美国FDA生产过程(工艺)验证总则指南中英文版

美国FDA生产过程(工艺)验证总则指南中英文版GUIDELINEONGENERALPRINCIPLESOFPROCESSVALIDATIONMay,1987Preparedby:  CenterforDrugsandBiologicsandCenterforDevicesandRadiologicalHealthFoodandDrugAdministrationMaintainedby: DivisionofManufacturingandProductQuality(HFN-320)OfficeofComplianceCenterforDrugsandBiologicsFoodandDrugAdministration5600FishersLaneRockville,Maryland20857GeneralPrinciplesofProcessValidationMay1987GENERALPRINCIPLESOFPROCESSVALIDATIONI. PURPOSEThisguidelineoutlinesgeneralprinciplesthatFDAconsiderstobeacceptableelementsofprocessvalidationforthepreparationofhumanandanimaldrugproductsandmedicaldevices.II. SCOPEThisguidelineisissuedunderSection10.90(21CFR10.90)andisapplicabletothemanufactureofpharmaceuticalsandmedicaldevices. ItstatesprinciplesandpracticesofgeneralapplicabilitythatarenotlegalrequirementsbutareacceptabletotheFDA. ApersonmayrelyuponthisguidelinewiththeassuranceofitsacceptabilitytoFDA,ormayfollowdifferentprocedures.Whendifferentproceduresareused,apersonmay,butisnotrequiredto,discussthematterinadvancewithFDAtopreventtheexpenditureofmoneyandeffortonactivitiesthatmaylaterbedeterminedtobeunacceptable. Inshort,thisguidelinelistsprinciplesandpracticeswhichareacceptabletotheFDAfortheprocessvalidationofdrugproductsandmedicaldevices;itdoesnotlisttheprinciplesandpracticesthatmust,inallinstances,beusedtocomplywithlaw.-1-Thisguidelinemaybeamendedfromtimetotime. Interestedpersonsareinvitedtosubmitcommentsonthisdocumentandanysubsequentrevisions. WrittencommentsshouldbesubmittedtotheDocketsManagementBranch(HFA-305),FoodandDrugAdministration,Room4-62,5600FishersLane,Rockville,Maryland20857. Receivedcommentsmaybeseeninthatofficebetween9\a.m.and4\p.m.,MondaythroughFriday.III. INTRODUCTIONProcessvalidationisarequirementoftheCurrentGoodManufacturingPracticesRegulationsforFinishedPharmaceuticals,21CFRParts210and211,andoftheGoodManufacturingPracticeRegulationsforMedicalDevices,21CFRPart820,andtherefore,isapplicabletothemanufactureofpharamaceuticalsandmedicaldevices.SeveralfirmshaveaskedFDAforspecificguidanceonwhatFDAexpectsfirmstodotoassurecompliancewiththerequirementsforprocessvalidation. ThisguidelinediscussesprocessvalidationelementsandconceptsthatareconsideredbyFDAasacceptablepartsofavalidationprogram. Theconstituentsofvalidationpresentedinthisdocumentarenotintendedtobeall-inclusive.FDArecognizesthat,becauseofthegreatvarietyofmedicalproducts(drugproductsandmedicaldevices),processesand-2-manufacturingfacilities,itisnotpossibletostateinonedocumentallofthespecificvalidationelementsthatareapplicable. Severalbroadconcepts,however,havegeneralapplicabilitywhichmanufacturerscanusesuccessfullyasaguideinvalidatingamanufacturingprocess. Althoughtheparticularrequirementsofprocessvalidationwillvaryaccordingtosuchfactorsasthenatureofthemedicalproduct(e.g.,sterilevsnon-sterile)andthecomplexityoftheprocess,thebroadconceptsstatedinthisdocumenthavegeneralapplicabilityandprovideanacceptableframeworkforbuildingacomprehensiveapproachtoprocessvalidation.DefinitionsInstallationqualification-Establishingconfidencethatprocessequipmentandancillarysystemsarecapableofconsistentlyoperatingwithinestablishedlimitsandtolerances.Processperformancequalification-Establishingconfidencethattheprocessiseffectiveandreproducible.Productperformancequalification-Establishingconfidencethroughappropriatetestingthatthefinishedproductproducedbyaspecifiedprocessmeetsallreleaserequirementsforfunctionalityandsafety.-3-Prospectivevalidation-Validationconductedpriortothedistributionofeitheranewproduct,orproductmadeunderarevisedmanufacturingprocess,wheretherevisionsmayaffecttheproduct'scharacteristics.Retrospectivevalidation-Validationofaprocessforaproductalreadyindistributionbaseduponaccumulatedproduction,testingandcontroldata.Validation-Establishingdocumentedevidencewhichprovidesahighdegreeofassurancethataspecificprocesswillconsistentlyproduceaproductmeetingitspre-determinedspecificationsandqualityattributes.Validationprotocol-Awrittenplanstatinghowvalidationwillbeconducted,includingtestparameters,productcharacteristics,productionequipment,anddecisionpointsonwhatconstitutesacceptabletestresults.Worstcase-Asetofconditionsencompassingupperandlowerprocessinglimitsandcircumstances,includingthosewithinstandardoperatingprocedures,whichposethegreatestchanceofprocessorproductfailurewhencomparedtoidealconditions. Suchconditionsdonotnecessarilyinduceproductorprocessfailure.-4-IV. GENERALCONCEPTSAssuranceofproductqualityisderivedfromcarefulattentiontoanumberoffactorsincludingselectionofqualitypartsandmaterials,adequateproductandprocessdesign,controloftheprocess,andin-processandend-producttesting. Duetothecomplexityoftoday'smedicalproducts,routineend-producttestingaloneoftenisnotsufficienttoassureproductqualityforseveralreasons. Someend-producttestshavelimitedsensitivity.1 Insomecases,destructivetestingwouldberequiredtoshowthatthemanufacturingprocesswasadequate,andinothersituationsend-producttestingdoesnotrevealallvariationsthatmayoccurintheproductthatmayimpactonsafetyandeffectiveness.2Thebasicprinciplesofqualityassurancehaveastheirgoaltheproductionofarticlesthatarefitfortheirintendeduse. These1 Forexample,USPXXIstates: "Nosamplingplanforapplyingsterilityteststoaspecifiedproportionofdiscreteunitsselectedfromasterilizationloadiscapableofdemonstratingwithcompleteassurancethatalloftheuntestedunitsareinfactsterile."2 Asanexample,inoneinstanceavisualinspectionfailedtodetectadefectivestructuralweldwhichresultedinthefailureofaninfantwarmer. Thedefectcouldonlyhavebeendetectedbyusingdestructivetestingorexpensivetestequipment.-5-principlesmaybestatedasfollows: (1)quality,safety,andeffectivenessmustbedesignedandbuiltintotheproduct;(2)qualitycannotbeinspectedortestedintothefinishedproduct;and(3)eachstepofthemanufacturingprocessmustbecontrolledtomaximizetheprobabilitythatthefinishedproductmeetsallqualityanddesignspecifications. Processvalidationisakeyelementinassuringthatthesequalityassurancegoalsaremet.Itisthroughcarefuldesignandvalidationofboththeprocessandprocesscontrolsthatamanufacturercanestablishahighdegreeofconfidencethatallmanufacturedunitsfromsuccessivelotswillbeacceptable. Successfullyvalidatingaprocessmayreducethedependenceuponintensivein-processandfinishedproducttesting.Itshouldbenotedthatinmostallcases,end-producttestingplaysamajorroleinassuringthatqualityassurancegoalsaremet;i.e.,validationandend-producttestingarenotmutuallyexclusive.TheFDAdefinesprocessvalidationasfollows:Processvalidationisestablishingdocumentedevidencewhichprovidesahighdegreeofassurancethataspecificprocesswillconsistentlyproduceaproductmeetingitspre-determinedspecificationsandqualitycharacteristics.-6-Itisimportantthatthemanufacturerprepareawrittenvalidationprotocolwhichspecifiestheprocedures(andtests)tobeconductedandthedatatobecollected. Thepurposeforwhichdataarecollectedmustbeclear,thedatamustreflectfactsandbecollectedcarefullyandaccurately. Theprotocolshouldspecifyasufficientnumberofreplicateprocessrunstodemonstratereproducibilityandprovideanaccuratemeasureofvariabilityamongsuccessiveruns. Thetestconditionsfortheserunsshouldencompassupperandlowerprocessinglimitsandcircumstances,includingthosewithinstandardoperatingprocedures,whichposethegreatestchanceofprocessorproductfailurecomparedtoidealconditions;suchconditionshavebecomewidelyknownas"worstcase"conditions. (Theyaresometimescalled"mostappropriatechallenge"conditions.) Validationdocumentationshouldincludeevidenceofthesuitabilityofmaterialsandtheperformanceandreliabilityofequipmentandsystems.Keyprocessvariablesshouldbemonitoredanddocumented. Analysisofthedatacollectedfrommonitoringwillestablishthevariabilityofprocessparametersforindividualrunsandwillestablishwhetherornottheequipmentandprocesscontrolsareadequatetoassurethatproductspecificationsaremet.-7-Finishedproductandin-processtestdatacanbeofvalueinprocessvalidation,particularlyinthosesituationswherequalityattributesandvariabilitiescanbereadilymeasured. Wherefinished(orin-process)testingcannotadequatelymeasurecertainattributes,processvalidationshouldbederivedprimarilyfromqualificationofeachsystemusedinproductionandfromconsiderationoftheinteractionofthevarioussystems.V. CGMPREGULATIONSFORFINISHEDPHARMACEUTICALSProcessvalidationisrequired,inbothgeneralandspecificterms,bytheCurrentGoodManufacturingPracticeRegulationsforFinishedPharmaceuticals,21CFRParts210and211. Examplesofsuchrequirementsarelistedbelowforinformationalpurposes,andarenotall-inclusive.Arequirementforprocessvalidationissetforthingeneraltermsinsection\211.100--Writtenprocedures;deviations--whichstates,inpart:"Thereshallbewrittenproceduresforproductionandprocesscontroldesignedtoassurethatthedrugproductshavetheidentity,strength,quality,andpuritytheypurportorarerepresentedtopossess."-8-SeveralsectionsoftheCGMPregulationsstatevalidationrequirementsinmorespecificterms. Excerptsfromsomeofthesesectionsare:Section211.110,Samplingandtestingofin-processmaterialsanddrugproducts.(a) "....controlproceduresshallbeestablishedtomonitortheoutputandVALIDATEtheperformanceofthosemanufacturingprocessesthatmayberesponsibleforcausingvariabilityinthecharacteristicsofin-processmaterialandthedrugproduct."(emphasisadded)Section211.113,ControlofMicrobiologicalContamination.(b) "Appropriatewrittenprocedures,designedtopreventmicrobiologicalcontaminationofdrugproductspurportingtobesterile,shallbeestablishedandfollowed. SuchproceduresshallincludeVALIDATIONofanysterilizationprocess."(emphasisadded)VI. GMPREGULATIONFORMEDICALDEVICESProcessvalidationisrequiredbythemedicaldeviceGMPRegulations,21CFRPart\820. Section820.5requireseveryfinisheddevicemanufacturerto:"...prepareandimplementaqualityassuranceprogramthatisappropriatetothespecificdevicemanufactured..."-9-Section820.3(n)definesqualityassuranceas:"...allactivitiesnecessarytoverifyconfidenceinthequalityoftheprocessusedtomanufactureafinisheddevice."Whenapplicabletoaspecificprocess,processvalidationisanessentialelementinestablishingconfidencethataprocesswillconsistentlyproduceaproductmeetingthedesignedqualitycharacteristics.Agenerallystatedrequirementforprocessvalidationiscontainedinsection\820.100:"Writtenmanufacturingspecificationsandprocessingproceduresshallbeestablished,implemented,andcontrolledtoassurethatthedeviceconformstoitsoriginaldesignoranyapprovedchangesinthatdesign."Validationisanessentialelementintheestablishmentandimplementationofaprocessprocedure,aswellasindeterminingwhatprocesscontrolsarerequiredinordertoassureconformancetospecifications.Section820.100(a)(1)states:"...controlmeasuresshallbeestablishedtoassurethatthedesignbasisforthedevice,componentsandpackagingiscorrectlytranslatedintoapprovedspecifications."-10-Validationisanessentialcontrolforassuringthatthespecificationsforthedeviceandmanufacturingprocessareadequatetoproduceadevicethatwillconformtotheapproveddesigncharacteristics.VII. PRELIMINARYCONSIDERATIONSAmanufacturershouldevaluateallfactorsthataffectproductqualitywhendesigningandundertakingaprocessvalidationstudy.Thesefactorsmayvaryconsiderablyamongdifferentproductsandmanufacturingtechnologiesandcouldinclude,forexample,componentspecifications,airandwaterhandlingsystems,environmentalcontrols,equipmentfunctions,andprocesscontroloperations. Nosingleapproachtoprocessvalidationwillbeappropriateandcompleteinallcases;however,thefollowingqualityactivitiesshouldbeundertakeninmostsituations.Duringtheresearchanddevelopment(R&D)phase,thedesiredproductshouldbecarefullydefinedintermsofitscharacteristics,suchasphysical,chemical,electricaland-11-performancecharacteristics.3 Itisimportanttotranslatetheproductcharacteristicsintospecificationsasabasisfordescriptionandcontroloftheproduct.Documentationofchangesmadeduringdevelopmentprovidetraceabilitywhichcanlaterbeusedtopinpointsolutionstofutureproblems.Theproduct'senduseshouldbeadeterminingfactorinthedevelopmentofproduct(andcomponent)characteristicsandspecifications. Allpertinentaspectsoftheproductwhichimpactonsafetyandeffectivenessshouldbeconsidered. Theseaspects3 Forexample,inthecaseofacompressedtablet,physicalcharacteristicswouldincludesize,weight,hardness,andfreedomfromdefects,suchascappingandsplitting. Chemicalcharacteristicswouldincludequantitativeformulation/potency;performancecharacteristicsmayincludebioavailability(reflectedbydisintegrationanddissolution). Inthecaseofbloodtubing,physicalattributeswouldincludeinternalandexternaldiameters,lengthandcolor. Chemicalcharacteristicswouldincluderawmaterialformulation. Mechanicalpropertieswouldincludehardnessandtensilestrength;performancecharacteristicswouldincludebiocompatibilityanddurability.-12-includeperformance,reliabilityandstability. Acceptablerangesorlimitsshouldbeestablishedforeachcharacteristictosetupallowablevariations.4 Theserangesshouldbeexpressedinreadilymeasurableterms.Thevalidityofacceptancespecificationsshouldbeverifiedthroughtestingandchallengeoftheproductonasoundscientificbasisduringtheinitialdevelopmentandproductionphase.Onceaspecificationisdemonstratedasacceptableitisimportantthatanychangestothespecificationbemadeinaccordancewithdocumentedchangecontrolprocedures.VIII.ELEMENTSOFPROCESSVALIDATIONA.ProspectiveValidationProspectivevalidationincludesthoseconsiderationsthatshouldbemadebeforeanentirelynewproductisintroducedbyafirmorwhenthereisachangeinthemanufacturingprocesswhichmayaffecttheproduct'scharacteristics,suchasuniformityandidentity. Thefollowingareconsideredaskeyelementsofprospectivevalidation.4  Forexample,inordertoassurethatanoral,ophthalmic,orparenteralsolutionhasanacceptablepH,aspecificationmaybeestablishedbywhichalotisreleasedonlyifithasbeenshowntohaveapHwithinanarrowestablishedrange. Foradevice,aspecificationfortheelectricalresistanceofapacemakerleadwouldbeestablishedsothattheleadwouldbeacceptableonlyiftheresistancewaswithinaspecifiedrange.-13-1. EquipmentandProcessTheequipmentandprocess(es)shouldbedesignedand/orselectedsothatproductspecificationsareconsistentlyachieved. Thisshouldbedonewiththeparticipationofallappropriategroupsthatareconcernedwithassuringaqualityproduct,e.g.,engineeringdesign,productionoperations,andqualityassurancepersonnel.a. Equipment: InstallationQualificationInstallationqualificationstudiesestablishconfidencethattheprocessequipmentandancillarysystemsarecapableofconsistentlyoperatingwithinestablishedlimitsandtolerances. Afterprocessequipmentisdesignedorselected,itshouldbeevaluatedandtestedtoverifythatitiscapableofoperatingsatisfactorilywithintheoperatinglimitsrequiredbytheprocess.5 Thisphaseofvalidationincludesexaminationofequipmentdesign;determinationofcalibration,maintenance,andadjustmentrequirements;andidentifyingcriticalequipmentfeaturesthatcouldaffecttheprocessandproduct. Informationobtainedfromthesestudiesshouldbeusedtoestablishwrittenprocedurescoveringequipmentcalibration,maintenance,monitoring,andcontrol.5 Examplesofequipmentperformancecharacteristicswhichmaybemeasuredincludetemperatureandpressureofinjectionmoldingmachines,uniformityofspeedformixers,temperature,speedandpressureforpackagingmachines,andtemperatureandpressureofsterilizationchambers.-14-Inassessingthesuitabilityofagivenpieceofequipment,itisusuallyinsufficienttorelysolelyupontherepresentationsoftheequipmentsupplier,oruponexperienceinproducingsomeotherproduct.6 Soundtheoreticalandpracticalengineeringprinciplesandconsiderationsareafirststepintheassessment.Itisimportantthatequipmentqualificationsimulateactualproductionconditions,includingthosewhichare"worstcase"situations.6 TheimportanceofassessingequipmentsuitabilitybaseduponhowitwillbeusedtoattaindesiredproductattributesisillustratedinthecaseofdeionizersusedtoproducePurifiedWater,USP. Inonecase,afirmusedsuchwatertomakeatopicaldrugproductsolutionwhich,inviewofitsintendeduse,shouldhavebeenfreefromobjectionablemicroorganisms. However,theproductwasfoundtobecontaminatedwithapathogenicmicroorganism. Theapparentcauseoftheproblemwasfailuretoassesstheperformanceofthedeionizerfromamicrobiologicalstandpoint. Itisfairlywellrecognizedthatthedeionizersarepronetobuild-upofmicroorganisms--especiallyiftheflowratesarelowandthedeionizersarenotrechargedandsanitizedatsuitableintervals. Therefore,thesefactorsshouldhavebeenconsidered. Inthiscase,however,thefirmreliedupontherepresentationsoftheequipmentitself,namelythe"recharge"(i.e.,conductivity)indicator,tosignalthetimeforregenerationandcleaning. Consideringthedesiredproductcharacteristics,thefirmshouldhavedeterminedtheneedforsuchproceduresbaseduponpre-usetesting,takingintoaccountsuchfactorsasthelengthoftimetheequipmentcouldproducedeionizedwaterofacceptablequality,flowrate,temperature,rawwaterquality,frequencyofuse,andsurfaceareaofdeionizingresins.-15-Testsandchallengesshouldberepeatedasufficientnumberoftimestoassurereliableandmeaningfulresults. Allacceptancecriteriamustbemetduringthetestorchallenge. Ifanytestorchallengeshowsthattheequipmentdoesnotperformwithinitsspecifications,anevaluationshouldbeperformedtoidentifythecauseofthefailure. Correctionsshouldbemadeandadditionaltestrunsperformed,asneeded,toverifythattheequipmentperformswithinspecifications. Theobservedvariabilityoftheequipmentbetweenandwithinrunscanbeusedasabasisfordeterminingthetotalnumberoftrialsselectedforthesubsequentperformancequalificationstudiesoftheprocess.7Oncetheequipmentconfigurationandperformancecharacteristicsareestablishedandqualified,theyshouldbedocumented. Theinstallationqualificationshouldincludeareviewofpertinentmaintenanceprocedures,repairpartslists,andcalibrationmethodsforeachpieceofequipment. Theobjectiveistoassurethatallrepairscanbeperformedinsuchawaythatwillnotaffectthe7 Forexample,theAAMIGuidelineforIndustrialEthyleneOxideSterilizationofMedicalDevicesapproved2December1981,states: "Theperformancequalificationshouldincludeaminimumof3successful,plannedqualificationruns,inwhichalloftheacceptancecriteriaaremet.....(5.3.1.2.).-16-characteristicsofmaterialprocessedaftertherepair. Inaddition,specialpost-repaircleaningandcalibrationrequirementsshouldbedevelopedtopreventinadvertentmanufactureaofnon-conformingproduct. Planningduringthequalificationphasecanpreventconfusionduringemergencyrepairswhichcouldleadtouseofthewrongreplacementpart.b. Process: PerformanceQualificationThepurposeofperformancequalificationistoproviderigoroustestingtodemonstratetheeffectivenessandreproducibilityoftheprocess. Inenteringtheperformancequalificationphaseofvalidation,itisunderstoodthattheprocessspecificationshavebeenestablishedandessentiallyprovenacceptablethroughlaboratoryorothertrialmethodsandthattheequipmenthasbeenjudgedacceptableonthebasisofsuitableinstallationstudies.Eachprocessshouldbedefinedanddescribedwithsufficientspecificitysothatemployeesunderstandwhatisrequired.-17-Partsoftheprocesswhichmayvarysoastoaffectimportantproductqualityshouldbechallenged.8Inchallengingaprocesstoassessitsadequacy,itisimportantthatchallengeconditionssimulatethosethatwillbeencounteredduringactualproduction,including"worstcase"conditions. Thechallengesshouldberepeatedenoughtimestoassurethattheresultsaremeaningfulandconsistent.8 Forexample,inelectroplatingthemetalcaseofanimplantablepacemaker,thesignificantprocessstepstodefine,describe,andchallengeincludeestablishmentandcontrolofcurrentdensityandtemperaturevaluesforassuringadequatecompositionofelectrolyteandforassuringcleanlinessofthemetaltobeplated. Intheproductionofparenteralsolutionsbyasepticfilling,thesignificantasepticfillingprocessstepstodefineandchallengeshouldincludethesterilizationanddepyrogenationofcontainers/closures,sterilizationofsolutions,fillingequipmentandproductcontactsurfaces,andthefillingandclosingofcontainers.-18-Eachspecificmanufacturingprocessshouldbeappropriatelyqualifiedandvalidated. Thereisaninherentdangerinrelyingonwhatareperceivedtobesimilaritiesbetweenproducts,processes,andequipmentwithoutappropriatechallenge.9c. Product:PerformanceQualificationForpurposesofthisguideline,productperformancequalificationactivitiesapplyonlytomedicaldevices.Thesestepsshouldbeviewedaspre-productionqualityassuranceactivities.9 Forexample,intheproductionofacompressedtablet,afirmmayswitchfromonetypeofgranulationblendertoanotherwiththeerroneous