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

2. 内容提要 开发仿制药的重要性和机遇 开发仿制药的重要性和机遇 开发仿制药的挑战 开发仿制药的挑战 申报仿制药的分类 申报仿制药的分类 仿制药研发团队 仿制药研发团队 仿制药的研发过程 仿制药的研发过程 QbD 在制剂开发中怎么体现 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 研发 ( 高难 ) 仿制药的一些体会：案例研究

3. 开发仿制药的重要性 新药与仿制药 -NDA and ANDA 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 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

4. 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 仿制药厂之间的竞争 由品牌药转成仿制药 由品牌药转成仿制药

5. 仿制药竞争的方式 HOW TO COMPETE Cost-IR Product Cost-IR Product –Raw Materials –Process –Finished Product Technology-Modified Release Products Technology-Modified Release Products

6. 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 (1 st to file) 中国市场（ sFDA ） 1类1类1类1类 2类2类2类2类 3类3类3类3类 4类4类4类4类 5类5类5类5类 6类6类6类6类

7. 仿制药研发团队 CONCEPT-1 BUILD UP A TEAM INFORMATION FORMULATION PRODUCT REGULATORY ANALYTICAL BIO- PHARMACEUTICAL PROJECT LEGEL

8. DRUG DELIVERY SYSTEMS FOR ORAL SOLID FORMULATIONS-MR 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

9. Product Development Roadmap 仿制药的研发过程

10. 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’ Quality by Design ) What is QbD (Quality by Design )? QbD 在制剂开发中怎么体现？

11. What is QbD? QbD 在制剂开发中怎么体现？ Pharmaceutical Quality by Design (QbD) 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 Understanding and controlling formulation and manufacturing process variables affecting the quality of a drug product

12. 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？

13. Raw Materials Equipment Environment Operators Variable Inputsx“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？

14. 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？

15. What is QbD? QbD 在制剂开发中怎么体现？ Raw Materials Wet Granulation Fluid Bed Drying BlendingCompressionProduct

16. 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 BlendingCompression

17. 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 BlendingCompression

18. What is QbD? QbD 在制剂开发中怎么体现？ Raw Materials Wet Granulation Fluid Bed Drying BlendingCompression Air Flow Temp RH Shock Cycle P.S.

19. What is QbD? QbD 在制剂开发中怎么体现？ Raw Materials Wet Granulation Fluid Bed Drying BlendingCompression Fill Volume Rotation Speed End Point (Time) Blend Uniformity Densities Angle of Repose

20. What is QbD? QbD 在制剂开发中怎么体现？ Raw Materials Wet Granulation Fluid Bed Drying BlendingCompression Feed Frame Tooling Punch Penetration Depth Compression Force Press Speed Feeder Speed …

21. Quality Assessment under QbR Question-based Review (QbR) is a general framework for a science and risk-based assessment of product quality 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 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

22. 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

23. AspectsTraditionalQbD 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

24. 研发 ( 高难 ) 仿制药的一些体会

25. 案例研究 -1 CASE STUDY 1-IR Tablets Very Low Water Solubility ( 低水溶性 ) Very Low Water Solubility ( 低水溶性 ) Very Low Potency ( 低剂量 ) Very Low Potency ( 低剂量 ) Micronized API used ( 微粉化原料药 ) Micronized API used ( 微粉化原料药 ) Wet Granulation Process ( 湿法制粒 ) Wet Granulation Process ( 湿法制粒 )

26. Dissolution Profile- 体外溶出曲线

27. 生物等效 (BE) 结果 AUC0-tAUC0-infCmax Fast Ratio108.01%108.12%86.26% 90% Geometric C.I. 103.49% to 112.73% 103.64% to 112.79% 75.28% to 98.84% Fed Ratio111.21%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

28. 原因调查

29. 案例研究 -2 CASE STUDY 2-ER CAPSULES No Patent ( 无专利 ) No Patent ( 无专利 ) Coated Pellets ( 包衣微丸 ) Coated Pellets ( 包衣微丸 ) 1 st Bio Study Failed 1 st Bio Study Failed –Fast: Close –Fed(Compared with Fast): Brand: BA Reduced Brand: BA Reduced Tested: BA Increased Tested: BA Increased

30. TEAM WORK More Information Collected More Information Collected Analytical Support Analytical Support –Identify the Process Used –Provide the Info for Functional Coating One more Pilot and One Full Bio---Passed One more Pilot and One Full Bio---Passed

31. 案例研究 -3 CASE STUDY 3 - ER CAPSULES Brand Product Brand Product –Micro-Tablets in Capsules –95% of API existed in Finished Product –System and Process Patented

32. UNIQUE SYSTEM-CREATIVE DESIGN Compressed Granules in Capsules Compressed Granules in Capsules –Requirement Same Dissolution Behavior Same Dissolution Behavior Uniform Uniform Yield Acceptable Yield Acceptable

33. SYSTEM COMPARISON

34. 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 10690.4; 12322.0 Cmax 10480.1; 13436.4 Test B vs Reference AUC 133114; 15522.0 Cmax129100; 16736.4

35. 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 96.175.4; 12332.7 Cmax 10983.5; 14135.3 Test B vs Reference AUC 92.472.5; 11832.7 Cmax10983.7; 141 35.3

36. PIVOTAL BIO-STUDY PRODUCT P DATA ( Log Transformed Data) Ratio of Geometric Means x 100 90% CI of Log Transformed Data CV (%) FAST AUC 10293; 11133,9 Cmax 10594.5; 11638.8 FED AUC 98.891.6; 10726.4 Cmax 99.689.2; 11138.4

37. 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).

38. PILOT BIO-STUDY PRODUCT DATA (Log Transformed Data) AUC0-tAUC0-infCmax T-1 Ratio111.21%112.48%140% 90% Geometric C.I. 104.40% to 118.47% 105.78% to 119.60% 133.7% to 147.0% T-2 Ratio117.5%117.2%135.9% 90% Geometric C.I. 113.2% to 122.2% 112.4% to 122.1% 129.5% to 142.4%

39. Further Investigation

40. 谢谢 ! 139-1866-7400paxhp@yahoo.com