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1、开发报批美国FDA的仿制药与相关问题探讨,上海复星普适医药科技有限公司 何平,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,药物制剂 目标主流市场,开发仿制药的挑战性,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 Proc
2、ess Finished Product Technology-Modified Release Products,申报(仿制)新药的分类,规范市场(FDA) 1。P-I 2。P-II 3。P-III 4。P-IV (1st to file),中国市场（sFDA） 1类 2类 3类 4类 5类 6类,仿制药研发团队 CONCEPT-1 BUILD UP A TEAM,REGULATORY,DRUG DELIVERY SYSTEMS FOR ORAL SOLID FORMULATIONS-MR MATRIX SYSTEMS RESERVIOR SYSTEMS OSMOTICAL PUMP SYS
3、TEMS 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 characterist
4、ics scientifically designed to meet specific objectives, not merely empirically derived from performance of test batches,What is QbD (Quality by Design )? QbD在制剂开发中怎么体现？,What is QbD? QbD在制剂开发中怎么体现？,Pharmaceutical Quality by Design (QbD) QbD means designing and developing formulations and manufacturi
5、ng processes to ensure predefined product quality Understanding and controlling formulation 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 r
6、elease (dissolution/disintegration time), pharmacokinetic profile, etc. Critical quality attributes (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 p
7、rocess parameters which have effect on product CQAs Design Space: The multidimensional combination 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? Q
8、bD在制剂开发中怎么体现？,Raw Materials,Equipment,Environment,Operators,Variable Inputs,x,“Locked” Process,=,Variable Quality,How Did We Work in the Past,What is QbD? QbD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,
9、Flexible Process Design Space,How Can We Work in the Future,What is QbD? QbD在制剂开发中怎么体现？,What is QbD? QbD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？,Water Binder Temp Spra
10、y Rate Speed Time P.S,What is QbD? QbD在制剂开发中怎么体现？,What is QbD? QbD在制剂开发中怎么体现？,Air Flow Temp RH Shock Cycle P.S.,What is QbD? QbD在制剂开发中怎么体现？,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？,Feed Frame Tooling Punch Penetration Depth Co
11、mpression 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 formulation an
12、d 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 include all the cr
13、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 ar
14、e 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,QbD小结-SUMMARY,研发(高难)仿制药的一些体会,案例研究-1 CASE STUDY 1-IR Tablets,Very Low Wat
15、er Solubility (低水溶性) Very Low Potency (低剂量) Micronized API used (微粉化原料药) Wet Granulation Process (湿法制粒),Dissolution Profile-体外溶出曲线,生物等效(BE)结果,Summary of in vivo study results of Test Formulation vs. RLD,原因调查,案例研究-2 CASE STUDY 2-ER CAPSULES,No Patent (无专利) Coated Pellets (包衣微丸) 1st Bio Study Failed F
16、ast: Close Fed(Compared with Fast): Brand: BA Reduced Tested: BA Increased,TEAM WORK,More Information Collected Analytical Support Identify the Process Used Provide the Info for Functional Coating One more Pilot and One Full Bio-Passed,案例研究-3 CASE STUDY 3 - ER CAPSULES,Brand Product Micro-Tablets in Capsules 95% of API existed in Finished Product System and Process Patented,UNIQUE SYSTE
