1、CHINA ANNUAL CONFERENCE16th 17th April 2012, Beijing,Commissioning & Qualification Services Integrated into the Pharmaceutical Project Lifecycle 与制药工程项目全过程相整合的调试与确认服务,Presented by Lu, Haorong 卢浩荣 Reviewed by Henk Man,Agenda 议程,Introduction 导言 Definition and Contents Of I-C&Q ServiceI-C&Q服务的定义与内容 Ser
2、vices Provider and Stakeholders 服务提供商及相关方 Necessity必要性 Implementation 实施 References and Acknowledgements 参考文献与致谢,2012 ISPE CHINA ANNUAL CONFERENCE,Introduction 导言,Concepts 概念 Good Engineering Practice良好工程规范 Established engineering methods and standards that are applied throughout the project lifecyc
3、le to deliver appropriated cost-effective solution.在项目周期中全程采用已建立的工程方法和标准，以交付合理的、经济有效的解决方案。Commissioning调试 A well planned, documented and managed engineering approach to the start-up and turnover of facilities, systems, and equipment to the End-User that results in a safe and function environment tha
4、t meets established design requirements and stakeholder expectations.采用一套良好计划的、有文件记录并受管理的工程方法，对工程设施、系统和设备进行试车并交付最终用户，以建立符合既定设计要求及股东期望的安全、功能良好的环境。,2012 ISPE CHINA ANNUAL CONFERENCE,Introduction 导言,Concepts (cont.)概念（续） DQ设计确认 The documented verification that engineering design of a facility, utility
5、or equipment that can affect product quality adhere to approved User Requirement and design specifications. 对可能影响产品质量的设施、公用工程和设备的工程设计进行有文件记录的查证，确认与被批准的用户需求和设计描述一致。IQ安装确认 The documented verification that all aspects of a facility, utility or equipment that can affect product quality adhere to approve
6、d specifications and are correctly installed. 对设施、公用工程和设备所有可能影响产品质量的方面进行有文件记录的查证，确认与被批准的描述一致并已得到正确的安装。,2012 ISPE CHINA ANNUAL CONFERENCE,Introduction 导言,Concepts (cont.)概念（续） OQ操作确认 The documented verification that all aspects of a facility, utility, or equipment that can affect product quality oper
7、ate as intended throughout all anticipated ranges. 对设施、公用工程和设备所有可能影响产品质量的方面进行有文件记录的查证，确认它们在预期的操作极限内运行正确。PQ性能确认 The documented verification that all aspects of facility, utility, or equipment that can affect product quality perform as intended meeting predetermined acceptance criteria. 对设施、公用工程和设备所有可
8、能影响产品质量的方面进行有文件记录的查证，确认其性能符合预先确定的验收标准。,2012 ISPE CHINA ANNUAL CONFERENCE,Introduction 导言,Concepts (cont.)概念（续） PV工艺验证 The process of establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined speci
9、fications and quality attributes. 建立文件证据，高度保证在特定生产工艺条件下，可均一地生产符合预定标准和质量属性的产品的过程。More concepts 更多的概念 Risk Based Commensurate with risk 基于风险与风险相适应 Science Based CQA, CPPs 基于科学关键质量属性、关键工艺参数 Quality by Design Verify throughout 质量源于设计全过程的验证 Subject Matter Expert Defined Role 学科问题专家角色定义,2012 ISPE CHINA AN
10、NUAL CONFERENCE,Introduction 导言,Current Issues Relative to C&Q in Chinese Pharmaceutical Industry 当前中国医药工业中调试与确认的相关问题 Limited resource and focus on DQ and QBD is not well acknowledged. 投入资源有限，对设计确认、质量源于设计等的重点未充分认识。 Very rare professional C&Q consultants aligned with international standard and practi
11、ce. 专业的、与国际标准、规范接轨的调试与确认咨询服务提供商非常罕见。 Lack of local presence of international C&Q consulting expertise and the corresponding local professional engineer supportive team. 国际知名调试与确认专家罕有常驻中国本地，同时缺乏与其配套的本地专业工程师支持团队。 Importance of establishing a real QMS based on good C&Q practices is not well acknowledge
12、d by endorser top management. 以良好的调试与确认实践为基础建立一个真正的质量管理体系的重要性并未被企业高层管理人员充分认识。,2012 ISPE CHINA ANNUAL CONFERENCE,Introduction 导言,Current Issues Relative to C&Q in Chinese Pharmaceutical Industry （cont.） 当前中国医药工业中调试与确认的相关问题 （续） Seldom correct applications of risk assessment approach and over-interpret
13、ing of GMP regulations without understanding their rationales led to overinvestment of the project. 风险分析方法罕有正确应用，未能从基本原理上进行理解，若干GMP法规被过度解读导致项目过度投资。 Seldom systematic planning at the very beginning, most are crash jobs in the final phase of the project. 鲜有在项目开始即进行系统性的策划，大部分在项目后期进行突击。 Frequent change
14、orders due to issues exposed in the final C&Q phase led to significant cost of remedy and delay. 因最终调试与确认阶段暴露的问题而产生的变更导致可观的索赔及工期延误。,2012 ISPE CHINA ANNUAL CONFERENCE,Introduction 导言,Current Issues Relative to C&Q in Chinese Pharmaceutical Industry （cont.） 当前中国医药工业中调试与确认的相关问题 （续） Unclear interfaces a
15、nd poor communications of the different project parties led to considerable overlapping or missing of project works, commissioning integration with qualification is rare. 不同项目参与方节点不清，沟通不畅导致相当的项目工作重叠或漏项, 罕有调试与确认进行整合。 Due to lack of specialized C&Q people, most of the C&Q jobs rely on sub-contractors
16、or vendors, the jobs quality is not under control, and the owner or the EPC contractor has to pay extra charges for each equipment or system. 由于缺乏专业的调试与确认人员，大部分的调试与确认工作依赖于分包商或供应商，工作质量不可控，而业主或总承包商不得不为每一设备或系统付出额外的费用。,2012 ISPE CHINA ANNUAL CONFERENCE,Introduction 导言,Current Issues Relative to C&Q in C
17、hinese Pharmaceutical Industry （cont.） 当前中国医药工业中调试与确认的相关问题 （续） Though several Q&V consultants available, the scope and standards of works are undetermined, and therefore both quantity and quality of their works are hard to evaluate. 尽管有数家确认与验证咨询服务提供商，但工作范围与标准不明确，因而工作的数量与质量都很难评估。 Due to absence of SM
18、E in some disciplines , the Q&V consultants sometimes can only reveal the defects in the project, but fail to present the cost-effective solutions for them, especially when the GMP conflicts with local codes, e.g. fire fighting or EHS codes. 由于某些专业的专家欠缺，确认与验证咨询服务提供商有时仅能揭示项目的某些缺陷，但不能给出相应的经济有效的解决方案，尤其
19、是在GMP与国内规范，如消防、环保、职业安全卫生规范发生冲突时。,2012 ISPE CHINA ANNUAL CONFERENCE,Introduction 导言,Gap to Current Good Practices of the International Pharmaceutical Industry 与当前国际医药工业良好实践的差距,2012 ISPE CHINA ANNUAL CONFERENCE,Definition 定义 Commissioning & qualification services integrated into the pharmaceutical pro
20、ject lifecycle（I-C&Q Services) are the valuable consulting services provided by a professional C&Q consultant to help owner or EPC contractor to implement the commissioning and qualifications of design, installation, operation, performance of facilities, systems, and equipments, and finally the proc
21、ess validation of the facilities of a pharmaceutical project by applying GEP, GMP principles and engineering experiences，beginning with developing the OPR and extending through all phases of project delivery and into operation and maintenance. 与制药工程项目全过程相整合的调试与确认服务(I-C&Q服务）系由专业调试与确认咨询商提供有价值的咨询服务，应用G
22、EP、GMP原则和工程经验，从形成业主项目需求开始扩展到项目交付、直到运行和维护等所有阶段，提供有价值的咨询服务，帮助业主或总承包商完成制药工程项目中设施、系统、设备的调试以及设计、安装、运行、性能等一系列确认乃至设施的工艺验证等。,Definition and Contents of I-C&Q Services I-C&Q服务的定义与内容,Definition (cont.)定义（续） When Does Commissioning Occur? 调试的时机 Commissioning can begin during pre-design, design, construction or
23、 building start-up. The process can offer significantly greater and more cost effective benefits when it begins during pre-design or early design. 调试可从设计前、设计、施工或开车的时候开始。当从设计前或者设计早期开始时，该过程能产生更大并更经济有效的效益。Commissioning integration into qualification调试与确认的整合 Commissioning can support qualification if pe
24、rformed within a qualification regime. In this case, it is critical to define the over-all scope of the tests and verifications to be performed for a system, before starting any commissioning or qualification work. 当按确认的制度来进行时，调试可用以支持确认，关键是在开展调试与确认工作前，应定义系统测试与查证的所有范围。,13,Definition and Contents of I
25、-C&Q Services I-C&Q服务的定义与内容,Pre-Design,Design,Construction,Start-Up,Operations & Maintenance,Test & Balance,Start-up Testing,Definition (cont.)-Commissioning Span of Control 定义(续)-调试跨度的控制,Commissioning,设计前,调试,开车测试,设计,施工,开车,运行及维护,测试及平衡,Source（来源）: D. Colburn et al. (2003),I-C&Q,C&Q,Risk Management 风险
26、管理 Design Review 设计审核 Change Management 变更管理,Good Engineering Practice良好工程规范,ASTM E2500-07: Standards for Specification, Design & Verification of Pharmaceutical & Biopharmaceutical Manufacturing Systems & Equipment,Definition (cont.)-Flexible Approach ASTM E2500 定义(续)-ASTM E2500 -07柔性方法,15,ISPE Base
27、line Guide 5, Design Inputs设计输入 Impact Assessment 影响评估 Design Qualification 设计确认 Commissioning 调试 Multiple Trial Runs to Get Things Right 多次试运行以达标 IQ, OQ, PQ and Acceptance Criteria IQ,OQ, PQ及接受标准 GEP scope and QA scope overlapped GEP和QA范围重叠 Focused on Documentation Deliverables 注重关注文件 Rigid Change
28、Management刚性的变更管理,ASTM E2500, Design Inputs设计输入 Design Review设计审核 Risk Mitigation降低风险 Critical Control Parameters Define Acceptance Criteria 关键控制参数定义接受标准 Verification Testing确认测试 Performance Testing 性能测试 GEP scope and QA scope have clear boundary GEP和QA界限清晰 Process, Product Quality and Patient Safet
29、y工艺，产品质量和病人安全 Quality by Design, Design Space and Continuous Improvement质量源于设计，设计空间及持续改进,Definition and Contents of I-C&Q Services I-C&Q服务的定义与内容,Definition (cont.)定义（续）,Source（来源）: IT Pharma Validation Europe (2008),16,2012 ISPE CHINA ANNUAL CONFERENCE,Contents服务内容 Represents “owner “ as an objectiv
30、e advocate 作为目标宣传者代表业主 Guides the development of F-URS, URS 指导编制设施URS及系统URS Organizes or attends gap analysis, impact assessment, risk assessment and DR or DQ组织或参加偏差分析、影响分析、风险评估以及设计审核或设计确认 Reviews standards/strategies early in design 在设计阶段审核标准/策略 Develops the Cx Plan and VMP编制调试计划及验证总计划,Definition a
31、nd Contents of I-C&Q Services I-C&Q服务的定义与内容,2012 ISPE CHINA ANNUAL CONFERENCE,Contents (cont.) 服务内容（续） Develops Cx contract language for the A/E & Construction contracts 编制建筑/工程设计及施工合同中的调试条款 Guides the Development Quality System Program and Implementation Plan 指导编制质量体系程序及实施方案 Guides the total C&Q pr
32、ocess 指导调试、确认全过程 Ensures implementation of selected measures identified in the OPR 确保业主项目需求中明确的选择措施的实施 Verifies minimum targets have been met 查证最低目标已满足 Completes final C&Q report 完成最终调试、确认报告,Definition and Contents of I-C&Q Services I-C&Q服务的定义与内容,2012 ISPE CHINA ANNUAL CONFERENCE,Contents (cont.) 服务
33、内容（续） Guides Computer System Validation指导计算机系统验证 Guides Analytical Instrument Qualification and Analytical Method Analysis指导分析仪器确认与分析方法验证Guides Cleaning, Sterilization, and Fumigation Validation指导清洁、灭菌、熏蒸验证 Guides the PV process, completes PV report 指导工艺验证过程，完成工艺验证报告 Coordinates system testing and o
34、perator training 协调系统测试和操作人员培训,Definition and Contents of I-C&Q Services I-C&Q服务的定义与内容,2012 ISPE CHINA ANNUAL CONFERENCE,Service Packets Breakdown 服务工作包分解,Gap analysis and URS development guidance偏差分析及设施用户需求编制指导 GMP review GMP审核 System Impact Assessment and Validation Master Plandevelopment 系统影响评估与验
35、证总计划编制 Quality system program and implementation plan development Guidance 质量体系程序及实施方案编制指导,Definition and Contents of I-C&Q Services I-C&Q服务的定义与内容,2012 ISPE CHINA ANNUAL CONFERENCE,Service Packets Breakdown (cont.) 服务工作包分解 （续）,Risk Analysis and S-E/URS SOP, VP development guidance风险分析及设备/系统用户需求、验证计划
36、编制指导 Commissioning Plan and Qualification Protocol development guidance调试计划和确认方案编制指导 Component Impact Assessment, Risk Assessment guidance and DQ 组件影响分析、风险分析指导与设计确认 IQ，OP，PQ guidance安装确认、运行确认、性能确认指导 Computer System Validation guidance计算机系统验证指导,Definition and Contents of I-C&Q Services I-C&Q服务的定义与内容,
37、2012 ISPE CHINA ANNUAL CONFERENCE,Service Packets Breakdown (cont.) 服务工作包分解 （续）,Analytical Instrument Qualification and Analytical Method Validation Guide分析仪器确认与分析方法验证指导 Cleaning, Sterilization, and Fumigation Validation guide 清洁、灭菌、熏蒸验证指导 Process Validation guide工艺验证指导,Definition and Contents of I-
38、C&Q Services I-C&Q服务的定义与内容,2012 ISPE CHINA ANNUAL CONFERENCE,Services Provider and Stakeholders 服务提供商及相关方,The Qualified Service Team Structure 合格的服务团队人员构成 Based on the project scope, resource requirements, and the key stakeholders; 取决于项目的范围、资源需求以及主要相关方; Experienced and professional in individual fie
39、ld; 在相应领域具有经验和专业素养 Need to understand the roles, responsibilities, and levels of authority; 应能理解自身的角色、责任以及权力层次； Have excellent communication, planning, and coordination between different parties.与不同的项目参与方间有很好的沟通、计划与协调。,2012 ISPE CHINA ANNUAL CONFERENCE,Services Provider and Stakeholders 服务提供商及相关方,Th
40、e Qualified Service Team Structure (cont.)合格的服务团队人员构成（续） Including but not limited to, 包括但不限于， Team leader 团队领导 Compliance and regulatory expert 合规和法规专家 Mechanical C&Q engineer (HVAC, utilities) 机械调试与确认工程师（暖通、公用） Process equipment/system C&Q engineer 工艺设备、工艺系统调试与确认工程师,2012 ISPE CHINA ANNUAL CONFEREN
41、CE,Services Provider and Stakeholders 服务提供商及相关方,The Qualified Service Team Structure (cont.)合格的服务团队人员构成（续） Computer system validation engineer (software and hardware) 计算机系统验证工程师 AMV engineer and process validation engineer 分析方法验证工程师及工艺验证工程师 Cleaning，sterilization, and fumigation validation engineer
42、清洁，灭菌，熏蒸验证工程师 Document coordinator and technical writer 文件协调控制员及技术文件编制人员,2012 ISPE CHINA ANNUAL CONFERENCE,Services Provider and Stakeholders 服务提供商及相关方,The Qualified Service Team Structure (cont.)合格的服务团队人员构成（续） Outsource support subject matter experts of compliance and regulatory, mechanical (HVAC,
43、utilities), process & equipment, clean finishing, operation, QC/QA, QMS etc. 合规和法规、机械（暖通、公用）、工艺与设备、洁净装修、运行、质量控制与质量保证、质量管理体系等外部学科问题支持专家。,2012 ISPE CHINA ANNUAL CONFERENCE,Other Project Parties 其它项目参与方A/E consultants 工程设计 Procurement 采购 Construction 施工 Project management 项目管理 Commissioning leaders or
44、coordinator from contractors and owner 承包商、业主调试负责人或协调员 Operations/Production, maintenance, R&D, EHS, QC, QA, Qualification &Validation from the owner 业主生产运行、维护、研发、环保及健康安全、QC、QA、确认与验证等部门,Services Provider and Stakeholders 服务提供商及相关方,2012 ISPE CHINA ANNUAL CONFERENCE,The Authorities 监管部门 Food & Drug Ad
45、ministration食品药品监督部门 Municipal planning & construction administration规划、建设管理部门 Environmental Protection环保部门 Fire authority消防部门 Safety Supervision Administration安全监督部门 Labor Protection 劳动保护部门 Quality Supervision 质量监督部门,Services Provider and Stakeholders 服务提供商及相关方,2012 ISPE CHINA ANNUAL CONFERENCE,Reg
46、ulatory Requirements 法规要求,Necessity必要性,Source（来源）: R. E. Chew and D. Petko (2007),EU GMP Annex 15 and SFDA GMP Chap. 7 “Qualification and Validation” define the requirements. 欧盟GMP附录15和中国GMP第七章“确认与验证”有明确要求。Relationship of ASTM Standard to GMP regulations and guidance documents ASTM标准与GMP法规和指南文件的关系,日
47、本,美国,欧盟,诸如CFR 211.68 “设备应按书面程序进行校验、检查、或核对以确保其恰当性能”等条款是确认的基础,ICH Q9 质量风险管理可用来决定“确认”的范围,指导如何执行ASTM标准的主要原理及基本原则,阐明基于风险的查证（或确认）的原理及基本原则,Benefits to the Owner 为业主带来的好处Risk controlled earlier 风险及早得到控制 Reduce time and cost to achieve and maintain compliance 降低项目完成所耗费用与时间并维持项目的合规性 Reduce change orders durin
48、g construction 减少施工过程的变更令 Less waste & repetition 更少的浪费与重复 Reduce project delays 较少项目推迟 Shorten building turnover period 缩短建筑交付周期 Validation team and QMS set up 建立验证团队和质量管理体系Earlier released and commercial manufacture 更早地通过认证并投入商业生产,Necessity必要性,Benefits to the Owner (cont.) 为业主带来的好处(续）Cost effectiv
49、e operation and maintenance 经济高效的运行及维护 Reduce equipment replacement减少设备更换 Better knowledge, understanding of systems对系统更好的认识和理解 Better trained operations staff更好地培训运行团队 Operations and maintenance manuals are complete and submitted at project turnover.运行及维护手册完成并在项目交付时提交,Necessity必要性,Benefits to the C
50、ontractors对承包商的好处Better planning will result in improved installation更好的计划可导致安装的改进 More emphasis on quality control on what matters 对质量控制更加强调 Quicker resolution of problems (identify problems during QC) 更快地解决问题（在QC过程中界定问题） Increase likelihood of completing project on schedule maximize profit 提高按时完成项目的可能性利润最大化 Reduce post-construction callbacks preserve profit 减少施工后召回保护利润,
