1、ApplicationInformationRequirementsofChemicalDrugsaspernewregistrationcategoryChapterIApplicationInformationRequirementsforCategory1,2,3,5.1I.Requireditems(I) Summary1. Nameofthedrug2. CertifiedDocuments2.1 Certifieddocumentsforcategory1,2,32.2 Certifieddocumentsforcategory5.13. Objectivesandbasisfor

2、R&D4. Self-AssessmentReport5. InformationofMarketingAuthorizationHolder6. Informationoforiginaldrug7. Draftofpackaginginsert,notetothedraft,andrelevantreferenceliterature8. Specimenofthedesignedpackageandlabel(II) SummaryofthemainStudies9. Summaryofpharmaceuticalstudies10. Summaryofnon-clinicals

3、tudies11. Summaryofclinicalstudies(III) Pharmaceuticalstudiesdata/documents12. (3.2.S)DrugSunstance(3.2.SistheNo.ofCTDformat)12.1 (3.2.S.1)Generalinformation12.2 (3.2.S.2)Manufacture12.3 (3.2.S.3)Characterisation12.4 (3.2.S.4)Controlofdrugsubstance12.5 (3.2.S.5)Referencestandardsormaterials12.6 (3.2

4、.S.6)ContainerClosureSystem13. (3.2.P)DrugProduct13.1 (3.2.P.1)Descriptionandcompositionofthedrugproduct13.2 (3.2.P.2)Pharmaceuticaldevelopment13.3 (3.2.P.3)Manufacture13.4 (3.2.P.4)Controlofdrugsubstanceandexcipients13.5 (3.2.P.5)ControlDrugProduct13.6 (3.2.P.6)Referencestandardsormaterials13.7 (3.

5、2.P.7)Stability(IV) Nonclinicalstudiesdata/documents14.Summaryofnonclinicalstudies15.Mainpharmacologytestsdocumentsandliteratures16.Safetypharmacologytestsdocumentsandliteratures17.Singe-dosetoxicitytestsdocumentsandliteratures18 .Repeat-dosetoxicitytestsdocumentsandliteratures19 .Genotoxicitytestsd

6、ocumentsandliteratures20 .Reproductivetoxicitytestsdocumentsandliteratures21 .Carcinogenicitytestsdocumentsandliteratures22 .Dependencetestsdocumentsandliteratures23 .Specialsafetytestsdocumentsandliteraturesincludingbutnotlimitedtohypersusceptibility(topic,pantasomatousandphotosenstitivetoxicity),h

7、emocytolysisandtopicaltopicalirritation(bloodvessel,skin,mucousmemberbrance,muscleandetc.)24 .Othersafetytestsdocumentsandliteratures25 .Nonclinicalpharmacokineticstestsdocumentsandliteratures26 .Testsdocumentsandliteraturesonmutualeffectbetweenpharmacology,toxicityandpharmacokineticsofthemultiplein

8、gredientsincompounddrugproducts/formulation(V)Clinicaltestsdocuments27.Summaryofclinicaltestsdocuments28 .Clinicaltestsplanandstudyprotocol29 .Datamanagementplan,statisticalanalysis30.Investigator'sbrochure31 .Draftofinformedconsentform,approvaloftheethicscommittee,reviewreportofsciencecommittee

9、32 .Clinicaltestsreport33 .Electronicfileofclinicaltestsdata34 .Reportofdatamanagement,reportofstatisticalanalysis(III)Pharmaceuticalstudiesdata/documents12. (3.2.S)DrugSubstance12.1 (3.2.S.1)GeneralInformation.1 NameofthedrugPleaseprovideChineseandEnglishgenericnames,chemicalnames,CASnumbers

10、andothernamesofdrugsubstance(includingthoseinforeignpharmacopoeia)..2 StructurePleaseprovidethestructuralformula,molecularformula,andmolecularweightofDrugsubstance.Iftherearethree-dimensionalstructuresandpolymorphs,itshouldbespecified..3 PhysicochemicalpropertiesPleaseprovidethephysica

11、landchemicalpropertiesofthedrugsubstance(generallyderivedfrompharmacopoeiaandMerckindex,etc.),includingthefollowinginformation:character(suchasappearance,color,physicalstate);meltingpointorboilingpoint;specificrotation,solubility,solutionpH,Partitioncoefficient,dissociationconstant,physicalform(such

12、aspolymorph,solvate,orhydrate)thatwillbeusedforpreparationproduction,particlesize,etc..4 S.2)Manufacture.1 ManufacturerPleaseprovidethemanufacturer'sname(fullname),address,telephonenumber,faxnumber,andtheaddressoftheproductionsite(specificallytotheplant/shop,productionline),telepho

13、ne,fax,etc..2 Manufacturingprocessandcontrol(1) Flowchart:Aflowchartisprovidedaccordingtotheprocesssteps,indicatingtheprocessparametersandthesolventused.Forchemicallysynthesizeddrugsubstance,itshouldalsoprovideitschemicalreactionformula,whichshouldincludethestartingmaterials,intermediates,mol

14、eculeformula/moleculeweight/structureofthereagents.(2) Descriptionofthemanufactureprocess:Theprocessoperationisdescribedbytheprocessflow,representedbytheregisteredbatch.Theamountsofeachreactionmaterialandtheyieldrangeofeachsteparelisted,andthekeyproductionsteps,keyprocessparametersandqualitycontroli

15、ndicatorsoftheintermediatesareclarified.(3) Equipments:Pleaseprovidetheinformationofthemainandspecialequipments(suchastype,technicalparameters,commonbatchsizerange,manufacturer,thereactionstepsused).(4) Indicatethebatchsizerangeofcommercialbatches.Thedetaileddegreeofproductionprocessdescriptionshoul

16、denablethetechniciansofthisspecialtytocompletelyrepeattheproductionprocessaccordingtothedeclaredproductionprocessandproduceproductsthatmeetthestandards..3 ControlofmaterialsAccordingtotheprocessintheprocessflowchart,allthematerialsusedintheproduction(suchasstartingmaterials,reagents,solvents,

17、catalysts,etc.)arelistedintheformofatable,andthestepsusedareexplained.Anexampleisasfollows:Table1(Note:serialnumber,thesamebelow):materialcontrolinformationNameofmaterialQualitystandardManufacturerStepsforusagePleaseprovidequalitycontrolinformationfortheabovematerials,specifyreferencestandards,orpro

18、videinternalcontrolstandards(includingitems,testingmethodsandlimits),andprovidenecessarymethodologicalverificationdata.Forthekeystartingmaterials,thepreparationprocessdatashouldbeprovidedaccordingtotherelevanttechnicalguidelinesandtechnicalrequirements..4 Controlofcriticalstep&intermediat

19、eListallkeysteps(includingfinalproductrefiningandpurificationprocesssteps)andcontrolrangeofprocessparameters.Listthequalitycontrolstandardsforisolatedintermediates,includingitems,methodsandlimits,andprovidenecessarymethodologicalverificationdata..5 Evaluationandvalidationofthemanufactureproce

20、ssProcessvalidationdata,includingprocessvalidationprotocolandvalidationreport,shouldbeprovidedforsteriledrugsubstance.Forotherdrugsubstance,onlyprocessvalidationprotocolsandbatchproductionrecordsamplescanbeprovided,butthecommitmenttovalidatethefirstthreebatchesofcommercialproductionbatchesafterappro

21、valshouldbesubmittedatthesametime.Validationprotocol,validationreport,batchproductionrecordshouldbenumbered,andshouldbesignedbyappropriatepersonnel(suchasQA,QC,qualityandproductionmanager,etc.)..6 ManufacturingprocessdevelopmentProvidetheselectionbasisofthemanufactureprocess(includingliteratu

22、rebasisandtheorybasis).Detailedresearchdata(includingresearchmethods,researchresultsandresearchconclusions)areprovidedtoillustratetherationalityofkeystepsdeterminationandtherationalityofprocessparameterscontrolrange.Themainchangesofproductionprocessintheprocessofprocessdevelopment(includingbatch,equ

23、ipment,processparametersandprocessroutes)andrelatedsupportingvalidationresearchdataaredescribedindetail.Asummarytableofprocessresearchdataisprovided.Anexampleisasfollows:TableXX:AsummarytableofprocessresearchdataBatchnumberDateofmanufactureSiteofObjectiveofmanufacture1/sampleBatchYieldProcess2Sample

24、qualitymanufactureAssay_ImpurityCharacterNote:Describethepurposeofproducingthebatchandtheuseofthesample,suchasprocessvalidation/stabilitystudies;2:ExplainwhethertheproductionprocessofthebatcheslistedinthetableisconsistentwiththeprocessunderS.2.2.Iftheyareinconsistenthedifferencesshouldbeclarified.12

25、.3(3.2.S.3.)Characterizations3.2.S.3.1Structureandphysiochemicalproperties(1) ConfirmationofthestructureThestructureoftheproductisanalyzedbycombiningthesyntheticrouteandvariousstructuralconfirmationmethods.Ifitmaycontainthree-dimensionalstructure,crystallinewater/crystallinesolventorpolycrystallinef

26、orm,itshouldbeexplainedindetail.Providethemethodofpurification,purity,batchnumberofthesampleforstructuralconfirmation.Ifthereferencesubstanceisused,thesource,purityandbatchnumberofthereferencesubstanceshouldbeexplained;specificresearchdataandspectraareprovidedandanalyzed.Forspecificrequirements,plea

27、serefertotheTechnicalGuidelinesforthePreparationandStructuralConfirmationofDrugsubstanceofChemicalDrugs.(2) PhysicochemicalpropertiesProvidedetailedphysicochemicalinformation,including:character(suchasappearance,color,physicalstate);meltingpointorboilingpoint;specificrotation,solubility,hygroscopici

28、ty,solutionpH,partitioncoefficient,dissociationconstant,physicalmorphology(suchaspolycrystalline,solventsorhydrates)tobeusedinpreparationproduction,particlesize,etc3.2.S.3.2ImpuritiesListthepossibleimpurities(includingorganicimpurities,inorganicimpurities,residualsolventsandcatalysts)intheproduct,an

29、alyzethesourcesofimpurities(fromsyntheticrawmaterials,byproductsproducedintheproductionprocessorfromdegradation),andprovidecontrollimits.Anexampleisasfollows:TableXX:AnalysisofImpuritiesNameofimpurityStructureofimpuritySourceofimpurityControllimitsofimpurityWhetherornottoenterthequalitystandardThede

30、gradationproductscanbeexplainedbyacceleratedstabilitytestandforceddegradationtest,andthebasisforcontrollingthefinalqualitystandardandthelimitofcontrolshouldbeprovided.Forknownimpurities,preparation,structuralconfirmationandotherinformationarerequired.Thepossiblegenotoxicimpuritieswereanalyzed,studie

31、dandcontrolledincombinationwiththestartingmaterialsandthepreparationprocessoftheproduct.12.4(3.2.S.4)Qualitycontrolofdrugsubstance.1 QualitystandardProvidethequalitystandardaccordingtothefollowingtable.Ifthemethodandlimitofreleasestandardandshelflifestandardaredifferent,theyshouldbeexplaineds

32、eparately.TableXX:QualitystandardofdrugsubstanceTestitemsMethod(listthenumberofthemethod)LimitofreleasestandardLimitofshelflifestandardAppearanceColorandclarityofsolutionpHIdentificationRelatedsubstanceResidualsolventWatercontentHeavymetalsSulphatesIgnitionresidueParticlesizedistributionCrystallinef

33、ormOtherAssay.2 AnalyticalmethodProvidespecifictestingmethodsforeachiteminthequalitystandard..3 ValidationofanalyticalmethodProvidemethodologicalverificationdataaccordingtotheTechnicalGuidelinesfortheValidationofAnalyticalMethodsforChemicalDrugQualityControl,theTechnicalGuidelinesforth

34、eStandardizationofChemicalDrugQualityStandards,theTechnicalGuidelinesfortheStudyofChemicalDrugImpurities,theTechnicalGuidelinesfortheStudyofResidualSolventsforChemicalDrugandtherelevantGuidelinesintheAppendixtotheCurrentPharmacopoeiaofthePeople'sRepublicofChina.Thedatacanbeprovideditembyitemacco

35、rdingtothetestingmethod,andtheverificationresultscanbecompiledintabularform,andtherelevantverificationdataandspectracanbeprovided.Anexampleisasfollows:TableXX:SummaryofmethodologicalvalidationofassayItemValidationresultsspecificityLinearityandrangeLimitofquantitationAccuracyPrecisionStabilityDurabil

36、ity.4 BatchanalysisreportProvideanalysisreportsforatleastthreebatchesofsamples..5 JustificationofqualitystandardExplaintheconsiderationsofitemsetting,summarizeandanalyzethebasisofselectionofanalysismethodsanddeterminationoflimits.Ifthedomesticandforeignpharmacopoeiahasbeenpublishedompa

37、rethemtogether..6 (3.2.S.5)ReferencestandardsormaterialsIfthePharmacopoeiareferencesubstanceisusedinthedrugdevelopmentprocess,thesourceshouldbestatedandtheinstructionsandbatchnumbershouldbeprovided.Ifaself-madereferenceisusedduringthedevelopmentofthedrug,thecalibratingprocessoftheassayandpuri

38、tyshouldbeprovided..7 (3.2.S.6)Packagingmaterialsandcontainers(1) Typeofpackagingmaterials,sourceandrelevantcertificatedocuments:TableXX:Typeofpackagingmaterials,sourceandrelevantcertificatedocumentsItemPackagingcontainerr-r,1TypeofpackagingmaterialsManufacturerofpackagingmaterialsregistrationcertificatenumberofpackagingmaterialsValidityofregistrationcertificateofpackagingmaterialsQualitystandardnumberofpackagingmaterials:Asforthetypeofpackagingmaterials,thestructuralmaterialsandspecificationsshou