IPECActivitiesandExcipientRegulationintheUnitedStatesPresentationtoSFDADavidR.SchonekerDirectorofGlobalRegulatoryAffairsOctober13,20041OutlineIPECBackgroundIPECGuidelinesandInitiativesExcipient&ColorantRegulationintheU.S.ExcipientMasterFilesExcipientQualificationProcessPharmacopeialHarmonizationPre-mixedExcipientsSUPAC&PostApprovalChanges2WhatisIPEC?3WhatisIPEC?4Colorcon’sInvolvementwithIPECColorconwasafoundingmemberofIPECColorconisafullmemberinIPECAmericas,IPECEurope,andJPECColorconactivelyparticipatesinthefollowingIPECCommittees:ExecutiveCompendialReview–HarmonizationWorkingGroupsGMPExcipientQualificationRegulatoryAffairsManyCommitteesarechairedbyColorconpersonnel5IPECMission6BuildingBridgeswithRegulators

IPECisactivelymeetingwithhighleveldirectorsatFDA,EMEA,MHLW,USP,PhEur,andJP/JPEtodiscussmanytopicsrelatedtoexcipientsRegulatoryRepresentativesroutinelyparticipateinIPECprojectsasadvisorsIPECprovidestechnicalassistanceandpracticalexperience7ExcipientGMPsintheU.S.U.S.FD&CActstatesthatcomponentsofdrugs(ie;excipients)shouldbemadeusing“appropriate”GMPsThereisnoactualregulationwhichdefineswhatisthe“appropriate”levelofGMPforpharmaceuticalexcipientsFDAdoesNOTroutinelyinspectexcipientmanufacturers;only“forcause”8ExcipientGMPsintheU.S.9IPECExcipientGMP’s10IPECExcipientGMP’s11PublishedIPEC-AmericasGuidelines

12IPECInitiatives13IPECInitiativesDevelopingGuidelinesforExcipientQualificationIncludesboththeUser’sandMaker’sperspectiveDevelopmentofStandardQuestionnairetemplatesThirdPartySupplierAssessment(IPEA)IPEAprovidesassessmentsofexcipientmanufacturingfacilitiesvs.IPECGMPIPEAAudits()14CurrentIPEAAuditReportsReportsReportNumberExcipientChemical/

CompendiaNameManufacturerLocationExcipientTradeNameEQ-01Alcohol,USPEquistarIllinois,USAEthylAlcoholEQ-02Alcohol,USP:denaturing&packagingEquistarNewJersey,USADenaturing&packagingPendingHydroxypropylatedStarchNFPendingPendingPendingPendingCarrageenanNFPendingPendingPendingCPK-01XanthanGumNFCPKelcoOklahoma,USAXantural180NS-01DisodiumSuccinateHexahydrateNipponShokbaiHimeji,JapanSS-50PQ-01SulfuricAcidNFProductosQuimicosNeuvoLeon,MexicoSulfuricAcidSE-01DisodiumSuccinateHydrateShivaEnterprisesPune,IndiaSodiumSuccinateHydratePendingMagnesiumSilicateNFPendingUSAPendingCL-01SodiumHydroxideNFCantonLaboratoriesVadodara,IndiaSodiumHydroxide15UseofExcipientsinNDA’s

intheU.S.FD&CActstatesthatexcipients(otherthancolors)mustmeetUSP/NFrequirementsifamonographexistsUSP/NFexcipientsdonotrequiresubmissionofsignificantqualityinformationwithNDA’s.However,functionalityinformationmaybenecessarybasedontheapplication16UseofExcipientsinNDA’s

intheU.S.17

U.S.GenericApplicationsForU.S.genericdrugapplications,allingredientsneedtobelistedintheFDA’sInactiveIngredientDatabase(formerlyknownastheInactiveIngredientGuideorIIG)ThelevelsofuseofeachexcipientinthedosageformmustbebelowlevelsexperiencedinpreviouslyapproveddrugsIfnot,safetydatamaybeneeded18

U.S.GenericApplications1920GlobalCOLORANTRegulationsForPharmaceuticalsUnitedStates-21CFR(Parts70-82)Europe-ECDirectives78/25/EEC and81/464/EECJapan-MinisterialOrdinanceNo.30(August

31,1966),JP,JPE,JPED,PrecedentListWHO-JECFARequirementsIndividualCountriesmayhaveuniquerequirementsandrestrictionsbasedonlocalrequirements21OneColorForTheWorld:

GlobalFormulationProblemsListofacceptablecolorsvariesSpecificationsaredifferentforthesamecolorantsColorsandspecificationsfornutritionalsupplementsvs.pharmaceuticalsaresometimesdifferentUserestrictionsmayapplyandmayvaryTheseissuescauseonlyafewcolorstobeavailableforinternationalformulations….22KeyColorsUsedInGlobalPharmaceuticalsFD&CBlue#1FD&CYellow#6TitaniumDioxideRedIronOxideYellowIronOxideBlackIronOxide23DesiredGlobalColorRegulationsCurrently,thereisnoharmonizationprocessforcolorsEachcountrymaintainstheirownlistsofapprovedcolorswhichcreatesglobaldevelopmentproblemsShouldbebasedprimarilyonsafetyUseofJECFAfoodcolorlistasaglobalstandardwouldbeveryhelpful!!!24DrugMasterFiles25USDMFFacts(J.Clark,FDA,2003)

March31,2003:16481DMFsonfile“Inactive”presumablymeansnoLOA/annualreport recentlysubmitted26USDMFFilings,2002(J.Clark,FDA,2003)DMFs DMFs/yearAll 585TypeII 358TypeIII 172TypeIV 51TypeV 427DrugMasterFileRequirements

Specifiedin1989guidancedocumentDMFTypesI.Manufacturingsite,facilitiesII.Drugsubstance,intermediate,drug

productIII.PackagingmaterialIV.Excipient,colorant,flavor,etc.V.FDAAcceptedReferenceInformation28TypeIVDMFInformationRequirements29IPECProposals:

Global“ExcipientMasterFiles”ExcipientMasterFile,astandardformatforsubmittinginformationIPECguidancepublished2004UnderconsiderationatFDASimplifyfilingprocessApplicabletoallexcipientsStandardformatandinformationrequirementsGlobalsubmissionsSimplifyreviewprocessStandardformatandinformationrequirements30ExcipientMasterFiles:ConsistentwithCTDSubmissionsWouldcontainallinformationrequiredinSectionP4ofCTDP4.1Specifications(Q6B)P4.2AnalyticalProcedures(Q2A,Q6B)P4.3ValidationofAnalyticalProcedures(Q2A,Q2B,Q6B)P4.4JustificationofSpecifications(Q3C,Q6B)P4.5ExcipientsofHumanorAnimalOrigin(Q5A,Q5D,Q6B)P4.6NovelExcipients31ExcipientMasterFileComponents32EMFOrganizationSummariesTechnicalReportsandDataRegionalInfoCoreTechnicalDocumentAdministrativeSection33TheIncreasingVisibilityofExcipients

ImpactoftheHaitiglycerindisasterCounterfeitDrugsandBioterrorismFutureneeds:WideinternationalacceptancetofacilitatethedesignofglobalpharmaceuticalformulationsAssurethatappropriateGMPandqualitystandardsareappliedtothedesignandmanufactureofthesematerialsForregulatoryagenciestogainabetterunderstandingofthepurposeandfunctionalityofexcipientsindrugformulations34Qualificationof

ExcipientSuppliers35SupplierQualification36IPECExcipientQualificationGuidelineCurrentProject37ExcipientQualification

Guideline3839ExcipientQualification

Process-User4041PharmacopeialHarmonization4243HarmonizationofExcipientStandardsPharmacopeiasUsersManufacturersRegulatory44Today’sHarmonizationOutcomes45ChinesePharmacopeiaCantheChinesePharmacopeia(CP)beharmonizedwiththeUSP?CanUSPgradeexcipientsbeusedinChinesedrugapplicationsifaCPmonographexists?ArethereanyGMPrequirementsforexcipientswhichcomplywithChinesePharmacopeiamonographs46ProductFilingInformation

Pre-MixedExcipients47ProductFilingInformation

Pre-mixedExcipientsTypicalinformationRequired:ProductcodenumberListofcomponents(chemicalnamesincludingviscosity/MWinformation)QuantitativepercentagesforeachcomponentGradeofeachcomponent(USP/NF,PhEur,JP/JPE,CFR,FCC,ECDirective,etc.)Evidenceofprioruseofeachcomponentinoralapplicationsatsimilarlevels4849DrugMasterFiles

Pre-mixedExcipients50Post-ApprovalChanges

UnitedStatesGuidanceforIndustry:ChangestoanApprovedNDAorANDA

ComponentandCompositionsectionrefersbacktoSUPAC(ScaleUpandPostApprovalChanges)guidancesSUPACcanbeusedtomakecertainchangesinexcipientlevelsMinorChangesareLevel1-AnnualReport,nopriorapprovalSUPACcoversdeletionofacolororflavorasaLevel1changeSUPACalsoallowsforadditionofanimprintcodeorqualitativechangesinprintinginksasa