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ChineseJournalofNewDrugs20142389212014238。01068585566E-mailjiangy@cde．org．cn。··“”100038。“”QbD。QTPP、CQA、CMAs。Ｒ95C1003－3734201408－0921－05Applicationof“qualitybydesign”intheformulationandprocessresearchofgenericinjectionsJIANGYuYANGJian-hongWANGYa-minCenterforDrugEvaluationChinaFoodandDrugAdministrationBeijing100038ChinaAbstractInjectionshavebeenconsideredhighlyriskybecausetheyaredesignedtobeinjecteddirectlyintothebloodsystem．Basedontheconceptof“qualitybydesignQbD”thesourcesofqualityrisksininjec-tionswereanalyzed“qualitytargetproductprofileQTPP”andthe“criticalqualityattributesCQA”ofinjec-tionswerediscussed．BesidesrisksofinjectionformulationandprocessvariableswereanalyzedandcriticalprocessparametersandcontrolstrategieswereexploredonthefoundationofcriticalmaterialattributesCMAs．KeywordsqualitybydesignQbDgenericinjectionsformulationandprocessresearchapplication、。。“”qualitybytestingQbT2070“”qualitybyproductionQbP、、、、、GMP。FDA。、、、。FDA2006“”qualitybyde-signQbD。ICHICHQ8-Q8Ｒ2-Q9-Q10-1－4。FDAQbDQbDcGMP、、5。ICH-Q8Ｒ2QbD①QTPP、、、、、。②CQA。、pH、pKChineseJournalofNewDrugs20142389222014238、。③。④。⑤。FDA20112012QbD《》《》6－7。QbD。1、。5①。②。③、。④。⑤。5。、、、、、、、、、。、、。2QbD2．1QTPP、、、、、QTPP。、、。2．2CQA。1。①。②。③。④pH、、、。ASAL≤10E-6。pH、、、、、、。pHpHpH、。1。1CQA——a、、、、pHa、、、、b、、、、、c、、、ca。b。c、。、、、。、、2．3CMAs2．3．1ChineseJournalofNewDrugs20142389232014238、pKa、、pH、、、。、、、、、。A。、pH、。。2．3．2。。、。。≤10－6。F0。。。pH、、pH、pH、、pH、。。A。23。2ApHdeedeeffffggggggggd。eA。f。g、。3A、j、、、、、、hijhijkllkmmnhA、、。i。j。。k、、。l。m。n。ChineseJournalofNewDrugs201423892420142382．4CPP、pH、。。①。②-。③。④。designspace。A。。。。。119℃121℃20min。121℃10minF040F012。F0。。。/USPⅠ。。。/、、。3QbD。。Ｒanbaxy30GMP20089FDA。FDA8－9。FDA。。954ChineseJournalofNewDrugs20142389542014238、、、、、、、QbD、。1ICH．ICHharmonizedtripartiteguidelinepharmaceuticaldevelop-mentQ8S/OL．20092014－03－15．http//．ich．org/products/guidelines．html．2ICH．ICHharmonizedtripartiteguidelinequalityriskmanagementQ9S/OL．20082014－03－15．http//．ich．org/products/guidelines．html．3ICH．ICHharmonizedtripartiteguidelinepharmaceuticalqualitysystemQ10S/OL．20082014－03－15．http//．ich．org/products/guidelines．html．4PAULADWANGWLPAULWSetal．ClinicalrelevanceofdissolutiontestinginqualitybydesignJ．AAPSJ2008102380－390．5SIEGFＲIEDADANIELESCHAＲLESＲetal．AnintegratedQualitybyDesignQbDapproachtowardsdesignspacedefinitionofablendingunitoperationbyDiscreteElementMethodDEMsimulationJ．EurJPharmSci201142106－115．6ANNAGANTONELLOABDAVIDEF．Ontheuseofmathe-maticalmodelstobuildthedesignspacefortheprimarydryingphaseofapharmaceuticallyophilizationprocessJ．JPharmSci20111001311－324．7HUIQUANWMAUＲYWMANSOOＲAK．Quality-by-sesignQbDAnintegratedprocessanalyticaltechnologyPATap-proachforadynamicpharmaceuticalco-precipitationprocesschar-acterizationandprocessdesignspacedevelopmentJ．IntJPharm20114051－263－78．8VEＲALDIＲKLGABＲIELEＲetal．AqualitybydesignstudyappliedtoanindustrialpharmaceuticalfluidbedgranulationJ．EurJPharmBiopharm2012812438－447．9ANASTASIAGLJOHNWM．EvaluationofthemicrobialgrowthpotentialofpharmaceuticaldrugproductsandqualitybydesignJ．PDAJPharmSciTech201165163－70．10LAWＲENCEXY．PharmaceuticalqualitybydesignproductandprocessdevelopmentunderstandingandcontrolJ．PharmＲes2008254781－791．11FＲEDEＲICKGVALIＲEZASK．Developmentofquality-by-de-signanalyticalmethodsJ．JPharmSci20111003797－812．12KOCHLINGJBＲIDGEWATEＲJNAJIＲ．Introducingasci-ence-basedqualitybydesignconcepttoanalyticalmethodsdevel-opment．BiotechnologyPharmaceuticalAspectsPharmaceuticalStabilityTestingtoSupportGlobalMarketsM．Vol12．NewYorkSpringer2010169－179．13GAVINPFOLSENBA．AqualitybydesignapproachtoimpuritymethoddevelopmentforatomoxetinehydrochlorideLY139603J．JPharmBiomedAnal2008463431－441．14DAVIDFJACQKSANDＲAPetal．AnalysisofpotentialgenotoxicimpuritiesinpharmaceuticalsbytwodimensionalgaschromatographywithDeansswitchingandindependentcolumntemperaturecontrolusingalow-thermal-massovenmoduleJ．AnalBioanalChem201039631291－1300．15PUEＲTOLLANOMCAＲTWＲIGHTTAYLOTTMetal．As-sessingananalyticalmethodforthedissolutionprofileofanex-tended-releasetabletinaccordancewithQbDJ．TabletsandCapsules20097130－39．16KＲULLISWAＲTZMTUＲPINJetal．Aquality-by-designmethodologyforrapidLCmethoddevelopmentpartIIJ．LCGCNAm20092748－61．/櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃2014－02－10924QTPPCQACMAs。。1ICH．Q8pharmaceuticaldevelopmentS//2006．2ICH．Q8Ｒ2pharmaceuticaldevelopmentS//2011．3ICH．Q9ＲualityＲiskManagementS//2006．4ICH．Q10PharmaceuticalQualitySystemS//2011．5．QbD、、J．20082910446－447．6FDA．QualitybydesignforANDAsanexampleformodifiedre-leasedosageformsEB/OL．2011－12．http//．fda．gov/downloads/drugs/developmentapprovalprocess/houdrgsaredevelope-dandapproved/approvalapplications/abbreciatednewdrugapplication-andagenerics/ucm286595．pdf．7FDA．QualitybydesignforANDAsanexampleformodifiedre-leasedosageformsEB/OL．2012－4．http//．fda．gov/downloads/drugs/developmentapprovalprocess/houdrgsaredevelo-pedandapproved/approvalapplications/abbreciatednewdrugapplica-tionandagenerics/ucm304305．pdf．8NicholasBuhay．FDAJ．201221182128－2135．9FDA．FDAIssuesWarningLetterstoＲanbaxyLaboratoriesLtd．andanimportalertfordrugsfromtworanbaxyplantsinInd