Cleaning-Process-Development-and-Validation.ppt

CleaningProcessDevelopmentandValidation,June16,2006BrianKimVPofQualityTanox,Inc.,PartI,Regulatory/ComplianceOverview,Applicableregulationsandrequirements21CFR211.65a)Equipment.surfaceswhichcontactcomponents,in-processmaterials,ordrugproductsshallnotbereactive,additiveorabsorptive.21CFR211.67Equipmentandutensil.cleaned,maintained,andsanitizedatappropriateintervalstopreventorcontaminationthatwouldalterthesafety,identity,strength,quality,orpurity,Regulatory/ComplianceOverview,21CFR211.182WrittencleaningProcedureCleaninganduselogCholestyramineResinUSPrecallduetothelowlevelcontaminationwithintermediatesanddegradantsafterreuseofrecoveredsolventsfrompesticideproductionincreasedFDAawareness.,Regulatory/ComplianceOverview,GuidanceGuidetoInspectionforValidationofCleaningProcesses.FDA,1993ICHQ7A,GMPforPharmaceuticalActiveIngredients,Regulatory/ComplianceOverview,FDA21CenturyRisk-BasedQualitySystemInitiativeDefinecriticalproductattributesandcontrolofcriticalprocesses(ProcessCapacity)toensure:SAFETY,PURITY,EFFICACY,QUALITYDesign“Quality”intoprocessesScience-basedriskmanagementRealtimeQA,CleaningValidationOverview,ObjectivesAssuranceofproductpurity,safety,efficacyandqualityPreventionofproductcrosscontaminationbybyproduct,residualproduct,microbialresidueandresidualdetergentWhencleaningvalidationisrequiredIntroductionofnewequipment/productManufacturing/cleaningprocesschangesRawmaterial/cleaningagentchanges,CleaningValidationOverview,GoodsystemdesignComprehensiveMasterValidationProgramEffectivecleaningprocessdevelopmentAdequateanalyticaltechniqueJustifiableacceptancecriteriaproductspecific(HowCleanisClean?)ContinuousdatamonitoringandevaluationAcceptancecriteriaadjustmentasnecessary,CleaningValidationOverview,Routinereviewofdeviations,excursionsandchangecontrolrelatedtocleaningprocessparameters,equipment,andmaterialsRe-validationasrequiredDefinewhatandhowtorevalidateDefinewhentorevalidateApplicationofvalidationlifecyclemanagement,CleaningValidationOverview,CleaningValidationLifecycleManagement,ValidationMasterPlan,CleaningCycleDevelopment,(Re)Validation(IQ/OQ/PQ),Newproduct/Equipment,RoutineTesting,RegularDataReview,EvaluationofCleaningParameters,CleaningCycleDevelopment,ElementstoconsiderDesign/ConstructioncomplexityofequipmentCharacteristicsofresiduals/producttocleanCleaningagentsTypeofcleaningprocess(Automatedvs.Manual)ManufacturingprocessAnalyticalmethodsandtheirsensitivity,EquipmentDesign/ConstructionforEffectiveCleaning,Adequatedesign/structuralcomplexityandconfigurationMaterialandSurfaceNon-ReactiveandcleanabilityCompatibilitywithdetergentsStageofManufacturingProcessUpstreamDownstreamIncreasedRiskDrugproduct,EquipmentDesign/ConstructionforEffectiveCleaning,Structural/designcomplexitySizeandprocesspipingconfigurationforCIPPotentialdeadleg/spaceAdequateturbulenceAdequateslopeNozzledesignandlocationsBranchpipingorientation,EquipmentDesign/ConstructionforEffectiveCleaning,InstrumentTeeforCIP:L/D1.5,D,L,Adequateturbulence(Flowrate)forCIP,ft/sec,5ft/sec,5ft/sec,EquipmentDesign/ConstructionforEffectiveCleaning,CIPReturn,CIPReturn,Good,Bad,EquipmentDesign/ConstructionforEffectiveCleaning,Branchpipingorientation,BadDesign,GoodDesign,Up,Down,Parallel,CharacteristicsofProducts,Understand(Bio)chemicalcharacteristicsofProduct(s)ProductmatrixTypeofactivemolecule(e.g.,protein,DNA,peptide,smallmolecule)Excipients/ProcessrelatedcomponentsProductmatrixisacriticalelementfor:CleaningprocessdesignForthedeterminationofadetergentandprocessparameters,CharacteristicsofProducts,PhysicochemicalcharacteristicsSolubilitywithmedium(e.g.,water,organicsolvent)ReactivityisacriticalelementforthedeterminationofprocessparametersDegreeofareactionwithadetergentormediumatdifferentconditions.DegradantsChemicalstateLiquidSemi-solidSolid,CharacteristicsofProducts,MicrobestaticpropertyCriticalfordetergentselectionToxicity/PharmacologicalpotencyCriticalforacceptancecriteriaPotentialproductand/orcomponentdegradantsafterreactionwithadetergentCriticalforacceptancecriteria,CleaningAgentSelection,SelectionofaCleaningAgentDependingontheparticulartypeofchemicals(soils)toremoveconsidering:Chemical/Physicalnatureofthemolecule(soil)toremoveReactivityPhysicochemicalcharacteristicsofthemoleculeChemicalstateofsoils,CleaningAgentSelection,TypeofDetergent,CleaningAgentSelection,BiologicalsoilsalkalineBlendingofothercleaningcomponentswithalkalinedetergentenhancescleaningeffects.BuildersthegroupofcomplexingagentsthatenhancethecleaningeffectandtheeffectofsurfactantEDTA,polyphosphate,NTA,citrates,CleaningAgentSelection,SurfactantsseveraltypesbasedontheioncharacteristicsoftheactivegroupAnionic,cationic,non-ionicandamphotericAnionicandNon-ionic:usedascomponentsfordetergentCationicandamphoteric:usedintheformulationsofdisinfectantsfortheirmicrocidaleffectSurfacetensioncapillaryaction,CleaningAgentSelection,ComplexingagentscomplexingwithmineralsandinorganiccomponentsSequesteringagentpreventionofscaleformation(crystallizationofwaterhardness)MayreducetheneedforacidcleaningfollowingthebasecleaningDeformersOxidizingagentsH2O2Corrosioninhibitors-Silicates,CleaningAgentSelection,02468101214CleaningTime(mins),80706050403020100,%RemovedSoil,Cleaningagent+Builder+Surfactant,Singlecleaningagent,Surfactant,Builder,CleaningAgentSelection,ApplicationparametersforcleaningagentsTypeofcleaningagentDependingonthetypeofsoilstoremoveConcentrationEffectivenessEH&SconsiderationTemperatureContacttime,CleaningProcessDevelopment,SelectionofCleaningProcessAutomatedvs.ManualAutomatedCIPand/orCOPConsistencyandreproducibilityReadilyvalidatableBetterprocesscontrolManualInconsistencyHardtovalidateInadequateformostofthestate-of-the-artfacilities,CleaningProcessDevelopment,Consider:Historicalcleaningdata(trending)PreviousvalidationdataifavailableComplexityanddelicacyofmanufacturingequipmentLeveloffacilityautomationCleaningcycledevelopmentCIPorCOPdesignandcapacityNatureofsoils,CleaningProcessDevelopment,ComplexityanddelicacyofequipmentNatureofproductcontactingsurfaceSequenceCriticalparametersLeggingtimebetweentheendofequipmentuseandcleaningTemperaturePressureVolumeProcesstime,CleaningProcessDevelopment,TypesofCIP(Clean-in-place)PortableCIPSimplecontrolandnonre-circulationMultiple-TankRe-useCIPSeparatetanksfordetergents(Acid,Base)andwashingsolution(e.g.,water)Re-circulationandre-useofdetergentsandwashingsolutionMaynotbeadequateforbiopharmaceuticalintermsofpreventcrosscontamination(e.g.,viralcontamination),CleaningProcessDevelopment,Singleandmultiple-tanksingleuseCIPAppropriateforBiopharmaceuticals:re-circulationRelativelyeasyforvalidationbutdependingonnumberofpumps,valves,andthecomplexityofcycleHighdegreeofcycleflexibilityNore-useofcleaningagentforbiopharmaceuticalsValidationisdependingonthecomplexityofthecleaningsequence.,CleaningProcessDevelopment,COP(Clean-outofplace)Usedformiscellaneousfittingsandpartsoutofthemainequipment(disassembly)AsingleopentankforrinsingandwashingRe-circulationofdetergentusingadetergentfeedpumpAppropriatecycledevelopment,CleaningProcessDevelopment,AutomatedCIPsystemcomponentsandfunctionsTemperaturesensorsTwoforre-circulationsystemcleaningsolutionsupplyandreturnmonitoringTemperatureisaprimaryindicatorofcleaningcycleperformanceConductivitysensorsDetergentconc.monitoringConductivityaprimaryindicatorofcleaningcycleperformance,CleaningProcessDevelopment,pHsensorsMonitoringofrinsingefficacyCIPsupplyflowsensorsFlowrateandtotalizationaredirectlyrelatedtocontacttimeMagneticflowsensorsnotrecommendedbecauseofinabilitytosensenon-conductivefluidCIPsupplypressuresensorsIndicatorofspraydeviceperformanceandsolutioncontacttime,CleaningProcessDevelopment,CIPvessellevelsensorsIndirectindicatorofperformanceofthesystemReturnflowswitchConductancebasedprobePreventionofinadvertenteventssuchasmis-connectionofsupplyandreturncircuitsproductcontaminationSpraydeviceFixedandrotating,PartII,Safety,Purity,Efficacy,CleaningProcessDevelopment,SequencedevelopmentPre-rinse:pipingandequipmenttobecleanedbypressurewashingEndpointTotalvolumeortimeOn-lineturbidity,conductivityorreturnflowMustbedrainedortokill-tank,CleaningProcessDevelopment,DetergentwashingAcidoralkalidependingonthetypeofsoilContinuousfeedEndpointVolumeortimeMustbedrainedSoakingwithdetergentasnecessaryChromatographysystem,CleaningProcessDevelopment,PostrinseanddrainsToremoveresidueafterpre-rinseanddetergentwashingContinuousflowanddrainUsuallynotheatedNeutralizationwashanddrainEndpointtotalvolumeand/orelapsetimeFinalrinseanddrainEndpointtotalvolumeand/orelapsetime,pH,conductivity,CleaningProcessDevelopment,ParameterandrangedeterminationFactoringexperimentaldesign(example),CleaningProcessDevelopment,StudyapproachCouponstudySamematerialsasmanufacturingequipmentEquivalentsurfacetreatmentExperimentalrunWorstcaseapproachResiduestobecleanedEquipmentsurfaceAppropriatesamplingandanalyticalmethods,CleaningProcessDevelopment,SamplingDirectsurfacesamplingSelectionof:AppropriatesampledissolvingmediumSamplecontainerSamplingmaterial(s)SwabInterferencebyadhesive,Variability,Swabbingunidirectionallywithanewwetswabforeachdirection,Wetswabandfinishwithadryswab,CleaningProcessDevelopment,RinsewatersampleDilutioneffectUnreliable,inconsistentrecoveryVisualinspection,CleaningProcessDevelopment,AnalyticalMethodsDependingonthetypesofanalytesProteinsOrganiccompoundsInorganiccompoundsOtherbiologicalcontaminantsAdversaryagentsMycoplasma,virusResidualhostbacteria,CleaningProcessDevelopment,TypeofanalyticalmethodsSpecificMulti-productequipmentPotentproductToxicorpotentdegradantsorcontaminantsNon-specificBroadapplicationHolisticevaluationSelectionofmethodsbasedonthenatureofanalytes,CleaningProcessDevelopment,Developmentofspecificmethod(s)requireslongertimeMatrixofthematerialformethoddevelopmentshouldbetherepresentativeofthecleaningsample.Inhibitoryorenhanceeffectsofthesamplematrixmustbeevaluatedandappropriatesamplepreparationandmethodshouldbedeveloped.Sensitiveandspecific,CleaningProcessDevelopment,Selectionofappropriatemethod(s)isakeyforsuccessfulcleaningvalidationRoutineandvalidationMethodsmustbevalidatedforSensitivity(LOD/LOQ)SpecificityPrecisionAccuracy,CleaningProcessDevelopment,Examplesofmethodswidelyusedinbiopharmaceuticalcleaningprocess,CleaningProcessDevelopment,UsemethodsincombinationValidationandroutinecleaningsampleanalysisTestintendedroutinecleaningsamplesduringthevalidationstudyandestablishco-relationshipbetweenspecificandnon-specificsampletestresults.Usetheratioasacorrectionfactorduringtheroutinecleaningsampleanalysisiftheresultsshowrelativedifferenceinaconsistentmanner.,CleaningValidation,ValidationApproachDevelopmentofValidationMasterPlantodescribe:Objective,scope,references,responsibilitiesNatureofproducts(dosageformandtherapeuticareas)allproductsManufacturingprocessIncludeequipmentlistCleaningsystemandprocessforeachtypeofequipment,CleaningValidation,ValidationStrategyMulti-usevs.dedicatedequipmentIndividualvs.groupvs.matrixScopeofusevs.configurationEachproductbasisvs.worstcaseapproachDefinetheworstcaseorgroupProvideascientificallysoundjustificationifchosen(e,g.,degreeofdifficultyincleaning,toxicity)ListofEquipmentandqualificationstatusEquipmentP&IDsCleaningsystem(e.g.,CIP)qualification(I/OQ)status,CleaningValidation,AnalyticalmethodselectionandvalidationrequirementsRecoverystudyrequirementsrecoveryfactorDeterminationofsamplingmethodsLotrequirementsforvalidationDocumentationrequirementsProtocolReportsRawdataRe-validationrequirementsandfrequencyValidationprojectplanning(Generic),CleaningValidation,CleaningValidationPrerequisitesEnsurethatallcleaningprocessequipmentareadequatelyqualified.DraftacleaningSOPbasedonthedevelopmentstudy.PrepareP&IDforeachpieceofequipmentanddefinesamplinglocationsand/ormethods.Ensurethatanalyticalmethodsarevalidated.,CleaningValidation,Conductarecoverystudypertypeofequipmentconstructionmaterial.ProtocoldrivenReportrecoveryfactorforeachtypeofequipmentconstructionmaterialDefineacceptancecriteria.Justificationmustbeestablished.Developadetailedplanandresponsibilities.,CleaningValidation,RecoverystudyRecoveryrateisdirectlyrelatedtotheconditionofequipmentsurfaceandsamplingtechnique.Defineappropriatesamplingmethodsandtechniques.Recoveryfactormustbereflectedontheresiduecalculationduringthecleaningvalidation.,CleaningValidation,ConsiderationsforrecoverystudyCouponsandothermaterialsRepresentativeofalltypesofequipment(316LSS,Glass,plastic)Samesurfacetreatment(e.g.,electropolishing)SamplingmaterialsSamplecontainerSamplingmethodsSpikingsolutionpreparationSimulatedcleaningsampleConcentrationshouldbeatalevelofacceptanceacceptancecriteria,CleaningValidation,SpikingandspikedcouponhandlingproceduresCleancouponsbeforespikingSimulateactualcleaningconditionAllowthespikedsolutiontobeonthecouponthemaximumtimeascleaningtimelimitisdefinedtheSOP.Evenlyspikethesolutiononthedefinedareaofthecoupon.Thecouponspikingareashouldbeanequaltotheactualsamplingareaontheactualequipment.,CleaningValidation,CouponarrangementCoupontobearrangedtohaveareasorseparatecouponsfor:BackgroundblankControlspikingsampleprepsolutionSamplespikingareaSamplingProtocolandreportDefineexpectedacceptancecriteriaExample:60120%RECOVERYTherecoveryfactor=Spikedvalue/recoveredvalue,CleaningValidation,AcceptanceCriteriaApproachVisuallycleanlinessPrerequisiteofcleaningacceptance.Cannotbeanacceptancecriterionalone.CleaningcapabilityStatisticalanalysisofhistoricalcleaningdataProductspecificdataNon-specificdata(e.g,rinsewaterTOC)tobeevaluatedbasedontheworstcase(toxicity)residual.Datashouldbeanalyzedfromthetoxicityanddosagelevelperspective,CleaningValidation,Maximumdailydosebasedcarryover0.001ofanycontaminantinmaximumdailydoseofthesubsequentbatch(3factors)10%ofmaximumdailydoseinactive10%ofmaximumdailydosesafetyfactor10%ofmaximumdailydosecleaningcapabilityToxicitybasedcarryoverToxicitydatabasedcriterionsafetyfactor(110%ofthetoxicity)isappliedtothetoxicity.Applicabletodetergent,sanitizingagentandcross-contaminatingproduct.,CleaningValidation,Thelowestvaluetobechosenasacceptancecriteria.Processcapabilitytoremovecontaminantsmustbeconsidered.Applydifferentcriteriatodifferentmanufacturingprocessstepconsideringdownstreamimpurity/contaminantremovalcapacity.Themoststringentcriteriatofinishedproductmanufacturing.Justificationmustbeclearlydocumented.,Acceptancecriteriashouldinclude:Numberofbatches(consecutive)SampletesttimelimitCleaningtimelimit(numberofhoursafterproduction)DeviationhandlingAllowedcontaminantlevelperswabareaorpervolumeofsample,CleaningValidation,CleaningValidation,AnalyticalMethodApplicationNon-specificmethodfortheequipmentatthemanufacturingste