蒸汽灭菌和冻干工艺的验证及风险分析-意大利CTPGius

G.Ruggirello,Ph.D.QualificationandRiskAnalysis1/XXVALIDATIONandRISKANALYSISSteamSterilizationandLyophilizzationAroutefromprocessprinciplestoasafeandcompliantproduct.Theawarenessofadocumentedevidence.G.Ruggirello,Ph.D.QualificationandRiskAnalysis2/XXCONTENT•Regulatoryaspects•MoistHeatSterilization•Choosingtherightprocess•Validatingasterilizationprocess•Calibrationofinstruments•Chamberleaktest•“Utilities”•Validation–Physicalissues•Validation–Microbiologicalissues•Validatingalyophilizationprocess•ProcessController•RiskAnalysisG.Ruggirello,Ph.D.QualificationandRiskAnalysis3/XXGMP&VALIDATION1972DEVENPORTINCIDENT(UK)Infusionalsolutions,producedattheDevemportHospital,causedthreepatientdeceases.TheROSENHEIMReportfoundthecausesinanotcorrectsterilizationtreatment.G.Ruggirello,Ph.D.QualificationandRiskAnalysis4/XXExtractedfromtheROSENHEIMReport•TheAIRwasnotproperlyremovedfromthechamber•Thedrainofthechamberwasblockedbypiecesofglasses•Thelowersectionoftheloaddidnotreachthesterilizationtemperature•Thetemperaturerecordershowedthisanomalybutpeoplethoughtitwasnotworkingproperly•SterilitytestswerecarriedoutonlyontheupperlayersoftheloadGMP&VALIDATIONG.Ruggirello,Ph.D.QualificationandRiskAnalysis5/XXValidationMainconcepts•Personnel•Equipment•Process/Products•Instruments•DocumentsandSOPQualified,trainedTobequalified(IQ,OQ,PQ)TobevalidatedSuitable,calibrationhastobeplannedanddocumentedUp-todate,distributed,maintainedundercontrolG.Ruggirello,Ph.D.QualificationandRiskAnalysis6/XXTerminalMoist-HeatSterilizationEngineering–EquipmentImplicationsChapter3ofEU-GMP(PremisesandEquipment)21CFRpart211.63,211.65,211.67(Equipment)Annex11–UEGMP(Computerisedsystems)21CFRpart211.68(Automatic,mechanicalandelectronicequipment)21CFRpart11(Electronicrecords–ElectronicSignatures)GAMP(GoodAutomatedManufacturingPractice)G.Ruggirello,Ph.D.QualificationandRiskAnalysis7/XXValidation21CFRparts210-211(211.100,211.110,211.213)21CFRpart820(820.75)EU–GMP(Cap.5.21–5.24)EU–GMPAnnex15:(QualificationandValidation)CompliancePolicyGuideSec.490.100(ProcessValidationRequirementsforDrugProductsSubjecttoPre-MarketApproval)TerminalMoist-HeatSterilizationG.Ruggirello,Ph.D.QualificationandRiskAnalysis8/XXCONTENT•Regulatoryaspects•MoistHeatSterilization•Choosingtherightprocess•Validatingasterilizationprocess•Calibrationofinstruments•Chamberleaktest•“Utilities”•Validation–Physicalissues•Validation–Microbiologicalissues•Validatingalyophilizationprocess•ProcessController•RiskAnalysisG.Ruggirello,Ph.D.QualificationandRiskAnalysis9/XXWhatisbeingSterilized?PorousLoadsHardGoodsEquipmentPartsComponentsGlassStainlesssteelPolymericMaterialsWasteLiquidsNon-PorousLoadsFinishedProductsLaboratoryMediaIn-processFluidsWasteLiquidsPolymericMaterialsDefiningthesterilizationprocessG.Ruggirello,Ph.D.QualificationandRiskAnalysis10/XXDefiningthesterilizationprocessTemperatureandTimeforaneffectivesterilization1.Cannotbedefinedbyphysicalmethods2.Havetobepreliminaryinvestigatedaccordingtoamicrobiologicalapproach3.Shouldcomplywithminimumrequirementsuchasthetraditional“Foof8ormore”reportedintheProposedRulesoftheFDA(1976,Clause212.240),orthegridoftable4oftheguidelineHTM2010,Part2,Clause3.24(i.e.15minutes@121°-124°C),reportedalsointhestandardEN285,point8.3.1.2G.Ruggirello,Ph.D.QualificationandRiskAnalysis11/XX•BIOBURDEN•Thermicresistanceoftheproduct•Overkill•Bioburden•Integrated(Bioburden/Biologicalindicators)Validationapproaches:DefiningthesterilizationprocessG.Ruggirello,Ph.D.QualificationandRiskAnalysis12/XXBalancemustbeMaintainedAttainingsterilitymustnotbeaccomplishedwithlossofproductstability.Maintainingstabilitymustbeaccompaniedwithadequateassuranceofsterility.Component/ProductSterilityComponent/ProductStabilityDefiningthesterilizationprocessG.Ruggirello,Ph.D.QualificationandRiskAnalysis13/XXDefiningthesterilizationprocessDemonstratedPNSUExpectedShelfLifeInformationNeededForValidationHeatInputtoMaterialsBioburdenMethodBioburden/BIMethodOverkillMethodG.Ruggirello,Ph.D.QualificationandRiskAnalysis14/XXCONTENTOFTHEPRESENTATION•Regulatoryaspects•MoistHeatSterilization•Choosingtherightprocess•Causesoffailure•Validatingasterilizationprocess•Calibrationofinstruments•Chamberleaktest•“Utilities”•Validation–Physicalissues•Validation–Microbiologicalissues•SterilizerProcessController•RiskAnalysisG.Ruggirello,Ph.D.QualificationandRiskAnalysis15/XXValidationWhathastobevalidated?•Aprocess?•Aproduct?•Apieceofequipment?Let’sconsiderthedefinitionof“validation”……G.Ruggirello,Ph.D.QualificationandRiskAnalysis16/XX«Validationisestablishingdocumentedevidencewhichprovidesahighdegreeofassurancethataspecificprocesswillconsistentlyproduceaproductmeetingitspre-determinedspecificationsandqualitycharacteristics»(FDAGuidelineonGeneralPrinciplesofValidation,1987)«Validationisadefinedstrategyofinter-relatedpracticesandprocedureswhichincombinationwithroutineproductionmethodsandqualitycontroltechniquesprovidesdocumentedassurancethatasystemisperformingrepetitivelyasintendedand/orthataproductconformstoitspre-