顾博士GenericDrug_CMCRequirement_2012Nov1

1、A Discussion from Chemistry, Manufacturing, and Controls PerspectiveGeneric DrugGeneric Drug仿制药仿制药1Definition of a Generic Drug仿制药的定义仿制药的定义o A drug product that is comparable to a brand/reference listed drug (RLD) product in dosage form, strength, route of administration, quality and performance cha

2、racteristics, and intended use.该药品其剂型，剂量，给药途径，质量和作用特点，该药品其剂型，剂量，给药途径，质量和作用特点，以及其适应症应与原创药相同以及其适应症应与原创药相同23Requirements for Generic Drug 美国美国 FDA 对仿制药申请的要求对仿制药申请的要求Compared to reference listed drug (RLD)o Same active ingredient(s)相同的原料相同的原料o Same route of administration 相同的给药途径相同的给药途径o Same dosage for

3、m相同的剂型相同的剂型o Same strength 相同的剂量相同的剂量o Same indication (Labeling) 相同的适应症相同的适应症o Bioequivalent 生物等效生物等效o Same GMP requirements相同的相同的GMP要求要求 Generic Injections 注射剂仿制药注射剂仿制药q Q1 and Q2 RequirementsnQualitative and quantitative of active and inactive excipients requirements for generic drug as that in R

4、LD, including diluent.仿制注射剂中的活性成分和辅料的种类仿制注射剂中的活性成分和辅料的种类(Q1)和用量和用量(Q2)应于原创药中一致应于原创药中一致nBuffer system and preservative may be changed缓冲系统和防腐剂可改变缓冲系统和防腐剂可改变qNo bioequivalent (BE) study is required 对注射剂无生物等效临床试验的要求对注射剂无生物等效临床试验的要求4Generic Oral Solid Dosage Forms 仿制口服固体制剂仿制口服固体制剂oThe following may be ch

5、anged for OSD 下例各项在口服固体制剂仿制药中可改变下例各项在口服固体制剂仿制药中可改变vTablet weight 片重片重vExcipient 辅料辅料 (Include type and amount) vTablet shape 片型状片型状vColor 颜色颜色vImprinting 刻字刻字nOther changes need to submit Suitability Petition under 21 CFR 314.93(b) 其它改变可通过其它改变可通过适应性请愿的方式向适应性请愿的方式向FDA申请，例如：申请，例如：vDosage Form or stren

6、gth 剂型剂型 或或 剂量剂量56ANDA Patent Certification 非专利药申请的分类非专利药申请的分类o Paragraph I Certification （从无有专利）从无有专利）Patent was never submitted - immediately effective approval dateo Paragraph II Certification （专利已过期）专利已过期）Patent expired - immediately effective approval dateo Paragraph III Certification （专利没过期）专利

7、没过期）Patent will expire tentative approvalo Paragraph IV Certification （挑战专利）挑战专利）Patent challenge (patent invalid, not infringed, not enforceable) notification to patent holder and sponsor, tentative approval, may have six-month exclusivity if win.Completeness of ANDAqMODULE 1: Administrativev Draft

8、 LabelingqMODULE 2: Quality Overall Summaryv Sample can be found on the OGD webpage /cder/ogd/qMODULE 3: v 3.2.S Drug Substancev 3.2.P Drug Product3.2.P.2 Pharmaceutical Development3.2.P.3.5 Process Validation and/or EvaluationMicrobiological sterilization validation (Sterility assu

9、rance package)v 3.2.R Regional InformationDS (EBR, CP, MV)DP (EBR, Info on Components, CP, MV)q MODULE 5: Clinical Study Reports (BE)73.2.S Drug Substance3.2.S.1General Information3.2.S.2Manufacture3.2.S.3Characterization of Drug Substance3.2.S.4 Control of Drug Substance3.2.S.5Reference Standard3.2

10、.S.6Container Closure System3.2.S.7Stability8CTD-Format3.2.S.2 Manufacture 3.2.S.2.1 Manufacturer(s)3.2.S.2.2 Description of Manufacturing Process and Process Controls3.2.S.2.3 Control of Materials3.2.S.2.4 Controls of Critical Steps and Intermediates3.2.S.2.5 Process Validation and/or Evaluation3.2

11、.S.2.6 Manufacturing Process Development(QbD concept approach)将将QbD概念应用于生产工艺的开发概念应用于生产工艺的开发Reference: ICH Q11, Development and Manufacture of Drug Substance, 201193.2.SDrug Substance Drug Substance 原料药原料药 *CMC requirements for DS when DMF is referenced* 10Active Pharmaceutical Ingredient(Drug Substa

12、nce) 原料药原料药Drug Substance Source: 原料药的来源原料药的来源1. Manufactured in-house 本公司生产本公司生产v Submit DMF for drug substance, orv Include DS section in ANDA3.2.S.2.6 Manufacturing Process Development(QbD concept approach)2. Purchased from API supplier 购买购买v Reference DMF for drug substanceSee ANDA checklist for

13、 detailed requirements in application (discussed in following slides)11Understand How to Apply QbD concept in API development 理解如何将理解如何将QbD概念应用于原料药开发中概念应用于原料药开发中123.2.S.1General Information原料药的概况原料药的概况o The following information should be provided in ANDA (Do not refer to DMF)n 3.2.S.1.1 Nomenclatur

14、e 命名命名n 3.2.S.1.2 Structure 结构结构n 3.2.S.1.3 General Properties 特性特性o Polymorphic forms and crystalline forms o Solubility and pKa 133.2.S.2 Manufacturer 原料药生产商原料药生产商 o DS Manufacturer 原料药生产商原料药生产商nName and Full Address(es)of the Facility(ies)nContact name, phone and fax numbers, emailaddress nU.S Ag

15、ents name (if applicable) nSpecify Function or Responsibility nType II DMF number for API nCFN, FEI or DUNS numbers (if available)nUser fee payment I.D. Numbero Certificate on CGMP compliance status of DS manufacturing site 原料药生产设施的原料药生产设施的CGMP状况状况143.2.S.3 Characterization of DS 原料药结构解析原料药结构解析 q If

16、 a DMF is referenced in ANDA, the detailed characterization of DS is NOT required.q However, the following information should be provided in tabular format.如果如果DMF被引用了，以下信息应以表格的方式提供被引用了，以下信息应以表格的方式提供vName of Impurity(ies) 杂质的名字杂质的名字vStructure of Impurity(ies) 杂质的结构杂质的结构vOrigin of Impurity(ies) 杂质的来源

17、杂质的来源15Impurity Information 杂质信息杂质信息(Example)NameStructureOrigin(S)-9-Fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H- pyrido1,2,3-de-1,4-benzoxazinePotential degradation product from de-carboxylation of XXXXX(S)-9-Fluoro-2,3-dihydro-3-methyl-10-(1-piperazinyl)-7-oxo-7H-pyrido1,2,3-

18、de-1,4-benzoxazine-6-carboxylic acidProcess impurity results from the final step probably due to piperazine impurity.(S)-2,3-Dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido1,2,3-de-1,4-benzoxazine-6-carboxylic acidThis process impurity probably originates from mono fluorinated impurity

19、present in the di-fluorinated starting material. 163.2.S.4 Control of DS 原料药质量控制原料药质量控制3.2.S.4.1 DS Specification 原料药质量标准原料药质量标准o Specification should be established based on:nUSP monographnEP or BP monographnAPI suppliers COAnICH guidelines, etc.q Specification established should be suitable for in

20、tended use.nParticle size distributionnMicrobial limitnBacterial endotoxin17DS Specification 原料药质量标准原料药质量标准(Example) TestAcceptance CriteriaAnalytical ProcedureAppearanceWhite powderVisual inspectionIdentification (IR)Conform to standardUSP Assay (HPLC)98.0 102.0%USP Related SubstanceKnown impurityU

21、nknown, eachTotalNMT 0.50%NMT 0.10%NMT 1.0%USP HPLCChiral ImpurityNMT 1.0%Chiral HPLCHeavy MetalNMT 20 ppmUSP Water ContentNMT 2.0%USP KFResidue SolventAcetone NMT 500 ppmUSPMicrobial LimitUSP B. EndotoxinsUSP 18DS Test Results 原料药检验结果原料药检验结果(Example) TestAcceptance CriteriaTest Results (Lot# XX)App

22、earanceWhite powderConformedIdentification (IR)Conform to standardConformedAssay (HPLC)98.0 102.0%99.2%Related SubstanceKnown impurityUnknown, eachTotalNMT 0.50%NMT 0.10%NMT 1.0%0.20%0.05%0.50%Chiral ImpurityNMT 1.0%0.05%Heavy MetalNMT 20 ppmNMT 20 ppmWater ContentNMT 2.0%1.2%Residue SolventAcetone

23、NMT 500 ppm200 ppmMicrobial LimitNMT XX CFU/gXXB. EndotoxinsNMT XX EU/gXX193.2.S.4.2 Analytical Procedures 原料药分析方法原料药分析方法q Analytical procedures should be established 建立分析方法建立分析方法n Compendial methodsn Provided by API manufacturern Developed in-houseq Representative spectra and chromatograms for refe

24、rence standards and test samples should be provided. 应提供有代表性的分析图谱应提供有代表性的分析图谱203.2.S.4.3 Validation of Analytical Procedures 分析方法验证分析方法验证q Analytical procedures should be properly validated or verified分析方法应验证或适当的确认分析方法应验证或适当的确认v Verification for USP proceduresv Validation for any non-USP procedureso

25、 USP for Method validationo USP for Method verification21Reserved Sample for DS原料药的留样原料药的留样o Samples statement of availability and identification (lot number) of drug substance should be provided in ANDA.在在ANDA中应提供原料药留样的声明中应提供原料药留样的声明n Statement for Reserve Samples (Example)Samples of XXXXX drug sub

26、stance (lot #: 88888) used in the manufacturing of ANDA exhibit batch of XXXXXX drug product, 200 mg will be reserved on site for any future tests in accordance with 21 CFR 211.170. The reserved drug substance samples are available and consist of at least twice the quantity necessary for all tests.2

27、23.2.S.4.4 Batch Analysis 原料药批分析结果原料药批分析结果 o COA, including specification and test results from the manufacturer should be provided in ANDA提供原料药供应商的质量标准和检验结果提供原料药供应商的质量标准和检验结果 (COA)o COA of in-house testing results should be included in ANDA 提供提供ANDA申请者的检验结果申请者的检验结果 (COA)233.2.S.4.5 Justification of

28、 Spec 提供提供建立该质量标准的依据建立该质量标准的依据 o Proper justification for the acceptance criteria for the tests listed in the specification should be provided. For example:24TestAcceptance CriteriaJustificationRelated Substance:Impurity AImpurity B Total impurityNMT 0.5%NMT 0.2%NMT 1.0%The limits is in-line with US

29、P monograph.Assay95.0 to105.0% of labeled amountThe specification is in-line with USP monograph.Residual SolventsAcetone 2000 ppmMeet the requirement of USP 3.2.S.5 Reference Standard 标准品标准品q Do not refer to DMF 不要在不要在ANDA中引用中引用DMFq Provide information on the reference standard you used, such as: 提供

30、使用的标准品的信息提供使用的标准品的信息n USP Reference Standard (RS) 美国药典标准品美国药典标准品n In-house established standard (with COA)自己建立的标准品自己建立的标准品25RS NameLot #SourcePurposeZidovudineA666USPPrimary RSZidovudineZ888In-houseWorking Standard3.2.S.6 Container Closure System包装材料系统包装材料系统o If the container used is LDPE bag, the f

31、ollowing statement can be provide:n The LDPE bags used for packaging of XXXXX drug substance meet with food grade requirements and comply with 21 CFR 177.1520(a)(2) and 177.1520(c)(2.2).o Or, refer to DMF for detailed information regarding to CCS used.263.2.S.7 Stability 稳定性数据稳定性数据o Refer DS DMF for

32、 available stability data for the drug substance and the post-approval stability protocol and stability commitment.可引用可引用DMF来参照其稳定性数据，药品批准后的稳定来参照其稳定性数据，药品批准后的稳定性方案和承诺性方案和承诺o The DMF should include stability data from three batches of DS at Pilot scale.DMF中应包括三批原料药的稳定性数据中应包括三批原料药的稳定性数据o Retest date o

33、r expiration date of DS should be included. 应提供原料药的有效期应提供原料药的有效期27制剂制剂Drug Product(Finished Dosage Forms)283.2.PDrug Product3.2.P.1Description and Composition of DP3.2.P.2Pharmaceutical Development3.2.P.2.1 Pharmaceutical development report3.2.P.3Manufacture3.2.P.3.5 Process validation/or evaluation

34、3.2.P.4Control of Excipients3.2.P.5Control of Drug Product3.2.P.7Container Closure System3.2.P.8Stability293.2.P.1 Composition of the DP制剂的配方成分制剂的配方成分ComponentQuality StandardFunctionAmount per Tablet(mg)Percentage(%)XXXXXXUSPActive Ingredient20050%Excipient 1NFFiller10025%Excipient 2Excipient 3Exci

35、pient 4USPLubricantXX2.0%Total weight-400 mg100%30Comparison of Inactive Ingredient Used in the Proposed Generic Drug with FDA Approved Formulations in IIG DatabaseIngredientAmount in Proposed Generic DrugLimit in IIG DatabaseStarch150 mg500 mgExcipient 230 mg100 mgExcipient 310 mg40 mgMagnesium Ste

36、arate5.0 mg50 mg/scripts/cder/iig/index.cfm31Formulation Comparison配方比较配方比较IngredientProposed FormulationRLD FormulationActive Ingredient3 mg3 mgSodium Chloride, USP25.800 mg25.800 mgGlacial Acetic Acid, USP1.530 mg1.530 mgSodium Acetate0.612 mg0.612 mgWater for Injection

37、, USP2980.683 mg2980.683 mgNitrogen, NFoverlayoverlay323.2.P.2 Pharmaceutical Developmento Pharmaceutical Development Reportn Apply QbD approach concept Reference:1. ICH Q8: Pharmaceutical Development, November 2009QbD concept will be briefly discussed in the following slides33Quality by Design (QbD

38、)质量源于设计质量源于设计Definitionp Systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management.p应用合理的科学方法和质量风险管理原则，始于预定产品质应用合理的科学方法和质量风险管理原则，始于预定产品质量的目标，着重于对产品和工艺的理解以及工艺控制的系统量

39、的目标，着重于对产品和工艺的理解以及工艺控制的系统性的研究和开发方法。性的研究和开发方法。Reference: ICH Q8(R)(2) Pharmaceutical Development, 20093435Quality by Design质量源于设计质量源于设计TerminologynQuality Target Product Profile 目标产品质量概况目标产品质量概况nCritical Quality Attributes 关键质量属性关键质量属性nCritical Material Attributes 关键物料属性关键物料属性nCritical Process Parame

40、ters 关键工艺参数关键工艺参数nRisk Assessment 风险评估风险评估nDesign Space 设计空间设计空间nControl Strategy 控制策略控制策略QbD Approachq Process understanding links Critical Material Attributes (CMAs) and Critical Process Parameters (CPPs) to Critical Quality Attributes (CQAs)/specifications and hence to the desired performance of

41、the product工艺研发应将关健物料参数，关健工艺参数与产品质量标准工艺研发应将关健物料参数，关健工艺参数与产品质量标准联系联系q Implementation of QbD, including establishment of Proven Acceptable Range (PAR), Operational Range (OR), development of design space and control strategy.应用应用QbD建立被证明的接受范围，生产控制范围，设计空间，建立被证明的接受范围，生产控制范围，设计空间，和控制策略等和控制策略等3637QbD Appr

42、oachQbD 原则的探讨原则的探讨nDefining Quality Target Product Profile (QTPP)nDetermine Critical Quality Attributes (CQAs)nLink Critical Material Attributes (CMAs) and Critical Process Parameters (CPPs) to CQAs nPerform risk assessment nDevelop a design space (DOE etc.)nDesign and implement a control strategynM

43、anage product lifecycle, including continual improvementMinimum Elements for Manufacturing Process Development生产工艺研发中的最基本要求生产工艺研发中的最基本要求qIdentifying potential CQAs associated with the productqDefining an appropriate manufacturing processvCPP, CMA, PAR, ORqDefining a control strategy to ensure proces

44、s performance and drug substance quality38 Comparison of Process Development 工艺开发过程的比较工艺开发过程的比较391QbD Concept ApproachTraditional Approach QTPP/CQA2Process Route IdentificationProcess Route Identification3Piloting Scale-up and Process OptimizationPiloting Scale-up and Process Optimization4Process Ch

45、aracterizationvCPP, CMA, PAR (OR)vControl strategy5Process Understanding (Design Space, etc.)6Process Qualification (Validation)Process Qualification (Validation)Important Understanding Design Space 设计空间设计空间oDesign space is potentially scale- and equipment-dependent 设计空间与批量和设备有关设计空间与批量和设备有关oDesign s

46、pace determined at the laboratory scale may not be relevant to the process at the commercial scale 实验室决定的设计空间也许与商业批量的生产工艺无关实验室决定的设计空间也许与商业批量的生产工艺无关oTherefore, design-space verification at the commercial scale becomes essential unless it is demonstrated that the design space is scale-independent. 因此，

47、用商业批量的生产工艺来确认设计空间是必须的因此，用商业批量的生产工艺来确认设计空间是必须的403.2.P.3 Manufacture3.2.P.3.1 Drug Product ManufacturerThe following information should be provided:1. Name and Full Address(es)of the Facility(ies) 2. Contact name, phone and fax numbers, email address 3. U.S Agents name (if applicable) 4. Specify Funct

48、ion or Responsibility 5 CGMP Certification (from both applicant and drug product manufacturer if different entities) 6. CFN, FEI or DUNS numbers (if available) 413.2.P.3 Manufactureo 3.2.P.3.2 Batch Formulationo 3.2.P.3.3 Description of Manufacturing Process and Process Controlsn Manufacturing flow

49、diagramn Brief description of manufacturing processo 3.2.P.3.4 Controls of Critical Steps and Intermediateso 3.2.P.3.5 Process Validation and/or Evaluationn Microbiological sterilization validation (package)42In-process Control Parameters 中控参数中控参数q 常见的中控参数常见的中控参数 ：nAppearance 外观外观nAssay (active cont

50、ent) 含量含量npH 酸碱度酸碱度nBioburden 细菌的总量及其种类细菌的总量及其种类 nSolvent temperature 溶媒的温度溶媒的温度nStirring time 搅拌时间搅拌时间nHolding time 保存时间保存时间nEtc. 等等等等q 参数控制范围的建立参数控制范围的建立43Sterility Assurance Package(Information should be included in this package)q Equipment QualificationnQualification of Moisture Heat AutoclavenQ

51、ualification of Dry-heat OvennQualification of Dry-heat TunnelnQualification of Vial Washing MachinenQualification of Rubber Stopper Washing MachinenQualification of Sterility and Endotoxin Test methodsnQualification of WFI Systemq Other InformationnAseptic Process Simulation (Media Fill)nEnvironmen

52、tal monitoringnSterile Filtration ValidationnContainer Closure Integrity StudynEtc. etc.443.2.P.4. Controls of Excipients 药用辅料的控制药用辅料的控制o 3.2.P.4.1 Specifications nTesting specifications nSuppliers COAnApplicant COA for test resultso 3.2.P.4.2 Analytical Procedures o 3.2.P.4.3 Validation/verificatio

53、n of Analytical Procedures o 3.2.P.4.4 Justification of SpecificationsnA statement for no animal sourced excipient used should be provided 提供无动物来源的辅料的声明提供无动物来源的辅料的声明45 3.2.P.4. Controls of Excipients 药用辅料的控制药用辅料的控制For compendial excipients: 美国药典辅料美国药典辅料q Testing excipients with USP methods 用美国药典方法测试

54、辅料用美国药典方法测试辅料q Meet USP/NF monograph quality standard 辅料需达到美国药典质量标准辅料需达到美国药典质量标准q The amount used should be less than that listed in FDA inactive ingredient guide (IIG) 用量应小于该辅料在美国用量应小于该辅料在美国FDA批准药品中的用量批准药品中的用量/scripts/cder/iig/index.cfmFor Novel excipient, reference a DM

55、F463.2.P.5 Controls of Drug Product制剂的质量控制制剂的质量控制3.2.P.5.1 Specification(s) 3.2.P.5.2 Analytical Procedures 3.2.P.5.3 Validation of Analytical Procedures vProvide verification of USP procedurev Statement for reserved samples 3.2.P.5.4 Batch Analysis v Certificate of Analysis 3.2.P.5.5 Characterizati

56、on of Impurities 3.2.P.5.6 Justification of Specifications47Specifications for Drug Product 制剂的质量标准制剂的质量标准制订制剂的质量标准依据：制订制剂的质量标准依据：o USP or USP PFo EP or BPo ICH Guidelineo Other Sourcesn API specificationn In-house Quality Standard and testing results48Specification for Liquid Injection 针剂的质量标准针剂的质量

57、标准TestAcceptance CriteriaAnalytical ProcedureAppearanceClear, yellowishVisual Identification (IR)Conform to standardUSP pH5.3 - 5.6USPAssay90% - 110%USP HPLCRelated SubstanceKnow impurityUnknown, eachTotal impuritiesNMT0.8%NMT0.10%NMT1.5%USP HPLCParticulate MatterMeet USP requirementUSP Endotoxins LimitNMT XX EU/mgUSP SterilitySterileUSP 49Specification for Oral Solid Dosage Forms 固体制剂的质量标准固体制剂的质量标准TestAcceptance Cr