原料药生产申报支持性文件的递交指南.docx

原料药生产申报支持性文件的递交指南.docx

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原料药生产申报支持性文件的递交指南

GUIDELINEFORSUBMITTINGSUPPORTING

DOCUMENTATIONINDRUGAPPLICATIONSFORTHE

MANUFACTUREOFDRUGSUBSTANCES

CenterforDrugEvaluationandResearch

FoodandDrugAdministration

DepartmentofHealthandHumanServices

February1987

Forfurtherinformationregardingtheguidelinepleasecontact:

FoodandDrugAdministration

CenterforDrugEvaluationandResearch

OfficeofDrugEvaluationI（HFD-100）

5600FishersLane

Rockville,Maryland20857

（301-443-4330）

Note:

ThisGuidelinewaspreparedbyDr.ArthurShaw,FoodandDrugAdministration,foraCourseofferedbytheCenterforProfessionalAdvancementinMarchof1994.TherehavebeennochangesinthetextfromtheprintedversionoftheGuideline.Howeverthetexthasbeenreformattedtoreducethenumberofpages.TheTableofContentsreflectsthenewpagination.Theoldpaginationisnotedinthe

Guideline.

原料药生产申报支持性资料的递交指南

健康与人类效劳部

食物药品治理局

药品评估与研究中心

1987年2月

有关指南的更多信息，请联系：

5600FishersLane

Rockville,Maryland20857

（301-443-4330）

食物药品治理局

药品评估与研究中心

药品评估办公室1（HFD-100）

注：

本指南是食物药品治理局的ArthurShaw博士于1994年为职业深造中心提供的一门课程而编写。

指南的印刷版正文不曾有变更。

可是正文通过从头排版，减少了页数。

目录显示了新的页码。

老的页码也在指南中注明。

TABLEOFCONTENTS目录

I.INTRODUCTION介绍......................................................................................6

II.REQUIREMENTSFORANEWDRUGAPPLICATION新药申请的要求...............7

A.PhysicalandChemicalCharacteristics物理和化学特点..............................7

1.Properties性质........................................................................................7

2.Structure结构..........................................................................................8

B.Stability稳固性............................................................................................9

C.NameandAddressoftheManufacturer生产商的名称与地址.....................9

D.ManufactureoftheDrugSubstance原料药的生产......................................9

1.MaterialControls物料的操纵.........................................................10

a.Startingmaterials起始物料..................................................10

（1）Definitionofstartingmaterial起始物料的概念...........10

（2）Controlproceduresforstartingmaterials起始物料的操纵程序.......................................................................11

b.Reagents,solvents,andauxiliarymaterialscontrols试剂、溶剂与辅料的操纵....................................................................12

2.SyntheticDrugSubstance合成原料药.........................................12

a.Flowchartofthesynthesis合成的流程图............................12

b.Descriptionofthesynthesis合成进程的描述.......................13

c.Purificationofthedrugsubstance原料药的精制................14

d.Changesinthesynthesis合成进程的变更...........................15

3.ReferenceStandard对照品............................................................17

4.InSituProducts（notisolated）原位产品（没有分离）..................17

5.Microencapsulation微型包囊法........................................................17

6.AntibioticsandOtherDrugSubstancesfromFermentationorNaturalSources由发酵或天然来源生成的抗生素和其他原料药.....................................................................................................18

a.Fermentation发酵................................................................18

（1）Controlproceduresforstartingmaterials/起始物料的操纵程序...................................................................................18

（2）Microbialidentification,source,deposition微生物的辨别、来源和沉积...............................................................................19

（3）Fermentationprocessmonitoringandcontrol发酵工艺的监督和操纵...............................................................................19

b.Extraction,isolation,analysis,characterization萃取、隔离、分析和鉴定.................................................................................20

c.Drugsubstancesobtainedfromplantsandanimals/从植物和动物中取得的原料药.............................................................22

（1）Plants植物.......................................................................22

（2）Animals动物....................................................................23

d.Semisyntheticantibioticsandotherdrugsubstancesderivedfromfermentationandnaturalsources由发酵和天然来源取得的半合成抗生素和其他原料药................................................23

E.ProcessControls工艺操纵.........................................................................24

1.IntermediatesandIn-processControls/中间体和进程操纵...............24

a.Pivotalintermediate（s）枢轴中间体......................................26

b.Keyintermediate（s）关键中间体...........................................26

c.Finalintermediate最后中间体...............................................26

2.Reprocessing返工.........................................................................27

F.DrugSubstanceControls原料药的操纵......................................................29

1.Sampling取样................................................................................29

2.ReleaseControls放行操纵............................................................29

a.Appearance/description外观/性状......................................29

b.Physicalproperties物理性质.............................................29

c.Specificidentitytest（s）专属辨别实验..................................30

d.Impurityprofileandlimits杂质概况和限度.............................30

e.Assay含量.........................................................................31

3.ReferenceStandard对照品............................................................32

G.Solid-StateDrugSubstanceForms:

RelationshiptoBioavailability固体原料药类型：

与生物利费用的关系....................................................................34

1.Polymorphism多晶型现象.............................................................36

2.Solvation（includinghydration）溶化作用（包含水合作用）..........37

3.ParticleSize（andsurfacearea）粒度（和表面积）………….…....37

III.REQUIREMENTSFORANINVESTIGATIONALNEWDRUG（IND）临床研究新药的要求..................................................................................................................38

A.NewChemicalEntity新化学实体.......................................................................38

1.Phases1and2/第1和第2时期.......................................................38

a.Physicalandchemicalcharacteristics理化特点…………....38

b.Manufactureofthenewdrugsubstance新原料药的生产...39

c.Analyticalmethods分析方式..............................................39

2.Phase3第三时期...........................................................................40

a.Manufactureofthenewdrugsubstance新原料药的生产…..40

b.Analyticalmethods分析方式...............................................40

B.KnownChemicalEntity已知化学实体........................................................40

1.Sponsor-InvestigatorResearchStudy（documentationonfile）研究发起人的调查研究（档案文件）..................................................................41

2.Sponsor-InvestigatorResearchStudyorCommercialSponsor（nodocumentationoffile）研究发起人的调查研究或商业发起人（无档案文件）....................................................................................................41

IV.CURRENTGOODMANUFACTURINGPRACTICEREQUIREMENTS现行药品生产质量治理标准的要求........................................................................................42

GLOSSARY术语表....................................................................................................43

GUIDELINEFORSUBMITTINGSUPPORTINGDOCUMENTATIONINDRUG

APPLICATIONSFORTHEMANUFACTUREOFDRUGSUBSTANCES

原料药生产申报支持性资料的递交指南

I.INTRODUCTION/介绍

Thisguidelineisintendedtoprovidesponsors/applicantswithproceduresacceptabletotheagencyforcomplyingwithregulationspertainingtothesubmissionofadequateinformationontheproductionandcontrolofnewdrugsubstances.Thisguidelineaddressesnewdrugsubstancesmanufacturedbychemicalsynthesis,byfermentation,orbyisolationfromnaturalsources（andcombinationsthereof）;itdoesnotcoverdrugsubstancesmanufacturedbyrecombinantDNAsynthesis（biotechnologymethods）.Theguidelinedoesnotimposemandatoryrequirements[21CFR（b）].Itdoes,however,offerguidanceonacceptableapproachestomeetingregulatoryrequirements.

本指南旨在为发起人/申请人提供FDA所同意且符合法规要求的新原料药生产与操纵资料的递交程序。

本指南要紧针对通过化学合成、发酵或天然源离析（或其结合）所生产的新原料药；而不包括通过重组DNA合成（生物工艺学方式）所生产的原料药。

本指南并未施增强制性的要求[21CFR（b）]。

可是它确实提供了符合法规要求的可同意方式的指导。

Differentapproachesmaybefollowed,buttheapplicantisencouragetodiscusssignificantvariationsinadvancewithFDAreviewerstoprecludespendingtime

andeffortinpreparingasubmissionthatFDAmaylaterdeterminetobeunacceptable.

可遵循不同的方式，可是咱们鼓舞申请人提早与FDA评审员讨论这些重大变更，从而幸免把时刻和精力花费在预备以后FDA可能以为并不合格的申报资料上。

Theneedtoprovideadequateinformationrelatedtodrugmanufacturingisimposedinsection505（b）oftheFood,Drug,andCosmeticAct,whichrequiresafulldescriptionofthe"methodsusedinthemanufactureofsuchdrug."Suchadescriptionincludesthemethodofpreparationofthedrugsubstance,andthecontroltestingusedtomonitoritsidentity,strength,quality,andpurity.

食物、药品与化妆品法案505（b）部份有要求提供药品生产相关资料的强制性规定，要求详细描述“此类药品的生产方式”。

如此的描述包括原料药的配制方式和用于监控其均一性、浓度、质量和纯度的操纵查验。

Adescriptionofthemethodsofpreparationandprocesscontrolsispertinentnotonlytoanewdrugapplication（NDA）,butalsotoanabbreviatednewdrugapplication（ANDA）,aninvestigationalnewdrugapplication（IND）,andappropriateportionsofadrugmasterfile（DMF）.Foranewdrugsubstance,adescriptionofthe"sourceandpreparation"isarequirementintheINDstageofstudyunder21CFRPart312.Subsequently,whenanNDAissubmitted,adescriptionofthe"methodsusedinthesynthesis"arerequiredunder21CFR（d）

（1）（i）.

配制与进程控制方式的描述不仅与新药申请（DNA