1、,原料药工艺研发流程与QbD,技术转化为价值 GMP 医药化工法规约束 稳定的工艺 实施GMP的基础 QbD(质量源于设计）- 工艺开发指导,法规符合,Quality by Design 质量源于设计 前控制 质量源于生产 过程控制 质量源于检测 后控制,法规符合,Quality by Design 质量源于设计,Definition 定义 Systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and p
2、rocess control, based on sound science and quality risk management. 以合理的科学和质量风险管理为依据的，起始于预定的质量目标，注重对产品和工艺的理解以及对生产工艺过程控制的系统的研发方法Reference: ICH Q8(R)(2) Pharmaceutical Development, 2009,4,法规符合,What is Quality by Design ? 什么是质量源于设计 (Reference: ICH Q8 (R2), 2009),法规符合,Goals of Implementing QbD 应用质量源于设计的
3、目的,Achieve meaningful product specifications that are based on clinical performance.根据临床需求建立有意义的产品质量标准 Reduce product variability and detects by increasing product and process understanding 通过对产品和其工艺的理解，减少产品质量的变异和瑕疵 Enhance product development and manufacturing efficiencies 提高产品开发和生产效率 Improve post-
4、approval change management 改善和方便批准后更改的管理,7,QbD Terminology,Quality Target Product Profile 目标产品质量概况 Critical Quality Attributes 关键质量属性 Critical Material Attributes 关键物料属性 Critical Process Parameters 关键工艺参数 Risk Assessment 风险评估 Design Space 设计空间 Control Strategy 控制策略 Continual Improvement 继续改进,Systema
5、tic Approach by QbD,Overview of QbD 质量源于设计的概括,法规符合,Process Comparison 工艺比较,10,11,Process Development Procedure - 产品开发流程,路线评估,工艺开发/路线确定,工艺优化,工艺确认,放大研究,工艺验证,明确目标,商业化 生产,QTPP/CQA（杂质、晶型、粒度等）,文献综述 路线可行性分析（成本、绿色、设备、质量、原料）合理的科学和技术积累 创新,起始物料确认，每步考察，最终工艺确定 确定潜在产品质量属性及初步质量风险评估,每步工艺优化 CPP确认/优化工艺 质量风险控制DoE Desi
6、gn Space(允许/操作范围),实验室三批确认,放大工艺/步骤合理性说明/评估,验证方案/验证报告,Continuous Process Improvement,Example Identify CQA in Drug Substance,13,Quality Risk Management Process,Risk Assessment Tools 风险评估的工具,Tools for parameter screening Examples: Ishikawa (Fishbone) diagrams, What-if Analysis, HAZOP analysis Tools for
7、risk ranking Examples: FMEA/FMECA, Pareto analysis, Relative ranking Experimental tools for process understanding Examples: Statistically designed experiments (DOE), mechanistic models,14,Selected Tools Used in the Risk Assessment 用于风险评估的工具举例,Ishikawa (Fishbone) Diagram to identify all potential var
8、iables, such as raw materials, compression parameters, and environmental factors, which can have an impact on a particular CQA, such as tablet hardness. Failure Mode Effect Analysis (FMEA) to rank the variables based on risk (i.e., a combination of probability, severity, and detectability) and to se
9、lect the process parameters with higher risks for further studies to gain greater understanding of their effects on CQAs.,15,16,Ishikawa (Fishbone) Diagrams,Also known as Cause & Effect Diagram Includes all the potential inputs that affect a desired output (CQA) Effective for initial brainstorming o
10、f potential design space parameters,Quality Attribute (Effect),Material Attributes Process Parameters Operational Factors (Causes),17,Failure Mode Effects Analysis (FMEA),Cross-functional team evaluation Product and process understanding applied Potential failure modes identified and related to prod
11、uct quality and performance Product and process risks prioritized Output/results can be used as a basis for design of experiment or further analysis Risk quantitatively assessedRisk = Severity X Likelihood X Detectability严重性 X 可能性 X 可测试性,18,Preliminary Process Risk Assessment Map,19,Design Space 设计空
12、间,Definition 定义 The multidimensional combination and interaction of input variables (e.g., material attributes and process parameters) that have been demonstrated to provide assurance of quality输入变数(物料属性和工艺参数)的多维结合和相互作用已证明能提 供产品质量的保障 Working within the design space is not considered as a change. Mov
13、ement out of the design space is considered to be a change Design space is proposed by the drug applicant and is subject to regulatory assessment and approval,Design Space 设计空间,Design space is potentially scale- and equipment-dependent 设计空间与批量和设备有关 Design space determined at the laboratory scale may
14、 not be relevant to the process at the commercial scale 实验或小试中取得的设计空间也许与商业生产工艺没有直接的关联 Therefore, design-space verification at the commercial scale becomes essential unless it is demonstrated that the design space is scale-independent. 与生产批量有关的设计空间参数应在商业批生产过程中证实,20,Important Note,For generic drug/API
15、 applications: Design space is optional QbD can be implemented without a design space because product and process understanding can be established without a formal design space.Implementation of QbD is strongly encouraged by FDA. For some complex drug substances or drug products, implementation of Q
16、bD is considered a required component of the application.,21,Control Strategy 控制策略,ICH Q8 defines Control Strategy as: A planned set of controls, derived from current product and process understanding that ensures process performance and product quality.基于在对产品和工艺的理解基础上制定的控制要点以确保工艺稳定和产品质量 The control
17、s can include parameters and attributes related to drug substance and drug-product materials and components, facility and equipment operating conditions, in-process controls, finished-product specifications, and the associated methods and frequency of monitoring and control.,22,Control Strategy 控制策略
18、,Control strategy may include: Control of input material attributes (CMAs) Controls for unit operations (CPPs and process endpoints) In-process or real-time release testing Product specifications (CQAs),23,24,Optimized Process Risk Assessment Map,25,Critical Quality Control Strategy of Drug Substanc
19、e,Process Development Report 工艺硏发报吿,All written documents should follow Good Document Practice Document numbers Author and approver signatures Data traceability (notebook numbers) Individual report can reference other reports,26,Process Development Report 工艺硏发报吿,Not a written regulatory requirement
20、Absence of the report is not a reason for a FDA-483 observationHowever, Companies must produce documented data to justify critical process parameters, controls ranges and specifications, etc. No documented supportive data will result in 483 observation (GMP deficiency).,27,Process Development Report
21、 工艺硏发报吿,Objective Summarize development history to support proposed commercial process Support qualification/validation protocol Demonstrate knowledge and control strategy over the commercial process Prepare for Pre-Approval Inspection (PAI) Reference for future optimization and investigation activi
22、ties, such as OOS and deviations Support CMC/DMF filing (Section 3.2.S.2.6),28,29,1. Introduction: Drug Substance Identity and Attributes 2. Synthetic Route Development Evaluation 3. Potential Quality Attributes of the Drug Substance 4. Preliminary Risk Assessment for Critical Quality Attributes 5.
23、Starting Material Discussion 6. Optimization of Manufacturing Process 7. Manufacturing7.1. Brief Description7.2. Synthetic Scheme7.3. Detailed Description of the Process Control 8. Critical Quality Control Strategy of Drug Substance 9. History of Manufacturing Process,Process Development Report - 产品
24、开发报告,30,Attachments:Supplier Specifications for Starting MaterialSpecifications for Starting Material and IntermediatesProcess Control Map Detailed Risk AssessmentC of A Summary of Manufactured BatchesGlossary of Abbreviations,Process Development Report - 产品开发报告,31,QbD - 产品开发流程 工艺开发报告 比较,Quality by Design 质量源于设计 目标：设计和开发的工艺能够在可控风险的情况下生产出符合质量标准的产品 满足产品质量要求的工艺开发是执行GMP全过程的基础 - 全程可控,法规符合,
