研发流程与简介

RIA46
RIA35
RIA30
Reaction Work-up Reaction Isolation Purification Drying/Milling
Appearance Chemical Identity Physical Identity Residual Precursors S.M. Related Impurities Process Related Impurities Enantiomeric Purity Phthalimide Products EDC.HCl + urea by-product DMAP methylamine Inorganic Salts DMF Dichloromethane Isopropanol Ethanol Acetic Acid Acetone Assay Particle Size
Risk = Severity X Likelihood X Detectability
严重性 X 可能性 X 可测试性
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Preliminary Process Risk Assessment Map
Critical Quality Attribute (right)
Process Stage (below)
Water Content
XXX: NMT 0.5% Any unknown NMT 0.2% Total: NMT 1.0%
NMT 4.0%
Yes They may impact safety No Unlikely to impact safety
Quality Risk Management Process
depቤተ መጻሕፍቲ ባይዱndent
Assay (purity)
100% of label claim
Yes Assay value will affect safety and efficacy
Solubility
Information
No Not control by process
Degradation Products
(Validation)
Process Qualification (Validation)
Process Development Procedure - 产品开发流程
明确目标 路线评估
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
研发流程与简介
法规符合
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
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Selected Tools Used in the Risk Assessment 用于风险评估的工具举例
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Ishikawa (Fishbone) Diagrams
Material Attributes Process Parameters Operational Factors (Causes)
工艺开发/ 路线确定
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
工艺优化 工艺确认
每步工艺优化 CPP确认/优化工艺 质量风险控制 DoE Design Space(允许/操作范围)
实验室三批确认
放大研究
工艺验证 商业化 生产
放大工艺/步骤合理性说明/评估 验证方案/验证报告 Continuous Process Improvement
Starting Material RIA10 Starting Material RIA20
Reaction Isolation Drying Reaction Isolation Drying Reaction Work-up Starting Material RIA60
Overall
RIA
RIA56
• Based on sound science and quality risk management (ICH Q9)
Goals of Implementing QbD
应用质量源于设计的目的
Achieve meaningful product specifications that are based on clinical performance.
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 ?
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Systematic Approach by QbD
Predefined Objective
预定的目标
Product and Process Understanding
对产品和工艺的理解
Process Control
生产工艺过程控制
Sound Science
合理的科学
Quality Risk Management
Tools for risk ranking
Examples: FMEA/FMECA, Pareto analysis, Relative ranking
Experimental tools for process understanding
Examples: Statistically designed experiments (DOE), mechanistic models
Critical Quality Attributes (CQA) 关键质量属性
Product Design and Process Understanding (CMA, CPP)
Control Strategy (PAR, OR. Etc.)
Continual Improvement
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Process Comparison 工艺比较
1
QbD Concept Approach
QTPP/CQA
2 Process Route Identification
Traditional Approach Process Route Identification
3 Piloting Scale-up and Process Piloting Scale-up and Process
Optimization
Optimization
4 Process Characterization and Process Understanding
❖ CPP, CMA, PAR (OR)
5
Control strategy
(Design Space, etc.)
6
Process Qualification
Process Development
Control Strategy Development
Continual Improvement
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Risk Assessment Tools
风险评估的工具
Tools for parameter screening
Examples: Ishikawa (Fishbone) diagrams, What-if Analysis, HAZOP analysis
CPP and CQA
▪ Establish appropriate control strategy ▪ Define Proven Acceptable Range (PAR) and
Operational Range (OR)
▪ Literature ▪ Prior knowledge ▪ Development study
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Example
Identify CQA in Drug Substance
Quality Attributes
Target
Critical
Justification
Solid State
Form II
Yes Directly link to solubility & stability
PSD
Defined range Yes/No Formulation and process do
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
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Failure Mode Effects Analysis (FMEA)
Cross-functional team evaluation Product and process understanding applied Potential failure modes identified and related to product 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 assessed
▪ Risk based approach through development to commercial manufacturing, as well as continual improvement
法规符合 Overview of QbD 质量源于设计的概括
Quality Target Product Profile (QTPP) 产品质量概括
什么是质量源于设计
(Reference: ICH Q8 (R2), 2009)
• Systematic approach to development
• Begins with predefined objectives
• Emphasizes product and process understanding and process control
Improve post-approval change management
改善和方便批准后更改的管理
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
质量风险管理
▪ Defined Quality Target Product Profile (QTPP) ▪ Identify Critical Quality Attributes (CQA)
▪ Define Critical Material Attributes (CMA) ▪ Identify Critical Process parameters (CPP) ▪ Understanding the relationship between CMA,
Quality Attribute (Effect)
Also known as Cause & Effect Diagram Includes all the potential inputs that affect a desired output (CQA) Effective for initial brainstorming of potential design space parameters
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 process control, based on sound science and quality risk