药物BCS分类系统.ppt

PharmaceuticalDevelopmentwithFocusonPaediatricformulations WHO FIPTrainingWorkshopHyattRegencyHotelSaharAirportRoadAndheriEast Mumbai India28April2008 2May2008 BiopharmaceuticalClassificationSystem BCS Presentedby LembitR goMD PhDContactdetails DrLembitR goCoordinator QualityAssuranceandSafety MedicinesMedicinesPolicyandStandardsWorldHealthOrganizationGenevaSwitzerlandE Mail ragol who int BiopharmaceuticalClassificationSystem BCS BackgroundWhatisaproblem WhatisWHOdoingandplanningtodo Whatresourcesareavailable Conclusions Whatisthekeyformultisource generic pharmaceuticalproducts Newmedicines applicanthastoprovequality safetyandefficacyMultisource generic pharmaceuticalproducts applicanthastoprovequality incaseofsafetyandefficacyitreferstotheoriginatorproductThekeyisTHERAPEUTICINTERCHANGEABILITYItisassumedthatiftheconcentrationpatterninthebloodisessentiallythesamethenthesafetyandefficacyprofilemustbeessentiallythesame Therapeuticinterchangeability prerequisites ConstantandreproduciblequalityofMPPsManufacturedunderGMPCompliancewithallqualityspecificationsVariationscontrolNoconstantandreproduciblequality noneedforprovinginterchangeabilityasitismeaningless allbatchesdifferentanyhow Optionstoshowtherapeuticinterchangeabilityofmultisourcepharmaceuticalproducts MPP TheinvitroapproachreferstotheBiopharmaceuticsClassificationSystem BCS DrugsubstanceclassificationaccordingtotheBCS Activepharmaceuticalingredients APIs areclassifiedintoclassesbasedontheiraqueoussolubilityandpermeabilitycharacteristics InVitroApproaches Biowaiveroptions Thepossibilityof invitrodocumentationofbioequivalence for certainmedicinesanddosageforms isspecifiedinSection9oftheWHOguidancedocument 1 Ifthedrugsubstanceinquestionishighlysolubleandhighlypermeable BCSclassI andismanufacturedasanimmediatereleasedosageform exemptionfromaninvivopharmacokineticbioequivalencestudymaybeconsideredprovidedthatrelevantdissolutionrequirementsarefulfilled Principles Thesolubilityisnotmeanttobetheabsolutesolubilityhere Incontrasthighsolubilityreferstothehighestsingleunitdosetobecompletelysolublein250mlaqueousbuffermediumwithinthepHrangeof1 2to6 8withoutanystabilityproblems AsanotherrelatedphysicochemicalcharacteristichighpermeabilityshouldbedemonstratedfortheparticularAPIdemonstratingthatthefractiondoseabsorbedamountstoatleast85 Accordingly highpermeabilitywouldstandforalmostcompleteabsorptionofthecompoundinhumans PhysicochemicalmeasuresneededforBCSclassificationpurposesmaybetakenfromsoundliterature TheWHOModelListofEssentialMedicineshasbeenreviewedbasedontheBCSconceptandactivecompoundsareclassifiedaccordinglyintheappendixofrespectiveWHOdocument 1 Atheoreticalriskassessmentismandatorytominimizeriskforfalselywaivinganecessaryinvivostudy SituationswhereBCS basedbiowaiversarenotapplicable Assessmentofrisks practicalpoints Inpracticesomeofthecriterialistedinthetableforriskassessmentaredifficulttoassesse g themeaningof criticaluse or bioavailabilityproblems andareprobablynoteasytobedefined However publishedliteratureprovidesvaluableexamplesofhowtoevaluatetheapplicabilityoftheBCSbasedbiowaiverapproach seebiowaivermonographsonthefollowingslide Availableresources BiowaiverMonographs BiowaivermonographsareworkedoutbygroupofwellestablishedscientistslinkedtoFIPandpublishedinJournalofPharmaceuticalSciencesThesecanbeusefulscientificmaterialformanufacturerswhenconsideringapplicationsforbiowaiverbasedonBCSThemonographsassuchhaveno regulatoryauthority decisionswillbemadebyregulatorswhomayormaynotacceptbiowaiverdependingontheirnationallegislationandrequirements 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 TheinvitrodissolutioninvestigationsincludingexperimentalconditionsandcharacteristicsareoutlinedinSection9oftheWHOguideline 1 Itisofutmostimportancetonotethatitisnotsufficienttodemonstratetheinvitrodissolutioncharacteristicsfortheparticularmultisourceproduct buttoensure thesimilarityofdissolutionprofilesbetweenthetestandcomparatorproducts 1 WHOguidance 2 TheWHOguidanceinbasicaspectsissimilartotheUSFDAguidanceonthebiowaiverapproach August2000 Inaddition thecurrentscientificdiscussionsintermsofsocalled biowaiverextensions arealsoconsidered Accordingly BCSbasedbiowaiversmaybeacceptablefordrugscontainingBCSclass2and3drugsubstancesmanufacturedasimmediatereleasedosageforms Asanexample abiowaivermaybepossibleforBCSclass3drugproductsthatare veryrapidly i e atleast85 dissolutionwithin15mininallrequiredmedia dissolving Therelevantdissolutioncriteriaareoutlinedinsection9 2 1oftheWHOguideline 1 Regulatorsguidanceforindustry USFDArelevanttobiowaiverguidelines www fda gov 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 http healthtech who int pq 4 Shah V P