运用过程分析技术实现高效稳健的生物工艺 PAT solution for efficient and robust bioprocess Shelly Ren(任雪芸), Marketing Manager Sartorius China Contents 1 2 Importance of PAT in BioprocessImportance of PAT in Bioprocess PATPAT在生物工艺中的重要性在生物工艺中的重要性 How to use Sartorius & PAT Tools 怎样利用PAT工具箱 3 Application of Chemometrics in Bioprocess 化学计量法在生物工艺中的应用 Contents 目录 Main Challenges in Process Development 工艺开发中的主要挑战 Which process parameters significantly influence the yield? 哪些工艺参数显著影响产率？ Which parameter settings result in optimal operation conditions? 哪些参数的设定产生合适的操作条件？ How to achieve a good product quality with low risk of failure? 怎么才能得到高质量的产品同时降低失败的风险呢？ Higher yields, higher efficiencies in cell culture 细胞培养中高产率和高效 Increasing cost pressure due to loss of patent protection and public health authorities 因为专利失去保护和政府卫生部门的要求面临不断增加的成本压力 Personalized medicine: more different products produced in lower quantities 个性化药物：少量不同产品的生产 Page 3 General Information PAT Definition 过程分析技术的定义 * Source: US FDA, Guidance for Industry PAT., Rockville, Sept. 2004 PAT 是一个通过即时即时测量原 料、过程中物料和过程本身 的关键质量指标关键质量指标来实现设设 计、分析和生产控制计、分析和生产控制的系 统，目的是确保最终产品的 质量安全 General Information PAT Implementation results in Cost Savings, Smart Process Transfers and Risk Mitigation PAT的实施将节省成本，实现工艺转移，同时降低风险 Process Optimization &Process Optimization & Process Process Understanding Understanding 工艺优化和工艺理解工艺优化和工艺理解 Critical Process Parameters Design Space 关键工艺参数的设计范围 Ease of process changes 工艺易于改变 Robust Manufacturing生产稳健 ProcessProcess AnalyticsAnalytics SensorsSensors SCADASCADA DoEDoE MVDAMVDA Yields & Titers 产量与浓度 CoGs | R&D costs Tech Transfer 技术转移 Time to Market 上市时间 General Information Robust Quality Control 稳定的质量控制 Step 1 Step 1 找到与关键质量属性相关的关键工艺参数找到与关键质量属性相关的关键工艺参数 P Critical Quality Attributes (CQAs) 关键质量属性 ? Crictical Process Parameters (CPPs) 关键工艺参数 General Information Robust Quality Control 稳定的质量控制 Step 2 Step 2 预测与控制工艺变化预测与控制工艺变化 ，保证稳定的生产，保证稳定的生产 process step 工艺步骤 控制工艺 output materials 产品 input materials 原料 你了解你的工艺并可以控制工艺变化你了解你的工艺并可以控制工艺变化 Feed forward control 正向控制 Feed backward control 反向控制 General Information Designed to Meet the Needs of Development, Scale-up and Production 满足工艺开发、放大和生产的需求 Chemometrics Data Consistency & Scalability Enable Direct Tech-Transfer 数据的稳定性和可放大性使得技术能直接转移 General Information R&D PD PRD Upstream Downstream Contents 2 1 Importance of PAT in Bioprocess PAT在生物工艺中的重要性 How to use Sartorius & PAT Tools 怎样利用PAT工具箱 3 Application of Application of ChemometricsChemometrics in Bioprocessin Bioprocess 化学计量法在生物工艺中的应用化学计量法在生物工艺中的应用 Contents 目录 Page 9 Design of Experiments 实验设计 A structured, organized method for determining the relationship between factors affecting a process and the output of that process.” FDA, Q8(R2) 确认影响工艺的因子与工艺结果的关系的有结构 有组织的方法 Typical objective is to identify optimal process conditions with a reduced number of experiments to increase product yield / productivity. 典型的目标是用少量的实验确认合适的工艺条件 来增加产品的产率和产量 2-D Contour Plot Regression Coefficient Plot 3-D Response Surface Plot Probability Plot (Design Space) Design of Experiments Page 10 DoE The Efficient Way of Experimentation 实验的有效方法 Random Approach Efficient Approach (DoE) Intuitive Approach (COST) Changing all factors arbitrarily 主观的改变所有因子 High number of experiments 大量的实验 Pure luck to find optimum 靠运气找到合适点 Changing One Single factor at a Time 一次改变一个因子 High number of experiments 大量实验 Only “quasi”-optimum can be found 只能找到类似的合适点 Changing all factors at the same time according to a well designed plan 所有的因子在设计好的计 划下同时改变 Perform least number of experiments 作最少量的实验 Optimum can be found 找到合适 的点 Design of Experiments Three Typical DoE-Applications in Biotechnology Upstream Processing 在 生物技术上游工艺中的DoE典型应用 Medium Optimization Parameter Optimization #3#3 Parameter Screening #2#2 #1#1 Optimization of the composition of growth and production culture media 优化生长和生产培养基的组成 Typical objective is to identify a better selection & quantitative composition of medium factors 典型的目标是定 义筛选合适的培养基和组成 Screening of control parameters and basic process state variables 筛选控制 参数和基本工艺变数 Typical objective is to identify a subset of a few important factors which can be used in a new optimization design 基本目标是定义几个重要因子的组 合，可用于新的优化设计 Optimization of control parameters including feeding strategy 优化包括 补料策略在内的控制参数 Typical objective is to define a better physical environment for cell growth and protein production 典型的目标 是定义更好的物理环境使细胞生长 和生产目标蛋白 Design of Experiments Parallel Systems: the Ideal Equipment for DoE 平行实验：DoE的理想设备 Although a DoE investigation can be carried out in one vessel, systems designed for parallel operation provide the optimal basis to implement a series of experiments in an economical way. 尽管DoE调查可以只在一个罐中进行，为平行实验设计的系统提供了合适的基础可以经济的 形式实施系列实验 Medium Screening with 培养及筛选 15 parameters = 32 experiments15 parameters = 32 experim