药物BCS分类系统专家讲座

PharmaceuticalDevelopmentwithFocusonPaediatricformulationsWHO/FIPTrainingWorkshopHyattRegencyHotelSaharAirportRoadAndheriEast,Mumbai,India28April–2May药物BCS分类系统专家讲座第1页

BiopharmaceuticalClassificationSystem(BCS)

Presentedby:LembitRägoMD,PhDContactdetails:DrLembitRägoCoordinator,QualityAssuranceandSafety:MedicinesMedicinesPolicyandStandardsWorldHealthOrganizationGenevaSwitzerlandE-Mail:ragol@药物BCS分类系统专家讲座第2页

BiopharmaceuticalClassificationSystem(BCS)

BackgroundWhatisaproblem?WhatisWHOdoingandplanningtodo?Whatresourcesareavailable?Conclusions药物BCS分类系统专家讲座第3页Whatisthekeyformultisource(generic)pharmaceuticalproducts?Newmedicines–applicanthastoprovequality,safetyandefficacyMultisource(generic)pharmaceuticalproducts–applicanthastoprovequality,incaseofsafetyandefficacyitreferstotheoriginatorproductThekeyisTHERAPEUTICINTERCHANGEABILITYItisassumedthatiftheconcentrationpatterninthebloodisessentiallythesamethenthesafetyandefficacyprofilemustbeessentiallythesame药物BCS分类系统专家讲座第4页Therapeuticinterchangeability:prerequisitesConstantandreproduciblequalityofMPPsManufacturedunderGMPCompliancewithallqualityspecificationsVariationscontrolNoconstantandreproduciblequality,noneedforprovinginterchangeabilityasitismeaningless(allbatchesdifferentanyhow…)药物BCS分类系统专家讲座第5页Optionstoshowtherapeuticinterchangeabilityofmultisourcepharmaceuticalproducts(MPP)Sensitivity/useExperimentalsettingGenerallyregardedasmostsensitive

Comparativepharmacokineticstudiesinhumans–evaluationofsystemicexposurebymeansofpharmacokineticmeasureslikee.g.AUCandCmax(andTmax)

PrerequisitesshouldbenotedComparativeinvitrotests–BCS-basedbiowaiverSensitivitymaynotbeoptimal,rarelyusedComparativepharmacodynamicstudiesinhumans–evaluationofrelevantpharmacodynamicendpointslikee.g.,loweredbloodpressureinmmHgRarelyusedfororalMPPformulationswithsystemicactionscomparativeclinicaltrials–evaluationofe.g.,non-inferioritytrials药物BCS分类系统专家讲座第6页TheinvitroapproachreferstotheBiopharmaceuticsClassificationSystem(BCS)

BCSclassificationSolubilityPermeabilityBCSclassIHighHighBCSclassIILowHighBCSclassIIIHighLowBCSclassIVLowLowDrugsubstanceclassificationaccordingtotheBCS.Activepharmaceuticalingredients(APIs)areclassifiedintoclassesbasedontheiraqueoussolubilityandpermeabilitycharacteristics

药物BCS分类系统专家讲座第7页InVitroApproaches/Biowaiveroptions

Thepossibilityof‘invitrodocumentationofbioequivalence’for‘certainmedicinesanddosageforms’isspecifiedinSection9oftheWHOguidancedocument[1].Ifthedrugsubstanceinquestionishighlysolubleandhighlypermeable(BCSclassI)andismanufacturedasanimmediatereleasedosageform,exemptionfromaninvivopharmacokineticbioequivalencestudymaybeconsideredprovidedthatrelevantdissolutionrequirementsarefulfilled.药物BCS分类系统专家讲座第8页PrinciplesThesolubilityisnotmeanttobetheabsolutesolubilityhere.Incontrasthighsolubilityreferstothehighestsingleunitdosetobecompletelysolublein250mlaqueousbuffermediumwithinthepHrangeof1.2to6.8withoutanystabilityproblems.AsanotherrelatedphysicochemicalcharacteristichighpermeabilityshouldbedemonstratedfortheparticularAPIdemonstratingthatthefractiondoseabsorbedamountstoatleast85%.Accordingly,highpermeabilitywouldstandforalmostcompleteabsorptionofthecompoundinhumans.PhysicochemicalmeasuresneededforBCSclassificationpurposesmaybetakenfromsoundliterature.TheWHOModelListofEssentialMedicineshasbeenreviewedbasedontheBCSconceptandactivecompoundsareclassifiedaccordinglyintheappendixofrespectiveWHOdocument[1].药物BCS分类系统专家讲座第9页AtheoreticalriskassessmentismandatorytominimizeriskforfalselywaivinganecessaryinvivostudyImmediatereleasedosageformswithintendedsystemicaction

Formulationrelatedconsiderations-criticalusemedicines(e.g.hormones)-non-oral,non-parenteralproductswithsystemicaction(e.g.transdermaltherapeuticsystems(TTS),suppositories,etc.)-narrowtherapeuticrange(steepdose-responsecurve)drugs-modifiedreleaseproductswithsystemicaction-wheretherearedocumentedevidenceofbioavailabilityproblems(orbio-inequivalence-fixedcombinationproductswithatleastoneAPIrequiringaninvivostudyi.e.,thisAPIisnoteligiblefortheBCSbasedbiowaiverapproach-polymorphs,certainexcipients,oramanufacturingprocesswhichmayhaveimplicationsforbioavailability-non-solutionproductswithnon-systemicaction(andwithoutsystemicabsorption*),e.g.,topical,locallyactingemulsionsSituationswhereBCS-basedbiowaiversarenotapplicable

药物BCS分类系统专家讲座第10页Assessmentofrisks–practicalpointsInpracticesomeofthecriterialistedinthetableforriskassessmentaredifficulttoassesse.g.,themeaningof‘criticaluse’or‘bioavailabilityproblems’,andareprobablynoteasytobedefined.However,publishedliteratureprovidesvaluableexamplesofhowtoevaluatetheapplicabilityoftheBCSbasedbiowaiverapproach(seebiowaivermonographsonthefollowingslide).药物BCS分类系统专家讲座第11页Availableresources:BiowaiverMonographsBiowaivermonographsareworkedoutbygroupofwellestablishedscientistslinkedtoFIPandpublishedinJournalofPharmaceuticalSciencesThesecanbeusefulscientificmaterialformanufacturerswhenconsideringapplicationsforbiowaiverbasedonBCSThemonographsassuchhaveno"regulatoryauthority"–decisionswillbemadebyregulatorswhomayormaynotacceptbiowaiverdependingontheirnationallegislationandrequirements药物BCS分类系统专家讲座第12页BiowaivermonographspublishedStosikA.G.,JungingerH.E.,KoppS.,MidhaK.K.,ShahV.P.,StavchanskyS.,DressmanJ.B.,BarendsD.M.:Biowaivermonographsforimmediatereleasesolidoraldosageforms:metoclopramidehydrochloride.JPharmSciFeb12()BeckerC.,DressmanJ.B.,AmidonG.L,JungingerH.E.,KoppS.,MidhaK.K.,ShahV.P.,StavchanskyS.,BarendsD.M.:Biowaivermonographsforimmediatereleasesolidoraldosageforms:Pyrazinamide.JPharmSciFeb12()BeckerC.,DressmanJ.B.,AmidonG.L,JungingerH.E.,KoppS.,MidhaK.K.,ShahV.P.,StavchanskyS.,BarendsD.M.:Biowaivermonographsforimmediatereleasesolidoraldosageforms:ethambutoldihydrochloride.JPharmSciAug21()BeckerC.,DressmanJ.B.,AmidonG.L,JungingerH.E.,KoppS.,MidhaK.K.,ShahV.P.,StavchanskyS.,BarendsD.M.:Biowaivermonographsforimmediatereleasesolidoraldosageforms:isoniazid.JPharmSci96()522-31药物BCS分类系统专家讲座第13页WHOGuidance(1)TheinvitrodissolutioninvestigationsincludingexperimentalconditionsandcharacteristicsareoutlinedinSection9oftheWHOguideline[1].Itisofutmostimportancetonotethatitisnotsufficienttodemonstratetheinvitrodissolutioncharacteristicsfortheparticularmultisourceproduct,buttoensure‘thesimilarityofdissolutionprofilesbetweenthetestandcomparatorproducts’[1].药物BCS分类系统专家讲座第14页WHOguidance(2)TheWHOguidanceinbasicaspectsissimilartotheUSFDAguidanceonthebiowaiverapproach(August)Inaddition,thecurrentscientificdiscussionsintermsofsocalled‘biowaiverextensions’arealsoconsidered.Accordingly,BCSbasedbiowaiversmaybeacceptablefordrugscontainingBCSclass2and3drugsubstancesmanufacturedasimmediatereleasedosageforms.Asanexample,abiowaivermaybepossibleforBCSclass3drugproductsthatare‘veryrapidly’(i.e.atleast85%dissolutionwithin15mininallrequiredmedia)dissolving.Therelevantdissolutioncriteriaareoutlinedinsection9.2.1oftheWHOguideline[1].药物BCS分类系统专家讲座第15页RegulatorsguidanceforindustryUSFDArelevanttobiowaiverguidelines:/cder/Guidance/3618fnl.pdf药物BCS分类系统专家讲座第16页ConclusionsBiowaiverconceptisadevelopingconceptandnewguidancedocumentsandscientificdataareappearingPropercomparatorproductsarealsocrucialforbiowaiverRegulatoryacceptanceandpracticeofbiowaiversneedstocatchuptheconceptdevelopmentWHOwillsoonissuemorepracticalimplementationguidelinesforPQprogrammeWHOPQprogrammestartsacceptingbiowaivers,asappropriate药物BCS分类系统专家讲座第17页Someusefulreferences(1)Multisource(generic)pharmaceuticalproducts:Guidelinesonregistrationrequirementstoestablishinterchangeability.In:WHOExpertCommitteeonSpecificationsforPharmaceuticalPreparations,FortiethReport.Geneva,WorldHealthOrganization,,WHOTechnicalReportSeries,No.937,Annex7:347-390.(2)vanFaassenF.,VromansH.etal.

Biowaiversfororalimmediate-releaseproducts:implicationsoflinearpharmacokinetics.ClinPharmacokinet43()1117.(3)NotetoApplicantsontheChoiceofComparatorProductsfortheP