药物BCS分类系统

药物药物BCSBCS分类系统分类系统|Slide2of25DrRgo28April2May2008BiopharmaceuticalClassificationSystemBiopharmaceuticalClassificationSystem(BCS)(BCS)Presentedby:LembitRgoMD,PhDContactdetails:DrLembitRgoCoordinator,QualityAssuranceandSafety:MedicinesMedicinesPolicyandStandardsWorldHealthOrganizationGenevaSwitzerlandE-Mail:ragolwho.int|Slide3of25DrRgo28April2May2008BiopharmaceuticalClassificationSystem(BCS)lBackgroundlWhatisaproblem?lWhatisWHOdoingandplanningtodo?lWhatresourcesareavailable?lConclusions|Slide4of25DrRgo28April2May2008Whatisthekeyformultisource(generic)pharmaceuticalproducts?lNewmedicinesapplicanthastoprovequality,safetyandefficacylMultisource(generic)pharmaceuticalproductsapplicanthastoprovequality,incaseofsafetyandefficacyitreferstotheoriginatorproductlThekeyisTHERAPEUTICINTERCHANGEABILITYItisassumedthatiftheconcentrationpatterninthebloodisessentiallythesamethenthesafetyandefficacyprofilemustbeessentiallythesame|Slide5of25DrRgo28April2May2008Therapeuticinterchangeability:prerequisiteslConstantandreproduciblequalityofMPPsManufacturedunderGMPCompliancewithallqualityspecificationslVariationscontrollNoconstantandreproduciblequality,noneedforprovinginterchangeabilityasitismeaningless(allbatchesdifferentanyhow)|Slide6of25DrRgo28April2May2008Optionstoshowtherapeuticinterchangeabilityofmultisourcepharmaceuticalproducts(MPP)Sensitivity/useExperimentalsettingGenerally regarded as most sensitiveComparativepharmacokineticstudiesinhumansevaluationofsystemicexposurebymeansofpharmacokineticmeasureslikee.g.AUCandCmax(andTmax)Prerequisites should be notedComparativein vitrotestsBCS-basedbiowaiverSensitivity may not be optimal,rarely usedComparativepharmacodynamicstudiesinhumansevaluationofrelevantpharmacodynamicendpointslikee.g.,loweredbloodpressureinmmHgRarely used for oral MPP formulations with systemic actionscomparativeclinicaltrialsevaluationofe.g.,non-inferioritytrials|Slide7of25DrRgo28April2May2008Thein vitro approachreferstotheBiopharmaceuticsClassificationSystem(BCS)BCSclassificationSolubilityPermeabilityBCSclassIHighHighBCSclassIILowHighBCSclassIIIHighLowBCSclassIVLowLowDrugsubstanceclassificationaccordingtotheBCS.Activepharmaceuticalingredients(APIs)areclassifiedintoclassesbasedontheiraqueoussolubilityandpermeabilitycharacteristics|Slide8of25DrRgo28April2May2008In Vitro Approaches/BiowaiveroptionslThepossibilityofinvitrodocumentationofbioequivalenceforcertainmedicinesanddosageformsisspecifiedinSection9oftheWHOguidancedocument1.lIfthedrugsubstanceinquestionishighlysolubleandhighlypermeable(BCSclassI)andismanufacturedasanimmediatereleasedosageform,exemptionfromanin vivo pharmacokineticbioequivalencestudymaybeconsideredprovidedthatrelevantdissolutionrequirementsarefulfilled.|Slide9of25DrRgo28April2May2008PrincipleslThesolubilityisnotmeanttobetheabsolutesolubilityhere.Incontrasthighsolubilityreferstothehighestsingleunitdosetobecompletelysolublein250mlaqueousbuffermediumwithinthepHrangeof1.2to6.8withoutanystabilityproblems.lAsanotherrelatedphysicochemicalcharacteristichighpermeabilityshouldbedemonstratedfortheparticularAPIdemonstratingthatthefractiondoseabsorbedamountstoatleast85%.Accordingly,highpermeabilitywouldstandforalmostcompleteabsorptionofthecompoundinhumans.lPhysicochemicalmeasuresneededforBCSclassificationpurposesmaybetakenfromsoundliterature.TheWHOModelListofEssentialMedicineshasbeenreviewedbasedontheBCSconceptandactivecompoundsareclassifiedaccordinglyintheappendixofrespectiveWHOdocument1.|Slide10of25DrRgo28April2May2008Atheoreticalriskassessmentismandatorytominimizeriskforfalselywaivinganecessaryin vivostudyImmediate release dosage forms with intended systemic actionFormulation related considerations-criticalusemedicines(e.g.hormones)-non-oral,non-parenteralproductswithsystemicaction(e.g.transdermaltherapeuticsystems(TTS),suppositories,etc.)-narrowtherapeuticrange(steepdose-responsecurve)drugs-modifiedreleaseproductswithsystemicaction-wheretherearedocumentedevidenceofbioavailabilityproblems(orbio-inequivalence-fixedcombinationproductswithatleastoneAPIrequiringanin vivostudyi.e.,thisAPIisnoteligiblefortheBCSbasedbiowaiverapproach-polymorphs,certainexcipients,oramanufacturingprocesswhichmayhaveimplicationsforbioavailability-non-solutionproductswithnon-systemicaction(andwithoutsystemicabsorption*),e.g.,topical,locallyactingemulsionsSituations where BCS-based biowaivers are not applicable|Slide11of25DrRgo28April2May2008AssessmentofriskspracticalpointslInpracticesomeofthecriterialistedinthetableforriskassessmentaredifficulttoassesse.g.,themeaningofcriticaluseorbioavailabilityproblems,andareprobablynoteasytobedefined.lHowever,publishedliteratureprovidesvaluableexamplesofhowtoevaluatetheapplicabilityoftheBCSbasedbiowaiverapproach(seebiowaivermonographsonthefollowingslide).|Slide12of25DrRgo28April2May2008Availableresources:BiowaiverMonographslBiowaivermonographsareworkedoutbygroupofwellestablishedscientistslinkedtoFIPandpublishedinJournal of Pharmaceutical Sciences lThesecanbeusefulscientificmaterialformanufacturerswhenconsideringapplicationsforbiowaiverbasedonBCSlThemonographsassuchhavenoregulatoryauthoritydecisionswillbemadebyregulatorswhomayormaynotacceptbiowaiverdependingontheirnationallegislationandrequirements|Slide13of25DrRgo28April2May2008BiowaivermonographspublishedlStosikA.G.,JungingerH.E.,KoppS.,MidhaK.K.,ShahV.P.,StavchanskyS.,DressmanJ.B.,BarendsD.M.:Biowaivermonographsforimmediatereleasesolidoraldosageforms:metoclopramidehydrochloride.JPharmSciFeb12(2008)lBeckerC.,DressmanJ.B.,AmidonG.L,JungingerH.E.,KoppS.,MidhaK.K.,ShahV.P.,StavchanskyS.,BarendsD.M.:Biowaivermonographsforimmediatereleasesolidoraldosageforms:Pyrazinamide.JPharmSciFeb12(2008)lBeckerC.,DressmanJ.B.,AmidonG.L,JungingerH.E.,KoppS.,MidhaK.K.,ShahV.P.,StavchanskyS.,BarendsD.M.:Biowaivermonographsforimmediatereleasesolidoraldosageforms:ethambutoldihydrochloride.JPharmSciAug21(2007)lBeckerC.,DressmanJ.B.,AmidonG.L,JungingerH.E.,KoppS.,MidhaK.K.,ShahV.P.,StavchanskyS.,BarendsD.M.:Biowaivermonographsforimmediatereleasesolidoraldosageforms:isoniazid.JPharmSci96(2007)522-31|Slide14of25DrRgo28April2May2008WHOGuidance(1)WHOGuidance(1)lTheinvitrodissolutioninvestigationsincludingexperimentalconditionsandcharacteristicsareoutlinedinSection9oftheWHOguideline1.lItisofutmostimportancetonotethatitisnotsufficienttodemonstratethein vitrodissolutioncharacteristicsfortheparticularmultisourceproduct,buttoensurethesimilarityofdissolutionprofilesbetweenthetestandcomparatorproducts1.|Slide15of25DrRgo28April2May2008WHOguidance(2)lTheWHOguidanceinbasicaspectsissimilartotheUSFDAguidanceonthebiowaiverapproach(August2000)lInaddition,thecurrentscientificdiscussionsintermsofsocalledbiowaiverextensionsarealsoconsidered.Accordingly,BCSbasedbiowaiversmaybeacceptablefordrugscontainingBCSclass2and3drugsubstancesmanufacturedasimmediatereleasedosageforms.lAsanexample,abiowaivermaybepossibleforBCSclass3drugproductsthatareveryrapidly(i.e.atleast85%dissolutionwithin15mininallrequiredmedia)dissolving.Therelevantdissolutioncriteriaareoutlinedinsection9.2.1oftheWHOguideline1.|Slide16of25DrRgo28April2May2008RegulatorsguidanceforindustrylUSFDArelevanttobiowaiverguidelines:www.fda.gov/cder/Guidance/3618fnl.pdf|Slide17of25DrRgo28April2May2008ConclusionslBiowaiverconceptisadevelopingconceptandnewguidancedocumentsandscientificdataareappearinglPropercomparatorproductsarealsocrucialforbiowaiverlRegulatoryacceptanceandpracticeofbiowaiversneedstocatchuptheconceptdevelopmentlWHOwillsoonissuemorepracticalimplementationguidelinesforPQprogrammelWHOPQprogrammestartsacceptingbiowaivers,asappropriate|Slide18of25DrRgo28April2May2008Someusefulreferencesl(1)Multisource(generic)pharmaceuticalproducts:Guidelinesonregistrationrequirementstoestablishinterchangeability.In:WHOExpertCommitteeonSpecificationsforPharmaceuticalPreparations,FortiethReport.Geneva,WorldHealthOrganization,2006,WHOTechnicalReportSeries,No.937,Annex7:347-390.l(2)vanFaassenF.,VromansH.etal.Biowaiversfororalimmediate-releaseproducts:implicationsoflinearpharmacokinetics.ClinPharmacokinet43(2004)1117.l(3)NotetoApplicantsontheChoiceofComparatorProductsforthePrequalificationProject.LocatedontheWorldHealthOrganization(WHO)PrequalificationofMedicineswebsite,Guidanceonselectionofcomparatorproduct.Webpage:http:/healthtech.who.int/pq/l(4)Shah,V.P.etal.Bioanalyticalmethodvalidationarevisitwithadecadeofprogress.PharmaceuticalReseach,17(2000)1551-1557.l(5)Schuirmann,D.J.Acomparisonofthetwoone-sidedtestsprocedureandthepowerapproachforassessingtheequivalenceofaveragebioavailability.JournalofPharmacokineticsandBiopharmaceutics,15(1987)657-680.l(6)Westlake,W.J.Bioavailabilityandbioequivalenceofpharmaceuticalformulations.In:Peace,K.E.ed.Biopharmaceuticalstatisticsfordrugdevelopment.NewYork,MarcelDekker,Inc.,1988:329-352.l(7)Guidelinesforregistrationoffixed-dosecombinationmedicinalproducts.In:WHOExpertCommitteeonSpecificationsforPharmaceuticalPreparations,Thirty-ninthreport.Geneva,WorldHealthOrganization,2005(WHOTechnicalReportSeries,No.929,Annex5):94-142.结束语结束语谢谢大家聆听！谢谢大家聆听！19