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首页 FDA资料汇编FDA液体制剂检查指南

FDA资料汇编FDA液体制剂检查指南 .doc

FDA资料汇编FDA液体制剂检查指南

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液体制剂检查指南 doc》,可适用于医药卫生领域

GUIDETOINSPECTIONSORALSOLUTIONSANDSUSPENSIONSNote:ThisdocumentisreferencematerialforinvestigatorsandotherFDApersonnelThedocumentdoesnotbindFDA,anddoesnoconferanyrights,privileges,benefits,orimmunitiesfororonanyperson(s)IINTRODUCTIONThemanufactureandcontroloforalsolutionsandoralsuspensionshaspresentedsomeproblemstotheindustryWhilebioequivalencyconcernsareminimal(exceptfortheantisepticproductssuchasphenytoinsuspension),thereareotherissueswhichhaveledtorecallsTheseincludemicrobiological,potencyandstabilityproblemsAdditionally,becausethepopulationusingtheseoraldosageformsincludesnewborns,pediatricsandgeriatricswhomaynotbeabletotakeoralsoliddosageformsandmaybecompromised,defectivedosageformscanposeagreaterriskbecauseofthepopulationbeingdosedThus,thisguidewillreviewsomeofthesignificantpotentialproblemareasandprovidedirectiontotheinvestigatorwhengivinginspectionalcoverageIIFACILITIESThedesignofthefacilitiesarelargelydependentuponthetypeofproductsmanufacturedandthepotentialforcrosscontaminationandmicrobiologicalcontaminationForexample,thefacilitiesusedforthemanufactureofOTCoralproductsmightnotrequiretheisolationthatasteroidorsulfaproductwouldrequireReviewtheproductsmanufacturedandtheproceduresusedbythefirmfortheisolationofprocessestominimizecontaminationObservetheadditionofdrugsubstanceandpowderedexcipientstomanufacturingvesselstodetermineifoperationsgeneratedustObservethesystemsandtheefficiencyofthedustremovalsystemThefirm'sHVAC(HeatingVentilationandAirConditioning)systemmayalsowarrantcoverageparticularlywherepotentorhighlysensitizingdrugsareprocessedSomemanufacturersrecirculateairwithoutadequatefiltrationWhereairisrecirculated,reviewthefirm'sdatawhichdemonstratestheefficiencyofairfiltrationsuchshouldincludesurfaceandorairsamplingIIIEQUIPMENTEquipmentshouldbeofsanitarydesignThisincludessanitarypumps,valves,flowmetersandotherequipmentwhichcanbeeasilysanitizedBallvalves,packinginpumpsandpocketsinflowmetershavebeenidentifiedassourcesofcontaminationInordertofacilitatecleaningandsanitization,manufacturingandfillinglinesshouldbeidentifiedanddetailedindrawingsandSOPsInsomecases,longdeliverylinesbetweenmanufacturingareasandfillingareashavebeenasourceofcontaminationAlso,SOPs,particularlywithregardtotimelimitationsbetweenbatchesandforcleaninghavebeenfounddeficientinmanymanufacturersReviewcleaningSOPs,includingdrawingsandvalidationdatawithregardtocleaningandsanitizationEquipmentusedforbatchingandmixingoforalsolutionsandsuspensionsisrelativelybasicGenerally,theseproductsareformulatedonaweightbasiswiththebatchingtankonloadcellssothatafinalQScanbemadebyweightVolumetricmeans,suchasusingadipstickorlineonatank,havebeenfoundtobeinaccurateInmostcases,manufacturerswillassaysamplesofthebulksolutionorsuspensionpriortofillingAmuchgreatervariabilityhasbeenfoundwithbatchesthathavebeenmanufacturedvolumetricallyratherthanbyweightForexample,onemanufacturerhadtoadjustapproximatelyofthebatchesmanufacturedafterthefinalQSbecauseoffailuretocomplywithpotencyspecificationsUnfortunately,themanufacturerreliedsolelyonthebulkassayAfterreadjustmentofthepotencybasedontheassay,batchesoccasionallywerefoundoutofspecificationbecauseofanalyticalerrorsThedesignofthebatchingtankwithregardtothelocationofthebottomdischargevalvehasalsopresentedproblemsIdeally,thebottomdischargevalveisflushwiththebottomofthetankInsomecasesvalves,includingundesirableballvalves,havebeenfoundtobeseveralinchestoafootbelowthebottomofthetankInothers,drugorpreservativewasnotcompletelydissolvedandwaslyinginthe"deadleg"belowthetankwithinitialsamplesbeingfoundtobesubpotentForthemanufactureofsuspensions,valvesshouldbeflushReviewandobservethebatchingequipmentandtransferlinesWithregardtotransferlines,theyaregenerallyhardpipedandeasilycleanedandsanitizedInsomecasesmanufacturershaveusedflexiblehosestotransferproductItisnotunusualtoseeflexiblehoseslyingonthefloor,thussignificantlyincreasingthepotentialforcontaminationSuchcontaminationcanoccurbyoperatorspickinguporhandlinghoses,andpossiblyevenplacingthemintransferorbatchingtanksaftertheyhadbeenlyingonthefloorItisalsoagoodpracticetostorehosesinawaythatallowsthemtodrainratherthanbecoiledwhichmayallowmoisturetocollectandbeapotentialsourceofmicrobialcontaminationObservemanufacturingareasandoperatorpractices,particularlywhenflexiblehoseconnectionareemployedAnothercommonproblemoccurswhenamanifoldorcommonconnectionsareused,especiallyinwatersupply,premixorrawmaterialsupplytanksSuchcommonconnectionshavebeenshowntobeasourceofcontaminationIVRAWMATERIALSThephysicalcharacteristics,particularlytheparticlesizeofthedrugsubstance,areveryimportantforsuspensionsAswithtopicalproductsinwhichthedrugissuspended,particlesareusuallyveryfinetomicronized(lessthanmicrons)Forsyrups,elixirorsolutiondosageformsinwhichthereisnothingsuspended,particlesizeandphysicalcharacteristicsofrawmaterialsarenotthatimportantHowever,theycanaffecttherateofdissolutionofsuchrawmaterialsinthemanufacturingprocessRawmaterialsofafinerparticlesizemaydissolvefasterthanthoseofalargerparticlesizewhentheproductiscompoundedExamplesofafewoftheoralsuspensionsinwhichaspecificandwelldefinedparticlesizespecificationforthedrugsubstanceisimportantincludephenytoinsuspension,carbamazepinesuspension,trimethoprimandsulfamethoxazolesuspension,andhydrocortisonesuspensionReviewthephysicalspecificationsforanydrugsubstancewhichissuspendedinthedosageformVCOMPOUNDINGInadditiontoadeterminationofthefinalvolume(QS)aspreviouslydiscussed,therearemicrobiologicalconcernsFororalsuspensions,thereistheadditionalconcernwithuniformity,particularlybecauseofthepotentialforsegregationduringmanufactureandstorageofthebulksuspension,duringtransfertothefillinglineandduringfillingReviewthefirm'sdatathatsupportstoragetimesandtransferoperationsThereshouldbeestablishedproceduresandtimelimitsforsuchoperationstoaddressthepotentialforsegregationorsettlingaswellasotherunexpectedeffectsthatmaybecausedbyextendedholdingorstirringFororalsolutionsandsuspensions,theamountandcontroloftemperatureisimportantfromamicrobiologicalaswellasapotencyaspectForthoseproductsinwhichtemperatureisidentifiedasacriticalpartoftheoperation,thefirm'sdocumentationoftemperature,suchasbycontrolcharts,shouldbereviewedTherearesomemanufacturersthatrelyonheatduringcompoundingtocontrolthemicrobiologicallevelsinproductForsuchproducts,theadditionofpurifiedwatertofinalQS,thebatch,andthetemperaturesduringprocessingshouldbereviewedInadditiontodrugsubstances,someadditives,suchastheparabensaredifficulttodissolveandrequireheatThecontrolandassuranceoftheirdissolutionduringthecompoundingstageshouldbereviewedFromapotencyaspect,thestorageofproductathightemperaturesmayincreasethelevelofdegradantsStoragelimitations(timeandtemperature)shouldbejustifiedbythefirmandevaluatedduringyourinspectionTherearealsosomeoralliquidswhicharesensitivetooxygenandhavebeenknowntoundergodegradationThisisparticularlytrueofthephenothiazineclassofdrugs,suchasperphenazineandchlorpromazineThemanufactureofsuchproductsmightrequiretheremovalofoxygensuchasbynitrogenpurgingAdditionally,suchproductsmightalsorequirestorageinsealedtanks,ratherthanthosewithlooselidsManufacturingdirectionsfortheseproductsshouldbereviewedVIMICROBIOLOGICALQUALITYTherearesomeoralliquidsinwhichmicrobiologicalcontaminationcanpresentsignificanthealthhazardsForexample,someoralliquids,suchasnystatinsuspensionareusedininfantsandimmunocompromisedpatients,andmicrobiologicalcontaminationwithorganisms,suchasGramnegativeorganisms,isobjectionableThereareotheroralliquidpreparationssuchasantacidsinwhichPseudomonasspcontaminationisalsoobjectionableForotheroralliquidssuchascoughpreparations,thecontaminationwithPseudomonasspmightnotpresentthesamehealthhazardObviously,thecontaminationofanypreparationwithGramnegativeorganismsisnotdesirableInadditiontothespecificcontaminantbeingobjectionable,suchcontaminationwouldbeindicativeofadeficientprocessaswellasaninadequatepreservativesystemThepresenceofaspecificPseudomonasspmayalsoindicatethatotherplantorrawmaterialcontaminantscouldsurvivetheprocessForexample,thefactthataPseudomonasputidacontaminantispresentcouldalsoindicatethatPseudomonasaeruginosa,asimilarsourceorganism,couldalsobepresentBoththetopicalandmicrobiologicalinspectionguidesdiscussthemethodsandlimitationsofmicrobiologicaltestingSimilarmicrobiologicaltestingconceptsdiscussedapplytothetestingoforalliquidsformicrobiologicalcontaminationReviewthemicrobiologicaltestingofrawmaterials,includingpurifiedwater,aswellasthemicrobiologicaltestingoffinishedproductsSinceFDAlaboratoriestypicallyutilizemoresensitivetestmethodsthanindustry,considersamplinganyoralliquidsinwhichmanufacturershavefoundmicrobiologicalcounts,nomatterhowlowSubmitsamplesfortestingforobjectionablemicroorganismsVIIORALSUSPENSIONSUNIFORMITYThoseliquidproductsinwhichthedrugissuspended(andnotinsolution)presentmanufacturerandcontrolproblemsThoseliquidproductsinwhichthedrugissuspended(andnotinsolution)presentmanufactureandcontrolproblemsDependingupontheviscosity,manysuspensionsrequirecontinuousorperiodicagitationduringthefillingprocessIfdeliverylinesareusedbetweenthebulkstoragetankandthefillingequipment,somesegregationmayoccur,particularlyiftheproductisnotviscousReviewthefirm'sproceduresforfillinganddiagramsforlinesetuppriortothefillingequipmentGoodmanufacturingpracticewouldwarranttestingbottlesfromthebeginning,middleandendtoassurethatsegregationhasnotoccurredSuchsamplesshouldnotbecompositedInprocesstestingforsuspensionsmightalsoincludeanassayofasamplefromthebulktankMoreimportant,however,maybetestingforviscosityVIIIPRODUCTSPECIFICATIONSImportantspecificationsforthemanufactureofallsolutionsincludeassayandmicrobiallimitsAdditionalimportantspecificationsforsuspensionsincludeparticlesizeofthesuspendeddrug,viscosity,pH,andinsomecasesdissolutionViscositycanbeimportantfromaprocessingaspecttominimizesegregationAdditionally,viscosityhasalsobeenshowntobeassociatedwithbioequivalencypHmayalsohavesomemeaningregardingeffectivenessofpreservativesystemsandmayevenhaveaneffectontheamountofdruginsolutionWithregardtodissolution,thereareatleastthreeproductswhichhavedissolutionspecificationsTheseproductsincludephenytoinsuspension,carbamazepinesuspension,andsulfamethoxazoleandtrimethoprimsuspensionParticlesizeisalsoimportantandatthispointitwouldseemthatanysuspensionshouldhavesometypeofparticlesizespecificationAswithotherdosageforms,theunderlyingdatatosupportspecificationsshouldbereviewedIXPROCESSVALIDATIONAswithotherproducts,theamountofdataneededtosupportthemanufacturingprocesswillvaryfromproducttoproductDevelopment(data)shouldhaveidentifiedcriticalphasesoftheoperation,includingthepredeterminedspecifications,thatshouldbemonitoredduringprocessvalidationForexample,forsolutionsthekeyaspectsthatshouldbeaddressedduringvalidationincludeassurancethatthedrugsubstanceandpreservativesaredissolvedParameters,suchasheatandtimeshouldbemeasuredAlso,inprocessassayofthebulksolutionduringandoraftercompoundingaccordingtopredeterminedlimitsarealsoanimportantaspectsofprocessvalidationForsolutionsthataresensitivetooxygenandorlight,dissolvedoxygenlevelswouldalsobeanimportanttestAgain,thedevelopmentdataandtheprotocolshouldprovidelimitsReviewfirm'sdevelopmentdataandordocumentationfortheirjustificationoftheprocessAsdiscussed,themanufactureofsuspensionspresentsadditionalproblems,particularlyintheareaofuniformityAgain,developmentdatashouldhaveaddressedthekeycompoundingandfillingstepsthatassureuniformityTheprotocolshouldprovideforthekeyinprocessandfinishedproducttests,alongwiththeirspecificationsFororalsolutions,bioequivalencystudies<<<Continuedtonextmessage>>><<<Thismessageispartofapreviousmessage>>>maynotalwaysbeneededHowever,oralsuspensions,withthepossibleexceptionofsomeoftheantacids,OTCproducts,usuallyrequireabioequivalencyorclinicalstudytodemonstrateeffectivenessAswithoralsoliddosageforms,comparisontothebiobatchisanimportantpartofvalidationoftheprocessReviewthefirm'sprotocolandprocessvalidationreportand,ifappropriate,comparedataforfullscalebatchestobiobatch,dataandmanufacturingprocessesXSTABILITYOneareathathaspresentedanumberofproblemsincludestheassuranceofstabilityoforalliquidproductsthroughouttheirexpiryperiodForexample,therehavebeenanumberofrecallsofthevitaminswithfluorideoralliquidproductsbecauseofvitamindegradationDrugsinthephenothiazineclass,suchasperphenazine,chlorpromazineandpromethazinehavealsoshownevidenceofinstabilityGoodpracticeforthisclassofdrugproductswouldincludequantitationofboththeactiveandprimarydegradantDosageformmanufacturersshouldknowandhavespecificationsfortheprimarydegradantReviewthefirm'sdataandvalidationdataformethodsusedtoquantitateboththeactivedruganddegradantBecauseinteractionsofproductswithclosuresystemsarepossible,liquidsandsuspensionsundergoingstabilitystudiesshouldbestoredontheirsideorinvertedinordertodeterminewhethercontactofthedrugproductwiththeclosuresystemaffectsproductintegrityMoisturelosswhichcancausetheremainingcontentstobecomesuperpotentandmicrobiologicalcontaminationareotherproblemsassociatedwithinadequateclosuresystemsXIPACKAGINGProblemsinthepackagingoforalliquidshaveincludedpotency(fill)ofunitdoseproducts,accuratecalibrationofmeasuringdevicessuchasdroppersthatareoftenprovidedTheUSPdoesnotprovidefordoseuniformitytestingfororalsolutionsThus,forunitdosesolutionproducts,theyshoulddeliverthelabelclaimwithinthelimitsdescribedintheUSPReviewthefirm'sdatatoassureuniformityoffillandtestprocedurestoassurethatunitdosesamplesarebeingtestedAnotherprobleminthepackagingofOralLiquidsisthelackofcleanlinessofcontainerspriortofillingFibersandeveninsectshavebeenidentifiedasdebrisincontainers,andparticularlyplasticcontainersusedfortheseproductsManymanufacturersreceivecontainersshrinkwrappedinplastictominimizecontaminationfromfiberboardcartonsManymanufacturersutilizecompressedairtocleancontainersVapors,suchasoilvapors,fromthecompressedairhaveoccasionallybeenfoundtopresentproblemsReviewthefirm'ssystemsforthecleaningofcontainersTherearenoreferencesfromthisdocument

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