FDA溶出度指南

GuidanceforIndustryDissolutionTestingofImmediateReleaseSolidOralDosageFormsU.S.DepartmentofHealthandHumanServicesFoodandDrugAdministrationCenterforDrugEvaluationandResearch(CDER)August1997BP1GuidanceforIndustryDissolutionTestingofImmediateReleaseSolidOralDosageFormsAdditionalcopiesareavailablefrom:OfficeofTrainingandCommunicationsDivisionofCommunicationsManagementTheDrugInformationBranch,HFD-2105600FishersLaneRockville,MD20857(Tel)301-827-4573(Internet)(CDER)August1997BP1iTableofContentsI.INTRODUCTION.....................................................1II.BACKGROUND......................................................1III.BIOPHARMACEUTICSCLASSIFICATIONSYSTEM.......................2IV.SETTINGDISSOLUTIONSPECIFICATIONS..............................3A.ApproachesforSettingDissolutionSpecificationsforaNewChemicalEntity...4B.ApproachesforSettingDissolutionSpecificationsforGenericProducts.......5C.SpecialCases...................................................6D.MappingorResponseSurfaceMethodology............................7E.InVivo-InVitroCorrelations.......................................7F.ValidationandVerificationofSpecifications............................8V.DISSOLUTIONPROFILECOMPARISONS................................8A.ModelIndependentApproachUsingaSimilarityFactor...................8B.ModelIndependentMultivariateConfidenceRegionProcedure............10C.ModelDependentApproaches.....................................10VI.DISSOLUTIONANDSUPAC-IR.......................................11VII.BIOWAIVERS......................................................11AppendixA..............................................................A-1REFERENCESThisguidancehasbeenpreparedbytheImmediateReleaseExpertWorkingGroupoftheBiopharmaceutics1CoordinatingCommitteeintheCenterforDrugEvaluationandResearch(CDER)attheFoodandDrugAdministration.ThisguidancedocumentrepresentstheAgency’scurrentthinkingonthedissolutiontestingofimmediatereleasesolidoraldosageforms.ItdoesnotcreateorconferanyrightsfororonanypersonanddoesnotoperatetobindFDAorthepublic.Analternativeapproachmaybeusedifsuchapproachsatisfiestherequirementsoftheapplicablestatute,regulations,orboth.GUIDANCEFORINDUSTRY1DissolutionTestingofImmediateReleaseSolidOralDosageFormsI.INTRODUCTIONThisguidanceisdevelopedforimmediaterelease(IR)dosageformsandisintendedtoprovide(1)generalrecommendationsfordissolutiontesting;(2)approachesforsettingdissolutionspecificationsrelatedtothebiopharmaceuticcharacteristicsofthedrugsubstance;(3)statisticalmethodsforcomparingdissolutionprofiles;and(4)aprocesstohelpdeterminewhendissolutiontestingissufficienttograntawaiverforaninvivobioequivalencestudy.Thisdocumentalsoprovidesrecommendationsfordissolutionteststohelpensurecontinuousdrugproductqualityandperformanceaftercertainpostapprovalmanufacturingchanges.Summaryinformationondissolutionmethodology,apparatus,andoperatingconditionsfordissolutiontestingofIRproductsisprovidedinsummaryforminAppendixA.ThisguidanceisintendedtocomplementtheSUPAC-IRguidanceforindustry:ImmediateReleaseSolidOralDosageForms:Scale-upandPost-ApprovalChanges:Chemistry,ManufacturingandControls,InVitroDissolutionTesting,andInVivoBioequivalenceDocumentation,withspecificreferencetothegenerationofdissolutionprofilesforcomparativepurposes.II.BACKGROUNDDrugabsorptionfromasoliddosageformafteroraladministrationdependsonthereleaseofthedrugsubstancefromthedrugproduct,thedissolutionorsolubilizationofthedrugunderphysiologicalconditions,andthepermeabilityacrossthegastrointestinaltract.Becauseofthecriticalnatureofthefirsttwoofthesesteps,invitrodissolutionmayberelevanttothepredictionofinvivoperformance.Basedonthisgeneralconsideration,invitrodissolutiontestsforimmediatereleasesolidoraldosageforms,suchastabletsandcapsules,areusedto(1)assessthelot-to-lotqualityofadrugproduct;(2)guidedevelopmentofnewformulations;2and(3)ensurecontinuingproductqualityandperformanceaftercertainchanges,suchaschangesintheformulation,themanufacturingprocess,thesiteofmanufacture,andthescale-upofthemanufacturingprocess.Currentknowledgeaboutthesolubility,permeability,dissolution,andpharmacokineticsofadrugproductshouldbeconsideredindefiningdissolutiontestspecificationsforthedrugapprovalprocess.Thisknowledgeshouldalsobeusedtoensurecontinuedequivalenceoftheproduct,aswellastoensuretheproduct'ssamenessundercertainscale-upandpostapprovalchanges.Newdrugapplications(NDAs)submittedtotheFoodandDrugAdministration(FDA)containbioavailabilitydataandinvitrodissolutiondata,that,togetherwithchemistry,manufacturing,andcontrols(CMC)data,characterizethequalityandperformanceofthedrugproduct.Invitrodissolutiondataaregenerallyobtainedfrombatchesthathavebeenusedinpivotalclinicaland/orbioavailabilitystudiesandfromotherhumanstudiesconductedduringproductdevelopment.AcceptablebioequivalencedataandcomparableinvitrodissolutionandCMCdataarerequiredforapprovalofabbreviatednewdrugapplicat