冻干工艺开发和配方特性研究-王德潜

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1、FormulationCharacterizationIstheKeyforDevelopment,Scale-upandValidationofaLyophilizationProcessD.Q.Wang,Ph.D.DirectorofInnovationManagement,GlobalCMCGlobalDrugDiscovery–InnovationCenterChinaBayerBerkeleySiteFVIIImoleculeDeficiencyofFVIIIresultsinHemophiliaA.Repl

2、acementofFVIIIisthetreatmentforHemophiliaATherapeuticallyFVIIIisanidealrecombinantprotein,butFactorVIIIbiochemistryiscomplex3-Dstructureof.factorVIIII-•FVIIIis2351a.a.protein•25N-linkedglycosylationsites•6tyr-sulfationsites•Circulatingformisadimerwithheavy(A1A2B

3、)andlight(A3C1C2)chainsassociatedbyametalbridge•TheroleoftheBdomainisunclear(Lentinget.al.Blood,Vol.92No.11(December1),1998:pp.3983-3996FVIIIisanextremelychallengingprotein•rFVIIIisthelargestprotein120madebybiotechindustry100•MultiplemodificationsrequiredProtein

4、#2forproperfunction80•CellSpecificproductivity60Protein#1(rFVIII)islow40•Proteinisveryunstable200061218243036424854Time(hours)TheFormulationGlycine2.2%,Sucrose1%,NaCl30mM,Histdine20mM,CaCl22.5mM,Tween-8080ppmand0.2-0.5mg/mLrFVIII.CrystallineMatrixformulationGlyc

5、inecrystallizestoformacrystallinematrixforthesucroseandotherstocollapseupon.Theglycineprovidesexcellentcake,goodreconstitutioncharacteristics,andeaseinfreezedrying.ThesucrosestabilizesrFVIIIduringprocessingandstorage.CycleDevelopmentSteps•Characterizetheformulat

6、ion.•Optimizetheprocessbasedontheunderstandingoftheformulation.•Scale-uptheprocessandtransfertheprocesstoproduction.•Validatetheprocess.CharacterizetheFormulation•UtilizeDifferentialScanningCalorimetry(DSC)todetermineTg’.•ConfirmresultswithLyo-microscopeanddeter

7、minethemaximumallowableproducttemperatureduringlyophilization.•Generateawaterabsorption/desorptioncurveforcharacterizingthesecondarydryingprocess.•Conductmoistureoptimizationstudyfordevelopingsecondarydrying.CharacterizetheFormulationCharacterizetheFormulation(C

8、ont.)Freeze-dryingmicrographsofformulationshowingcollapseandretentionofstructure(mag=140x)CharacterizetheFormulation(Cont.)Figure8.T-prodasafunctionofT-shelfandPressu