FDA-Draft-Guidance-Budesonide-Suspension-for-Inhal

ContainsNonbindingRecommendationsDraftGuidanceonBudesonideThisdraftguidance,oncefinalized,willrepresenttheFoodandDrugAdministration's(FDA's)currentthinkingonthistopic.ItdoesnotcreateorconferanyrightsfororonanypersonanddoesnotoperatetobindFDAorthepublic.Youcanuseanalternativeapproachiftheapproachsatisfiestherequirementsoftheapplicablestatutesandregulations.Ifyouwanttodiscussanalternativeapproach,contacttheOfficeofGenericDrugs.Activeingredient:BudesonideForm/Route:Suspension/InhalationRecommendedstudies:1.TestingRequirementsfortheHighestStrength(1mg/2mL)Product:Thegenericbudesonidesuspension/inhalationproductmustbequalitatively(Q1)andquantitatively(Q2)thesameasthereferencelisteddrugproduct(RLD).OptionA.InVitroBioequivalenceStudiesAlone:Thefollowinginvitrocomparativetestsarerecommended.PariLCPlusNebulizer/PariMastercompressorsystemisrecommendedforthosetestsrequiringnebulization.Thetestsinclude:1)SamenessofpolymorphicformofthedrugsubstancebasedonX-raydiffraction.2)Samenessofshape(crystallinehabit)ofthedrugsubstance.3)ComparativeUnitDoseContent(UDC)ofdrugintheampules.4)ComparativeMeanNebulizationTime(MNT)andMeanDeliveredDose(MDD):Thetestshouldbeconductedatthemouthpiece(%nominaldose)atthelabeledflowrateof5.5L/minthroughsuchtimethatmistisnolongercomingoutofthemouthpiece.5)ComparativedrugparticleandagglomerateParticleSizeDistribution(PSD)inthesuspension(intheampoule):ThePSDdeterminationshouldbebasedonavalidatedmethod.Validationshoulddemonstratemethodsensitivitytodrugparticlesizeovertheexpectedsizerangeinthesuspension.6)ComparativedrugparticleandagglomeratePSDinthenebulizedaerosol:Recommendedmethodforthistestistheaerodynamicparticlesizedistribution(APSD)ofthenebulizedaerosolbasedonApparatus5(USP601)ataflowrateof15L/minthroughtheApparatus.WerecommendthestudybeconductedbasedonUSP1601usingthePariLCPlusNebulizer/PariMastercompressorsystem.Theamountofdrugdepositedontheinductionport,thesevenstagesofthecascadeimpactor,andthesumoftheback-upfilterandmicro-orificecollector(MOC)shouldbesubmitted.RecommendedSep20127)ComparativeaqueousdropletsizedistributionofthenebulizedaerosolbyaLaserdiffractionmethod.OptionB.CombinationofInVitroandInVivoBioequivalenceStudies:1)Testsshouldincludealldescribedabovein1.OptionA,withtheexceptionofcomparativedrugparticleandagglomeratePSDinthenebulizedaerosolreferredin1.OptionA.6)2)Aclinicalendpointbioequivalencestudy,withdemonstrationofacceptabledose-responsefortestandreferenceproductstoassurestudysensitivity.Atthistime,theAgencyhasnorecommendationsregardingtheclinicalbioequivalencestudydesign.3)Asystemicexposure(pharmacokinetic)bioequivalencestudy.2.TestingRequirementsfortheTwoLowerStrengths(0.5mg/2mLor0.25mg/2mL)Products:Ifthemicronizedbudesonide(bulkdrug)usedinthelowerstrengthproductisthesameasthatusedinthehigherstrengthproduct,i.e.,sameparticlesize,PSD,polymorphicform,andshape,andtherespectivelowerstrengthtestandreferenceformulationsareQ1andQ2thesame,theDivisionofBioequivalence(DB)recommendsthatthefirmconductthefollowingtestsforthelowerstrengthsofthetestproduct:OptionA.InVitroBioequivalenceStudiesAlone:IfthecomparativedrugparticleandagglomeratePSDinthenebulizedaerosolbetweenthetestandreferenceproductsforboththehigherandlowerstrengthscanbedetermined,thefollowinginvitrotestingshouldbesufficienttodemonstratetheequivalenceofthelowerstrengths:1)Documentationofbioequivalenceofthehigherstrengthproductbasedonacceptablecomparativeinvitrodataoutlinedabove.2)ComparativedrugparticleandagglomeratePSDinthesuspension(intheampoule)betweentherespectivelowerstrengthsofthetestandreferenceproducts:ThePSDdeterminationshouldbebasedonavalidatedmethod.Validationshoulddemonstratemethodsensitivitytodrugparticlesizeovertheexpectedsizerangeinthesuspension.3)ComparativedrugparticleandagglomeratePSDinthenebulizedaerosolbetweentherespectivelowerstrengthsofthetestandreferenceproducts:Recommendedmethodforthistestistheaerodynamicparticlesizedistribution(APSD)oftheRecommendedSep2012nebulizedaerosolbasedonApparatus5(USP601)ataflowrateof15L/minthroughtheApparatus.WerecommendthestudybeconductedbasedonUSP1601usingthePariLCPlusNebulizer/PariMastercompressorsystem.Theamountofdrugdepositedontheinductionport,thesevenstagesofthecascadeimpactor,andthesumoftheback-upfilterandmicro-orificecollector(MOC)shouldbesubmitted.4)ComparativeUnitDoseContent(UDC)ofdrugbetweentherespectivelowerstrengthsofthetestandreferenceproducts.5)ComparativeMeanNebulizationTime(MNT)andMeanDeliveredDose(MDD):Thetestshouldbeconductedatthemouthpiece(%nominaldose)atthelabeledflowrateof5.5L/minthroughsuchtimethatmistisnolongercomingoutofthemouthpiece,betweentherespectivelowerstrengthsofthetestandreferenceproducts.6)TheMeanDeliveredDose(MDD)ratioofthehighertolowerstrengthofthetestproductshouldbesimilartothatofthereferenceproduct.OptionB.CombinationofInVitroandInVivoBioequivalenceStudies:IfthedrugparticleandagglomeratePSDinthenebulizedaerosolsofthehigherandlowerstrengthsofthetestandreferenceproductscannotbedeterminedasdescribedabove,thefollowingtestingshouldbesuff