已上市化学药品变更研究的技术指导原则英文版

GUIDELINENo.:HGB(1)T-1TechnicalGuidelineforMakingPostApprovalChangestoChemicalDrugProducts(I)1April20082TableofcontentsI.Overview......................................................................................................................................2II.Basicprinciplesforperformingstudiespost-approvalchangestochemicaldrugproducts.........3III.ChangestoDrugSubstanceManufacturingProcess..................................................................6IV.Changestoexcipientsinadrugformulation.............................................................................14V.Changestothemanufacturingprocessforadrugproduct........................................................22VI.Changestodrugproductstrengthandpackagingsize............................................................30VII.Changetodrugprodcugtspecificication36VIII.Changestothedrugprodcutshelf-life(expirationdatingperiod)and/orstorageconditions.41IX.Changestodrugproductpackagingmaterialsandthecontainerclosuresyatem...37X.Changestothemanufacturingsiteofanimporteddrugproduct...............................................51XI.ChangetothemanufacturingsiteofAPIusedinanimporteddrugproductandchangetothemanufacturingsiteofanimportedAPI...........................................................................................48XII.ChangesinthesiteofManufactureforAPIusedinadomesticdrugproduct.....Error!Bookmarknotdefined.AppendixIBasicmethodsforcomparisoninvestigationofdrugdissolution/release......................36AppendixIIGeneralconsiderationsforexemptionofinvivobioequivalence(BEwaiver).............72AppendixIIIApartiallistofofmedicineswithnarrowtherapeuticwindows...........................Error!Bookmarknotdefined.References....................................................................................................................................77Glossary........................................................................................................................................79Authors..........................................................................................................................................801I.OverviewThisguidelineisprimarilyusedtoguidepharmaceuticalmanufacturerstocarryoutstudiesforpost-approvalchanges(orchanges)tochemicaldrugproducts.Changeshererefertothechangesthatinvolvesource,methods,controlconditionswithrespecttothemanufacture,quality-controlanduseconditionandrelatedareasforadrugproductthathasbeenapprovedformarketing.Thesechangesmayaffecttheproduct’ssafety,efficacyandqualitycontrollability.Thechangestudyherereferstothestudyandqualificationworktosupportaproposedchange.Atpresent,thechangesandchangestudiescoveredinthisguideline’sincludethefollowingareas:thechangestoAPI/drugsubstance(DS)manufacturingprocess,excipientforpharmaceuticaluseinformulationanditsmanufacturingprocess,registeredspecifications,strengths,shelflife(expirationdatingperiod),storageconditions,drugproductpackagingmaterialsandcontainerclosuresystem,theimporteddrugproductmanufacturingsite,manufacturingsiteofimportedAPI/DSorAPI/DSusedinimportdrugproducts,andAPImanufacturingsitesusedindomesticdrugproducts.Thisguidelinedescribesfromtechnicalpointofviewthestudiesandqualificationsthatshouldbeperformedwhenchangesaretobemadetotheproducts.Pharmaceuticalmanufacturersshouldperformchangestudiesandqualificationsinaccordancewiththetechnicalrequirementsofthisguideline,andaftertheworkiscompleted,submitsupplementalapplicationtoappropriatefoodanddrugregulatoryauthoritiesaccordingtotherequirementsofDrugRegistrationRegulation(DRR).Inordertocontrolthepotentialimpactofachangetothesafety,efficacyandqualitycontrollabilityoftheaffectedproduct,thisguidelinedividestheallchangesinto3categories:TypeI,minorchangesthatbasicallyhavenoimpactonthesafety,efficacyandqualitycontrollabilityoftheaffectedproduct;TypeII,moderatechanges,forwhichstudiesshouldbeperformedtodemonstratethatthechangeshavenoeffectonthesafety,effectivenessandqualitycontrollabilityoftheaffectedproduct;TypeIII,majorchangesthatneedaseriesofstudiestodemonstratethatthechangeshavenonegativeimpactonthesafety,efficacyandqualitycontrollabilityoftheaffectedproduct.ThecategoryofchangetypeshastakenintoconsiderationtherelevantregulationforsupplementalapplicationinofthecurrentDrugRegistrationandRegulation(DRR)aswellasrelevanttechnicalrequirementsofothercountriesinordertohelpthemanufacturerstoperformtargetedchangestudies,summarizethestudyresultsintosupportinginformationandmakesupplementalapplicationtotheregulatoryagencies.2Thechangesreferredtointhisguidelinearepostapprovalchangesaimingatmarketedchemicaldrugproducts.Therefore,changesandchangestudiesshouldbebasedonthestudiesandcumulativedatainthepastfromthedrugregistrationstageandactualmanufacturingprocesses.Themoresystematicandthoroughtheresearchworkinregistrationphasewasandthemoresufficientthedatawereaccumulatedfromthemanufacturingprocesses,themorehelpfulitwouldbeforthepost-approvalchangestudy.Forspecificrequirementsinthisguideline,pleaserefertothetechnic