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首页 FDA资料汇编FDA工艺验证指南

FDA资料汇编FDA工艺验证指南 .doc

FDA资料汇编FDA工艺验证指南

longyun918
2018-09-07 0人阅读 0 0 0 暂无简介 举报

简介:本文档为《FDA资料汇编FDA工艺验证指南 doc》,可适用于医药卫生领域

GUIDELINEONGENERALPRINCIPLESOFPROCESSVALIDATIONMay,Preparedby:CenterforDrugsandBiologicsandCenterforDevicesandRadiologicalHealthFoodandDrugAdministrationMaintainedby:DivisionofManufacturingandProductQuality(HFN)OfficeofComplianceCenterforDrugsandBiologicsFoodandDrugAdministrationFishersLaneRockville,MarylandGeneralPrinciplesofProcessValidationMayGENERALPRINCIPLESOFPROCESSVALIDATIONIPURPOSEThisguidelineoutlinesgeneralprinciplesthatFDAconsiderstobeacceptableelementsofprocessvalidationforthepreparationofhumanandanimaldrugproductsandmedicaldevicesIISCOPEThisguidelineisissuedunderSection(CFR)andisapplicabletothemanufactureofpharmaceuticalsandmedicaldevicesItstatesprinciplesandpracticesofgeneralapplicabilitythatarenotlegalrequirementsbutareacceptabletotheFDAApersonmayrelyuponthisguidelinewiththeassuranceofitsacceptabilitytoFDA,ormayfollowdifferentproceduresWhendifferentproceduresareused,apersonmay,butisnotrequiredto,discussthematterinadvancewithFDAtopreventtheexpenditureofmoneyandeffortonacnished(orinprocess)testingcannotadequatelymeasurecertainattributes,processvalidationshouldbederivedprimarilyfromqualificationofeachsystemusedinproductionandfromconsiderationoftheinteractionofthevarioussystemsVCGMPREGULATIONSFORFINISHEDPHARMACEUTICALSProcessvalidationisrequired,inbothgeneralandspecificterms,bytheCurrentGoodManufacturingPracticeRegulationsforFinishedPharmaceuticals,CFRPartsandExamplesofsuchrequirementsarelistedbelowforinformationalpurposes,andarenotallinclusiveArequirementforprocessvalidationissetforthingeneraltermsinsectionWrittenproceduresdeviationswhichstates,inpart:"Thereshallbewrittenproceduresforproductionandprocesscontroldesignedtoassurethatthedrugproductshavetheidentity,strength,quality,andpuritytheypurportorarerepresentedtopossess"SeveralsectionsoftheCGMPregulationsstatevalidationrequirementsinmorespecifictermsExcerptsfromsomeofthesesectionsare:Section,Samplingandtestingofinprocessmaterialsanddrugproducts(a)"controlproceduresshallbeestablishedtomonitortheoutputandVALIDATEtheperformanceofthosemanufacturingprocessesthatmayberesponsibleforcausingvariabilityinthecharacteristicsofinprocessmaterialandthedrugproduct"(emphasisadded)Section,ControlofMicrobiologicalContamination(b)"Appropriatewrittenprocedures,designedtopreventmicrobiologicalcontaminationofdrugproductspurportingtobesterile,shallbeestablishedandfollowedSuchproceduresshallincludeVALIDATIONofanysterilizationprocess"(emphasisadded)VIGMPREGULATIONFORMEDICALDEVICESProcessvalidationisrequiredbythemedicaldeviceGMPRegulations,CFRPartSectionrequireseveryfinisheddevicemanufacturerto:"prepareandimplementaqualityassuranceprogramthatisappropriatetothespecificdevicemanufactured"Section(n)definesqualityassuranceas:"allactivitiesnecessarytoverifyconfidenceinthequalityoftheprocessusedtomanufactureafinisheddevice"Whenapplicabletoaspecificprocess,processvalidationisanessentialelementinestablishingconfidencethataprocesswillconsistentlyproduceaproductmeetingthedesignedqualitycharacteristicsAgenerallystatedrequirementforprocessvalidationiscontainedinsection:"Writtenmanufacturingspecificationsandprocessingproceduresshallbeestablished,implemented,andcontrolledtoassurethatthedeviceconformstoitsoriginaldesignoranyapprovedchangesinthatdesign"Validationisanessentialelementintheestablishmentandimplementationofaprocessprocedure,aswellasindeterminingwhatprocesscontrolsarerequiredinordertoassureconformancetospecificationsSection(a)()states:"controlmeasuresshallbeestablishedtoassurethatthedesignbasisforthedevice,componentsandpackagingiscorrectlytranslatedintoapprovedspecifications"ValidationisanessentialcontrolforassuringthatthespecificationsforthedeviceandmanufacturingprocessareadequatetoproduceadevicethatwillconformtotheapproveddesigncharacteristicsVIIPRELIMINARYCONSIDERATIONSAmanufacturershouldevaluateallfactorsthataffectproductqualitywhendesigningandundertakingaprocessvalidationstudyThesefactorsmayvaryconsiderablyamongdifferentproductsandmanufacturingtechnologiesandcouldinclude,forexample,componentspecifications,airandwaterhandlingsystems,environmentalcontrols,equipmentfunctions,andprocesscontroloperationsNosingleapproachtoprocessvalidationwillbeappropriateandcompleteinallcaseshowever,thefollowingqualityactivitiesshouldbeundertakeninmostsituationsDuringtheresearchanddevelopment(RD)phase,thedesiredproductshouldbecarefullydefinedintermsofitscharacteristics,suchasphysical,chemical,electricalandperformancecharacteristicsItisimportanttotranslatetheproductcharacteristicsintospecificationsasabasisfordescriptionandcontroloftheproductDocumentationofchangesmadeduringdevelopmentprovidetraceabilitywhichcanlaterbeusedtopinpointsolutionstofutureproblemsTheproduct'senduseshouldbeadeterminingfactorinthedevelopmentofproduct(andcomponent)characteristicsandspecificationsAllpertinentaspectsoftheproductwhichimpactonsafetyandeffectivenessshouldbeconsideredTheseaspectsForexample,inthecaseofacompressedtablet,physicalcharacteristicswouldincludesize,weight,hardness,andfreedomfromdefects,suchascappingandsplittingChemicalcharacteristicswouldincludequantitativeformulationpotencyperformancecharacteristicsmayincludebioavailability(reflectedbydisintegrationanddissolution)Inthecaseofbloodtubing,physicalattributeswouldincludeinternalandexternaldiameters,lengthandcolorChemicalcharacteristicswouldincluderawmaterialformulationMechanicalpropertieswouldincludehardnessandtensilestrengthperformancecharacteristicswouldincludebiocompatibilityanddurabilityincludeperformance,reliabilityandstabilityAcceptablerangesorlimitsshouldbeestablishedforeachcharacteristictosetupallowablevariationsTheserangesshouldbeexpressedinreadilymeasurabletermsThevalidityofacceptancespecificationsshouldbeverifiedthroughtestingandchallengeoftheproductonasoundscientificbasisduringtheinitialdevelopmentandproductionphaseOnceaspecificationisdemonstratedasacceptableitisimportantthatanychangestothespecificationbemadeinaccordancewithdocumentedchangecontrolproceduresVIIIELEMENTSOFPROCESSVALIDATIONAProspectiveValidationProspectivevalidationincludesthoseconsiderationsthatshouldbemadebeforeanentirelynewproductisintroducedbyafirmorwhenthereisachangeinthemanufacturingprocesswhichmayaffecttheproduct'scharacteristics,suchasuniformityandidentityThefollowingareconsideredaskeyelementsofprospectivevalidationForexample,inordertoassurethatanoral,ophthalmic,orparenteralsolutionhasanacceptablepH,aspecificationmaybeestablishedbywhichalotisreleasedonlyifithasbeenshowntohaveapHwithinanarrowestablishedrangeForadevice,aspecificationfortheelectricalresistanceofapacemakerleadwouldbeestablishedsothattheleadwouldbeacceptableonlyiftheresistancewaswithinaspecifiedrangeEquipmentandProcessTheequipmentandprocess(es)shouldbedesignedandorselectedsothatproductspecificationsareconsistentlyachievedThisshouldbedonewiththeparticipationofallappropriategroupsthatareconcernedwithassuringaqualityproduct,eg,engineeringdesign,productionoperations,andqualityassurancepersonnelaEquipment:InstallationQualificationInstallationqualificationstudiesestablishconfidencethattheprocessequipmentandancillarysystemsarecapableofconsistentlyoperatingwithinestablishedlimitsandtolerancesAfterprocessequipmentisdesignedorselected,itshouldbeevaluatedandtestedtoverifythatitiscapableofoperatingsatisfactorilywithintheoperatinglimitsrequiredbytheprocessThisphaseofvalidationincludesexaminationofequipmentdesigndeterminationofcalibration,maintenance,andadjustmentrequirementsandidentifyingcriticalequipmentfeaturesthatcouldaffecttheprocessandproductInformationobtainedfromthesestudiesshouldbeusedtoestablishwrittenprocedurescoveringequipmentcalibration,maintenance,monitoring,andcontrolExamplesofequipmentperformancecharacteristicswhichmaybemeasuredincludetemperatureandpressureofinjectionmoldingmachines,uniformityofspeedformixers,temperature,speedandpressureforpackagingmachines,andtemperatureandpressureofsterilizationchambersInassessingthesuitabilityofagivenpieceofequipment,itisusuallyinsufficienttorelysolelyupontherepresentationsoftheequipmentsupplier,oruponexperienceinproducingsomeotherproductSoundtheoreticalandpracticalengineeringprinciplesandconsiderationsareafirststepintheassessmentItisimportantthatequipmentqualificationsimulateactualproductionconditions,includingthosewhichare"worstcase"situationsTheimportanceofassessingequipmentsuitabilitybaseduponhowitwillbeusedtoattaindesiredproductattributesisillustratedinthecaseofdeionizersusedtoproducePurifiedWater,USPInonecase,afirmusedsuchwatertomakeatopicaldrugproductsolutionwhich,inviewofitsintendeduse,shouldhavebeenfreefromobjectionablemicroorganismsHowever,theproductwasfoundtobecontaminatedwithapathogenicmicroorganismTheapparentcauseoftheproblemwasfailuretoassesstheperformanceofthedeionizerfromamicrobiologicalstandpointItisfairlywellrecognizedthatthedeionizersarepronetobuildupofmicroorganismsespeciallyiftheflowratesarelowandthedeionizersarenotrechargedandsanitizedatsuitableintervalsTherefore,thesefactorsshouldhavebeenconsideredInthiscase,however,thefirmreliedupontherepresentationsoftheequipmentitself,namelythe"recharge"(ie,conductivity)indicator,tosignalthetimeforregenerationandcleaningConsideringthedesiredproductcharacteristics,thefirmshouldhavedeterminedtheneedforsuchproceduresbaseduponpreusetesting,takingintoaccountsuchfactorsasthelengthoftimetheequipmentcouldproducedeionizedwaterofacceptablequality,flowrate,temperature,rawwaterquality,frequencyofuse,andsurfaceareaofdeionizingresinsTestsandchallengesshouldberepeatedasufficientnumberoftimestoassurereliableandmeaningfulresultsAllacceptancecriteriamustbemetduringthetestorchallengeIfanytestorchallengeshowsthattheequipmentdoesnotperformwithinitsspecifications,anevaluationshouldbeperformedtoidentifythecauseofthefailureCorrectionsshouldbemadeandadditionaltestrunsperformed,asneeded,toverifythattheequipmentperformswithinspecificationsTheobservedvariabilityoftheequipmentbetweenandwithinrunscanbeusedasabasisfordeterminingthetotalnumberoftrialsselectedforthesubsequentperformancequalificationstudiesoftheprocessOncetheequipmentconfigurationandperformancecharacteristicsareestablishedandqualified,theyshouldbedocumentedTheinstallationqualificationshouldincludeareviewofpertinentmaintenanceprocedures,repairpartslists,andcalibrationmethodsforeachpieceofequipmentTheobjectiveistoassurethatallrepairscanbeperformedinsuchawaythatwillnotaffecttheForexample,theAAMIGuidelineforIndustrialEthyleneOxideSterilizationofMedicalDevicesapprovedDecember,states:"Theperformancequalificationshouldincludeaminimumofsuccessful,plannedqualificationruns,inwhichalloftheacceptancecriteriaaremet()characteristicsofmaterialprocessedaftertherepairInaddition,specialpostrepaircleaningandcalibrationrequirementsshouldbedevelopedtopreventinadvertentmanufactureaofnonconformingproductPlanningduringthequalificationphasecanpreventconfusionduringemergencyrepairswhichcouldleadtouseofthewrongreplacementpartbProcess:PerformanceQualificationThepurposeofperformancequalificationistoproviderigoroustestingtodemonstratetheeffectivenessandreproducibilityoftheprocessInenteringtheperformancequalificationphaseofvalidation,itisunderstoodthattheprocessspecificationshavebeenestablishedandessentiallyprovenacceptablethroughlaboratoryorothertrialmethodsandthattheequipmenthasbeenjudgedacceptableonthebasisofsuitableinstallationstudiesEachprocessshouldbedefinedanddescribedwithsufficientspecificitysothatemployeesunderstandwhatisrequiredPartsoftheprocesswhichmayvarysoastoaffectimportantproductqualityshouldbechallengedInchallengingaprocesstoassessitsadequacy,itisimportantthatchallengeconditionssimulatethosethatwillbeencounteredduringactualproduction,including"worstcase"conditionsThechallengesshouldberepeatedenoughtimestoassurethattheresultsaremeaningfulandconsistentForexample,inelectroplatingthemetalcaseofanimplantablepacemaker,thesignificantprocessstepstodefine,describe,andchallengeincludeestablishmentandcontrolofcurrentdensityandtemperaturevaluesforassuringadequatecompositionofelectrolyteandforassuringcleanlinessofthemetaltobeplatedIntheproductionofparenteralsolutionsbyasepticfilling,thesignificantasepticfillingprocessstepstodefineandchallengeshouldincludethesterilizationanddepyrogenationofcontainersclosures,sterilizationofsolutions,fillingequipmentandproductcontactsurfaces,andthefillingandclosingofcontainersEachspecificmanufacturingprocessshouldbeappropriatelyqualifiedandvalidatedThereisaninherentdangerinrelyingonwhatareperceivedtobesimilaritiesbetweenproducts,processes,andequipmentwithoutappropriatechallengecProduct:PerformanceQualificationForpurposesofthisguideline,productperformancequalificationactivitiesapplyonlytomedicaldevicesThesestepsshouldbeviewedaspreproductionqualityassuranceactivitiesForexample,intheproductionofacompressedtablet,aForexample,intheproductionofacompressedtablet,afirmmayswitchfromonetypeofgranulationblendertoanotherwiththeerroneousassumptionthatbothtypeshavesimilarperformancecharacteristics,and,therefore,granulationmixingtimesandproceduresneednotbealteredHowever,iftheblendersaresubstantiallydifferent,useofthenewblenderwithproceduresusedforthepreviousblendermayresultinagranulationwithpoorcontentuniformityThis,inturn,mayleadtotabletshavingsignificantlydifferingpotenciesThissituationmaybeavertedifthequalityassurancesystemdetectstheequipmentchangeinthefirstplace,challengestheblenderperformance,precipitatesarevalidationoftheprocess,andinitiatesappropriatechangesInthisexample,revalidationcomprisesinstallationqualificationofthenewequipmentandperformancequalificationoftheprocessintendedforuseinthenewblenderBeforereachingtheconclusionthataprocesshasbeensuccessfullyvalidated,itisnecessarytodemonstratethatthespecifiedprocesshasnotadverselyaffectedthefinishedproductWherepossible,productperformancequalificationtestingshouldincludeperformancetestingunderconditionsthatsimulateactualuseProductperformancequalificationtestingshouldbeconductedusingproductmanufacturedfromthesametypeofproductionequipment,methodsandproceduresthatwillbeusedforroutineproductionOtherwise,thequalifiedproductmaynotberepresentativeofproductionunitsandcannotbeusedasevidencethatthemanufacturingprocesswillproduceaproductthatmeetsthepredeterminedspecificationsandqualityattributesForexample,amanufacturerofheartvalvesreceivedcomplaintsthatthevalvesupportstructurewasfracturingunderuseInvestigationbythemanufacturerrevealedthatallmaterialanddimensionalspecificationshadbeenmetbuttheproductionmachiningprocesscreatedmicroscopicscratchesonthevalvesupportingwireformThesescratchescausedmetalfatigueandsubsequentfractureComprehensivefatiguetestingofproductionunitsundersimulateduseconditionscouldhavedetectedtheprocessdeficiencyInanotherexample,amanufacturerrecalledinsulinsyringesbecauseofcomplaintsthattheneedleswerecloggedInvestigationrevealedthattheneedleswerecloggedbysiliconeoilwhichwasemployedasalubricantduringmanufacturingInvestigationfurtherrevealedthatthemethodusedtoextractthesiliconeoilwasonlypartiallyeffectiveAlthoughvisualinspectionofthesyringesseemedtosupportthatthecleaningmethodwaseffective,actualuseprovedotherwiseAfteractualproductionunitshavesucessfullypassedproductperformancequalification,aformaltechnicalreviewshouldbeconductedandshouldinclude:oComparisonoftheapprovedproductspecificationsandtheactualqualifiedproductoDeterminationofthevalidityoftestmethodsusedtodeterminecompliancewiththeapprovedspecificationsoDeterminationoftheadequacyofthespecificationchangecontrolprogramSystemtoAssureTimelyRevalidationThereshouldbeaqualityassurancesysteminplacewhichrequiresrevalidationwhenevertherearechangesinpackaging,formulation,equipment,orprocesseswhichcouldimpactonproducteffectivenessorproductcharacteristics,andwhenevertherearechangesinproductcharacteristicsFurthermore,whenachangeismadeinrawmaterialsupplier,themanufacturershouldconsidersubtle,potentiallyadversedifferencesintherawmaterialcharacteristicsAdeterminationofadversedifferencesinrawmaterialindicatesaneedtorevalidatetheprocessOnewayofdetectingthekindofchangesthatshouldinitiaterevalidationistheuseoftestsandmethodsofanalysiswhicharecapableofmeasuringcharacteristicswhichmayvarySuchtestsandmethodsusuallyyieldspecificresultswhichgobeyondthemerepassfailbasis,therebydetectingvariationswithinproductandprocessspecificationsandallowingdeterminationofwhetheraprocessisslippingoutofcontrolThequalityassuranceproceduresshouldestablishthecircumstancesunderwhichrevalidationisrequiredThesemaybebaseduponequipment,process,andproductperformanceobservedduringtheinitialvalidationchallengestudiesItisdesirabletodesignateindividualswhohavetheresponsibilitytoreviewproduct,process,equipmentandpersonnelchangestodetermineifandwhenrevalidationiswarrantedTheextentofrevalidationwilldependuponthenatureofthechangesandhowtheyimpactupondifferentaspectsofproductionthathadpreviouslybeenvalidatedItmaynotbenecessarytorevalidateaprocessfromscratchmerelybecauseagivencircumstancehaschangedHowever,itisimportanttocarefullyassessthenatureofthechangetodeterminepotentialrippleeffectsandwhatneedstobeconsideredaspartofrevalidationDocumentationItisessentialthatthevalidationprogramisdocumentedandthatthedocumentationisproperlymaintainedApprovalandreleaseoftheprocessforuseinroutinemanufacturingshouldbebaseduponareviewofallthevalidationdocumentation,includingdatafromtheequipmentqualification,processperformancequalification,andproductpackagetestingtoensurecompatibilitywiththeprocessForroutineproduction,itisimportanttoadequatelyrecordprocessdetails(eg,time,temperature,equipmentused)andtorecordanychangeswhichhaveoccurredAmaintenancelogcanbeusefulinperformingfailureinvestigationsconcerningaspecificmanufacturinglotValidationdata(alongwithspecifictestdata)mayalsodetermineexpectedvarianceinproductorequipmentcharacteristicsBRetrospectiveProcessValidationInsomecasesaproductmayhavebeenonthemarketwithoutsufficientpremarketprocessvalidationInthesecases,itmaybepossibletovalidate,insomemeasure,theadequacyoftheprocessbyexaminationofaccumulatedtestdataontheproductandrecordsofthemanufacturingproceduresusedRetrospectivevalidationcanalsobeusefultoaugmentinitialpremarketprospectivevalidationfornewproductsorchangedprocessesInsuchcases,preliminaryprospectivevalidationshouldhavebeensufficienttowarrantproductmarketingAsadditionaldataisgatheredonproductionlots,suchdatacanbeusedtobuildconfidenceintheadequacyoftheprocessConversely,suchdatamayindicateadecliningconfidenceintheprocessandacommensurateneedforcorrectivechangesTestdatamaybeusefulonlyifthemethodsandresultsareadequatelyspecificAswithprospectivevalidation,itmaybeinsufficienttoassesstheprocesssolelyonthebasisoflotbylotconformancetospecificationsiftestresultsaremerelyexpressedintermsofpassfailSpecificresults,ontheotherhand,canbestatisticallyanalyzedandadeterminationcanbemadeofwhatvarianceindatacanbeexpectedItisimportanttomaintainrecordswhichdescribetheoperatingcharacteristicsoftheprocess,eg,time,temperature,humidity,andequipmentsettingsWhenevertestdataareusedtodemonstrateconformancetospecifications,itisimportantthatthetestmethodologybequalifiedtoassurethattestresultsareobjectiveandaccurateForexample,sterilizertimeandtemperaturedatacollectedonrecordingequipmentfoundtobeaccurateandprecisecouldestablishthatprocessparametershadbeenreliablydeliveredtopreviouslyprocessedloadsAretrospectivequalificationoftheequipmentcouldbeperformedtodemonstratethattherecordeddatarepresentedconditionsthatwereuniformthroughoutthechamberandthatproductloadconfigurations,personnelpractices,initialtemperature,andothervariableshadbeenadequatelycontrolledduringtheearlierrunsIXACCEPTABILITYOFPRODUCTTESTINGInsomecases,adrugproductormedicaldevicemaybemanufacturedindividuallyoronaonetimebasisTheconceptofprospectiveorretrospectivevalidationasitrelatestothosesituationsmayhavelimitedapplicability,anddataobtainedduringthemanufacturingandassemblyprocessmaybeusedinconjunctionwithproducttestingtodemonstratethattheinstantrunyieldedafinishedproductmeetingallofitsspecificationsandqualitycharacteristicsSuchevaluationofdataandproducttestingwouldbeexpectedtobemuchmoreextensivethantheusualsituationwheremorereliancewouldbeplacedonprospectivevalidation<图片>|Home|Info
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