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Sterile|Slide1of62January2006Annex6.TRS902,2002SterilePharmaceuticalProductsSupplementaryTrainingModulesonGoodManufacturingPracticeSterile|Slide2of62January2006SterileProductionObjectivesToreviewbasicGMPrequirementsinthemanufactureofsterilepharmaceuticalproductsToreviewairclassificationsforactivitiesrelatedtothemanufactureofsterileproductsToreviewthedifferenttypesofsterilizationmethodsToreviewqualityassuranceaspectsinthemanufactureandcontrolofsterileproductsToconsidercurrentissuesapplicableinyourcountrySterile|Slide3of62January2006SterileProductionGMPRequirementsforSterileProductsAdditionalratherthanreplacementSpecificpointsrelatingtominimizingrisksofcontamination–microbiological–particulatematter–pyrogenSterile|Slide4of62January2006SterileProductionGeneralConsiderationsProductionincleanareasAppropriatestandardofcleanlinessFilteredairsuppliedAirlocksforentry–Personneland/orequipment–MaterialsSeparateareasforoperations–componentpreparation(containersandclosures)–productpreparation,filling,sterilization,etc.1.1–1-2Sterile|Slide5of62January20069.1–9.6SterileProductionPremisesDesign–Avoidunnecessaryentryofsupervisorsandcontrolpersonnel–OperationsobservedfromoutsideIncleanareas,allexposedsurfaces:–Smooth,impervious,unbroken–Minimizesheddingandaccumulationofparticles,microorganisms–Permitcleaninganddisinfection–Nouncleanablerecesses,ledges,shelves,cupboards,equipment–Slidingdoorsundesirable–FalseceilingssealedSterile|Slide6of62January20069.6.SterileProductionPremisesIncleanareas,allexposedsurfaces(2):–Properinstallationofpipesandducts,norecesses,nounsealedopenings–Sinksanddrainsavoided,andexcludedinGradeAandBareas•Whereinstalled,design,location,maintenance•Effectivecleanabletraps•Airbreakspreventingbackflow•FloorchannelsopenandeasilycleanableSterile|Slide7of62January20069.7–9.9SterileProductionPremisesChangingrooms–Designedasairlocks–Effectiveflushingwithfilteredair–Separateroomsforentryandexitdesirable–Handwashingfacilities–Interlockingsystemfordoors–Visualand/oraudiblewarningsystemUsefilteredairsupplytomaintainpressurecascadePressuredifferentialapproximately10to15PascalesZoneofgreatestrisk–immediateenvironmentSterile|Slide8of62January20069.9–9.12SterileProductionPremisesPathogenic,highlytoxic,radioactivematerialsPressurecascademaybedifferentDecontaminationprocedures–air,equipment,garmentsQualificationincludingairflowpatterns–NorisktotheproductWarningsystemtoindicatefailureinairsupplyPressureindicators–resultsregularlyrecordedRestrictedaccess–e.g.useofbarriersSterile|Slide9of62January200610.1–10.5SterileProductionEquipmentConveyerbeltsEffectivesterilizationofequipmentMaintenanceandrepairsfromoutsidethecleanarea–Iftakenapart,resterilizedbeforeuse–UsecleaninstrumentsandtoolsPlannedmaintenance,validationandmonitoring–Equipment,airfiltrationsystems,sterilizers,watertreatmentsystemsSterile|Slide10of62January200610.6SterileProductionEquipmentWatertreatmentplantsanddistributionsystem–Design,construction,maintenance–Operationanddesigncapacity–TestingprogrammeWaterforInjection(WFI)–Produced,stored,distributed–preventionofgrowthofmicroorganisms–Constantcirculationattemperatureabove70,ornotmorethan4degreesCelsiusSterile|Slide11of62January2006SterileProductionEnvironmentalMonitoring-IMicrobiologicalAirsamplesSurfaceswabsPersonnelswabsSterile|Slide12of62January2006SterileProductionEnvironmentalMonitoring-IIPhysicalParticulatematterDifferentialpressuresAirchanges,airflowpatternsClean-uptime/recoveryFilterintegrityTemperatureandrelativehumidityAirflowvelocitySterile|Slide13of62January2006SterileProductionSanitationFrequent,thoroughcleaningofareasnecessaryWrittenprogrammeRegularmonitoringtodetectresistantstrainsofmicroorganismsChemicaldisinfectionMonitoringofdisinfectantsanddetergentsDilutions–Cleancontainers,storedfordefinedperiodsoftime–Sterilizedbeforeuse,whenusedinGradeAorBareas3.1–3.2Sterile|Slide14of62January2006SterileProductionSanitationMonitoringofcleanareasMonitoringofpersonnelandsurfacesaftercriticaloperationsFrequentmonitoringinareaswhereasepticoperationsarecarriedout–Settleplates,volumetricairsamples,surfacesampling(swabsandcontactplates)–SamplingmethodsshouldnotcontaminatetheareaResultsconsideredwhenbatchreleaseisdone3.3Sterile|Slide15of62January2006SterileProductionSanitationLimitsofdetectionestablishedAlertandaction,andmonitoringtrendsofairqualityTable1.Limitsformicrobialcontamination(Informationonly)3.4GradeAirsample(CFU/m3)Settleplates(90mmdiameter)(CFU/4hours)Contactplates(55mmdiameter)(CFU/plate)Gloveprint(5fingers)(CFU/glove)A3333B10555C1005025-D20010050-Sterile|Slide16of62January20068.1–8.3SterileProductionPersonnelMinimumnumberofpersonnelincleanareas–EspeciallyduringasepticprocessingInspectionsandcontrolsfromoutsideTrainingtoallincludingcleaningandmaintenancestaff–Initialandregular–Manufacturing,hygiene,microbiologySpecialcases–Supervisionincaseofoutsidestaff–Decontaminationprocedures(e.g.staffwhoworkedwithanimaltissuematerials)Sterile|Slide17o