药物BCS分类系统

PharmaceuticalDevelopmentwithFocusonPaediatricformulations,WHO/FIPTrainingWorkshopHyattRegencyHotelSaharAirportRoadAndheriEast,Mumbai,India28April20082May2008,BiopharmaceuticalClassificationSystem(BCS),Presentedby:LembitRgoMD,PhDContactdetails:DrLembitRgoCoordinator,QualityAssuranceandSafety:MedicinesMedicinesPolicyandStandardsWorldHealthOrganizationGenevaSwitzerlandE-Mail:,BiopharmaceuticalClassificationSystem(BCS),BackgroundWhatisaproblem?WhatisWHOdoingandplanningtodo?Whatresourcesareavailable?Conclusions,Whatisthekeyformultisource(generic)pharmaceuticalproducts?,Newmedicinesapplicanthastoprovequality,safetyandefficacyMultisource(generic)pharmaceuticalproductsapplicanthastoprovequality,incaseofsafetyandefficacyitreferstotheoriginatorproductThekeyisTHERAPEUTICINTERCHANGEABILITYItisassumedthatiftheconcentrationpatterninthebloodisessentiallythesamethenthesafetyandefficacyprofilemustbeessentiallythesame,Therapeuticinterchangeability:prerequisites,ConstantandreproduciblequalityofMPPsManufacturedunderGMPCompliancewithallqualityspecificationsVariationscontrolNoconstantandreproduciblequality,noneedforprovinginterchangeabilityasitismeaningless(allbatchesdifferentanyhow),Optionstoshowtherapeuticinterchangeabilityofmultisourcepharmaceuticalproducts(MPP),TheinvitroapproachreferstotheBiopharmaceuticsClassificationSystem(BCS),DrugsubstanceclassificationaccordingtotheBCS.Activepharmaceuticalingredients(APIs)areclassifiedintoclassesbasedontheiraqueoussolubilityandpermeabilitycharacteristics,InVitroApproaches/Biowaiveroptions,ThepossibilityofinvitrodocumentationofbioequivalenceforcertainmedicinesanddosageformsisspecifiedinSection9oftheWHOguidancedocument1.Ifthedrugsubstanceinquestionishighlysolubleandhighlypermeable(BCSclassI)andismanufacturedasanimmediatereleasedosageform,exemptionfromaninvivopharmacokineticbioequivalencestudymaybeconsideredprovidedthatrelevantdissolutionrequirementsarefulfilled.,Principles,Thesolubilityisnotmeanttobetheabsolutesolubilityhere.Incontrasthighsolubilityreferstothehighestsingleunitdosetobecompletelysolublein250mlaqueousbuffermediumwithinthepHrangeof1.2to6.8withoutanystabilityproblems.AsanotherrelatedphysicochemicalcharacteristichighpermeabilityshouldbedemonstratedfortheparticularAPIdemonstratingthatthefractiondoseabsorbedamountstoatleast85%.Accordingly,highpermeabilitywouldstandforalmostcompleteabsorptionofthecompoundinhumans.PhysicochemicalmeasuresneededforBCSclassificationpurposesmaybetakenfromsoundliterature.TheWHOModelListofEssentialMedicineshasbeenreviewedbasedontheBCSconceptandactivecompoundsareclassifiedaccordinglyintheappendixofrespectiveWHOdocument1.,Atheoreticalriskassessmentismandatorytominimizeriskforfalselywaivinganecessaryinvivostudy,SituationswhereBCS-basedbiowaiversarenotapplicable,Assessmentofriskspracticalpoints,Inpracticesomeofthecriterialistedinthetableforriskassessmentaredifficulttoassesse.g.,themeaningofcriticaluseorbioavailabilityproblems,andareprobablynoteasytobedefined.However,publishedliteratureprovidesvaluableexamplesofhowtoevaluatetheapplicabilityoftheBCSbasedbiowaiverapproach(seebiowaivermonographsonthefollowingslide).,Availableresources:BiowaiverMonographs,BiowaivermonographsareworkedoutbygroupofwellestablishedscientistslinkedtoFIPandpublishedinJournalofPharmaceuticalSciencesThesecanbeusefulscientificmaterialformanufacturerswhenconsideringapplicationsforbiowaiverbasedonBCSThemonographsassuchhavenoregulatoryauthoritydecisionswillbemadebyregulatorswhomayormaynotacceptbiowaiverdependingontheirnationallegislationandrequirements,Biowaivermonographspublished,StosikA.G.,JungingerH.E.,KoppS.,MidhaK.K.,ShahV.P.,StavchanskyS.,DressmanJ.B.,BarendsD.M.:Biowaivermonographsforimmediatereleasesolidoraldosageforms:metoclopramidehydrochloride.JPharmSciFeb12(2008)BeckerC.,DressmanJ.B.,AmidonG.L,JungingerH.E.,KoppS.,MidhaK.K.,ShahV.P.,StavchanskyS.,BarendsD.M.:Biowaivermonographsforimmediatereleasesolidoraldosageforms:Pyrazinamide.JPharmSciFeb12(2008)BeckerC.,DressmanJ.B.,AmidonG.L,JungingerH.E.,KoppS.,MidhaK.K.,ShahV.P.,StavchanskyS.,BarendsD.M.:Biowaivermonographsforimmediatereleasesolidoraldosageforms:ethambutoldihydrochloride.JPharmSciAug21(2007)BeckerC.,DressmanJ.B.,AmidonG.L,JungingerH.E.,KoppS.,MidhaK.K.,ShahV.P.,StavchanskyS.,BarendsD.M.:Biowaivermonographsforimmediatereleasesolidoraldosageforms:isoniazid.JPharmSci96(2007)522-31,WHOGuidance(1),TheinvitrodissolutioninvestigationsincludingexperimentalconditionsandcharacteristicsareoutlinedinSection9oftheWHOguideline1.Itisofutmostimportancetonotethatitisnotsufficienttodemonstratetheinvitrodissolutioncharacteristicsfortheparticularmultisourceproduct,buttoensurethesimilarityofdissolutionprofilesbetweenthetestandcomparatorproducts1.,WHOguidance(2),TheWHOguidanceinbasicaspectsissimilartotheUSFDAguidanceonthebiowaiverapproach(August2000)Inaddition,thecurrentscientificdiscussionsintermsofsocalledbiowaiverextensionsarealsoconsidered.Accordingly,BCSbasedbiowaiversmaybeacceptablefordrugscontainingBCSclass2and3drugsubstancesmanufacturedasimmediatereleasedosageforms.Asanexample,abiowaivermaybepossibleforBCSclass3drugproductsthatareveryrapidly(i.e.atleast85%dissolutionwithin15mininallrequiredmedia)dissolving.Therelevantdissolutioncriteriaareoutlinedinsection9.2.1oftheWHOguideline1.,Regulatorsguidanceforindustry,USFDArelevanttobiowaiverguidelines:/cder/Guidance/3618fnl.pdf,Conclusions,BiowaiverconceptisadevelopingconceptandnewguidancedocumentsandscientificdataareappearingPropercomparatorproductsarealsocrucialforbiowaiverRegulatoryacceptanceandpracticeofbiowaiversneedstocatchuptheconceptdevelopmentWHOwillsoonissuemorepracticalimplementationguidelinesforPQprogrammeWHOPQprogrammestartsacceptingbiowaivers,asappropriate,Someusefulreferences,(1)Multisource(generic)pharmaceuticalproducts:Guidelinesonregistrationrequirementstoestablishinterchangeability.In:WHOExpertCommitteeonSpecificationsforPharmaceuticalPreparations,FortiethReport.Geneva,WorldHealthOrganization,2006,WHOTechnicalReportSeries,No.937,Annex7:347-390.(2)vanFaassenF.,VromansH.etal.Biowaiversfororalimmediate-releaseproducts:implicationsoflinearpharmacokinetics.ClinPharmacokinet43(2004)1117.(3)NotetoApplicantsontheChoiceofComparatorProductsforthePrequalificationProject.LocatedontheWorldHealthOrganization(WHO)PrequalificationofMedicineswebsite,Guidanceonselectionofcomparatorproduct.Webpage:/pq/(4)Shah,V.P.et