*  *  *  *  *  *  *  *  *  *  *  *  *  *  *  *  *  *  案例研究-3CASE STUDY 3 - ER CAPSULES Brand Product Micro-Tablets in Capsules 95% of API existed in Finished Product System and Process Patented UNIQUE SYSTEM-CREATIVE DESIGN Compressed Granules in Capsules Requirement Same Dissolution Behavior Uniform Yield Acceptable SYSTEM COMPARISON PILOT BIO-STUDY PRODUCT P DATA (Log Transformed Data, Fast, n-12) Ratio of Geometric Means x 100 90% CI of Log Transformed Data CV (%) Test A vs Reference AUC 106 90.4; 123 22.0 Cmax 104 80.1; 134 36.4 Test B vs Reference AUC 133 114; 155 22.0 Cmax 129 100; 167 36.4 PILOT BIO-STUDY PRODUCT P DATA (Log Transformed Data, FED, n-11) Ratio of Geometric Means x 100 90% CI of Log Transformed Data CV (%) Test A vs Reference AUC 96.1 75.4; 123 32.7 Cmax 109 83.5; 141 35.3 Test B vs Reference AUC 92.4 72.5; 118 32.7 Cmax 109 83.7; 141 35.3 PIVOTAL BIO-STUDY PRODUCT P DATA (Log Transformed Data) Ratio of Geometric Means x 100 90% CI of Log Transformed Data CV (%) FAST AUC 102 93; 111 33,9 Cmax 105 94.5; 116 38.8 FED AUC 98.8 91.6; 107 26.4 Cmax 99.6 89.2; 111 38.4 案例研究-4 CASE STUDY 4 - ER CAPSULES API is Water Soluble. Prototype formulation was proposed based on in vitro dissolution (OGD method). PILOT BIO-STUDY PRODUCT DATA (Log Transformed Data) AUC0-t AUC0-inf Cmax T-1 Ratio 111.21% 112.48% 140% 90% Geometric C.I. 104.40% to 118.47% 105.78% to 119.60% 133.7% to 147.0% T-2 Ratio 117.5% 117.2% 135.9% 90% Geometric C.I. 113.2% to 122.2% 112.4% to 122.1% 129.5% to 142.4% Further Investigation 谢谢! 139-1866-7400 paxhp@yahoo.com *  * 2011 年至2015 年间将有770 亿美元销售的专利药到期*  *  * MR Product-Not every company could produce the products * MR Product-Not every company could produce the products 开发仿制药的核心是时间和效率, 怎样在最短的时间里把产品开发出来. *  *  *  *  *  *  *  *  *  *  *  *  *  *  *  *  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 Process 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 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 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 manufacturing 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 release (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 process 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? QbD 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 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？Raw Materials Wet Granulation Fluid Bed Drying Blending Compression Water Binder Temp Spray Rate Speed Time P.S What is QbD? QbD 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？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？Raw Materials Wet Granulation Fluid Bed Drying Blending Compression Feed Frame Tooling Punch Penetration 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 formulation 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 include 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 –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 Aspects Traditional QbD Pharmaceutical development Empirical; univariate experiments Systematic; multivariate experiments Manufacturing process Fixed; validation on 3 initial full-scale batches; focus on reproducibility Adjustable within design space; continuous verification; focus on control strategy Process control In-process testing for go/nogo; offline analysis w/slow response PAT utilized for feedback & feed forward, real time Product specification Primary means of quality control; based on batch data Part of the overall quality control strategy; based on desired product performance Control strategy Mainly by intermediate and end product testing Risk-based; controls shifted upstream; real-time release Lifecycle management Reactive to problems & OOS; post-approval Continuous improvement enabled within design space QbD 小结-SUMMARY 研发( 高难) 仿制药的一些体会案例研究-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  ( 湿法制粒) Dissolution  Profile- 体外溶出曲线生物等效(BE) 结果AUC0-t AUC0-inf Cmax Fast Ratio 108.01% 108.12% 86.26% 90% Geometric C.I. 103.49% to 112.73% 103.64% to 112.79% 75.28% to 98.84% Fed Ratio 111.21% 112.48% 85.24% 90% Geometric C.I. 104.40% to 118.47% 105.78% to 119.60% 73.47% to 98.90% Summary of in vivo study results of Test Formulation vs. RLD  原因调查案例研究-2CASE STUDY 2-ER CAPSULES No Patent  ( 无专利) Coated Pellets  ( 包衣微丸) 1st Bio Study Failed Fast: 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  * 2011 年至2015 年间将有770 亿美元销售的专利药到期*  *  * MR Product-Not every company could produce the products * MR Product-Not every company could produce the products 开发仿制药的核心是时间和效率, 怎样在最短的时间里把产品开发出来. *  *  *  *  *  *  *  *  *  *  *  *  *  *  *  *  *  *  *  *  *  *  *  *  *  *  *  *  *  *  *  *  *  *