药品研发指南(英文)

ORALTABLETSDEVELOPMENTDEVELOPMENTCHAPTER2HHandbookofPPharmaceuticalSect:22.15GGenericDDevelopmentPRODUCTDEVELOPMENTGUIDEPRE-FORMULATION-TABLETSTABLETSIntroductionGuidelinesforthedevelopmentofaANDAproductfortheUSmarket,Note:sometestsorproceduresmaybeunnecessary.Theorderofperformingthevariousstagesmaychangedependingontheproductunderdevelopment.Theseguidelinesmaybemodifiedforothergeographiczones.DevelopmentStageScopeofProductDevelopmentStage1LiteratureSearchLiteratureResearchUSPBPPharm.Eur,PDR,Martindale,Merck,Florey,VidalFDA-FOISummaryBasisofApprovalOn-linecomputerizedsearchFDACDERElectronicDataBase(articlesandpublicationontestmethods,Dissolutionsynthesisprocedures,drugimpurities,pharmacokineticsanddynamics)EvaluationofBiostudyparameters,Dissolutionmethods.PatentevaluationOrangeGuide+FDACDER(ACIC-Canada)(AllChem-UK)(Lek-Czech),(Esteves;Moehs;Uquifa-Spain);(Biopharma,S.I.M,Midy-Italy)(Chemcaps,Reddy;Tricon-India);(Federa-Brussels)-Reviewsupplierscatalogues&datacritically.PotentialSuppliersListRequestsamplesandCofAandSpecificationsEvaluateatleasttwosuppliersfully.Stage3ActiveEvaluationEvaluatePotentialActivesEvaluateatleasttwotothreepotentialactivesuppliers•DMFavailability•CompliancewithUSPmonograph•Impurityprofileandstability•PotentialPolymorphicforms•Commitmentforphysicalspecifications•Statementofnon-patentinfringementStage4ActivePurchasingPurchase(Potential)ActiveMaterialEvaluateatleasttwopotentialactivematerialsuppliersforapprovedsupplierstatusStage5ActiveTestingTestingofActiveMaterialsampleChemicaltestingbytheR&Danalyticallabaspera.Pharmacopoeiamonograph(ifpresent)b.PharmacopoeiaForum(ifavailable)c.In-housemethod(basedonmanufacturer)d.Supplier'stestmethodsandspecificationsORALTABLETSDEVELOPMENTDEVELOPMENTCHAPTER2HHandbookofPPharmaceuticalSect:22.16GGenericDDevelopmentPRE-FORMULATIONDevelopmentStageScopeofProductDevelopmentStage6Innovator'sProductPurchasingDRUGPRODUCTInnovatorSamplesPurchaseatleast3differentlotsinsmallestandlargestpacksizeforeachproductstrengthStage7Innovator'sProductTestingInnovatorTestingEvaluatephysicalparameters:-tabletshape,tabletcolor,codeforpunchembossing,packsizescontainersmaterials,closuretypes;cottonanddesiccants.InnovatorPhysicalTestingPhysicaltestingWeight;Thickness;Hardness;LOD;Friability;Disintegration:Evaluationoftabletpunch;size;score;embossingandshapeEvaluationofInnovatorformulaingredientsSummaryFormulainPDR;InternationalPDRs(Italian,French,Swiss)andInnovatorsproduct'sinsert(obtainlatestFOI-FDA)Performactualanalyticaltestingoninnovator'sproduct.MicroscopicobservationParticle/crystalinformationonParticlesizeCrystalshape,habit,Differentiationonthepresenceofspecificexcipientscanbeverifiedfrommicroscopicobservation.E.g.,Cross-linkedcellulose'sStarchandAvicelhaveaspecificshapesandmorphologyandmaybeeasilydetected.EvaluationofBiostudyparametersReviewFDACDERHomepageforlistingandBiostudyparametersDissolutionprofileUSPmonographandFDAmethod-(wherepresent)Dissolution;12unitDissolutionProfile.Stage8BulkActiveTestingFIRSTBATCHFROMAPPROVEDSUPPLIERFullPhysicalcharacterizationPhysicalcharacterizationofbulkbatch•Polymorphism•B.E.T.•Particlesizedistribution(&methoddevelopment)•Bulkdensity;•MicroscopicobservationFULLCHEMICALCHARACTERIZATIONChemicalcharacterization•Assay•StressedAnalysis•Degradants(Expected)•Impurityprofile•Opticalrotation•Enantiomericpurity•O.V.I.TestingORALTABLETSDEVELOPMENTDEVELOPMENTCHAPTER2HHandbookofPPharmaceuticalSect:22.17GGenericDDevelopmentDEVELOPMENTBATCHESDevelopmentStageScopeofProductDevelopmentStage9ExcipientsEvaluationofformu-lationwithsuitableexcipientsExcipientcompatibilityusingDSCmethodsandstabilityassessmentStage10ContainerClosureSystemEvaluationofsuitableContainer-ClosureSystemChoiceofcontainer-closure-linersystemincluding:•materialcomposition,•typeofthermoplasticresinandresinpigments,•manufacturersandsuppliers,•linersandsealsusedbyclosuremanufacturer,•cottonanddesiccants.•manufacturer'sDMFnumbersforallcomponentparts•LettersofAccessforregulatoryauthoritiestoviewDMFdossiersStage11ManufacturingProcessEVALUATIONSUITABLEMANUFACTURINGPROCESSESWetGranulationDryGranulationSluggingandDryGranulation•Wetgranulation(aqueousornonaqueous)highshearmixing/lowshearmixing•FBDsprayprocedure),or•Drymixing,drygranulationand/'orSlugging•Determinationoforderofmixing•Determinationofpre-mixing(inGranulator)•Determinationoffluidaddition(ifrelevant)•Determinationofgranulationtime(chopperI&II)•Determinationoftorqueend-pointvalue•DeterminationofDryingparameters•DeterminationofLODlimits•DeterminationoftestingtemperatureforcheckingLODlimits(Statemachineusede.g.Mettler™,Computrac™).GRANULATIONPhysicalPropertiesofGranulate•Flowproperties,•Density,•Particle-sizedistribution•CompressibilityCompressionPhysicalPropertiesofCompressedTablets•Weight,•Hardness,•Thickness,•Friability•Disintegration•DissolutionFinalFormulaEstablishedAssessmentofFinalMasterFormulaandaccelerated1-3monthstabil