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首页 FDA资料汇编FDA制剂厂检查指南

FDA资料汇编FDA制剂厂检查指南 .doc

FDA资料汇编FDA制剂厂检查指南

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制剂厂检查指南 doc》,可适用于医药卫生领域

GUIDETOINSPECTIONSOFDOSAGEFORMDRUGMANUFACTURER'SCGMPR'SNote:ThisdocumentisreferencematerialforinvestigatorsandotherFDApersonnelThedocumentdoesnotbindFDA,anddoesnoconferanyrights,privileges,benefits,orimmunitiesfororonanyperson(s)IINTRODUCTIONThisdocumentisintendedtobeageneralguidetoinspectionsofdrugmanufacturerstodeterminetheircompliancewiththedrugCGMPR'sThisguideshouldbeusedwithinstructionsintheIOM,otherdruginspectionguides,andcomplianceprogramsAlistoftheinspectionguidesisreferencedinChapteroftheIOMSomeoftheseguidesare:·GuidetoInspectionsofBulkPharmaceuticalChemicals·GuidetoInspectionsofHighPurityWaterSystems·GuidetoInspectionsofPharmaceuticalQualityControlLaboratories·GuidetoInspectionsofMicrobiologicalPharmaceuticalQualityControlLaboratories·GuidetoInspectionsofLyophilizationofParenterals·GuidetoInspectionsofValidationofCleaningProcesses·GuidetoInspectionsofComputerizedSystemsinDrugProcessing·GuidelineonGeneralPrinciplesofProcessValidationIICURRENTGOODMANUFACTURINGPRACTICEREGULATIOon:Whensporeteststripsareusedtotesttheeffectivenessofethyleneoxidesterilization,beawarethatrefrigerationmaycausecondensationonremovaltoroomtemperatureMoistureonthestripsconvertsthesporetothemoresusceptiblevegetativeformsoftheorganismwhichmayaffectthereliabilityofthesterilizationtestThesporestripsshouldnotbestoredwheretheycouldbeexposedtolowlevelsofethyleneoxideIfbiologicalindicatorsareused,reviewthecurrentUSPonsterilizationandbiologicalindicatorsInsomecases,testingbiologicalindicatorsmaybecomeallorpartofthesterilitytestingBiologicalindicatorsareoftwoforms,eachofwhichincorporatesaviablecultureofasinglespeciesofmicroorganismInoneform,thecultureisaddedtorepresentativeunitsofthelottobesterilizedortoasimulatedproductthatoffersnolessresistancetosterilizationthantheproducttobesterilizedThesecondformisusedwhenthefirstformisnotpracticalasinthecaseofsolidsInthesecondform,thecultureisaddedtodisksorstripsoffilterpaper,ormetal,glass,orplasticbeadsDuringtheinspectionofafirmwhichreliesonbiologicalindicators,reviewbackgrounddatacompliedbythefirmtoinclude:oSurveysofthetypesandnumbersoforganismsintheproductbeforesterilizationoDataontheresistanceoftheorganismtothespecificsterilizationprocessoDatausedforselectingthemostresistantorganismanditsform(sporeorvegetativecell)oStudiesofthestabilityandresistanceoftheselectedorganismtothespecificsterilizationprocessoStudiesontherecoveryoftheorganismusedtoinoculatetheproductoIfasimulatedproductorsurfacesimilartothesolidproductisused,validationofthesimulationorsimilarityThesimulatedproductorsimilarsurfacemustnotaffecttherecoveryofthenumbersofindicatororganismsappliedoValidationofthenumberoforganismsusedtoinoculatetheproduct,simulatedproduct,orsimilarsurface,toincludestabilityoftheinoculumduringthesterilizationprocessSincequalifiedpersonnelarecrucialtotheselectionandapplicationoftheseindicators,reviewtheirqualificationsincludingexperiencedealingwiththeprocess,expectedcontaminants,testingofresistanceoforganisms,andtechniqueReviewthefirm'sinstructionsregardinguse,controlandtesting,ofthebiologicalindicatorbyproductincludingadescriptionofthemethodusedtodemonstratepresenceorabsenceofviableindicatorinorontheproductReviewthedatausedtosupporttheuseoftheindicatoreachtimeitisusedIncludethecountsoftheinoculumusedrecoverydatatocontrolthemethodusedtodemonstratethesterilizationoftheindicatororganismcountsonunprocessed,inoculatedmaterialtoindicatethestabilityoftheinoculumfortheprocesstimeandresultsofsterilitytestingspecificallydesignedtodemonstratethepresenceorabsenceoftheindicatororganismforeachbatchorfillingoperationInusingindicators,youmustassureyourselfthattheorganismsarehandledsotheydon'tcontaminatethedrugmanufacturingareaandproductFilledContainersEvaluatehowthefilledvialsorampulesleavethefillingroomIsthecappingorsealingdoneinthesterilefillareaIfnot,howissterilitymaintaineduntilcappedReviewthetestsdoneonfinishedvials,ampules,orothercontainers,toassureproperfillandsealForinstance,leakandtorquetestsReviewexaminationsmadeforparticulctecontaminationYoucanquicklycheckforsuspectedparticulatematterbyusingapolariscopeEmployeesdoingvisualexaminationsonlinemustbeproperlytrainedIfparticlecountsaredonebymachine,thisoperationmustbevalidatedPersonnelPracticesCheckhowtheemployeessterilizeandoperatetheequipmentusedinthefillingareaObservefillingroompersonnelpracticesAretheemployeesproperlydressedinsterilegowns,masks,caps,andshoecoveringsObserveandevaluatethegowningprocedures,anddetermineifgoodaseptictechniqueismaintainedinthedressingandfillingroomsCheckonthepracticesafterlunchandotherabsencesIsfreshsterilegarb<<<Continuedtonextmessage>>><<<Thismessageispartofapreviousmessage>>>supplied,oraresoiledgarmentsreusedDetermineifthedressingroomisnexttothefillingareaandhowemployeesandsuppliesenterthesterileareaoLaboratoryControlsForguidanceonhowtoinspectmicroandchemistrylabs,reviewthe"FDAGuidetoInspectionsofPharmaceuticalQualityControlLaboratories"and"FDAGuidetoInspectionsofMicrobiologicalPharmaceuticalQualityControlLaboratories"RetestingforSterilitySeetheUSPforguidanceonsterilitytestingSterilityretestingisacceptableprovidedthecauseoftheinitialnonsterilityisknown,andtherebyinvalidatestheoriginalresultsItcannotbeassumedthattheinitialsterilitytestfailureisafalsepositiveThisconclusionmustbejustifiedbysufficientdocumentedinvestigationAdditionally,spottyorlowlevelcontaminationmaynotbeidentifiedbyrepeatedsamplingandtestingReviewsterilitytestfailuresanddeterminetheincidence,proceduresforhandling,andfinaldispositionofthebatchesinvolvedRetestingforPyrogensAswithsterility,pyrogenretestingcanbeperformedprovideditisknownthatthetestsystemwascompromisedItcannotbeassumedthatthefailureisafalsepositivewithoutdocumentedjustificationReviewanyinitialpyrogentestfailuresanddeterminethefirm'sjustificationforretestingParticulateMatterTestingParticulatematterconsistsofextraneous,mobile,undissolvedsubstances,otherthangasbubbles,unintentionallypresentinparenteralsolutionsCleanlinessspecificationsorlevelsofnonviableparticulatecontaminationmustbeestablishedLimitsareusuallybasedonthehistoryoftheprocessTheparticulatemattertestprocedureandlimitsforLVP'sintheUSPcanbeusedasageneralguidelineHowever,thelevelsofparticulatecontaminationinsterilepowdersaregenerallygreaterthaninLVP'sLVPsolutionsarefilteredduringthefillingoperationHowever,sterilepowders,exceptpowderslyophilizedinvials,cannotincludefiltrationasapartofthefillingoperationConsiderableparticulatecontaminationisalsopresentinsterilepowderswhicharespraydriedduetocharringduringtheprocessReviewtheparticulatemattertestprocedureandreleasecriteriaReviewproductionandcontrolrecordsofanybatchesforwhichcomplaintsofparticulatematterhavebeenreceivedoProductionRecordsProductionrecordsshouldbesimilartothoseforotherdosageformsCriticalsteps,suchasintegritytestingoffilters,shouldbesignedanddatedbyasecondresponsiblepersonReviewproductionrecordstoensurethatdirectionsforsignificantmanufacturingstepsareincludedandreflectacompletehistoryofproductionOintments,Liquids,andLotionsMajorfactorsinthepreparationofthesedrugsaretheselectionofrawmaterials,manufacturingpractices,equipment,controls,andlaboratorytestingFollowingthebasicdruginspectionfundamentals,fullyevaluatetheproductionproceduresInaddition,evaluatespecificinformationregarding:oTheselectionandcompatibilityofingredientsoWhetherthedrugisahomogeneouspreparationfreeofextraneousmatteroThepossibilityofdecomposition,separation,orcrystallizationofingredientsoTheadequacyofultimatecontainerstoholdanddispensecontentsoProcedureforcleaningthecontainersbeforefillingoMaintenanceofhomogeneityduringmanufacturingandfillingoperationsThemostcommonproblemassociatedwiththeproductionofthesedosageformsismicrobiologicalcontaminationcausedbyfaultydesignandorcontrolofpurifiedwatersystemsDuringinspections,evaluatetheadequacyofthewatersystemReviewandevaluatethemicrochemistrytestresultsontheroutinemonitoringofthewatersystemincludingvalidationofthewatersystemReviewanymicrobiologicaltestsdoneonthefinisheddrugincludinginprocesstestingSomeofthesedrugshavepreservativesaddedwhichprotectthemfrommicrobialcontaminationThepreservativesareusedprimarilyinmultipledosecontainerstoinhibitthegrowthofmicroorganismsintroducedinadvertentlyduringoraftermanufacturingEvaluatetheadequacyofpreservativesystemPreservativeeffectivenesstestingfortheseproductsshouldbereviewedForadditionalinformation,reviewthe"AntimicrobialPreservativesEffectiveness"sectionoftheUSPEquipmentemployedformanufacturingtopicaldrugsissometimesdifficulttocleanThisisespeciallytrueforthosewhichcontaininsolubleactiveingredients,suchasthesulfadrugsThefirm'sequipmentcleaningproceduresincludingcleaningvalidationdatashouldbereviewedandevaluatedPackagingandLabelingCFRSubpartGPackagingandlabelingoperationsmustbecontrolledsoonlythosedrugswhichmeetthespecificationsestablishedinthemasterformularecordsaredistributedReviewindetailthepackagingandlabelingoperationstodecideifthesystemwillpreventdrugandlabelmixupsApproximatelyofalldrugrecallsoriginateinthisareaEvaluatewhatcontrolsorproceduresthefirmhastoprovidepositiveassurancethatalllabelsarecorrectDetermineifpackagingandlabelingoperationsinclude:oAdequatephysicalseparationoflabelingandpackagingoperationsfrommanufacturingprocessoReviewof:LabelcopybeforedeliverytotheprinterPrinter'scopyWhetherfirm'srepresentativeinspectstheprinterWhetherornotgangprintingisprohibitedWhetherlabelsarecheckedagainstthemasterlabelbeforereleasedtostockDeterminewhoisresponsibleforlabelreviewpriortoreleaseofthelabelstoproductionAlso,whetherthelabelsareidenticaltothelabelingspecifiedinthebatchproductionrecordsoSeparatestorageofeachlabel(includingpackageinserts)toavoidmixupsoInventoryoflabelstocksDetermineiftheprinter'scountisacceptedoriflabelsarecounteduponreceiptoDesignationofoneindividualtoberesponsibleforstorageandissuanceofalllabelsoReceiptbythepackagingandlabelingdepartmentofabatchrecord,orotherrecord,showingthequantityoflabelsneededforabatchDetermineifthebatchrecordisretainedbythepackagingsupervisororaccompaniesthelabelstotheactualpackagingandlabelinglineoAdequatecontrolsofthequantitiesoflabelingissued,used,andreturnedDetermineifexcesslabelsareaccountedforandifexcesslabelsbearingspecificcontrolcodes,andobsoleteorchangedlabelsaredestroyedoInspectionofthefacilitiesbeforelabelingtoensurethatallpreviouslyusedlabelinganddrugshavebeenremovedoAssurancethatbatchidentificationismaintainedduringpackagingoControlprocedurestofollowifasignificantunexplaineddiscrepancyoccursbetweenquantityofdrugpackagedandthequantityoflabelingissuedoSegregatedfacilitiesforlabelingonebatchofthedrugatatimeIfthisisnotpracticed,determinewhatstepsaretakentopreventmixupsoMethodsforcheckingsimilartypelabelsofdifferentdrugsorpotenciestopreventmixingoQuarantineoffinishedpackagedproductstopermitadequateexaminationortestingofarepresentativesampletosafeguardagainsterrorsAlso,topreventdistributionofanybatchuntilallspecifiedtestshavebeenmetoAnindividualwhomakesthefinaldecisionthatthedrugshouldgotothewarehouse,ortheshippingdepartmentoUtilizationofanyoutsidefirms,suchascontractpackers,andwhatcontrolsareexercisedoversuchoperationsSpecialattentionshouldbedevotedtofirmsusing"rolls"ofpressuresensitivelabelsInvestigatorshavefoundinstanceswhere:oPaperchipscutfromlabelbackingtohelprunningthelabelsthroughacoderinterferedwiththecodeprintercausingdigitsinthelotnumbertobeblockedoutoSomerollscontainedsplicedsectionsresultinginlabelchangesintherolloSomelabelsshiftedontherollwhenthelabelswereprintedresultinginomittingrequiredinformationTheuseofcutlabelscancauseasignificantproblemandshouldbeevaluatedindetailMostfirmsarereplacingtheircutlabelswithrolllabelsReviewprescriptiondrugsforwhichfulldisclosureinformationmaybelackingIfsuchproductsarefound,submitlabelsandotherlabelingasexhibitswiththeEIRSeeCFRfortherecommendedsequenceinwhichfulldisclosureinformationshouldbepresentedReviewlabelsofOTCproductsforwarningsrequiredbyCFRAcontrolcodemustbeusedtoidentifythefinishedproductwithalot,orcontrolnumberthatpermitsdeterminationofthecompletehistoryofthemanufactureandcontrolofthebatchDetermine:oThecompletekey(breakdown)tothecodeoWhetherthebatchnumberisthesameasthecontrolnumberonthefinishedpackageIfnot,determinehowthefinishedpackagecontrolnumberrelates,andhowitisusedtofindtheidentityoftheoriginalbatchBeginningAugust,thefollowingnewrequirementswillbecomeeffective:oUseofgangprintedlabelswillbeprohibitedunlesstheyareadequatelydifferentiatedbysize,shapeorcolor((f))oIfcutlabelsareusedoneofthefollowingspecialcontrolproceduresshallbeused((g)):()Dedicationofpackaginglines()Useofelectronicorelectromechanicalequipmenttoconductapercentexaminationoffinishedproduct()UseofvisualinspectiontoexaminepercentofthefinishedproductforhandappliedlabelingThevisualexaminationwillbeconductedbyonepersonandindependentlyverifiedbyasecondpersonoLabelingreconciliationrequiredbyiswaivedforcutorrolllabelingifapercentexaminationisperformedaccordingto(g)()HoldingandDistributionCFRsubpartHCheckthefinishedproductstorageandshippingareasforsanitarycondition,stockrotation,andspecialstorageconditionsneededforspecificdrugsEvaluateanydrugsthathavebeenrejected,orareonholdforotherthanroutinereasonsLaboratoryControlsCFRSubpartILaboratorycontrolsshouldincludeadequatespecificationsandtestprocedurestoassurethatcomponents,inprocessandfinishedproductsconformtoappropriatestandardsofidentity,strength,quality,andpurityInordertopermitproperevaluationofthefirm'slaboratorycontrols,determine:oWhetherthefirmhasestablishedamasterfileofspecificationsforallrawmaterialsusedindrugmanufactureThismasterfileshouldincludesamplingprocedures,samplesize,numberofcontainerstobesampled,mannerinwhichsampleswillbeidentified,teststobeperformed,andretestdatesforcomponentssubjecttodeteriorationoThefirm'spoliciesaboutprotocolsofassayThesereportsareoftenfurnishedbyrawmaterialsuppliershowever,themanufacturerisresponsibleforverifyingthevalidityoftheprotocolsbyperiodicallyperformingtheirowncompletetestingandroutinelyconductingidentitytestsonallrawmaterialsreceivedoLaboratoryprocedureforreleasingrawmaterials,finishedbulkdrugsorpackageddrugsfromquarantineDeterminewhoisresponsibleforthisdecisionRawmaterialspecificationsshouldincludeapprovedsuppliersForNDAorANDAdrugs,theapprovedsupplierslistedintheirspecificationsshouldbethesameasthoseapprovedintheNDAorANDAoIfthelaboratoryisstaffedandequippedtodoallrawmaterial,inprocess,andfinishedproducttestingthatisclaimedoWhetherdrugpreparationsaretestedduringprocessingIfso,determinewhattypeoftestsaremadeandwhetherarepresentativesampleisobtainedfromvariousstagesofprocessingoSpecificationsanddescriptionoflaboratorytestingproceduresforfinishedproductsoProceduresforcheckingtheidentityandstrengthofallactiveingredientsincludingpyrogenandsterilitytesting,ifapplicableoIfthelaboratoryconductspyrogentests,safetytests,orbioassaysdeterminethenumberoflaboratoryanimalsandiftheyareadequatelyfedandhousedDeterminewhatcareisprovidedonweekendsandholidaysoSterilitytestingproceduresEntriesshouldbepermanentlyrecordedandshowallresults,bothpositiveandnegativeExaminerepresentativesamplesbeingtestedandtheirrecordsWhencheckingthesterilitytestingprocedures,determine:PhysicalconditionsoftestingroomThefacilityusedtoconductsterilitytestingshouldbesimilartothoseusedformanufacturingproductsLaboratoryproceduresforhandlingsterilesampleUseofultravioletlightsNumberofunitstestedperbatchProcedureforidentifyingtestmediawithspecificbatchesTestmedia'sabilitytosupportgrowthoforganismsLengthofincubationperiodProcedurefordilutingproductstooffsettheeffectsofbacteriostaticagentsoPyrogentestingproceduresDetermineifanimalsinvolvedinpositivepyrogentestsarewithdrawnfromusefortherequiredperiodIftheLALTestisused,reviewtheFDA"GuidelineonValidationoftheLimulusAmebocyteLysateTest***"oIfanytestsaremadebyoutsidelaboratories,reportthenamesofthelaboratoriesandtheteststheyperformDeterminewhatprecautionsthefirmtakestoinsurethatthelaboratories'workisbonafideoMethodsusedtocheckthereliability,accuracy,andprecisionoflaboratorytestproceduresandinstrumentationoHowfinalacceptanceorrejectionofrawmaterials,intermediates,and<<<Continuedtonextmessage>>><<<Thismessageispartofapreviousmessage>>>finishedproductsisdeterminedReviewrecentrejectionsanddispositionofaffecteditemsoTheprovisionsforcompleterecordsofalldataconcerninglaboratorytestsperformed,includingdatesandendorsementsofindividualsperformingthetests,andtraceabilityoForcomponentsandfinishedproduct,thereservesampleprogramandproceduresshouldbeevaluatedChallengethesystemanddetermineifthesamplesaremaintainedandcanberetrievedThestoragecontainermustmaintaintheintegrityoftheproductoWhetherstabilitytestsareperformedon:ThedrugproductinthecontainerandclosuresysteminwhichmarketedSolutionspreparedasdirectedinthelabelingatthetimeofdispensingDetermineifexpirationdates,basedonappropriatestabilitystudies,areplacedonlabelsoIfpenicillinandnonpenicillinproductsaremanufacturedonthesamepremises,whethernonpenicillinproductsaretestedforpenicillincontaminationObtaincopiesoflaboratoryrecords,batchrecords,andanyotherdocumentsthatshowerrorsorotherdeficienciesControlRecordsCFRSubpartJMasterProductionandControlRecordsCFRThevariousmasterproductionandcontrolrecordsareimportantbecauseallphasesofproductionandcontrolaregovernedbythemMasterrecords,iferroneous,mayadverselyaffecttheproductTheserecordsmustbepreparedaccordingtothedrugCGMPR'soutlinedinCFRTheserecordsmightnotbeinonelocation,butshouldbereadilyavailableforreviewBatchProductionandControlRecordsCFRThebatchproductionandcontrolrecordsmustdocumenteachsignificantstepinthemanufacture,labeling,packaging,andcontrolofspecificbatchesofdrugsCFRprovidesthebasicinformationthebatchrecordsmustprovideAcompleteproductionandcontrolrecordmayconsistofseveralseparaterecordswhichshouldbereadilyavailabletotheinvestigatorRoutinelycheckthebatchrecordcalculationsagainstthemasterformularecordGivespecialattentiontothoseproductsonwhichtherehavebeencomplaintsBealertfortranscriptionerrorsfromthemasterformularecordtothebatchrecordBealertfortranscriptionorphotocopyingerrorsinvolvingmisinterpretationofsymbols,abbreviations,anddecimalpoints,etcItisimportantthatbatchproductionrecordsbespecificintermsofequipment(vblendervsribbonblender)andprocessingtimes(mixingtimeandspeed)TheequipmentshouldhaveitsownuniqueidentificationnumberThemanufacturingprocessfortheseproductsmustbestandardized,controlled,andvalidatedDistributionCFRCompletedistributionrecordsshouldbemaintainedperCFRBealertforsuspiciousshipmentsofproductssubjecttoabuseorwhichhavebeentargetedforhighpriorityinvestigationbytheagencyTheseincludesteroids,counterfeits,diverteddrugs(iephysiciansamples,clinicalpacks,etc)DetermineandevaluateifthefirmchecksontheauthenticityofordersreceivedWhatreferencesareused,egcurrenteditionsoftheAMADirectory,HaysDirectory,etcComplaintFilesCFRCFRrequiresthatrecordsofallwrittenandoralcomplaintsbemaintainedAlthoughFDAhasnoauthoritytorequireadrugfirm,exceptforprescriptiondrugs,toopenitscomplaintfiles,attempttoreviewthefirm'sfilesThecomplaintfilesshouldbereadilyavailableforreviewDoafollowupinvestigationonallapplicableconsumercomplaintsinthefirm'sdistrictfactoryjacketReviewandevaluatethefirm'sproceduresforhandlingcomplaintsDetermineifallcomplaintsarehandledascomplaintsandnotinappropriatelyexcludedReviewthecomplaintsanddetermineiftheywerefullyinvestigatedEvaluatethefirm'sconclusionsoftheinvestigation,anddetermineifappropriatecorrectiveactionwastakenDetermineiftheproductshouldberecalled,orwarrantacomprehensiveinvestigationbyFDAReturnedDrugProductsCFRSubpartKReturneddrugsoftenserveasanindicationthatproductsmayhavedecomposedduringstorage,arebeingrecalledordiscontinuedDeterminehowreturneddrugitemsarehandledForexample,aretheyquarantined,destroyedaftercredit,orreturnedtostorageIfanabnormallylargeamountofaspecificdrugitemisonhand,determinewhyCheckifreturneddrugitemsareexaminedinthelaboratory,andwhomakestheultimatedecisionastotheuseofthereturneddrugsNote:DumpingsalvagedrugsinthetrashisapotentiallydangerouspracticeAdvisemanagementtoproperlydisposeofthedrugstoprecludesalvageDrugsshouldbedisposedofinaccordancewithEPAregulationsTherearenoreferencesfromthisdocumen
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