上市化学资料新药品变更研究的技术指导原则英文版DOC 82页.docx

上市化学资料新药品变更研究的技术指导原则英文版DOC 82页.docx

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上市化学资料新药品变更研究的技术指导原则英文版DOC82页

GUIDELINENo.:

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TechnicalGuidelineforMakingPostApprovalChangestoChemicalDrug

Products

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April2008

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Tableofcontents

I.Overview2

II.Basicprinciplesforperformingstudiespost-approvalchangestochemicaldrugproducts3

III.ChangestoDrugSubstanceManufacturingProcess6

IV.Changestoexcipientsinadrugformulation14

V.Changestothemanufacturingprocessforadrugproduct22

VI.Changestodrugproductstrengthandpackagingsize30

VII.Changetodrugprodcugtspecificication36

VIII.Changestothedrugprodcutshelf-life（expirationdatingperiod）and/orstorageconditions41

IX.Changestodrugproductpackagingmaterialsandthecontainerclosuresyatem...37

X.Changestothemanufacturingsiteofanimporteddrugproduct51

XI.ChangetothemanufacturingsiteofAPIusedinanimporteddrugproductandchangetothemanufacturingsiteofanimportedAPI48

XII.ChangesinthesiteofManufactureforAPIusedinadomesticdrugproduct.....Error!

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AppendixIBasicmethodsforcomparisoninvestigationofdrugdissolution/release36

AppendixIIGeneralconsiderationsforexemptionofinvivobioequivalence（BEwaiver）72

AppendixIIIApartiallistofofmedicineswithnarrowtherapeuticwindowsError!

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References77

Glossary79

Authors80

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I.Overview

Thisguidelineisprimarilyusedtoguidepharmaceuticalmanufacturerstocarryoutstudiesforpost-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.

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Thechangesreferredtointhisguidelinearepostapprovalchangesaimingatmarketedchemicaldrugproducts.Therefore,changesandchangestudiesshouldbebasedonthestudiesandcumulativedatainthepastfromthedrugregistrationstageandactualmanufacturingprocesses.Themoresystematicandthoroughtheresearchworkinregistrationphasewasandthemoresufficientthedatawereaccumulatedfromthemanufacturingprocesses,themorehelpfulitwouldbeforthepost-approvalchangestudy.

Forspecificrequirementsinthisguideline,pleaserefertothetechnicalguidelinesforchemicaldrugresearchanddevelopmentorotherrelevanttechnicalguidelinespreviouslyissued.Ifthereareotherscientificinvestigationresultswithsufficientevidenceavailabletodemonstratethatthechangeshavenonegativeimpactonthedrug’ssafety,efficacyandqualitycontrollability,itisunnecessarytoperformthechangestudiesbyfollowingthisguideline.

II.Basicprinciplesforthestudiesinsupportofpost-approvalchangestochemicaldrugproducts

Thestudiesforpostapprovalchanges（orchanges）referredinthisguidelinearethoseperformedtosupportchangestochemicaldrugproductsthathavebeenapprovedformarketing.Researchanddevelopmentworkinthestudiesshouldgenerallyfollowtheprinciplesbelow:

（1）Pharmaceuticalmanufacturersshoulddrivethechangestudiesandself-assessmentofthestudyresults.

Basedontheneedsinmanufacturing,etc.,pharmaceuticalmanufacturersproposechangesandperformrelevantstudies.Pharmaceuticalmanufacturersshouldhaveacomprehensiveandaccurateunderstandingoftheresearch&developmentwork,manufacturingandpropertiesoftheirproducts.Theyshouldclearlyunderstandthereasonfortheproposedchange,extentofthechangetotheproductsandtheimpactofthechangetotheproductwhenachangeisbeingconsideration.Hence,changestoachemicaldrugproductshouldbedrivenbypharmaceuticalmanufacturers.

Pharmaceuticalmanufacturersshouldcarryoutacomprehensivestudyfortheproduct’squality,stabilityandbiologicalpropertiesbeforeandafterachange.Pharmaceuticalmanufacturersshouldalsocarefullyanalyzethestudyresultsandevaluatetheimpactoftheproposedchangetoproductquality,i.e.,whethertheproduct’squalityisthesameandtherapeuticeffectisequivalentbeforeandafterthechange.Self-assessmentforthestudyresultsisspecificallyemphasized.

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（2）Acompleteandcomprehensiveevaluationfortheimpactofchangetothesafety,efficacyandqualitycontrollabilityofthedrugproduct.

Becausedrugresearch&developmentworkandmanufacturingprocessesarecloselyrelated,changestomanufacturingprocess,excipientwithpharmaceuticalapplicationinthedrugproductformulationorqualitystandardsetc.,couldaffecttheoverallsafety,efficiencyandqualitycontrollabilityofthedrugproduct.Ifin-vitrostudiescannotaccuratelydeterminehowachangeaffectstheproduct,itisnecessarytoperformmorein-depthstudies,comprehensiveevaluationfortheimpactofthechangetothesafety,efficacyandqualitycontrollabilityofthedrugproduct.Thisisalsothestartingpointforthechangestudy.

Generally,achangestudyshouldtakeintoconsiderationofthefollowingaspects:

1.EvaluationofImpactofChangesonDrugProducts

Whenachangewasmadetoaproduct,astudyshouldbecarriedouttoevaluateandassesstheimpactofthechangetothesafety,efficacyandqualitycontrollabilityofthedrugproduct,includingevaluationofchangestoproductchemistry,physics,microbiology,biology,biologicalequivalence,and/orstability.Thestudyshouldbedesignedbaseduponacomprehensiveconsiderationaboutthespecificsandtypeofthechange,drugsubstanceand/ordosageforms,anddegreeofimpactofthechangetothedrugproduct,etc.Forexample,toevaluateanychangeofimpuritiesinadrugproductpriortoandpostachange,itisappropriatetofirstselectorestablishasuitablechromatographicmethod,andthenperformacomparativeanalysisoftheimpurityprofiles（typesandamountofimpurities）priortoandpostachange.Ifnewimpuritiesappearafterachange,oriflevelsofexistingimpuritiesexceedtheestablishedlimits,thenitisnecessarytodeterminewhethertheimpuritylevelsareacceptableornotwithrationalesaccordingtotheAppendix1or2of“TechnicalGuidelineforStudyofImpuritiesinChemicalDrugProducts”；Ifitisnotacceptable,thenadecisiontreeshouldbereferencedtodecidethesubsequentstepofworkincludingconsiderationforcarryingoutanyneededtoxicologystudies.

Inadditiontothestudiessuggestedundereachchangetypeinthisguideline,itisalsonecessarytoperformotherselectedimportantstudiesbytakingintoconsiderationofthecharacteristicsandspecificsofthechange.Forexample,forsomechangestoatabletmanufacturingprocess,besidescomparingdissolution/releaseperformances,itisalsonecessarytoassessifthereareanychangestootherphysicalparameters.

2.EvaluationofSamenessorEquivalencepriortoandpostChange

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Strictlyspeaking,itisunnecessaryforaproducttoremaincompletelyidenticalbeforeandafterachange,however,theproductmustkeepthesamenessandequivalence,namely,theproductmusthavethesamequalityandclinicalequivalence.

Basedonthestudyandqualificationaboutthechemistry,physics,microbiology,biology,biologyequivalenceandstabilityofaproduct,comprehensiveanalysisshouldbecarriedouttoevaluatehowachangewouldimpactdrugsafety,efficacyandqualitycontrollability.Ingeneral,