申报美国仿制药的体会

ExperienceinDevelopingANDAsforUSMarket申报美国仿制药的体会申报美国仿制药的体会YishengChen,Ph.D.3dlCfGFor3rdInternationalConferenceonGenericDrugsNanchang,Jiangxi2012年12月5-6日1Outline/要点Outline/要点‰NovastBranded‰南通联亚药业在美‰NovastBrandedgenericdrugs(ANDAs)intheUSmarket‰南通联亚药业在美国市场上的品牌仿制药intheUSmarket‰Requirementsand制药‰美国仿制药的要求challengesforUSANDAs与挑战‰美国FDA现场cGMP‰FDAcGMPInspection美国现场检查流程和要点2AboutNovast/南通联亚药业简介AboutNovast/南通联亚药业简介‰AtEPZinNantongtoprovide‰位于江苏南通出口加gphighqualityprescriptiondrugsforglobalmarkets‰位于江苏南通出口加工区，为全球市场提供高质量处方药物‰PassedFDA’scGMPinspectionin2008‰2008年通过美国FDA现场cGMP检查‰30highbarrierANDAssubmittedtoFDAf‰已向FDA申报30个高端仿制药品‰Total10approvalsofbrandedgenericsbyFDAwithproprietarynames‰已获FDA批文10个专有品牌的产品withproprietarynames‰9prescriptiondrugslaunchedinUS‰已有9个处方药物进入美国市场3NovastProductsinFDA’sOBFDA橙皮书已列联亚药品FDA橙皮书已列联亚药品11-14-2012Appl4RLD5ActiveDosageStrengthProprietaryApplicantApplNoTECode4ActiveIngredientForm;RouteProprietaryNameA090721AB1NoETHINYLESTRADIOL;LEVONORGESTRELTABLET;ORAL-280.02MG;0.1MGFALMINANOVASTLABSLTDA090719ABNoETHINYLESTRADIOL;LEVONORGESTRELTABLET;ORAL-280.03MG,0.04MG,0.03MG;0.05MG,0.075MG,0.125MGLEVONESTNOVASTLABSLTDA090948ABNoETHINYLESTRADIOL;NORETHINDRONETABLET;ORAL-280.035MG;1MGDASETTA1/35NOVASTLABSLTDA090946ABNoETHINYLESTRADIOL;NORETHINDRONETABLET;ORAL-280.035MG,0.035MG,0.035MG;0.5MG,0.75MG,1MGDASETTA7/7/7NOVASTLABSLTDA090947ABNoETHINYLESTRADIOL;NORETHINDRONETABLET;ORAL-280.035MG;0.4MGPHILITHNOVASTLABSLTDA091204ABNoETHINYLESTRADIOL;NORETHINDRONETABLET;ORAL-280.035MG;0.5MGWERANOVASTLABSLTDA090523ABNoETHINYLESTRADIOL;NORGESTIMATETABLET;ORAL-280.035MG;0.25MGMONO-LINYAHNOVASTLABSLTDA090524ABNoETHINYLESTRADIOL;NORGESTIMATETABLET;ORAL-280.035MG,0.035MG,0.035MG;0.18MG,0.215MG,0.25MGTRI-LINYAHNOVASTLABSLTDA091105ABNoETHINYLESTRADIOL;NORGESTRELTABLET;ORAL-280.03MG;0.3MGELINESTNOVASTLABSLTD4NORGESTRELORAL28LTDWhatIsCriticalforANDA？仿制药仿什么是关键？仿制药仿什么是关键？‰WhataspectsofanANDA‰仿制药的哪些方面应和原创pmustbethesameasRLD?oSpecifications?药一致？o质量标准？poDissolution?oFormulation?o溶出度？o处方？oFormulation?oManufacturingprocess?Thtiffto生产工艺？o疗效oTherapeuticeffectsoSafetyo安全性o生物等效性oBioequivalenceoOthers?o生物等效性o其它？5TechnicalChallengesforANDAs开发仿制药的技术挑战开发仿制药的技术挑战‰Dev.ofdosageformfor‰ANDA制剂的开发与原创制剂发样具有挑战gANDAisaschallengeasforRLDintechnicalaspects,especiallyforMRproducts制剂开发一样具有挑战性，特别是缓控释制剂‰原创药通常有专利和技especiallyforMRproducts‰PatentsarebarriersforANDA.Normallyformulaand/or‰原创药通常有专利和技术壁垒的保护，在专利未过期之前，ANDA处方和生产工艺不太可能与Normallyformulaand/orprocessofANDAaredifferentfromRLDifpatentsarevalid和生产工艺不太可能与原创药相同‰由于大部份药物制剂不‰DuetothelackofIVIVCformanyproducts,achievingBEhll‰由于大部份药物制剂不存在体内外相关性，生物等效性是个挑战isachallenge6FDARequirementsforANDAsFDA对仿制药申报的要求fdFDA对仿制药申报的要求‰FDAspecifiesRLDs‰FDA指定参照药（RLDs）‰ANDA&RLDmustbe:‰Pharmaceuticalequivalent1SAPI‰与参照药比，仿制药必须‰药物等效1含相同活性成份1.SameAPIs2.Samestrength,dosageform,&routeofdosing1.含相同活性成份2.相同剂量,剂型和用药途径3.Sameindications&similarlabeling‰Bioequivalence3.相同适应症和相似标签‰生物等效190%CI8000‰Bioequivalence1.90%CI:80.00-125.00%(C-max&AUCs)1.90%CI:80.00-125.00%(C-max&AUCs)2.MatchingdissolutionwithRLDnotrequired‰PatentCertification2.没有溶出与对照品一致的要求‰专利声明aeCecao‰专利声明7FDARequirementsforANDAsFDA对仿制药申报的要求FDA对仿制药申报的要求‰meetthesamebatch‰符合同等批控制要求（鉴别，requirementsforid,strength,purity,andqualityClhG符合同等批控制要求（鉴别，含量，纯度，质量）‰符合cGMP要求‰ComplywithcGMP‰Pilotscaleorlarger‰Stbilitdt‰申报批量为中试规模已上‰稳定性数据‰Stabilitydata•Past:1batch，3MAC&storagestabilitydataatfiling‰稳定性数据•过去:申报时1批3个月加速和常温稳定性数据•New:3batches，6MAC&storagestabilitydataatfiling•Followupwithlongtermdata•新要求:申报时3批6个月加速和常温稳定性数据•Followupwithlongtermdatatoconfirmshelflife•补交常温长期稳定性数据以确定有效期8FDARequirementsforANDAsFDA对仿制药申报的要求FDA对仿制药申报的要求‰QualitybyDesign(QbD)‰用质量源于设计（QbD)的理Qyyg(Q)•Science-based•Understand&control用质量源于设计Q)的念开发和申报仿制药•以科学为基础•Understand&controlofproducts•Pharmaceutical•对产品和生产工艺的理解和控制详细的产品和工艺研发报•PharmaceuticalReports•Ensureproductquality•详细的产品和工艺研发报告•保证药品质量Ensureproductquality‰UseCTDformats‰Electronicfiling保证药品质量‰用CTD模板申报‰用电子方式申报‰Electronicfiling‰用电子方式申报9FDARequirementsforANDAsFDA对仿制药申报的要求FDA对仿制药申报的要求‰FilingafterBEandstabilitydata‰在生物等效研究和3个月gyareavailable(applicationnotrequiredforBEclinicalstudy)‰PVlidtiit在物等效研究和个月（或6个月）稳定性考察完成后一次性递交ANDA申报（无需临床前的申报）‰ProcessValidationisnotrequiredforexhibitbatchesbutneedQbDdatainfiling申报（无需临床前的申报）‰申报批次没规定要做工艺验证但申报要有QbD数据‰Validationmaybedonebeforesubmissionorafterapprovalbeforecommercial验证但申报要有QbD数据‰生产工艺验证可在申报前，也可在批准后生产销售批beforecommercialmanufacturing‰Validationbatchesmeeting也可在批准后生产销售批次前进行‰符合要求的验证批次可销‰Validationbatchesmeetingpredefinedrequirementscanbeusedforsale‰符合要求的验证批次可销售10GeneralFlowforANDAs仿制药开发常见流程仿制药开发常见流程AnalysisofRLD,IdentifyQTPP&CQAs分析参照药初定Q&CQ分析参照药,初定QTPP&CQAs↓ARMethodsDev.,CompatibilityStudies,ProductDev.建立分析方法，辅料兼容性研究，筛选处方与工艺建立分析方法，辅料兼容性研究，筛选处方与工艺↕MayDoPilotStudies/可能做BE预试验↕PiltSlDIdtif&CtlfCPP/中试放大确定CPP及其控制PilotScaleDev.,Identify&ControlofCPPs/中试放大,确定CPPs及其控制↓ManufacturingANDABatches/申报批次的生产↓↓BE&StabilityStudies/BE和稳定性试验↓ANDASubmission/申报↔Amendment/补充材料，PAI/批前检查↓↓FDAApproval/FDA批准Scale-up&Validation/放大和验证↓CommercialManufacturing/商业性生产11CommercialManufactur