药品质量研究与药品质量标准制定的 QbD 理念

1. 药品质量研究与药品质量标准制定的QbD理念 上海市食品药品检验所 Shanghai Institute for Food and Drug Control 上海市食品药品检验所 陈桂良 chenguiliang@smda.gov.cn 13918584368 021-50798191

2. 内容 • 药品质量控制的四个阶段； • 药品质量研究与药品质量标准； • QbD 理念； • QbD 用于药品质量标准制订的方法； • QbD 用于HPLC法的建立； • 药品质量标准制订 QbD 理念初探举例

3. 药品质量控制的四个阶段

4. 药品质量-安全有效-生产过程-流通使用的关系图药品质量-安全有效-生产过程-流通使用的关系图

5. US FDA

7. ICH Q6A 决策特性 质量标准 过程控制 开发 设计 过程验证 GMP 控制 “…where the provision of greater understanding of pharmaceutical and manufacturing sciences can create a basis for flexible regulatory approaches.” ICH Q8 的主要内容

8. 药品质量 目标 • “The quality of drug substances and drug products is determined by their design, development, in-process controls, GMP controls, process validation, and by specifications applied to them throughout development and manufacture.” 特性 生命周期

9. 质量源于设计（QbD）与医药质量体系（PQS）之间的关系质量源于设计（QbD）与医药质量体系（PQS）之间的关系

10. Process Understanding Product Quality Attributes Product Knowledge Process Parameters Product Design Process Controls Product Specifications Unit operations, control strategy, etc. Continuous Improvement Process Design Desired Product Performance Dosage form, stability, formulation, etc. Process Performance Cpk, robustness, etc. Quality by Design

11. QbD –系统研究ICH Q8(R2)

12. 药品质量标准

13. 认识药品属性与药品质量标准的关系

14. 药品质量标准建立的过程

15. Generalized method development strategy (MDS) approach for QbD analyticalmethods.

19. Meet Criteria? (Rs, TF, time) 色谱系统建立中的QbD理念 KPSS = Key Predictive Sample Set KPSS ID. Known? Yes No Color Key Red: experimental studies Green:in silico modeling Black: Decision points RP column screening Plot of log D versus pH Alternative mechanisms Column& pH selection Gradient & Temperature Screening Gradient & Temperature Optimization No Verify Separation Draft method Yes

20. 梯度与柱温优化 Identifies a suitable design region (draft method) for further evaluation

21. 风险评估:鉴别 Risk Identification List Method Factors that could potentially affect method quality Brainstorm with SMEs and users Examples: Column Temperature Flow Rate Mixing accuracy Stationary phase reproducibility Detector wavelength accuracy Bandwidth Overview of typical quality risk management process (from ICH Q9)

22. Presentation of the Design Space for three factors described by 2D planes. Theworking point is in the middle of the cube and represents a result of the best criticalresolution. Three different resolution maps are shown here as individual parts ofthe whole Design Space

23. Experimental design for a four-dimensional HPLC method optimization

24. Work flow scheme followed during the present study

25. Four different runs constituting a gradient time–temperature (tG–T) model, showing different selectivities and the corresponding matched peak table. tG: 30 and90 min, T: 30◦C and 60 ◦C, pH 3.6, 100% acetonitrile

27. Chromatographic factors and response variables for Plackett–Burman experimentaldesign

28. Optimization method parameters for Box–Behnken experimental design

29. Chromatogram of protamine sulfate showing the four peptides

30. Response surface (3D) and contour plots showing the effects of pH, flow rate and temperature on peak resolution and USP tailing factor of protamine sulfate peaks

31. Overlay of four peptide peaks of protamine sulfate from five different sources

33. 中国药典中法莫替丁原料质量标准

34. 法莫替丁原料或制剂标准中所采用的有关物质检查方法

35. 有关物质检查方法 • BP2010版 • 《中国药典》2010年版法莫替丁注射液的有关物质检查方法 • USP34版法莫替丁口服液标准中有关物质检查方法 • 系统适用性试验方法的确定 • 有关物质限度的确定

36. 药品质量标准制订的QbD理念初探举例 • 作为药品质量标准制订的QbD理念探索，以沙丁胺醇气雾剂的质量标准制订为例，说明目前中国药典2010年版二部采用QbD进行质量标准制订的过程。