1、开发报批美国开发报批美国FDA的仿制药的仿制药与相关问题探讨与相关问题探讨 上海复星普适医药科技有限公司上海复星普适医药科技有限公司 何平何平 内容提要内容提要 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)仿制药的一些体会：案例研究 开发仿制药的重要性 新药与仿制药-NDA and ANDA 开发仿制药与我国药物研发的海外战略 US 40%EUROPE 38%JAPEN 10%CHINA 4%US 40%EUROPE 38%JAPEN 10%CHINA 4%药物制剂药物制剂 目标主流市场目标主流市场 开
2、发仿制药的挑战性 开发仿制药更具挑战性 药物制剂 专利 仿制药的竞争 仿制药厂之间的竞争 由品牌药转成仿制药 仿制药竞争的方式 HOW TO COMPETE Cost-IR Product Raw Materials Process Finished Product Technology-Modified Release Products 申报(仿制)新药的分类 规范市场规范市场(FDA)1。P-I 2。P-II 3。P-III 4。P-IV(1st to file)中国市场（中国市场（sFDA）1类类 2类类 3类类 4类类 5类类 6类类 仿制药研发团队 CONCEPT-1 BUILD U
3、P A TEAM INFORMATION FORMULATION PRODUCT REGULATORY ANALYTICAL BIO-PHARMACEUTICAL PROJECT LEGEL DRUG DELIVERY SYSTEMS FOR ORAL SOLID FORMULATIONS-MR MATRIX SYSTEMS RESERVIOR SYSTEMS OSMOTICAL PUMP SYSTEMS COMBO-SYSTEMS 缓控释给药的技术平台和给药系统 CONCEPT-2 BUILD UP A SYSTEM Product Development Roadmap 仿制药的仿制药的研
4、发过程研发过程 Quality Acceptably low risk of failing to achieve the desired clinical attributes Pharmaceutical Quality=f drug substance,excipients,manufacturing.QbD Product and process performance characteristics scientifically designed to meet specific objectives,not merely empirically derived from perfo
5、rmance of test batches What is QbD(Quality by Design)?QbD在制剂开发中怎么体现？在制剂开发中怎么体现？What is QbD?QbD在制剂开发中怎么体现？在制剂开发中怎么体现？Pharmaceutical Quality by Design(QbD)QbD means designing and developing formulations and manufacturing processes to ensure predefined product quality Understanding and controlling form
6、ulation and manufacturing process variables affecting the quality of a drug product Essential elements of QbD Definition of the quality target product profile High level quality aspects of the product:purity,drug release(dissolution/disintegration time),pharmacokinetic profile,etc.Critical quality a
7、ttributes(CQAs)for drug product Characteristics 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 have effect on product CQAs Design Space:The multidimensional combinat
8、ion and interaction of input variables 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在制剂开发中怎么体现？在制剂开发中怎么体现？Raw Materials Equipment Environment Operators Variable Inputs x“Locked”P
9、rocess=Variable Quality How Did We Work in the Past What is QbD?QbD在制剂开发中怎么体现？在制剂开发中怎么体现？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在制剂开发中怎么
10、体现？在制剂开发中怎么体现？What is QbD?QbD在制剂开发中怎么体现？在制剂开发中怎么体现？Raw Materials Wet Granulation Fluid Bed Drying Blending Compression Product Drug Substance Excipients Source Assay Impurities LOD PS What is QbD?QbD在制剂开发中怎么体现？在制剂开发中怎么体现？Raw Materials Wet Granulation Fluid Bed Drying Blending Compression Water Binde
11、r Temp Spray Rate Speed Time P.S What is QbD?QbD在制剂开发中怎么体现？在制剂开发中怎么体现？Raw Materials Wet Granulation Fluid Bed Drying Blending Compression What is QbD?QbD在制剂开发中怎么体现？在制剂开发中怎么体现？Raw Materials Wet Granulation Fluid Bed Drying Blending Compression Air Flow Temp RH Shock Cycle P.S.What is QbD?QbD在制剂开发中怎么体
12、现？在制剂开发中怎么体现？Raw Materials Wet Granulation Fluid Bed Drying Blending Compression Fill Volume Rotation Speed End Point(Time)Blend Uniformity Densities Angle of Repose What is QbD?QbD在制剂开发中怎么体现？在制剂开发中怎么体现？Raw Materials Wet Granulation Fluid Bed Drying Blending Compression Feed Frame Tooling Punch Pene
13、tration Depth Compression Force Press Speed Feeder Speed Quality Assessment under QbR Question-based Review(QbR)is a general framework for a science and risk-based assessment of product quality QbR contains the important scientific and regulatory review questions to Comprehensively assess critical f
14、ormulation and manufacturing process variables Set regulatory specifications relevant to quality Determine the level of risk associated with the manufacture and design of the product Examples of QbD questions under QbR Control of Drug Substance What is the drug substance specification?Does it includ
15、e all the critical 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
16、How are the 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 AspectsAspects TraditionalTraditional QbDQbD PharmaceuticalPharmaceutical developmentdevelopment Empirical;univariate experiments Systematic;multivariate experiments ManufacturingManufacturing processprocess Fixed;validation on 3 initial full-scale batches;focus on reprod
