关闭

关闭

关闭

封号提示

内容

首页 FDA资料汇编fda_cleaning_validation

FDA资料汇编fda_cleaning_validation.doc

FDA资料汇编fda_cleaning_validation

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_cleaning_validationdoc》,可适用于医药卫生领域

GUIDETOINSPECTIONSVALIDATIONOFCLEANINGPROCESSESNote:ThisdocumentisreferencematerialforinvestigatorsandotherFDApersonnelThedocumentdoesnotbindFDA,anddoesnoconferanyrights,privileges,benefits,orimmunitiesfororonanyperson(s)IINTRODUCTIONValidationofcleaningprocedureshasgeneratedconsiderablediscussionsinceagencydocuments,includingtheInspectionGuideforBulkPharmaceuticalChemicalsandtheBiotechnologyInspectionGuide,havebrieflyaddressedthisissueTheseAgencydocumentsclearlyestablishtheexpectationthatcleaningprocedures(processes)bevalidatedThisguideisdesignedtoestablishinspectionconsistencyanduniformitybydiscussingpracticesthathavebeenfoundacceptable(orunacceptable)Simultaneously,onemustrecognizethatforcleaningvalidation,aswithvalidationofotherprocesses,theremaybemorethanonewaytovalidateaprocessIntheend,thetestofanyvalidationprocessiswhetherscientificdatashowsthatthesystemconsistentlydoesasexpectedandproducesaresultthatconsistentlymeetspredeterminedspecificationsThisguideisintendedtocoverequipmentcleaningforchemicalresiduesonlyIIBACKGROUNDForFDAtorequirethatequipmentbecleanpriortouseisnothingnew,theGMPRegulations(Part)statedasfollows"Equipment***shallbemaintainedinacleanandorderlymanner***"Averysimilarsectiononequipmentcleaning()wasincludedintheCGMPregulationsOfcourse,themainrationaleforrequiringcleanequipmentistopreventcontaminationoradulterationofdrugproductsHistorically,FDAinvestigatorshavelookedforgrossinsanitationduetoinadequatecleaningandmaintenanceofequipmentandorpoordustcontrolsystemsAlso,historicallyspeaking,FDAwasmoreconcernedaboutthecontaminationofnonpenicillindrugproductswithpenicillinsorthecrosscontaminationofdrugproductswithpotentsteroidsorhormonesAnumberofproductshavebeenrecalledoverthepastdecadeduetoactualorpotentialpenicillincrosscontaminationOneeventwhichincreasedFDAawarenessofthepotentialforcrosscontaminationduetoinadequateprocedureswastherecallofafinisheddrugproduct,CholestyramineResinUSPThebulkpharmaceuticalchemicalusedtoproducetheproducthadbecomecontaminatedwithlowlevelsofintermediatesanddegradantsfromtheproductionofagriculturalpesticidesThecrosscontaminationinthatcaseisbelievedtohavebeenduetothereuseofrecoveredsolventsTherecoveredsolventshadbeencontaminatedbecauseofalackofcontroloverthereuseofsolventdrumsDrumsthathadbeenusedtostorerecoveredsolventsfromapesticideproductionprocesswerelaterusedtostorerecoveredsolventsusedfortheresinmanufacturingprocessThefirmdidnothaveadequatecontrolsoverthesesolventdrums,didnotdoadequatetestingofdrummedsolvents,anddidnothavevalidatedcleaningproceduresforthedrumsSomeshipmentsofthispesticidecontaminatedbulkpharmaceuticalweresuppliedtoasecondfacilityatadifferentlocationforfinishingThisresultedinthecontaminationofthebagsusedinthatfacility'sfluidbeddryerswithpesticidecontaminationThisinturnledtocrosscontaminationoflotsproducedatthatsite,asitewherenopesticideswerenormallyproducedFDAinstitutedanimportalertinonaforeignbulkpharmaceuticalmanufacturerwhichmanufacturedpotentsteroidproductsaswellasnonsteroidalproductsusingcommonequipmentThisfirmwasamultiusebulkpharmaceuticalfacilityFDAconsideredthepotentialforcrosscontaminationtobesignificantandtoposeaserioushealthrisktothepublicThefirmhadonlyrecentlystartedacleaningvalidationprogramatthetimeoftheinspectionanditwasconsideredinadequatebyFDAOneofthereasonsitwasconsideredinadequatewasthatthefirmwasonlylookingforevidenceoftheabsenceofthepreviouscompoundThefirmhadevidence,fromTLCtestsontherinsewater,ofthepresenceofresiduesofreactionbyproductsanddegradantsfromthepreviousprocessIIIGENERALREQUIREMENTSFDAexpectsfirmstohavewrittenprocedures(SOP's)detailingthecleaningprocessesusedforvariouspiecesofequipmentIffirmshaveonecleaningprocessforcleaningbetweendifferentbatchesofthesameproductanduseadifferentprocessforcleaningbetweenproductchanges,weexpectthewrittenprocedurestoaddressthesedifferentscenarioSimilarly,iffirmshaveoneprocessforremovingwatersolubleresiduesandanotherprocessfornonwatersolubleresidues,thewrittenprocedureshouldaddressbothscenariosandmakeitclearwhenagivenprocedureistobefollowedBulkpharmaceuticalfirmsmaydecidetodedicatecertainequipmentforcertainchemicalmanufacturingprocessstepsthatproducetarryorgummyresiduesthataredifficulttoremovefromtheequipmentFluidbeddryerbagsareanotherexampleofequipmentthatisdifficulttocleanandisoftendedicatedtoaspecificproductAnyresiduesfromthecleaningprocessitself(detergents,solvents,etc)alsohavetoberemovedfromtheequipmentFDAexpectsfirmstohavewrittengeneralproceduresonhowcleaningprocesseswillbevalidatedFDAexpectsthegeneralvalidationprocedurestoaddresswhoisresponsibleforperformingandapprovingthevalidationstudy,theacceptancecriteria,andwhenrevalidationwillberequiredFDAexpectsfirmstopreparespecificwrittenvalidationprotocolsinadvanceforthestudiestobeperformedoneachmanufacturingsystemorpieceofequipmentwhichshouldaddresssuchissuesassamplingprocedures,andanalyticalmethodstobeusedincludingthesensitivityofthosemethodsFDAexpectsfirmstoconductthevalidationstudiesinaccordancewiththeprotocolsandtodocumenttheresultsofstudiesFDAexpectsafinalvalidationreportwhichisapprovedbymanagementandwhichstateswhetherornotthecleaningprocessisvalidThedatashouldsupportaconclusionthatresidueshavebeenreducedtoan"acceptablelevel"IVEVALUATIONOFCLEANINGVALIDATIONThefirststepistofocusontheobjectiveofthevalidationprocess,andwehaveseenthatsomecompanieshavefailedtodevelopsuchobjectivesItisnotunusualtoseemanufacturersuseextensivesamplingandtestingprogramsfollowingthecleaningprocesswithouteverreallyevaluatingtheeffectivenessofthestepsusedtocleantheequipmentSeveralquestionsneedtobeaddressedwhenevaluatingthecleaningprocessForexample,atwhatpointdoesapieceofequipmentorsystembecomecleanDoesithavetobescrubbedbyhandWhatisaccomplishedbyhandscrubbingratherthanjustasolventwashHowvariablearemanualcleaningprocessesfrombatchtobatchandproducttoproductTheanswerstothesequestionsareobviouslyimportanttotheinspectionandevaluationofthecleaningprocesssinceonemustdeterminetheoveralleffectivenessoftheprocessAnswerstothesequestionsmayalsoidentifystepsthatcanbeeliminatedformoreeffectivemeasuresandresultinresourcesavingsforthecompanyDeterminethenumberofcleaningprocessesforeachpieceofequipmentIdeally,apieceofequipmentorsystemwillhaveoneprocessforcleaning,howeverthiswilldependontheproductsbeingproducedandwhetherthecleanupoccursbetweenbatchesofthesameproduct(asinalargecampaign)orbetweenbatchesofdifferentproductsWhenthecleaningprocessisusedonlybetweenbatchesofthesameproduct(ordifferentlotsofthesameintermediateinabulkprocess)thefirmneedonlymeetacriteriaof,"visiblyclean"fortheequipmentSuchbetweenbatchcleaningprocessesdonotrequirevalidationEquipmentDesignExaminethedesignofequipment,particularlyinthoselargesystemsthatmayemploysemiautomaticorfullyautomaticcleaninplace(CIP)systemssincetheyrepresentsignificantconcernForexample,sanitarytypepipingwithoutballvalvesshouldbeusedWhensuchnonsanitaryballvalvesareused,asiscommoninthebulkdrugindustry,thecleaningprocessismoredifficultWhensuchsystemsareidentified,itisimportantthatoperatorsperformingcleaningoperationsbeawareofproblemsandhavespecialtrainingincleaningthesesystemsandvalvesDeterminewhetherthecleaningoperatorshaveknowledgeofthesesystemsandtheleveloftrainingandexperienceincleaningthesesystemsAlsocheckthewrittenandvalidatedcleaningprocesstodetermineifthesesystemshavebeenproperlyidentifiedandvalidatedInlargersystems,suchasthoseemployinglongtransferlinesorpiping,checktheflowchartsandpipingdiagramsfortheidentificationofvalvesandwrittencleaningproceduresPipingandvalvesshouldbetaggedandeasilyidentifiablebytheoperatorperformingthecleaningfunctionSometimes,inadequatelyidentifiedvalves,bothonprintsandphysically,haveledtoincorrectcleaningpracticesAlwayscheckforthepresenceofanoftencriticalelementinthedocumentationofthecleaningprocessesidentifyingandcontrollingthelengthoftimebetweentheendofprocessingandeachcleaningstepThisisespeciallyimportantfortopicals,suspensions,andbulkdrugoperationsInsuchoperations,thedryingofresidueswilldirectlyaffecttheefficiencyofacleaningprocessWhetherornotCIPsystemsareusedforcleaningofprocessingequipment,microbiologicalaspectsofequipmentcleaningshouldbeconsideredThisconsistslargelyofpreventivemeasuresratherthanremovalofcontaminationonceithasoccurredThereshouldbesomeevidencethatroutinecleaningandstorageofequipmentdoesnotallowmicrobialproliferationForexample,equipmentshouldbedriedbeforestorage,andundernocircumstancesshouldstagnantwaterbeallowedtoremaininequipmentsubsequenttocleaningoperationsSubsequenttothecleaningprocess,equipmentmaybesubjectedtosterilizationorsanitizationprocedureswheresuchequipmentisusedforsterileprocessing,orfornonsterileprocessingwheretheproductsmaysupportmicrobialgrowthWhilesuchsterilizationorsanitizationproceduresarebeyondthescopeofthisguide,itisimportanttonotethatcontrolofthebioburdenthroughadequatecleaningandstorageofequipmentisimportanttoensurethatsubsequentsterilizationorsanitizationproceduresachievethenecessaryassuranceofsterilityThisisalsoparticularlyimportantfromthestandpointofthecontrolofpyrogensinsterileprocessingsinceequipmentsterilizationprocessesmaynotbeadequatetoachievesignificantinactivationorremovalofpyrogensCleaningProcessWrittenProcedureandDocumentationExaminethedetailandspecificityoftheprocedureforthe(cleaning)processbeingvalidated,andtheamountofdocumentationrequiredWehaveseengeneralSOPs,whileothersuseabatchrecordorlogsheetsystemthatrequiressometypeofspecificdocumentationforperformingeachstepDependinguponthecomplexityofthesystemandcleaningprocessandtheabilityandtrainingofoperators,theamountofdocumentationnecessaryforexecutingvariouscleaningstepsorprocedureswillvaryWhenmorecomplexcleaningproceduresarerequired,itisimportanttodocumentthecriticalcleaningsteps(forexamplecertainbulkdrugsynthesisprocesses)Inthisregard,specificdocumentationontheequipmentitselfwhichincludesinformationaboutwhocleaneditandwhenisvaluableHowever,forrelativelysimplecleaningoperations,themeredocumentationthattheoverallcleaningprocesswasperformedmightbesufficientOtherfactorssuchashistoryofcleaning,residuelevelsfoundaftercleaning,andvariabilityoftestresultsmayalsodictatetheamountofdocumentationrequiredForexample,whenvariableresiduelevelsaredetectedfollowingcleaning,particularlyforaprocessthatisbelievedtobeacceptable,onemustestablishtheeffectivenessoftheprocessandoperatorperformanceAppropriateevaluationsmustbemadeandwhenoperatorperformanceisdeemedaproblem,moreextensivedocumentation(guidance)andtrainingmayberequiredAnalyticalMethodsDeterminethespecificityandsensitivityoftheanalyticalmethodusedtodetectresidualsorcontaminantsWithadvancesinanalyticaltechnology,residuesfromthemanufacturingandcleaningprocessescanbedetectedatverylowlevelsIflevelsofcontaminationorresidualarenotdetected,itdoesnotmeanthatthereisnoresidualcontaminantpresentaftercleaningItonlymeansthatlevelsofcontaminantgreaterthanthesensitivityordetectionlimitoftheanalyticalmethodarenotpresentinthesampleThefirmshouldchallengetheanalyticalmethodincombinationwiththesamplingmethod(s)usedtoshowthatcontaminantscanberecoveredfromtheequipmentsurfaceandatwhatlevel,ierecovery,,etcThisisnecessarybeforeanyconclusionscanbemadebasedonthesampleresultsAnegativetestmayalsobetheresultofpoorsamplingtechnique(seebelow)SamplingTherearetwogeneraltypesofsamplingthathavebeenfoundacceptableThemostdesirableisthedirectmethodofsamplingthesurfaceoftheequipmentAnothermethodistheuseofrinsesolutionsaDirectSurfaceSamplingDeterminethetypeofsamplingmaterialusedanditsimpactonthetestdatasincethesamplingmaterialmayinterferewiththetestForexample,theadhesiveusedinswabshasbeenfoundtointerferewiththeanalysisofsamplesTherefore,earlyinthevalidationprogram,itisimportanttoassurethatthesamplingmediumandsolvent(usedforextractionfromthemedium)aresatisfactoryandcanbereadilyusedAdvantagesofdirectsamplingarethatareashardesttocleanandwhicharereasonablyaccessiblecanbeevaluated,leadingtoestablishingalevelofcontaminationorresiduepergivensurfaceareaAdditionally,residuesthatare"driedout"orareinsolublecanbesampledbyphysicalremovalbRinseSamplesTwoadvantagesofusingrinsesamplesarethatalargersurfaceareamaybesampled,andinaccessiblesystemsoronesthatcannotberoutinelydisassembledcanbesampledandevaluatedAdisadvantageofrinsesamplesisthattheresidueorcontaminantmaynotbesolubleormaybephysicallyoccludedintheequipmentAnanalogythatcanbeusedisthe"dirtypot"Intheevaluationofcleaningofadirtypot,particularlywithdriedoutresidue,onedoesnotlookattherinsewatertoseethatitiscleanonelooksatthepotChecktoseethatadirectmeasurementoftheresidueorcontaminanthasbeenmadefortherinsewaterwhenitisusedtovalidatethecleaningprocessForexample,itisnotacceptabletosimplytestrinsewaterforwaterquality(doesitmeetthecompendiatests)ratherthantestitforpotentialcontaminatescRoutineProductionInProcessControlMonitoringIndirecttesting,suchasconductivitytesting,maybeofsomevalueforroutinemonitoringonceacleaningprocesshasbeenvalidatedThiswouldbeparticularlytrueforthebulkdrugsubstancemanufacturerwherereactorsandcentrifugesandpipingbetweensuchlargeequipmentcanbesampledonlyusingrinsesolutionsamplesAnyindirecttestmethodmusthavebeenshowntocorrelatewiththeconditionoftheequipmentDuringvalidation,thefirmshoulddocumentthattestingtheuncleanedequipmentgivesanotacceptableresultfortheindirecttestVESTABLISHMENTOFLIMITSFDAdoesnotintendtosetacceptancespecificationsormethodsfordeterminingwhetheracleaningprocessisvalidatedItisimpracticalforFDAtodosoduetothewidevariationinequipmentandproductsusedthroughoutthebulkandfinisheddosageformindustriesThefirm'srationalefortheresiduelimitsestablishedshouldbelogicalbasedonthemanufacturer'sknowledgeofthematerialsinvolvedandbepractical,achievable,andverifiableItisimportanttodefinethesensitivityoftheanalyticalmethodsinordertosetreasonablelimitsSomelimitsthathavebeenmentionedbyindustryrepresentativesintheliteratureorinpresentationsincludeanalyticaldetectionlevelssuchasPPM,biologicalactivitylevelssuchasofthenormaltherapeuticdose,andorganolepticlevelssuchasnovisibleresidueCheckthemannerinwhichlimitsareestablishedUnlikefinishedpharmaceuticalswherethechemicalidentityofresidualsareknown(ie,fromactives,inactives,detergents)bulkprocessesmayhavepartialreactantsandunwantedbyproductswhichmayneverhavebeenchemicallyidentifiedInestablishingresiduallimits,itmaynotbeadequatetofocusonlyontheprincipalreactantsinceotherchemicalvariationsmaybemoredifficulttoremoveTherearecircumstanceswhereTLCscreening,inadditiontochemicalanalyses,maybeneededInabulkprocess,particularlyforverypotentchemicalssuchassomesteroids,theissueofbyproductsneedstobeconsideredifequipmentisnotdedicatedTheobjectiveoftheinspectionistoensurethatthebasisforanylimitsisscientificallyjustifiableVIOTHERISSUESaPlaceboProductInordertoevaluateandvalidatecleaningprocessessomemanufacturershaveprocessedaplacebobatchintheequipmentunderessentiallythesameoperatingparametersusedforprocessingproductAsampleoftheplacebobatchisthentestedforresidualcontaminationHowever,wehavedocumentedseveralsignificantissuesthatneedtobeaddressedwhenusingplaceboproducttovalidatecleaningprocessesOnecannotassurethatthecontaminatewillbeuniformlydistributedthroughoutthesystemForexample,ifthedischargevalveorchuteofablenderarecontaminated,thecontaminantwouldprobablynotbeuniformlydispersedintheplaceboitwouldmostlikelybeconcentratedintheinitialdischargeportionofthebatchAdditionally,ifthecontaminantorresidueisofalargerparticlesize,itmaynotbeuniformlydispersedintheplaceboSomefirmshavemadetheassumptionthataresidualcontaminantwouldbewornofftheequipmentsurfaceuniformlythisisalsoaninvalidconclusionFinally,theanalyticalpowermaybegreatlyreducedbydilutionofthecontaminateBecauseofsuchproblems,rinseandorswabsamplesshouldbeusedinconjunctionwiththeplacebomethodbDetergentIfadetergentorsoapisusedforcleaning,determineandconsiderthedifficultythatmayarisewhenattemptingtotestforresiduesAcommonproblemassociatedwithdetergentuseisitscompositionManydetergentsupplierswillnotprovidespecificcomposition,whichmakesitdifficultfortheusertoevaluateresiduesAswithproductresidues,itisimportantanditisexpectedthatthemanufacturerevaluatetheefficiencyofthecleaningprocessfortheremovalofresiduesHowever,unlikeproductresidues,itisexpectedthatno(orforultrasensitiveanalyticaltestmethodsverylow)detergentlevelsremainaftercleaningDetergentsarenotpartofthemanufacturingprocessandareonlyaddedtofacilitatecleaningduringthecleaningprocessThus,theyshouldbeeasilyremovableOtherwise,adifferentdetergentshouldbeselectedcTestUntilCleanExamineandevaluatetheleveloftestingandtheretestresultssincetestinguntilcleanisaconceptutilizedbysomemanufacturersTheytest,resample,andretestequipmentorsystemsuntilan"acceptable"residuelevelisattainedForthesystemorequipmentwithavalidatedcleaningprocess,thispracticeofresamplingshouldnotbeutilizedandisacceptableonlyinrarecasesConstantretestingandresamplingcanshowthatthecleaningprocessisnotvalidatedsincetheseretestsactuallydocumentthepresenceofunacceptableresidueandcontaminantsfromanineffectivecleaningprocessVIIREFERENCES)JRodehamel,"CleaningandMaintenance,"Pgs,UniversityofWisconsin'sControlProceduresinDrugProductionSeminar,July,,WilliamBlockstein,Editor,PublishedbytheUniversityofWisconsin,LOC#)JAConstance,"WhySomeDustControlExhaustSystemsDon'tWork,"PharmEng,JanuaryFebruary,())SWHarder,"TheValidationofCleaningProcedures,"PharmTechnol(),())WJMead,"Maintenance:ItsInterrelationshipwithDrugQuality,"PharmEng(),())JASmith,"AModifiedSwabbingTechniqueforValidationofDetergentResiduesinCleaninPlaceSystems,"PharmTechnol(),())Fourman,GLandMullen,MV,"DeterminingCleaningValidationAcceptanceLimitsforPharmaceuticalManufacturingOperations,"PharmTechnol(),())McCormick,PYandCullen,LF,inPharmaceuticalProcessValidation,ndEd,editedbyIRBerryandRANash,()Therearenoreferencesfromthisdocument

用户评价(0)

关闭

新课改视野下建构高中语文教学实验成果报告(32KB)

抱歉,积分不足下载失败,请稍后再试!

提示

试读已结束,如需要继续阅读或者下载,敬请购买!

评分:

/8

意见
反馈

立即扫码关注

爱问共享资料微信公众号

返回
顶部

举报
资料