1、开发报批美国FDA的仿制(fngzh)药与相关问题探讨,上海复星普适医药(yyo)科技有限公司何平,第一页，共四十一页。,内容提要(ni rn t yo),开发仿制药的重要性和机遇 开发仿制药的挑战申报仿制药的分类仿制药研发团队仿制药的研发过程QbD在制剂开发中怎么体现研发(高难(o nn)仿制药的一些体会：案例研究,第二页，共四十一页。,开发(kif)仿制药的重要性,新药与仿制(fngzh)药-NDA and ANDA开发仿制药与我国药物研发的海外战略,药物制剂目标(mbio)主流市场,第三页，共四十一页。,开发(kif)仿制药的挑战性,开发仿制药更具挑战性药物制剂专利 仿制药的竞争(jng
2、zhng)仿制药厂之间的竞争由品牌药转成仿制药,第四页，共四十一页。,仿制(fngzh)药竞争的方式HOW TO COMPETE,Cost-IR ProductRaw MaterialsProcessFinished ProductTechnology-Modified Release Products,第五页，共四十一页。,申报(仿制(fngzh)新药的分类,规范市场(FDA)1。P-I2。P-II3。P-III4。P-IV(1st to file),中国(zhn u)市场（sFDA）1类2类3类4类5类6类,第六页，共四十一页。,仿制(fngzh)药研发团队CONCEPT-1 BUILD
3、UP A TEAM,REGULATORY,第七页，共四十一页。,DRUG DELIVERY SYSTEMS FOR ORAL SOLID FORMULATIONS-MRMATRIX SYSTEMSRESERVIOR SYSTEMSOSMOTICAL PUMP SYSTEMSCOMBO-SYSTEMS,缓控释给药的技术(jsh)平台和给药系统CONCEPT-2 BUILD UP A SYSTEM,第八页，共四十一页。,Product Development Roadmap仿制(fngzh)药的研发过程,第九页，共四十一页。,Quality Acceptably low risk of faili
4、ng to achieve the desired clinical attributes Pharmaceutical Quality=f drug substance,excipients,manufacturing.QbD Product and process performance characteristicsscientifically designed to meet specific objectives,not merely empirically derived from performance of test batches,What is QbD(Quality by
5、 Design)?QbD在制剂(zhj)开发中怎么体现？,第十页，共四十一页。,What is QbD?QbD在制剂开发(kif)中怎么体现？,Pharmaceutical Quality by Design(QbD)QbD means designing and developing formulations and manufacturing processes to ensure predefined product qualityUnderstanding and controlling formulation and manufacturing process variables a
6、ffecting the quality of a drug product,第十一页，共四十一页。,Essential elements of QbD Definition of the quality target product profileHigh level quality aspects of the product:purity,drug release(dissolution/disintegration time),pharmacokinetic profile,etc.Critical quality attributes(CQAs)for drug product Ch
7、aracteristics of DP which have impact on desired profile Conscious attempt to study and control Critical Process Parameters(CPPs)Identification of material properties and process parameters which haveeffect on product CQAs Design Space:The multidimensional combination and interaction ofinput variabl
8、es and process parameters that have been demonstrated to provide assurance of quality Identification of a control strategy for critical process parameters,What is QbD?QbD在制剂开发中怎么(zn me)体现？,第十二页，共四十一页。,Raw Materials,Equipment,Environment,Operators,Variable Inputs,x,“Locked”Process,=,Variable Quality,
9、How Did We Work in the Past,What is QbD?QbD在制剂(zhj)开发中怎么体现？,第十三页，共四十一页。,Raw Materials,Equipment,Environment,Operators,Understood Variable Inputs,x,Understood and Controlled Process,=,Predefined Quality,Flexible Process Design Space,How Can We Work in the Future,What is QbD?QbD在制剂开发(kif)中怎么体现？,第十四页，共
10、四十一页。,What is QbD?QbD在制剂开发中怎么(zn me)体现？,Raw Materials,Wet Granulation,Fluid Bed Drying,Blending,Compression,Product,第十五页，共四十一页。,Drug Substance,Excipients,SourceAssayImpurities LODPS,What is QbD?QbD在制剂开发(kif)中怎么体现？,第十六页，共四十一页。,WaterBinderTempSpray RateSpeedTimeP.S,What is QbD?QbD在制剂开发(kif)中怎么体现？,第十七页
11、，共四十一页。,What is QbD?QbD在制剂(zhj)开发中怎么体现？,Air FlowTempRHShock CycleP.S.,第十八页，共四十一页。,What is QbD?QbD在制剂开发中怎么(zn me)体现？,Fill VolumeRotation SpeedEnd Point(Time)Blend UniformityDensitiesAngle of Repose,第十九页，共四十一页。,What is QbD?QbD在制剂开发中怎么(zn me)体现？,Feed FrameToolingPunch Penetration DepthCompression Force
12、Press SpeedFeeder Speed,第二十页，共四十一页。,Quality Assessment under QbR,Question-based Review(QbR)is a general framework for a science and risk-based assessment of product qualityQbR contains the important scientific and regulatory review questions toComprehensively assess critical formulation and manufact
13、uring process variablesSet regulatory specifications relevant to qualityDetermine the level of risk associated with the manufacture and design of the product,第二十一页，共四十一页。,Examples of QbD questions under QbR Control of Drug Substance What is the drug substance specification?Does it include all the cr
14、itical drug substance attributes that affect the manufacturing and quality of the drug product?(2 pages)Drug Product What attributes should the drug product possess?(1.5 pages)How were the excipients and their grades selected?How was the final formulation optimized?Manufacturing Process How are the
15、manufacturing steps(unit operations)related to the drug product quality?How were the critical process parameters identified,monitored,and/or controlled?Pharmaceutical Development Manufacture Container Closure System,第二十二页，共四十一页。,QbD小结(xioji)-SUMMARY,第二十三页，共四十一页。,研发(高难(o nn)仿制药的一些体会,第二十四页，共四十一页。,案例(n
16、 l)研究-1CASE STUDY 1-IR Tablets,Very Low Water Solubility(低水溶性)Very Low Potency(低剂量)Micronized API used(微粉化原料药)Wet Granulation Process(湿法制(fzh)粒),第二十五页，共四十一页。,Dissolution Profile-体外溶出曲线(qxin),第二十六页，共四十一页。,生物等效(dn xio)(BE)结果,Summary of in vivo study results of Test Formulation vs.RLD,第二十七页，共四十一页。,原因(yunyn)调查,第二十八页，共四十一页。,案例(n l)研究-2CASE STUDY 2-ER CAPSULES,No Patent(无专利(zhunl)Coated Pellets(包衣微丸)1st Bio Study FailedFast:CloseFed(Compared with Fast):Brand:BA Reduced Tested:BA Increased,第二十九页，共四十一页。