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叶渊明 多功能车间生产注册产品（中间体 / 原料药）的风险管理

Risk Management in the Manufacture of Different Regulated Products in Shared Workshops & Facilities多功能车间生产注册产品（中间体/原料药）的风险管理

Gary Ye叶渊明May 12, 2013

Agenda 议程

• Multi-purpose Workshop Risk Assessment 风险评估• Evolving Design Concept 设计理念变迁• MPW Management 多功能车间管理• Project Management 项目管理• People Management 人员管理• Summary 小结

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What is Risk? 什么是风险?

ICH Q9 Definition ICH Q9的定义

“Risk is defined as “the combination of the probability of occurrence of harm and severity of that harm.”风险的定义：”危害发生的可能性和严重性的组合”。

Risk Analysis Tools & Process Validation 3

保护的程度-外部的污染

层次II 层次III

层次I 层次II

层次I 层次I

关键程度

暴露程度

开放环境

密闭系统

产品受污染可能性-设备

专用设备，专用车间

多功能设备-多功能车间

污染来源：设备残留，管路残留，地面墙面残留，垫圈残留，包装桶残留，服装残留等。。。。

污染来源：灰尘，异物

Use Preliminary Hazard Analysis (PHA) in Assessing Risk at Dedicated Workshop & Multipurpose Workshop使用初步危害分析比较专用车间和多功能车间的风险

Frequency 频率 /Severity 严重性

Very Unlikely几乎不可能

Occasional 偶然的

Probable很可能的

Frequent频繁的

Catastrophic灾难性的

OOS/Contami-nation

Critical 关键的

Different Impurity profile

Major 主要的

Cleaning failure

Minor轻微的

Risk Analysis Tools6

Risk Ranking Matrix and Follow-up Actions风险排列矩阵和风险降低措施

Acceptable可接受的

Not Acceptable不可接受的

Not Acceptable不可接受的

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Typical Difficulties in Multi-purpose Workshop 多功能车间典型困难

• Changeover Cleaning 换产品清洗• Changeover Management 产品切换工作管理• Shared equipment and hoses 公用管路管线/设备• Production in Parallel 同时生产• People Management & Training 人员管理及培训

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1. Complaints 异物投诉2. Unexpected Impurities 异常杂质3. OOS/OOT4. GMP Audit Failure GMP 审计失败5. Mistakes Made by People 人员犯错

From Design Perspective 从设计视角来看

• Typical Old-fashion Design of Shared Workshop 传统车间设计

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Material Preparing Room

Weighting Room

Solid Material Temp-storage Liquid Material Temp-storage

Instrument RoomVacant

Spare Parts Room

Synthesize Area

Material Transfer

Material TransferMaterial Temp-storage

3F

Typical Old-fashion Design of Shared Workshop 传统车间设计

Material Transfer

Utility Room

Purify Water Room

Power RoomVacant Room

Fire Protection Room Centrifugal AreaCentrifugal Area

Vestibule

Office Room

Shoes Changing Room

Man's First Changing Room

Man's Second Changing Room

Woman's First Changing Room

Woman's Second Changing Room

Air Lock

Laundry Room

Tidy Room

Material Transfer

Drying Room

Anti-explosion Air Lock

Corridor

Cleaning Tool

Tool Cleaning

Container Storage

Container Cleaning

Waste Transfer Outer Packaging Room Inner-Packaging & Pending Room

Air Lock

Pulverizing Room

Inner Package Temp-Storage

Dust Collecter Unpack

Cleaning Tool

Tool Cleaning

Container Storage

Container Cleaning

Waste Transfer Outer Packaging Room Inner-Packaging & Pending Room

Air Lock

Pulverizing Room

Inner Package Temp-Storage

Dust Collecter Unpack

Anti-explosion Air Lock

Drying Room

Crystallize Room

Synthesize Area

Centrifugal Area

Intermediate Temp-storage Room

Crystallize Room

Drying Room Drying Room Drying Room

Drying Room Drying Room

Centrifugal AreaCentrifugal Area

Centrifugal Area Centrifugal Area

Cleaning Room

2F

1F

New Design Concept 全新设计理念

• Full HVAC System Supported Workshop 全空调系统配备的车间• Isolated Production Bay 分隔的生产区域• No Open Operation 无敞开操作• High Level of Using gravity 高度利用位差• Isolated Dispensing & Charging Area 单独配料及投料区• Solid Material Charging Devices 固体投料装置• Washing-Filtration-Drying Together 二合一/三合一设备的使用• CIP System Support CIP系统• TCU System TCU系统• Much Ideal Drying & packaging Area 更合理的烘房及包装区域

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Understanding of ICH Guidelines对ICH 指南的理解

• ICH Q8 Pharmaceutical Development 药品开发过程• ICH Q9 Quality Risk Management 质量风险管理• ICH Q10 Pharmaceutical Quality System 医药质量系统• ICH Q11 Development and Manufacturing of Drug Substance 开发和生产原

料药• QbD Concept 质量源于设计理念的贯穿

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ICH Q8/9/10 Adopted Separately分别采用

Q8 Q9 Q10

Enhanced Product and Process Understanding加强的产品和工艺理解

Challenge挑战:Acquisition and management of knowledge知识信息的获取和管理

Robust quality systems可靠的质量体系

Challenge挑战:What will our Quality System look like going forward?我们的质量体系以后会变成怎样？

Application of Quality Risk Management Principles/Tools质量风险管理原则/工具的应用

Challenge挑战:What do we assess against?我们评估的依据是什么？

12 Quality by Design (QbD)

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Combining Q8, Q9 & Q10 相结合

+ +

BENEFITS 优点

Quality by Design 质量源于设计

Lower Risk Operations低风险的操作

Innovation 创新

Continual Improvement 持续改进

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Combining Q8, Q9 & Q10

Q8 Q9 Q10

+ +

REGULATORY FLEXIBILITY 法规的灵活性

Risk based regulatory decisions 基于风险的管理决策

Higher degree of self management of product/process changes产品/ 工艺变更高水平的自我管理

Reduction of inspections 减少法规审查

Real time assurance of quality 即时质量保证

14 Quality by Design (QbD)

Project Management 项目管理

• R&D and Pilot Production Stage 研发及试生产阶段• Process Validation Stage and Commercial Production

工艺验证阶段及商业化生产阶段

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Process project from

MarketProject Team

Develop method for IPC

& product release

Write analytical method transfer

report

Analytical chemists

Process developmentLab sample

qualification

Write process transfer report

Development report

Process chemists

Pilot production

plan

Draft of M。batch sheet

Notify the production

EHS Evaluation/Plant

Production finalizes the batch sheet

Acceptance from EHS,

Engineering/production

Acceptance from QC

Pilot production

starts

EHS/QA approvalCompletion

of production Process chemists

tech and QC support

Campaign report

QA review and release the batch

Process R&D – Project Management 研发阶段的项目管理

Project evaluationProject notification

Formulation Trail

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Process Validation & Change Control工艺验证及变更管理

Pilot Production

Pilot Production Review

Quality Risk Assessment

PV Protocol Preparation

Master Batch Sheet Preparation

Trail Batch Production

Validation Batch Production

Validation Report

Registration

Change Management

People Management 人员管理

• EHS　Expertise　&　GMP　Expertise　EHS专业技能-Managerial Qualification Program 管理人员资格认定项目-Shared GMP/Quality Culture 对GMP文化的高度认同

• GMP　&　Technical　Professionals　GMP和技术人员-Operators Qualification Program 操作工资格认定

• Process　Understanding　工艺理解-QRA, CPP & CQA

• Clear　Role　&　Responsibilities　明晰的角色和职责-Equipment Management 设备管理-Material Management 物料管理-Housekeeping 定置管理-Documentations 文件记录

• Risk　Based　Tasks　Management　基于风险的任务管理-HAZOP 工艺安全及可操作性风险评估-FMEA 失败模式及影响分析-Checklists 检查表

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Summary 小结

• 多功能车间是原料药生产企业质量风险最大的区域之一，需要建立系统的管理方案。感谢ICH指南，企业可以运用质量风险管理的理念和工具，从车间及产品设计入手改善生产区的格局，同时运用QRA提高对工艺的理解，强化车间的内部管理（尤其是产品切换，人员管理，清洁验证等），从根源上降低质量风险。Multi-purpose workshop is one of the highest quality risk area in API production, systematical management protocol should be in place to tackle this difficulties. Thanks to ICH guidelines, enterprises can take advantage of quality risk management concept and its tool, to optimize production setup starting from design phase. Meanwhile, QRA and high level understanding of processes are needed. Enterprises also need to improve the production management (especially product changeover, people management and cleaning management etc. ), to decrease quality risk dramatically from bottom level.

• 以上经验和观点的分享，仅代表个人观点，欢迎同行批评指正及探讨。Personal perspective only, critics and feedbacks are highly appreciated.

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Questions?疑问？

Thanks!感谢！

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