatingsterilisationmechanisms.Thetransferofmaterialsintoandoutoftheunitisoneofthegreatestpotentialsourcesofcontamination.Ingeneraltheareainsidetheisolatoristhelocalzoneforhighriskmanipulations,althoughitisrecognisedthatlaminarairflowmaynotexistintheworkingzoneofallsuchdevices.Theairclassificationrequiredforthebackgroundenvironmentdependsonthedesignoftheisolatoranditsapplication.ItshouldbecontrolledandforasepticprocessingitshouldbeatleastgradeD.Isolatorsshouldbeintroducedonlyafterappropriatevalidation.Validationshouldtakeintoaccountallcriticalfactorsofisolatortechnology,forexamplethequalityoftheairinsideandoutside(background)theisolator,sanitisationoftheisolator,thetransferprocessandisolatorintegrity.Monitoringshouldbecarriedoutroutinelyandshouldincludefrequentleaktestingoftheisolatorandglove/sleevesystem.Blow/fill/sealtechnologyBlow/fill/sealunitsarepurposebuiltmachinesinwhich,inonecontinuousoperation,containersareformedfromathermoplasticgranulate,filledandthensealed,allbytheoneautomaticmachine.Blow/fill/sealequipmentusedforasepticproductionwhichisfittedwithaneffectivegradeAairshowermaybeinstalledinatleastagradeCenvironment,providedthatgradeA/Bclothingisused.Theenvironmentshouldcomplywiththeviableandnonviablelimitsatrestandtheviablelimitonlywheninoperation.Blow/fill/sealequipmentusedfortheproductionofproductswhichareterminallysterilisedshouldbeinstalledinatleastagradeDenvironment.Becauseofthisspecialtechnologyparticularattentionshouldbepaidto,atleastthefollowing:equipmentdesignandqualificationvalidationandreproducibilityofcleaning-in-placeandsterilisation-in-placebackgroundcleanroomenvironmentinwhichtheequipmentislocatedoperatortrainingandclothinginterventionsinthecriticalzoneoftheequipmentincludinganyasepticassemblypriortothecommencementoffilling.TerminallysterilisedproductsPreparationofcomponentsandmostproductsshouldbedoneinatleastagradeDenvironmentinordertogivelowriskofmicrobialandparticulatecontamination,suitableforfiltrationandsterilisation.Wheretheproductisatahighorunusualriskofmicrobialcontamination,(forexample,becausetheproductactivelysupportsmicrobialgrowthormustbeheldforalongperiodbeforesterilisationorisnecessarilyprocessednotmainlyinclosedvessels),thenpreparationshouldbecarriedoutinagradeCenvironment.FillingofproductsforterminalsterilisationshouldbecarriedoutinatleastagradeCenvironment.Wheretheproductisatunusualriskofcontaminationfromtheenvironment,forexamplebecausethefillingoperationissloworthecontainersarewide-neckedorarenecessarilyexposedformorethanafewsecondsbeforesealing,thefillingshouldbedoneinagradeAzonewithatleastagradeCbackground.Preparationandfillingofointments,creams,suspensionsandemulsionsshouldgenerallybecarriedoutinagradeCenvironmentbeforeterminalsterilisation.AsepticpreparationComponentsafterwashingshouldbehandledinatleastagradeDenvironment.Handlingofsterilestartingmaterialsandcomponents,unlesssubjectedtosterilisationorfiltrationthroughamicro-organism-retainingfilterlaterintheprocess,shouldbedoneinagradeAenvironmentwithgradeBbackground.PreparationofsolutionswhicharetobesterilefilteredduringtheprocessshouldbedoneinagradeCenvironment;ifnotfiltered,thepreparationofmaterialsandproductsshouldbedoneinagradeAenvironmentwithagradeBbackground.HandlingandfillingofasepticallypreparedproductsshouldbedoneinagradeAenvironmentwithagradeBbackground.Priortothecompletionofstoppering,transferofpartiallyclosedcontainers,asusedinfreezedryingshouldbedoneeitherinagradeAenvironmentwithgradeBbackgroundorinsealedtransfertraysinagradeBenvironment.Preparationandfillingofsterileointments,creams,suspensionsandemulsionsshouldbedoneinagradeAenvironment,withagradeBbackground,whentheproductisexposedandisnotsubsequentlyfiltered.PersonnelOnlytheminimumnumberofpersonnelrequiredshouldbepresentincleanareas;thisisparticularlyimportantduringasepticprocessing.Inspectionsandcontrolsshouldbeconductedoutsidethecleanareasasfaraspossible.Allpersonnel(includingthoseconcernedwithcleaningandmaintenance)employedinsuchareasshouldreceiveregulartrainingindisciplinesrelevanttothecorrectmanufactureofsterileproducts.Thistrainingshouldincludereferencetohygieneandtothebasicelementsofmicrobiology.Whenoutsidestaffwhohavenotreceivedsuchtraining(e.g.buildingormaintenancecontractors)needtobebroughtin,particularcareshouldbetakenovertheirinstructionandsupervision.Staffwhohavebeenengagedintheprocessingofanimaltissuematerialsorofculturesofmicro-organismsotherthanthoseusedinthecurrentmanufacturingprocessshouldnotentersterile-productareasunlessrigorousandclearlydefinedentryprocedureshavebeenfollowed.Highstandardsofpersonalhygieneandcleanlinessareessential.Personnelinvolvedinthemanufactureofsterilepreparationsshouldbeinstructedtoreportanyconditionwhichmaycausethesheddingofabnormalnumbersortypesofcontaminants;periodichealthchecksforsuchconditionsaredesirable.Actionstobetakenaboutpersonnelwhocouldbeintroducingunduemicrobiologicalhazardshouldbedecidedbyadesignatedcompetentperson.Wristwatches,make-upandjewelleryshouldnotbewornincleanareas.Changingandwashingshouldfollowawrittenproceduredesignedtominimizecontaminationofcleanareaclothingorcarry-throughofcontaminantstothecleanareas.Theclothinganditsqualityshouldbeappropriatefortheprocessandthegradeoftheworkingarea.Itshouldbeworninsuchawayastoprotecttheproductfromcontamination.Thedescriptionofclothingrequiredforeachgradeisgivenbelow:tGradeD:Hairand,whererelevant,beardshouldbecovered.Ageneralprotectivesuitandappropriateshoesorovershoesshouldbeworn.Appropriatemeasuresshouldbetakentoavoidanycontaminationcomingfromoutsidethecleanarea.GradeC:Hairandwhererelevantbeardandmoustacheshouldbecovered.Asingleortwo-piecetrousersuit,gatheredatthewristsandwithhighneckandappropriateshoesorovershoesshouldbeworn.Theyshouldshedvirtuallynofibresorparticulatematter.tGradeA/B:Headgearshouldtotallyenclosehairand,whererelevant,beardandmoustache;itshouldbetuckedintotheneckofthesuit;afacemaskshouldbeworntopreventthesheddingofdroplets.Appropriatesterilised,non-powderedrubberorplasticglovesandsterilisedordisinfectedfootwearshouldbeworn.Trouser-legsshouldbetuckedinsidethefootwearandgarmentsleevesintothegloves.Theprotectiveclothingshouldshedvirtuallynofibresorparticulatematterandretainparticlesshedbythebody.OutdoorclothingshouldnotbebroughtintochangingroomsleadingtogradeBandCrooms.ForeveryworkerinagradeA/Barea,cleansterile(sterilisedoradequatelysanitised)protectivegarmentsshouldbeprovidedateachworksession.Glovesshouldberegularlydisinfectedduringoperations.Masksandglovesshouldbechangedatleastforeveryworkingsession.Cleanareaclothingshouldbecleanedandhandledinsuchawaythatitdoesnotgatheradditionalcontaminantswhichcanlaterbeshed.Theseoperationsshouldfollowwrittenprocedures.Separatelaundryfacilitiesforsuchclothingaredesirable.Inappropriatetreatmentofclothingwilldamagefibresandmayincreasetheriskofsheddingofparticles.PremisesIncleanareas,allexposedsurfacesshouldbesmooth,imperviousandunbrokeninordertominimizethesheddingoraccumulationofparticlesormicro-organismsandtopermittherepeatedapplicationofcleaningagents,anddisinfectantswhereused.Toreduceaccumulationofdustandtofacilitatecleaningthereshouldbenouncleanablerecessesandaminimumofprojectingledges,shelves,cupboardsandequipment.Doorsshouldbedesignedtoavoidthoseuncleanablerecesses;slidingdoorsmaybeundesirableforthisreason.Falseceilingsshouldbesealedtopreventcontaminationfromthespaceabovethem.Pipesandductsandotherutilitiesshouldbeinstalledsothattheydonotcreaterecesses,unsealedopeningsandsurfaceswhicharedifficulttoclean.SinksanddrainsshouldbeprohibitedingradeA/Bareasusedforasepticmanufacture.Inotherareasairbreaksshouldbefittedbetweenthemachineorsinkandthedrains.Floordrainsinlowergradecleanroomsshouldbefittedwithtrapsorwatersealstopreventback-flow.Changingroomsshouldbedesignedasairlocksandusedtoprovidephysicalseparationofthedifferentstagesofchangingandsominimizemicrobialandparticulatecontaminationofprotectiveclothing.Theyshouldbeflushedeffectivelywithfilteredair.Thefinalstageofthechangingroomshould,intheat-reststate,bethesamegradeastheareaintowhichitleads.Theuseofseparatechangingroomsforenteringandleavingcleanareasissometimesdesirable.Ingeneralhandwashingfacilitiesshouldbeprovidedonlyinthefirststageofthechangingrooms.Bothairlockdoorsshouldnotbeopenedsimultaneously.Aninterlockingsystemoravisualand/oraudiblewarningsystemshouldbeoperatedtopreventtheopeningofmorethanonedooratatime.Afilteredairsupplyshouldmaintainapositivepressureandanairflowrelativetosurroundingareasofalowergradeunderalloperationalconditionsandshouldflushtheareaeffectively.Adjacentroomsofdifferentgradesshouldhaveapressuredifferentialof10-15pascals(guidancevalues).Particularattentionshouldbepaidtotheprotectionofthezoneofgreatestrisk,thatis,theimmediateenvironmenttowhichaproductandcleanedcomponentswhichcontacttheproductareexposed.Thevariousrecommendationsregardingairsuppliesandpressuredifferentialsmayneedtobemodifiedwhereitbecomesnecessarytocontainsomematerials,e.g.pathogenic,highlytoxic,radioactiveorliveviralorbacterialmaterialsorproducts.Decontaminationoffacilitiesandtreatmentofairleavingacleanareamaybenecessaryforsomeoperations.Itshouldbedemonstratedthatair-flowpatternsdonotpresentacontaminationrisk,e.g.careshouldbetakentoensurethatairflowsdonotdistributeparticlesfromaparticle-generatingperson,operationormachinetoazoneofhigherproductrisk.Awarningsystemshouldbeprovidedtoindicatefailureintheairsupply.Indicatorsofpressuredifferencesshouldbefittedbetweenareaswherethesedifferencesareimportant.Thesepressuredifferencesshouldberecordedregularlyorotherwisedocumented.EquipmentAconveyorbeltshouldnotpassthroughapartitionbetweenagradeAorBareaandaprocessingareaofloweraircleanliness,unlessthebeltitselfiscontinuallysterilised(e.g.inasterilisingtunnel).Asfaraspracticableequipment,fittingsandservicesshouldbedesignedandinstalledsothatoperations,maintenanceandrepairscanbecarriedoutoutsidethecleanarea.Ifsterilisationisrequired,itshouldbecarriedout,whereverpossible,aftercompletereassembly.Whenequipmentmaintenancehasbeencarriedoutwithinthecleanarea,theareashouldbecleaned,disinfectedand/orsterilisedwhereappropriate,beforeprocessingrecommencesiftherequiredstandardsofcleanlinessand/orasepsishavenotbeenmaintainedduringthework.Watertreatmentplantsanddistributionsystemsshouldbedesigned,constructedandmaintainedsoastoensureareliablesourceofwaterofanappropriatequality.Theyshouldnotbeoperatedbeyondtheirdesignedcapacity.Waterforinjectionsshouldbeproduced,storedanddistributedinamannerwhichpreventsmicrobialgrowth,forexamplebyconstantcirculationatatemperatureabove70°C.Allequipmentsuchassterilisers,airhandlingandfiltrationsystems,airventandgasfilters,watertreatment,generation,storageanddistributionsystemsshouldbesubjecttovalidationandplannedmaintenance;theirreturntouseshouldbeapproved.SanitationThesanitationofcleanareasisparticularlyimportant.Theyshouldbecleanedthoroughlyinaccordancewithawrittenprogramme.Wheredisinfectantsareused,morethanonetypeshouldbeemployed.Monitoringshouldbeundertakenregularlyinordertodetectthedevelopmentofresistantstrains.Disinfectantsanddetergentsshouldbemonitoredformicrobialcontamination;dilutionsshouldbekeptinpreviouslycleanedcontainersandshouldonlybestoredfordefinedperiodsunlesssterilised.DisinfectantsanddetergentsusedinGradesAandBareasshouldbesterilepriortouse.Fumigationofcleanareasmaybeusefulforreducingmicrobiologicalcontaminationininaccessibleplaces.ProcessingPrecautionstominimizecontaminationshouldbetakenduringallprocessingstagesincludingthestagesbeforesterilisation.Preparationsofmicrobiologicaloriginshouldnotbemadeorfilledinareasusedfortheprocessingofothermedicinalproducts;however,vaccinesofdeadorganismsorofbacterialextractsmaybefilled,afterinactivation,inthesamepremisesasothersterilemedicinalproducts.Validationofasepticprocessingshouldincludeaprocesssimulationtestusinganutrientmedium(mediafill).Selectionofthenutrientmediumshouldbemadebasedondosageformoftheproductandselectivity,clarity,concentrationandsuitabilityforsterilisationofthenutrientmedium.Theprocesssimulationtestshouldimitateascloselyaspossibletheroutineasepticmanufacturingprocessandincludeallthecriticalsubsequentmanufacturingsteps.Itshouldalsotakeintoaccountvariousinterventionsknowntooccurduringnormalproductionaswellasworst-casesituations.ProcesssimulationtestsshouldbeperformedasinitialvalidationwiththreeconsecutivesatisfactorysimulationtestspershiftandrepeatedatdefinedintervalsandafteranysignificantmodificationtotheHVAC-system,equipment,processandnumberofshifts.Normallyprocesssimulationtestsshouldberepeatedtwiceayearpershiftandprocess.Thenumberofcontainersusedformediafillsshouldbesufficienttoenableavalidevaluation.Forsmallbatches,thenumberofcontainersformediafillsshouldatleastequalthesizeoftheproductbatch.Thetargetshouldbezerogrowthandthefollowingshouldapply:Whenfillingfewerthan5000units,nocontaminatedunitsshouldbedetected.tWhenfilling5,000to10,000units:One(1)contaminatedunitshouldresultinaninvestigation,includingconsiderationofarepeatmediafill;Two(2)contaminatedunitsareconsideredcauseforrevalidation,followinginvestigation.Whenfillingmorethan10,000units:One(1)contaminatedunitshouldresultinaninvestigation;Two(2)contaminatedunitsareconsideredcauseforrevalidation,followinginvestigation.Foranyrunsize,intermittentincidentsofmicrobialcontaminationmaybeindicativeoflow-levelco