SterileProductManufacturing

IntroductionIntroduction To give an overview of the principles involved in theTo give an overview of the principles involved in theTogiveanoverviewoftheprinciplesinvolvedintheTogiveanoverviewoftheprinciplesinvolvedinthe

manufactureofsterileproductsmanufactureofsterileproducts

TheoverallobjectiveistoproduceproductthathasahighTheoverallobjectiveistoproduceproductthathasahighassuranceofsterility(andwhichmeetsallotherqualityassuranceofsterility(andwhichmeetsallotherqualityparameters)parameters)

Thispresentation:Thispresentation: SummarisesthegeneralapproachSummarisesthegeneralapproach GivesaframeworkforotherdetailedguidesonspecificaspectsofGivesaframeworkforotherdetailedguidesonspecificaspectsof

sterilisation&sterilemanufacturingsterilisation&sterilemanufacturing

IllustratestheunderlyingprinciplesIllustratestheunderlyingprinciplesy g p py g p p Providesadviceandgivesrecommendations.Providesadviceandgivesrecommendations.

GeneralPrinciplesofSterilepManufacturing

M i t H t St ili tiM i t H t St ili ti MoistHeatSterilizationMoistHeatSterilization DryHeatSterilizationDryHeatSterilization Aseptic ProcessingAseptic Processing AsepticProcessingAsepticProcessing EnvironmentalMonitoringEnvironmentalMonitoring Ethylene Oxide SterilizationEthylene Oxide Sterilization EthyleneOxideSterilizationEthyleneOxideSterilization SterileFiltrationSterileFiltration Water systems validationWater systems validationWatersystemsvalidationWatersystemsvalidation SterilitytestingSterilitytesting Radiation SterilizationRadiation SterilizationRadiationSterilizationRadiationSterilization VisualInspectionVisualInspection

FundementalsFundementals

S iliS ili ii hh bb ff li ili i ii SterilitySterility isis thethe absenceabsence ofof livingliving organismsorganisms ThisThis isis anan absoluteabsolute definitiondefinition

TheThe probabilityprobability ofof achievingachieving sterilitysterility dependsdepends onon thethe overalloverall processprocessp yp y gg yy pp pp

ItIt isis generallygenerally acceptedaccepted thatthat aa terminallyterminally sterilizedsterilized productproduct shouldshould havehave aa probabilityprobability ofofnonnonsterilitysterility ofof lessless thanthan 101066 (i(i..ee..,, aa lowerlower probabilityprobability thanthan oneone inin aa millionmillion ofof havinghaving aa nonnont ilt il it)it)sterilesterile unit)unit)

ThisThis isis oftenoften expressedexpressed asas anan SALSAL SterilitySterility AssuranceAssurance LevelLevel ofof 101066

ThisThis isis aa worstworstcasecase figurefigure (with(with aa challengechallenge moremore resistantresistant thanthan productproduct bioburdenbioburden)).. RealRealconfidenceconfidence levelslevels areare generallygenerally veryvery muchmuch higherhigher

AA fifi th tth t hh titi bb t dt d ff ti llti ll fill dfill d d td t ii b bilitb bilit ff AA figurefigure thatthat hashas sometimessometimes beenbeen quotedquoted forfor asepticallyaseptically filledfilled productproduct isis probabilityprobability ofof nonnonsterilitysterility ofof lessless thanthan 101033.. However,However, thisthis isis harderharder toto analyseanalyse asas contaminationcontamination doesdoes notnotfollowfollow aa clearclear statisticalstatistical distributiondistribution.. PotentialPotential contaminationcontamination sourcessources areare notnot randomlyrandomlydistributeddistributed..

Why Validate and Control?WhyValidateandControl?

ThTh ff iliili fifi hh hh h lh l TheThe testtest forfor sterilitysterility cannotcannot confirmconfirm thatthat thethe wholewholebatchbatch isis sterilesterile ItIt isis performedperformed onon aa samplesample fromfrom aa batchbatch andand hashas ItIt isis performedperformed onon aa samplesample fromfrom aa batchbatch andand hashasstatisticalstatistical limitationslimitations

ItIt cancan missmiss contaminationcontamination ifif onlyonly aa proportionproportion ofof unitsunits areare ItIt cancan missmiss contaminationcontamination ifif onlyonly aa proportionproportion ofof unitsunits arearenonnonsterilesterile

ItIt isis thusthus necessarynecessary toto recognizerecognize andand understandunderstand everyeveryaspectaspect thatthat couldcould leadlead toto lossloss ofof sterilitysterility assuranceassurance

SuchSuch conditionsconditions shouldshould bebe preventedprevented byby thetheapplicationapplication ofof carefullycarefully designeddesigned barriersbarriers and/orand/orcontrolcontrol measuresmeasures..

Development ValidationandControl

ii ii hh hh dd dd ItIt isis importantimportant thatthat thethe productproduct andand processprocess arearedesigneddesigned toto maximisemaximise sterilitysterility assuranceassurance

WhereverWherever possible,possible, thethe productproduct shouldshould bebedevelopeddeveloped toto withstandwithstand sterilizationsterilization inin thethe finalfinal

iicontainercontainer OnceOnce thethe productproduct designdesign isis defined,defined, aa suitablesuitableproductionproduction processprocess mustmust bebe developeddeveloped

ThisThis isis installedinstalled andand validatedvalidated TheThe processprocess mustmust thenthen bebe tightlytightly controlledcontrolled totoassureassure reliabilityreliability andand consistencyconsistency..yy yy

Product Design ConsiderationsProductDesignConsiderations

ForFor NeNe Prod ctsProd cts ForFor NewNew ProductsProducts:: DefineDefine productproduct andand processingprocessing requirementsrequirements ConsiderConsider stabilitystability ofof productproduct toto thethe sterilizationsterilization conditionsconditions BaseBase thethe processprocess onon achievingachieving thethe requiredrequired sterilitysterility assuranceassurance levellevel WhereWhere possiblepossible choosechoose terminalterminal sterilizationsterilization inin finalfinal containercontainer DefineDefine processprocess flowflow andand thethe importantimportant microbiologicalmicrobiological aspectsaspects EnsureEnsure changeschanges areare subjectsubject toto strictstrict changechange controlcontrol

ForFor reviewingreviewing existingexisting (marketed)(marketed) productsproducts:: EstablishEstablish thethe processprocess descriptiondescription andand assessassess inin detaildetail EstablishEstablish thethe processprocess descriptiondescription andand assessassess inin detaildetail Preferably,Preferably, sterilizationsterilization shouldshould bebe byby compendialcompendial proceduresprocedures WhereWhere otherother proceduresprocedures areare registered,registered, assessassess SALSAL WhereWhere necessarynecessary (if(if existingexisting SALSAL isis tootoo low)low) maymay needneed toto improveimprove WhereWhere necessarynecessary (if(if existingexisting SALSAL isis tootoo low)low) maymay needneed toto improveimprove

processprocess andand maybemaybe rereregisterregister RequireRequire justificationjustification && validationvalidation..

Facility DesignFacilityDesign

M st be in compliance ith compan policies and proced res forM st be in compliance ith compan policies and proced res for Mustbeincompliancewithcompanypoliciesandprocedures,forMustbeincompliancewithcompanypoliciesandprocedures,forexample:example: MustminimisetheriskofcontaminationatallcriticalstagesMustminimisetheriskofcontaminationatallcriticalstages R i d G d f Cl R d b i f hR i d G d f Cl R d b i f h RequiredGradesofCleanRooms:needtobeappropriatefortheRequiredGradesofCleanRooms:needtobeappropriateforthe

processprocess e.g.forTerminalSterilizationorAsepticFille.g.forTerminalSterilizationorAsepticFill PersonnelAccessandMaterialFlowPersonnelAccessandMaterialFlow R i d iR i d i Restrictedaccess,correctgowningRestrictedaccess,correctgowning Materialsflow,airlocks,decontamination,segregationMaterialsflow,airlocks,decontamination,segregation HVACHVACSystemSystem Segregation/DedicatedHVACofcorrectstandardSegregation/DedicatedHVACofcorrectstandard RequirescontrolofFiltration/P/AirFlow/Temp./Pressure/HumidityRequirescontrolofFiltration/P/AirFlow/Temp./Pressure/Humidity AirflowpatternsdemonstratedAirflowpatternsdemonstratedf pf p NosinksanddrainsinZoneA/Bareas,airbreakstodrainsinothersNosinksanddrainsinZoneA/Bareas,airbreakstodrainsinothers Surfacesandeaseofcleaning:smoothunbrokenimpervioussurfacesSurfacesandeaseofcleaning:smoothunbrokenimpervioussurfaces

CleaninganddisinfectionoftheFacility

Cleaning and disinfection is important in environmental controlCleaning and disinfection is important in environmental control CleaninganddisinfectionisimportantinenvironmentalcontrolCleaninganddisinfectionisimportantinenvironmentalcontrol EfficacyneedstobevalidatedEfficacyneedstobevalidated Validatedprocedures,conductedconsistentlyValidatedprocedures,conductedconsistentlyI l A & B h l i d di i f i l bI l A & B h l i d di i f i l b InclassA&Bareas,thecleaninganddisinfectantmaterialsmustbeInclassA&Bareas,thecleaninganddisinfectantmaterialsmustbesterilizedsterilized AndneedtominimisecontaminationriskinotherareasAndneedtominimisecontaminationriskinotherareas

i d i l d i ii d i l d i i Operatingproceduresmustinclude,atminimum:Operatingproceduresmustinclude,atminimum: Preparationofcleaningmaterials(andsterilizationifapplicable)Preparationofcleaningmaterials(andsterilizationifapplicable) Exactprocedureofcleaning&disinfection.Exactprocedureofcleaning&disinfection. Responsibility&scheduling.Responsibility&scheduling. Typeandconcentrationofdetergentsanddisinfectants.Typeandconcentrationofdetergentsanddisinfectants. Typeofcleaningtools.Typeofcleaningtools.

TrainingisrequiredforcleaninganddisinfectionofTrainingisrequiredforcleaninganddisinfectionofcleanroomscleanrooms Routinedecontaminationusingformaldehydegasshouldbeavoided.Routinedecontaminationusingformaldehydegasshouldbeavoided.

WaterWater

All t t i d d i d lid tiAll t t i d d i d lid ti AllwatersystemsrequiregooddesignandvalidationAllwatersystemsrequiregooddesignandvalidation

Typically,forTypically,forpharmacopoeialpharmacopoeial grades,validationincludesgrades,validationincludesyp y,yp y, p pp p g ,g , Twostudiesoveratotalof4weekstoassessagainsttheacceptancecriteria,Twostudiesoveratotalof4weekstoassessagainsttheacceptancecriteria, Additional11monthstoverifythatthesystemremainsundercontrolAdditional11monthstoverifythatthesystemremainsundercontrol

Must demonstrate consistent production of water of theMust demonstrate consistent production of water of theMustdemonstrateconsistentproductionofwateroftheMustdemonstrateconsistentproductionofwateroftherequiredqualityrequiredquality PhysicoPhysicochemical,chemical, Microbiological,Microbiological, Microbiological,Microbiological, Biological(Biological(endotoxinendotoxin,whereapplicable),whereapplicable)

Water systems must be regularly monitored following aWater systems must be regularly monitored following aWatersystemsmustberegularlymonitoredfollowingaWatersystemsmustberegularlymonitoredfollowingadefinedwrittenmonitoringplanbasedonresultsofthedefinedwrittenmonitoringplanbasedonresultsofthevalidationstudies.validationstudies.

Categories of WaterCategoriesofWater

W tW t ff I j tiI j ti (WFI)(WFI) WaterWater forfor InjectionsInjections (WFI)(WFI) ForFor injectablesinjectables formulationformulation FinalFinal rinserinse waterwater forfor productproductcontactcontact itemsitems (for(for injectablesinjectables))ff pp (f(f jj )) FreshlyFreshly preparedprepared oror fromfrom aa validatedvalidated hothot (e(e..gg..,, >>7575C)C) storagestorage

/distribution/distribution systemsystem oror otherwiseotherwise protectedprotected fromfrom microbialmicrobialcontaminationcontaminationo a a oo a a o

HighlyHighly PurifiedPurified WaterWater (HPW)(HPW) ToTo EuropeanEuropean PharmacopoeiaPharmacopoeia

PurifiedPurified WaterWater (PW)(PW) ForFor initialinitial washingwashing ofof productproductcontactcontact itemsitems PreparedPrepared suitablysuitably storedstored andand distributeddistributed toto maintainmaintain qualityquality Prepared,Prepared, suitablysuitably storedstored andand distributeddistributed toto maintainmaintain qualityquality

andand preventprevent microbiologicalmicrobiological proliferation,proliferation, followingfollowing thetherelevantrelevant companycompany proceduresprocedures..

Gasses and VacuumGassesandVacuum

GG GasesGases SpecificationequivalenttotheroomairqualitywhereitistobeusedSpecificationequivalenttotheroomairqualitywhereitistobeused Inasepticapplications,gasesaretobefiltersterilizedInasepticapplications,gasesaretobefiltersterilizedp pp , g fp pp , g f ConsidersterilefilteringnonConsidersterilefilteringnonproductcontactgasesforasepticproductcontactgasesforaseptic

applications.(But,notesafetyconsiderations,e.g.avoidanceofapplications.(But,notesafetyconsiderations,e.g.avoidanceofleakage)leakage)

AllgasfilterstobeintegritytestedoninstallationandatdefinedAllgasfilterstobeintegritytestedoninstallationandatdefinedintervalsintervals

VacuumSystemsVacuumSystemsyy SometimesusedforcleaninganddustcontrolSometimesusedforcleaninganddustcontrol Maybemobileunits,fittedwithexhaustHEPAfiltersMaybemobileunits,fittedwithexhaustHEPAfilters Or may have central dust collectionOr may have central dust collection OrmayhavecentraldustcollectionOrmayhavecentraldustcollection Onthese,usededicatedvacuumpumpsprotectedagainstbackOnthese,usededicatedvacuumpumpsprotectedagainstbackflowflow Designtopreventunprotectedrouteintotheasepticsuite.Designtopreventunprotectedrouteintotheasepticsuite.

Equipment (1)Equipment(1)

E i t Q lifi tiE i t Q lifi ti EquipmentQualificationEquipmentQualification ToincludethecriticalaspectsforsterileproductprocessingToincludethecriticalaspectsforsterileproductprocessing Qualificationofcriticalaspectsofmoistheatsterilization,asepticQualificationofcriticalaspectsofmoistheatsterilization,asepticf f p f , pf f p f , p

processing,dryheatsterilizationetc.processing,dryheatsterilizationetc.

CleaningandSanitizationofEquipmentCleaningandSanitizationofEquipment Equipment designed for easy cleaning and sanitizationEquipment designed for easy cleaning and sanitization EquipmentdesignedforeasycleaningandsanitizationEquipmentdesignedforeasycleaningandsanitization ForTerminalSterilizationapplications,lowmicrobialchallenge.ForTerminalSterilizationapplications,lowmicrobialchallenge.

Wherepossible,criticalsurfacesshouldbesterilizedWherepossible,criticalsurfacesshouldbesterilized For aseptic work the critical (product contact) surfaces must beFor aseptic work the critical (product contact) surfaces must be Forasepticwork,thecritical(productcontact)surfacesmustbeForasepticwork,thecritical(productcontact)surfacesmustbe

sterilizedbeforeuse.Inexceptionalcaseswherethisisnotpossiblesterilizedbeforeuse.Inexceptionalcaseswherethisisnotpossible(e.g.,somestopperbowls),theyshouldbesanitizedbyavalidated(e.g.,somestopperbowls),theyshouldbesanitizedbyavalidatedmethodmethod

Cleaningvalidationmustshoweffectivenessandabsenceofresidues.Cleaningvalidationmustshoweffectivenessandabsenceofresidues.

Equipment (2)Equipment(2)

ii S ili iS ili i dd h dlih dli EquipmentEquipment SterilizationSterilization andand handlinghandlingSterilizationSterilization mustmust followfollow aa validatedvalidated procedureprocedureAsepticAseptic processesprocesses designeddesigned toto minimiseminimise asepticasepticassemblyassembly andand interventionintervention

U id blU id bl ii blbl dd ll && iiUnavoidableUnavoidable asepticaseptic assemblyassembly needsneeds clearclear && precisepreciseproceduresprocedures

AsepticAseptic assemblyassembly mustmust bebe simulatedsimulated (worst(worst case)case) ininAsepticAseptic assemblyassembly mustmust bebe simulatedsimulated (worst(worstcase)case) ininmediamedia fillfill simulationsimulation trialstrials

SterilizationSterilization InIn PlacePlace isis aa goodgood methodmethod wherewhere SterilizationSterilization InIn PlacePlace isis aa goodgood methodmethod wherewherepossiblepossible mustmust bebe validatedvalidated..

PersonnelPersonnel

T i iT i i ll i t li t l t i dt i d ff t ilt il TrainingTraining personnelpersonnel appropriatelyappropriately trainedtrained forfor sterilesterileprocessing,processing, includingincluding assessmentassessment andand documentationdocumentation:: BasicBasic GMPGMP d ld l ff b lb l FundamentalsFundamentals ofof microbiologymicrobiology PersonalPersonal hygiene,hygiene, healthhealth andand cleanlinesscleanliness BehaviourBehaviour andand asepticaseptic workingworking techniquestechniques G iG i dd tt dd GowningGowning andand entryentry proceduresprocedures CleaningCleaning andand disinfectiondisinfection SterilizationSterilization procedures,procedures, validationvalidation andand routineroutine operationoperation EmergencyEmergency proceduresprocedures toto protectprotect productproduct qualityquality (e(e gg lossloss ofof HVACHVAC SystemSystem EmergencyEmergency proceduresprocedures toto protectprotect productproduct qualityquality (e(e..gg.. lossloss ofof HVACHVAC System,System,

lossloss ofof power,power, equipmentequipment interventionsinterventions etcetc..))

PersonnelPersonnel participatingparticipating inin asepticaseptic processingprocessing mustmust havehavepracticalpractical trainingtraining inin asepticaseptic techniquestechniques beforebefore doingdoing asepticasepticpracticalpractical trainingtraining inin asepticaseptic techniquestechniques beforebefore doingdoing asepticasepticmanipulationsmanipulations

TheyThey mustmust havehave participatedparticipated inin aa successfulsuccessful mediamedia fillfill runrun..

Gowning and Aseptic TechniqueGowningandAsepticTechnique

GowningGowning GowningGowning Personnelmustcorrectlywearappropriatecleanroomgarments Detailed,easilyunderstood,gowningprocedure(preferablyillustrated)

AsepticTechniquesAsepticTechniques Personnelintheasepticmanufacturingarea,mustunderstandtheprinciples

of aseptic proceduresofasepticprocedures Theymustonlybeconsideredqualifiedafterappropriatetraining,working

undersupervisionanddemonstrationofcompetence Thesupervisorshouldobservetechnique&correctasnecessary Allpersonneldirectlyinvolvedinasepticprocessingmustparticipateina

mediafillatleastonceperyear

Gl di i f tiGl di i f ti GlovedisinfectionGlovedisinfection Steriledisinfectantsmustbeavailable(e.g.,alcoholbased) Glovedisinfectionmustbereasonablyfrequent,definedinSOP.

Environmental Monitoring (1)EnvironmentalMonitoring(1)

ThescopeofenvironmentalmonitoringThescopeofenvironmentalmonitoringincludes:includes:Nonviableparticulates,Viable (microbial) countsViable(microbial)countsDifferentialpressuresTemperaturesHumiditiesAirflows

Environmental Monitoring (2)EnvironmentalMonitoring(2)

Monitoring D ring Room Q alificationMonitoring D ring Room Q alification MonitoringDuringRoomQualificationMonitoringDuringRoomQualification OperationalQualification(OQ)atrestconditionstoverifyoperation PerformanceQualification(PQ)inworstcaseoperationalconditions ActionlevelsshouldmeetUSPorEuroGMPasapplicable Alertlevelstightenoughtodetectdeterioration,butnotsotightthat

theybecomemeaninglessduetofrequenttransgression PQmustcoverasufficientperiodtoestablishconsistency

RoutineMonitoringRoutineMonitoring Ensuresarearemainssatisfactory.Resultsshouldbewithinalertlevelf y Resultsabovealertlevelsneedreviewandperhapscorrectiveactions Aboveactionlevels,musttriggerappropriateactions(describedin

guide),g ), Resultsmustbeassessedfortrendssothatprogressiveorsudden

changesintheresultsmaybeobserved.Thisshouldbereviewedregularly.

Environmental Monitoring (3)EnvironmentalMonitoring(3)

Deviation Reports and Failure InvestigationsDeviation Reports and Failure Investigations DeviationReportsandFailureInvestigationsDeviationReportsandFailureInvestigations Thedatamustbeanalysed Wherenecessaryfurtherinvestigationsinitiated Possible contamination sources to be assessed and eliminated Possiblecontaminationsourcestobeassessedand,eliminated Outcomeanddetailmustbereported

RecommendedMethodsforRoutineMonitoringRecommendedMethodsforRoutineMonitoring Physical measurements of the air supply Physicalmeasurementsoftheairsupply Physicalandmicrobiologicalmonitoringoftheenvironment Particles(viableandnonviable)intheair Microorganisms settling out of the air Microorganismssettlingoutoftheair Microorganismscontaminatingsurfaces Presenceofmicroorganismsonthehandsandgarments

Monitoring PlanMonitoring PlanMonitoringPlanMonitoringPlan Definedmonitoringplans:tests,locations,alert/actionlevels&frequencies Maycontaindetailsofwater,compressedgascleansteamtesting A review of environmental data is a requirement for batch release. Areviewofenvironmentaldataisarequirementforbatchrelease.

Bioburden and ComponentsBioburden andComponents

Active IngredientsActive Ingredients ExcipientsExcipients AdditivesAdditives ActiveIngredients,ActiveIngredients,ExcipientsExcipients,Additives,Additives Allingredientsshouldhaveappropriatebiologicalspecifications Anylimitationstosterilizationmustbedefined i i f i i ( i l i l / i i k) Descriptionoforigin(e.g.virological /prion risk)

MaterialsUsedintheProcessMaterialsUsedintheProcess Whereappropriate,determinebioburden (e.g.,ionexchangematerials)

PrimaryPackagingComponentsPrimaryPackagingComponents Containerandtheclosureandcleaning/sterilizationtobeclearlyspecified Stepssuchassiliconization mayneedmonitoringp y g Ifcleaning/sterilizationisbysupplier,sameexigenciesapply

ContainerContainerclosureintegrityclosureintegrity The integrity must be validated Theintegritymustbevalidated Simulate,whereappropriate:stressfromprocessing Methodappropriatetocontainer/closuresystem

Weighing,Compunding andSterilization

Weighing and compounding must be in suitably classified roomsWeighing and compounding must be in suitably classified rooms WeighingandcompoundingmustbeinsuitablyclassifiedroomsWeighingandcompoundingmustbeinsuitablyclassifiedrooms Vesselsmustbecleaned,andsterilizedorsanitisedasappropriateandstoreddryVesselsmustbecleaned,andsterilizedorsanitisedasappropriateandstoreddry

inawaytopreventmicrobialcontaminationinawaytopreventmicrobialcontamination

StorageofpreStorageofpresterilizationintermediatestobecontrolled&timelimitedsterilizationintermediatestobecontrolled&timelimited Followingaspectstobeconsidered:Followingaspectstobeconsidered:

Pre filtration bioburden (filter sterilized material) Prefiltrationbioburden (filtersterilizedmaterial) Presterilizationbioburden Appropriateinprocesscontrols

SterilizationofproductandproductcontactmaterialsSterilizationofproductandproductcontactmaterials SelectionofasuitablesterilizationprotocolmustbebasedonSAL Method must also consider the stability of the product Methodmustalsoconsiderthestabilityoftheproduct Validationalwaysrequired Changecontrolisvital;evenapparentlyminorchangemustbeassessed

Terminal SterilizationTerminalSterilization

Steam SterilizationSteam Sterilization SteamSterilizationSteamSterilization Byfarthemostcommonmethodforaqueousbasedpharmaceuticals PreferredcycleisthePharm Eur referencecycleis15minutesat121C The sterilization cycle chosen must be compatible with product stability Thesterilizationcyclechosenmustbecompatiblewithproductstability Sterilizationparametersclearlydefined Inconjunctionwithothercontrols,therequiredSALmustbedemonstrated Validationtoconfirmsterilizationconditionsconsistentlythroughouttheload

SterilizationbyIonizingRadiationSterilizationbyIonizingRadiation Commonformedicaldevices,butnotforpharmaceuticals. Pharm.Eur.referencecondition,25KiloGray (kGy),hasbeenwidelyaccepted.Other

conditions may be used if validated and accepted by the regulatorconditionsmaybeusedifvalidatedandacceptedbytheregulator Importanttoconsidersusceptibilityoftheproducttoradiationdamage

DryHeatSterilizationDryHeatSterilization Lower antimicrobial efficacy than moist heat thus higher temperatures and/or longer Lowerantimicrobialefficacythanmoistheat,thushighertemperaturesand/orlonger

exposures.Pharm Eur referencecycleis2hours@160C Rarelyusedforterminalsterilizationofpharmaceuticals;inrarecasesheatresistantnon

aqueousproductsmaybeterminallysterilized.

SterilizationofItemsforAsepticFill(1)

Steam SterilizationSteam Sterilization SteamSterilizationSteamSterilization Widelyused,butcarefulvalidationneeded particularlycomplexitems Broadlysimilartoterminalsteamsterilization,buttwoaspectsarecritical

Quality of saturated steamQualityofsaturatedsteam Removalofairandsubsequentsteampenetration

SterilizationbyIonizingRadiationSterilizationbyIonizingRadiation Maybeusedfortemperaturesensitiveprimarypackagingorcomponents Usedfordisposablesforsterileareasandsterilitytestingareas Validationincludesdosimetry, correct,even,irradiationoftheitems

DryHeatSterilization/DryHeatSterilization/DepyrogenationDepyrogenation Sterilization/depyrogenation ofheatresistantprimarypackagingmaterials Pharm Eur notesthattemperaturesinexcessof220oChavebeenfrequently

used,theUSPsuggests250 15oC V lid ti t i l d d t i h ll t di Validationmustincludeendotoxin challengestudies Dryheatmaybeusedtosterilizenonaqueouspreparations(e.g.Ointment

bases)atlowertemperature/timerelationships,withoutdepyrogenation.

SterilizationofItemsforAsepticFill(2)

Eth lene O ide Sterili ationEth lene O ide Sterili ation EthyleneOxideSterilizationEthyleneOxideSterilization Quitewidelyusedtosterilizeheatlabilecomponents EuropeanPharmacopoeiaandtheEuropeanGMPguideindicatethat

thi th d h ld l b d h th i it blthismethodshouldonlybeusedwherethereisnosuitablealternative

Hazardous toxic,potentiallycarcinogenic,flammable,potentiallyexplosiveexplosive

Generallyconductedbyspecializedcontractors Therearestrictregulatorylimitsonmaximumpermissibleproduct

residuesresidues Bulkpacksforsterilizationmustbegaspermeable,butsealed

againstmicrobialingress Sterilization must consider packaging load pattern gas penetration Sterilizationmustconsiderpackaging,loadpattern,gaspenetration

(ethyleneoxide&watervapour),bulkpackintegrity ValidationandroutinemonitoringmustincludeBiologicalindicators.

Sterilization by Filtration (Liquids)SterilizationbyFiltration(Liquids)

Principle:Principle: Principle:Principle: Contaminatingorganismsarenotkilled,butareretainedonthefilters.Anyfaultsinthe

filterstructure,maycompromisethis

Validationincludes:Validationincludes: Retentionofbacterialchallenge:B.diminuta at107percm2 Thisiscorrelatedwithanintegritytestvalue

Validationshouldaddress:Validationshouldaddress: Filtersuitability toxicity,extractables,sheddingofparticles Adsorptionofproduct Compatibilitywithproductsolvents h i d fil i d i bili f h fil i i Therequiredfiltersizeandsuitabilityofthefiltrationequipment RetentionofB.diminuta intheactualproductunderprocessconditions Parametersforthephysicalintegritytest

Routine FiltrationRoutine Filtration RoutineFiltrationRoutineFiltration Conductedinlinewiththevalidatedparameters Checkintegritytesting,processtime,differentialpressure,flowrates,sterilizationandreuse

offilters.

PerformanceQualificationofAsepticManufacturing

BasedBased onon simulatingsimulating thethe riskrisk ofof contaminationcontamination inin allallasepticaseptic operationsoperations

ForFor aa newnew process,process, aa minimumminimum ofof threethree consecutiveconsecutivesatisfactorysatisfactory mediamedia fillingfilling trialstrials

ForFor aqueousaqueous liquidliquid products,products, simulationsimulation trialstrials useuse aaliquidliquid microbiologicalmicrobiological mediummedium

ForFor solidsolid dosagedosage forms,forms, aa powderpowder placeboplacebo isis used,used,followedfollowed byby asepticaseptic reconstitutionreconstitution intointo aa liquidliquid

b l lb l l ddmicrobiologicalmicrobiological mediummedium

TheThe followingfollowing slideslide givesgives aa generalgeneral overviewoverview........

AsepticProcessSimulation(MediaFillTrial)

Media Fill Trials (MFTs)Media Fill Trials (MFTs) MediaFillTrials(MFTs)MediaFillTrials(MFTs) Allprocessstagessimulatedascloselyaspossible Particularlyinterventionsandmanualmanipulations Mustfollowroutineproceduresandincludeallinterventions Regularinterventionssimulatedwiththesamefrequencyasactualprocess Ineachcase,theworstcaseeventualitymustbecovered Processmustbesuccessfullyvalidatedbeforeproductfillingispermitted Revalidationbymediafillmustbeconductedeveryhalfyear(eachline)

ManufacturingEnvironmentManufacturingEnvironmentgg Microbiologicalmonitoringmustbeperformedduringthetrial

FillingConditionsandEquipmentFillingConditionsandEquipment All according to routine operating conditions and at normal times of day Allaccordingtoroutineoperatingconditionsandatnormaltimesofday Containersmustbepassedthroughallstages.

Thank YouThank You

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