下载

2下载券

加入VIP
  • 专属下载特权
  • 现金文档折扣购买
  • VIP免费专区
  • 千万文档免费下载

上传资料

关闭

关闭

关闭

封号提示

内容

首页 FDA资料汇编FDA口服制剂检查指南

FDA资料汇编FDA口服制剂检查指南 .doc

FDA资料汇编FDA口服制剂检查指南

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

简介:本文档为《FDA资料汇编FDA口服制剂检查指南 doc》,可适用于医药卫生领域

GUIDETOINSPECTIONSOFORALSOLIDDOSAGEFORMSPREPOSTAPPROVALISSUESFORDEVELOPMENTANDVALIDATIONJanuary,Note:ThisdocumentisreferencematerialforinvestigatorsandotherFDApersonnelThedocumentdoesnotbindFDA,anddoesnoconferanyrights,privileges,benefits,orimmunitiesfororonanyperson(s)IINTRODUCTIONThisinspectionguideprovidesinformationregardingtheinspectionandevaluationofthemanufacturingandcontrolprocessesusedtomanufacturesolidoraldosageformpharmaceuticalproductsThisdocumentprovidesguidancefortheFDAinvestigatorandpromotesuniformityandconsistencyduringtheinspectionandevaluationofthevalidationofthesolidoraldosageformmanufacturingandcontrolprocessesItcoversthreephasesofthevalidationprocessproductdevelopment,designofthevalidationprotocol,anddemonstrationruns(validation)oftheequipmentandprocessinthemanufactureoffullscalecommercialproductionbatchesAlthoughthisdocumentitisnotallinclusive,itaddressesmanyoftheissuesandexamplesofvalidationproblemsoforalsoliddosageformswhichinvestigatorsandanalystsmayencounterTichhavetobeconsideredinthecontrolofthemanufacturingandthevalidationprocessesThefollowingisabriefdescriptionofsomeissuesassociatedwithequipment:aBlendersManysolidoraldosageformsaremadebydirectcompressionTherearegenerallytwotypesofmixerslowenergyandhighenergyThelowenergymixersrepresenttheclassicaltypeofslowmixers,suchasribbonblenders,tumblers,andplanetaryponypanThehighenergymixersincludesomebasicfeaturesofthelowenergymixerbutalsocontainsometypeofhighspeedblade,commonlytermedanintensifierbarorchopperPonyPanTypeThismixerhashistoricallybeenusedforthemanufactureofwetgranulationsBecauseofitsopenpanorpot,granulatingagents,suchasstarchpaste,couldbeaddedwhilemixingSinceitisusuallyopenatthetoptoallowthemixingbladestopenetratethepowder,mixingoperationsareusuallydustyandcanleadtopotentialcrosscontaminationproblemsTheusefulnessofthesemixersislimitedtowetgranulatingWiththistypeofmixer,thereisgoodhorizontal(sidetoside)blendingHowever,vertical(toptobottom)mixingdoesnotoccurPowderplacedinthemixerfirstwillbepoorlymixedSegregationorunmixingisalsoarecognizedproblemTominimizethisproblem,somemanufacturershaveemptiedthepancontentshalfwaythroughthemixingcycleinanattempttoturnthepowderoveratthebottomofthemixerToalleviatetheproblemofthelackofmixingalongthesidesorwallsofthepan,manufacturershaveutilizedahandheldsteelpaddleatvarioustimesduringmixingThistypeofmixingisdifficulttocontrolandreproduceThus,itwouldbedifficulttovalidateThepotentialforsegregationandpoormixingalongthesidesandparticularlythebottomoftheponyblendermakesthistypeofblenderlessdesirableforthedryblendingofgranulationsofdrugproductsConsequently,wheneversuchdryblendingisencountered,theinvestigatorshouldbealerttopotentialproblemswithblendingvalidationandcontentuniformityWheneverinprocesssamplesofthegranulationarecollectedaspartofaninvestigationorinspection,theformulacardalongwiththeweightofthedosageunittobemanufacturedisneededforcalculationsRibbonBlenderIntheribbonblender,powderismixedbothhorizontallyandverticallyLoadingoperationscanbedustyHowever,duringtheactualblending,itisenclosed,therebylimitingtheamountofdustgeneratedtotheenvironmentThemajorandpotentiallythemostseriousproblemwiththeribbonblenderisthatthereisa"deadspot"orzoneatthedischargevalveinsomeoftheseblendersTocompensateforthis"deadspot",manufacturershavetorecyclethepowderfromthisareaatsomepointduringthemixingprocessObviously,thereshouldbeadequateandveryspecificdirectionsandproceduresforassuringthiscriticalstepisperformedVerifythatthisstepisincludedinthedirectionsAnotherconcernwiththismixeristhepoormixingattheendsofthecenterhorizontalmixingbarandattheshellwallbecauseofbladeclearanceThelevelofpowderplacedinthismixerisnormallyatthetopoftheouterribbonblade,andaswithothermixers,caremustbetakennottooverfillthemixerCleaningproblems,particularlyattheendsoftheribbonblenderwherethehorizontalbarenterstheblender,havebeenidentifiedIfmanufacturersdonotdisassembleandcleanthesealspackingbetweenbatches,theyshouldhavedatatodemonstratetheabsenceofforeigncontaminantsbetweenbatchesofdifferentproductsprocessedintheblenderTumblerBlenderCommonmixersofthistypeincludethetwinshellanddoubleconeThesemixersexertagentlemixingactionBecauseofthismildaction,lumpsofpowderwillnotbebrokenupandmixedPowdersmayalsoclumpduetostaticchargesandsegregationcanoccurLowhumiditycancontributetothisproblemBlendingunderverydryconditionshasbeenfoundtoleadtochargebuildupandsegregation,whileblendingofsomeproductsunderhumidconditionshasledtolumpingMoresothanwithothermixers,powderchargelevelsshouldnotexceedtoofthetotalvolumeofthemixerFabricatorsoftumblertypeblendersidentifythevolumeastheactualworkingcapacityandnottheactualvolumeoftheblenderItisimportanttocorrelatethebulkdensityofthegranulationwiththeworkingcapacityoftheblenderHighShear(highenergy)MixersThereareseveralfabricatorsofthesemixersthatincludeGRAL,DiosnaandLodigeorLittlefordThesemixersarehighlyefficientandideallysuitedforwetgranulationsEndpointofwetgranulationscanbedeterminedbyameasurementonagaugeoftheworkneededtoagitatetheblendThemixingvesselisenclosed,anddustonlyenterstheenvironmentwhenloadingOneoftheproblemsassociatedwiththesemixersisthetransferorconversionofproductsblendedintheoldertypesofmixerstotheseblendersMixingtimesaregoingtobedifferent,andthephysicalcharacteristicsoftheblendmayalsobedifferentThesemixersareveryefficientForwetgranulations,itisimportanttocontroltherateandamountofadditionofthesolventBecauseoftheirefficiency,drugsubstancemaypartiallydissolveandrecrystallizeupondryingasadifferentphysicalformThepresenceofanintensifierbarinthecenteroftheblenderwhichrotatesatveryhighspeedsbreaksdownsmaller,harderagglomeratesAmajordisadvantageofthistypeofblenderisthattheextremelyhighspeedoftheintensifierbargeneratesconsiderableheatthatcansometimesresultincharringofsomesugarbasegranulationsItshouldbepointedoutthatthesesamecommentsareapplicabletootherhighenergymixerswhichalsorelyonhighspeedchopperstodispersepowdersAlso,cleaningoftheblenderrequiresdisassemblyoftheintensifierbarbetweenproductsPlasticBagAnydiscussionofmixerswouldnotbecompletewithoutaddressingtheplasticbagFirmshaveresortedtotheblendingormanufactureofatriturationinaplasticbagObviously,itisverydifficulttoreproducesuchaprocess,andthereisthepotentialforlossofpowderasaresultofbreakageorhandlingTheuseofaplasticbagcannotbejustifiedinthemanufactureofapharmaceuticalproductWhentheplasticbaghasbeenused,directionsareusuallynotspecific,andonewouldnotknowbyreadingthedirectionsthataplasticbagwasemployedInarecentinspection,afirmwasnotedtomanufactureasmallkgsizebatchofatranquilizerBecauseallofthefirm'sblenderswereofmuchlargercapacity,aninquirywasmadeastothemixeremployedAlthoughtheprocessingrecordsindicatedalargeblenderwasemployed,itwaslaterdeterminedthatthebatchwasactuallyblendedinaplasticbagb)DryersTherearetwobasictypesofdryersOneistheovendryerwherethewetgranulationisspreadontraysanddriedinanovenTheseconddryeristhefluidbeddryerinwhichthewetgranulationis"fluidized"orsuspendedinairGenerally,thefluidbeddryeryieldsamoreuniformgranulationwithsphericalparticlesHowever,thismayresultincompressionproblemsthatmayrequireadditionalcompressionforceItisnotunusualtoseemanufacturerschangefromanovendryertothefluidbeddryerHowever,suchachangeshouldbeexaminedforequivalencywithinvitrotestingsuchashardness,disintegrationandcomparativedissolutionandstabilitytestingconductedOtherissuesofconcernwithdryingincludemoistureuniformityandcrosscontaminationTraydryerspresentmoremoistureuniformityproblemsthanfluidbeddryersObviously,adryershouldbequalifiedforheatuniformityandaprogramdevelopedtoassuremoistureuniformityingranulationsattheendpointofdryingWithrespecttofluidbeddryers,moistureproblemscanoccurifthegranulationisnotcompletelyfluidizedRegardingcrosscontamination,ovendryers,particularlythoseinwhichairisrecirculated,presentcrosscontaminationproblemsbecauseairrecirculatesthroughacommonfilterandductForfluidbeddryers,thebagfilterspresentcrosscontaminationproblemsInordertominimizeproblems,manufacturersuseproductdedicatedbagsc)TabletandCapsuleEquipmentAnotherimportantvariableinthemanufacturingprocessisthetabletpressorencapsulatingmachineThenewerdosageformequipmentrequiresgranulationswithgoodflowcharacteristicsandgooduniformityThenewertabletpressescontrolweightvariationbycompressionforceandrequireauniformgranulationtofunctioncorrectlySetupofthemicroprocessorcontrolledtabletpressusuallyincludessometypeofchallengetothesystemForexample,ashortpunchissometimesplacedamongtheotherpunchesIfthepressisoperatingcorrectly,itwillalarmwhenthelowerorhighweighttabletiscompressedDifferenttabletcompressionequipmentcancausedoseuniformity,weightuniformityandhardnessproblemsForexample,vibrationsduringtabletcompressioncancausesegregationofthegranulationinthefeedhopperSpeedofthemachinecanaffectfillofthedieandtabletweightTherefore,aspreviouslydiscussed,itisimportanttohavespecificoperatingdirectionsManyunitoperationsnowprovideforblendingintoteswithdischargeofthetotedirectlyintotabletcompressionequipmentBecauseofsegregationproblemsattheendofdischarge,tabletsfromtheendofcompressionshouldbetestedforcontentuniformityTheuseofinsertsintoteshasbeenshowntominimizesegregationWithregardtothenewercomputercontrolledtabletcompressionequipment,bucketsoftabletsareoftenrejectedbecauseofpotentialweightvariationproblemsThedispositionofthesetablets,aswellasthegranulationandtabletsusedtosetupthepress,shouldbeinvestigatedReworkingprocessesmustbevalidatedWithregardtoencapsulationoperations,thehygroscopicnatureofgelatincapsulesandsomeofthegranulations,requireshumiditycontrolsforstorageoftheemptycapsulesandtheirsubsequentfillingScaleupofcapsuleproductshasalsopresentedsomeproblemsbecauseofthedifferenttypesofencapsulationequipmentOlderequipmentthatoperatedongravityfill,suchastheLillyandParkeDavismachines,wascommonlyusedformanufacturingcapsulesinclinicalmanufacturingareasWhenformulationswerescaleduptohighspeedencapsulationequipment,flowproblemsandpoorweightvariationresultedAdditionally,someofthenewerequipmentprovidesfortheformationofaslugwhichcouldimpactondissolutionAspreviouslydiscussed,setupandreviewofoperatingdirectionsshouldbecoveredininspectionsTheinvestigationbyfirmsofweightvariationproblemsshouldalsobecoveredManyfirms,inordertorecondition(rework)batches,passthoseparticularbatchesthroughasorter,suchastheMoconVericapThismachineworksontheprincipalofcurrent(dielectricconstant),andmoisturevariationinthefilledcapsulescancauseinaccurateresultsCheckthedatausedtoqualifyequipmentandinvestigatetheequipmentlogforthissortingmachinestoidentifybatcheswithweightproblemsthatwereprocessedinitThedatasupportingtheaccuracyofequipmenttorejectloworhighweightcapsulesshouldbereviewedd)CoatingEquipmentManytabletsarenowcoatedwithanaqueousfilmcoatthatisusuallyverysolubleCurrenttechnologyprovidesforfixedspraysofthecoatingsolutionThevolumeofcoatingsolution,rateandtemperaturecanbecontrolledbysomeofthemorehighlyautomatedoperationsHowever,manysugarcoated,entericcoatedanddelayedreleaseproductsexistwheresomeportionsofthecoatingprocessarenothighlysolubleandareperformedmanuallyGenerally,theshellacundercoatusedforsugarcoatedtabletshaspresenteddisintegrationdissolutionproblems,particularlyinagedsamplesWithrespecttopoordisintegration,FerrousSulfatetabletsprobablyrepresentstheclassicalexampleOvertheyears,therehavebeenmanyrecallsfrommanydifferentmanufacturersforpoordisintegrationofcoatedFerrousSulfatetabletsLikewise,therehavebeenmanyproblemswithpoordissolutionattributedtothecoatingprocessAgain,theshellacundercoathardens,andevensometimescracks,resultinginpoordissolutionTherehavebeenmanyoccasionswhenthecoatingprocesswasnotvalidatedContinuedtonextmessage>>>Thismessageispartofapreviousmessage>>>Thenumberofapplicationsofcoats,volumeofcoatingsolutioninaspecificapplication,andtemperatureofthesolutionduringapplicationareallparametersthatneedtobeaddressedForexample,thetemperatureofapplicationandevenheatduringdryinghavebeenfoundtocausedissolutionfailuresinagedtabletsAnotherproblemassociatedwiththecoatingprocessconcernstheheatappliedtoproductsthataresensitivetoheatForexample,ithasbeenshownthatestrogentabletsareheatsensitiveandhaveexhibitedstabilityproblemsThus,itisimportanttocontrolthisphaseoftheprocessThereareafewproducts,suchassomeoftheantihistaminetablets,inwhichthedrugsubstanceisappliedduringthecoatingprocessOtherproductsrequiretheactivedrugsubstancetobeappliedasadustontackytabletsaspartofthecoatingprocessFortheseproducts,itisparticularlyimportanttoapplythedruginthecoatingsolutioninmanycontrolledapplicationsExamineprocessingrecordsforspecificityintheidentificationofcriticalstepsinthecoatingprocessReviewthefirm'sdatademonstratingthatcriticalstepsareconsistentandreproducibleAgain,itisimportantaspartofthevalidationoftheseprocessestodemonstratedoseuniformityanddissolutionandtocontroltheparametersofthecoatingprocessGranulationMixAnalysisAcriticalstepinthemanufactureofanoralsoliddosageformistheblendingofthefinalgranulationIfuniformityisnotachievedatthisstage,thenonecouldassumethatsomedosageunitswouldnotcomplywithuniformityrequirementsThemajoradvantageofblendanalysis(fromauniformityperspective)isthatspecificareasoftheblenderwhichhavethegreatestpotentialtobenonuniformcanbesampledThisisparticularlytrueoftheribbontypeblenderandplanetaryorponytypemixersInsomecases,suchasforlargeortumblertypeblenders,itisimpracticaltosamplefromtheblenderdirectlyInsuchcases,granulationsorblendscouldbesampledatthetimeofblenderdischargeordirectlyfromdrumsIfsamplingfromdrums,samplesfromthetop,middleandbottomofeachdrumshouldbecollectedInmostcasessamplingthievesarereadilyavailableforsamplingthesmallquantitiesthatneedtobetakenfromkeyareasoftheblenderorthedrumsIfsampleslargerthanonedosageunitmustbecollected,however,adequateprovisionsmustbemadetopreventexcessivehandlingmanipulationbetweenthetimeofsamplingandthetimeofanalysisAsamplingdeviceforsamplingdosageunitweightsisalsoavailableinCincinnatiDistrictforusebyinvestigatorsGoodscienceandlogicwouldseemtodictatethatsamplesizesoftheapproximateequivalentweightofthedosageunitshouldbesampledinordertotestforuniformityManyindustrialpharmacyandengineeringtextsconfirmthisapproachLargegranulationsamplesizes,suchasoneouncewillprovidelittleinformationwithrespecttouniformityGenerally,furthermixingaftersamplingandpriortoanalysisoccurswhichyieldsmisleadingresultsTheacceptancecriteriaforgranulationdoseuniformitytestingneedstobeevaluatedAlthoughmanyfirmsevaluatedoseuniformityusingthecompendialdoseuniformityspecifications(withanRSDofto),suchspecificationsshouldbetighterwheresupportedbythefirm'shistoricaldataonthelevelofblenduniformitywithitsequipmentforagivenproductInmanycasescompendialassaylimitsforthefinishedproduct(tooflabelclaim)arebroadenoughforthispurpose,andmostfirmsshouldbeabletodemonstrateblendassayresultswellwithintheselimitsIflargersamplesizesaretakenforassaytoevaluatetotalcompositeassay,thenthespecificUSPorfiledcriteriaforassayshouldbeusedThiskeyissueneedstobeexaminedduringtheinspectionInadditiontoanalysisofblendsfordoseuniformityandpotency,blendsaretestedforphysicalcharacteristicsAmajorphysicalparameterusedtodemonstrateequivalencebetweenbatchesistheparticlesizeprofileThisisparticularlyimportantforthecomparisonofthebiobatchwithproductionbatchesandalso,whenprocessesaremodifiedorchangedTheparticlesizeprofilewillprovideusefulinformationfordemonstratingcomparabilityParticlesizeprofilesareparticularlyimportantforthetabletmadebyawetgranulationprocessThesizeandeventhetypeofgranulecanaffecttheporesizeinatabletandhaveaneffectondissolutionForexample,arecentdissolutionfailurewasattributedtoachangeinthemillingscreensize,yieldingagranulationwithlargergranulesSinceitwasacoatedtablet,largerporespermittedincreasedpenetrationintothetabletbythecoatingsolution,resultinginslowerdissolutionAnothertestwhichistypicallyperformedonthegranulation,particularlywhenthewetgranulationprocessisused,islossondrying(LOD)andormoisturecontentIforganicsolventsareemployed,thenresidualsolventresiduesarealsotestedInthevalidationofadryingprocess,LODlevelsaredeterminedpriorto,duringandafterdryinginordertodemonstratetimesandlevelsAswithprocessingvariables,levels(specifications)areestablishedinthedevelopmentphasewiththevalidationphaseusedtoconfirmtheadequacyoftheprocessAswithotherspecificationsandprocesses,theinvestigatorshouldreviewthedatausedtosupportthedryingprocessanddeterminethesignificance(ifany)ofvariabledryingtimesandlevelsInProcessTestingForthepurposeofthisdocument,inprocesstestingisthetestingperformedondosageformsduringtheircompressionencapsulationstagestoassureconsistencythroughouttheseoperationsFortablets,individualtabletweights,moisture,hardness(compressionforce)anddisintegrationareperformedForcapsules,individualweightsandmoistureareperformedInmanyofthevalidationreportsreviewed,manufacturershaveneglectedtosupplyindividual(notcomposite)dosageunitweightsperformedthroughoutcompressionencapsulationThisisparticularlyimportantforcapsuleproductswhichmayexhibitweightvariationproblemsIfnotpartofvalidationreports,theindividualdosageunitweightsshouldbereviewedWithregardtoindividualcapsuleweights,amajorquestionthatarisesconcernsacceptablelevelsSincemostUSPassaylimitsareto,itwouldseemreasonablethateachunitmanufacturedcomplywiththesespecificationsItshouldbepointedoutthattolimitsareestablishedbytheUSPforvariabilityinbothblendingandcompressionorencapsulationoperationsSincehardnessanddisintegrationspecificationsareestablishedduringdevelopmentandbiobatchproduction,testingisperformedtodemonstratebothequivalency(comparability)andconsistencyWithregardtomoisture,sometabletshavesetupuponagingasaresultofpoormoisturecontrolandinadequatespecificationsForexample,thishasbeenshowntobeamajorproblemwithCarbamazepinetabletsTestResultsFinishedproducttesting,particularlyassay,contentuniformityanddissolution,shouldbereviewedWithregardtodissolution,itisimportanttoreviewdissolutionprofilesValidationbatcheswithdissolutionprofilesnotcomparabletobiobatchesindicatenonequivalencyofthemanufacturingprocessDependingonthediscriminatingnatureofthedissolutiontest,itmayalsoindicatelackofequivalenceofthedosageformsmadeduringvalidationwiththebiobatchInthereviewofdissolutiontestresults,itisimportanttoeventuallyseeresultsveryclosetodissolutionInsomecases,manufacturerswillprofilethedissolutionresultsonlytothespecificationHowever,iflower,butstillacceptableresultsareobtained(suchas),itisimportanttocontinuethetestThiscanbeperformedbyincreasingthespeedoftheapparatusIfaproductcompletelydissolves,yetonlyresultsinavalueof,itmayindicatesomeproblemwiththetestLikewise,highdissolutionresults()alsoindicatesomeproblemwiththetestObviously,unusualoratypicalresultsshouldbeexplainedinthevalidationreportInvestigationsProductFailuresInanyprocessvalidationexercise,abasicobjectiveistoprovethataprocessissatisfactoryUnfortunately,someprocessesareunsatisfactoryandmaysometimesyieldunacceptableresultsItisimportant,therefore,thatwhenthefinalvalidationreportisreviewed,allresults,includingfailingresults,bediscussedandevaluatedForexample,reviewofamanufacturingprocessshowedthatoneofeveryeightbatchesmanufacturedfailedcontentuniformityMembersofthecompanyrecognizedthattheprocesswasunsatisfactoryandnotvalidated,butfailedtodrawthisconclusioninthewrittenvalidationreportWhenreviewingavalidationreport,thebasisforconcludingthataprocessissatisfactory,particularlythosewithfailingresults,shouldbeevaluatedSiteReviewAmajoraspectandpossiblythemostcriticalphaseoftheinspectionofprocessvalidationisthereviewofdataatthemanufacturerManufacturershavepresentedvalidationreportswhichappearedtobeverycomplete,however,whendatawasactuallyreviewed,failingbatcheswereomittedwithoutjustificationAdditionally,reviewtherawdata,includinganalyticalrawdata,foraccuracyOnlythroughonsiteauditorreviewofdatacouldsuchsituationsbeidentifiedThus,eventhoughapreapprovalinspectionisperformed,apostapprovalinspectionprovidingforareviewofvalidationdataiswarranted,particularlyinthosecasesinwhichdeficienciesinvalidationdatahavebeenidentifiedNote:ThisdocumentdoesnotbindFDA,anddoesnotconferanyrights,privileges,benefits,orimmunitiesfororonanyperson(s)Therearenoreferencesfromthisdocumen

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:

/19

VIP

在线
客服

免费
邮箱

爱问共享资料服务号

扫描关注领取更多福利