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1、CHINA CHINA CHINA CHINA ANNUAL ANNUAL ANNUAL ANNUAL CONFERENCECONFERENCECONFERENCECONFERENCE 16th 17th April 2012,BeijingCommissioning&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
2、 导言Definition and Contents Of I-C&Q Service I-C&Q服务的定义与内容Services 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 CONFERENCEIntroduction 导言导言Concepts 概念概念Good Engineering Practice良好工程规范良好工程规范Established engineering methods
3、 and standards that are applied throughout the project lifecycle 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调试调试A well planned,documented and managed engineering approach to the start-up and turnover of facilities,systems,and equipment to the
4、End-User that results in a safe and function environment that 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 CONFERENCEIntroduction 导言导言Concepts(cont.)概念（续）概念（续）DQ设计确认设计确认The docume
5、nted verification that engineering design of a facility,utility 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安装确认安装确认 The documented verification that all aspects of a facility,util
6、ity or equipment that can affect product quality adhere to approved 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 CONFERENCEIntroduction 导言导言Concepts(cont.)概念（续）概念（续）OQ操作确认操作确认The documented verification that all aspects of
7、a facility,utility,or equipment that can affect product quality operate 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性能确认性能确认The documented verification that all aspects of facility,utility,or equipment that can affect product quality perform a
8、s intended meeting predetermined acceptance criteria.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，确认其性能符合预先确定的验收标准。2012 ISPE CHINA ANNUAL CONFERENCEIntroduction 导言导言Concepts(cont.)概念（续）概念（续）PV工艺验证工艺验证The process of establishing documented evidence which provides a high degree of assurance that a specific proc
9、ess will consistently produce a product meeting its pre-determined specifications 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
10、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 ANNUAL CONFERENCEIntroduction 导言导言Current Issues Relative to C&Q in Chinese Pharmaceutical Industry 当当前中国医药工业中调试与确认的相关问题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
11、。Very rare professional C&Q consultants aligned with international standard and practice.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。Importa
12、nce of establishing a real QMS based on good C&Q practices is not well acknowledged 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 CONFERENCEIntroduction 导言导言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当
13、前中国医药工业中调试与确认的相关问题 （续）（续）Seldom correct applications of risk assessment approach and over-interpreting 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 a
14、re 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 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 CONFERENCEIntroduction 导言导言Current Issues Relative to
15、 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当前中国医药工业中调试与确认的相关问题 （续）（续）Unclear interfaces and 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
16、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 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
17、不为每一设备或系统付出额外的费用。2012 ISPE CHINA ANNUAL CONFERENCEIntroduction 导言导言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当前中国医药工业中调试与确认的相关问题 （续）（续）Though several Q&V consultants available,the scope and standards of works are undetermined,and therefore both quanti
18、ty 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 SME 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 confli
19、cts 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 CONFERENCEIntroduction 导言导言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与当前国际医药工业良好实践的差距A
20、spects 方面方面China 中国中国International 国际国际Marketing Environment市场环境Obvious demand,limited investment,development required需求明显但投入有限，需要培育Regular demand,worth to invest,mature and normative需求一般，认为投入值得，成熟、规范Professionals专业人员Limited quantity,inexperienced,discipline-absent 数量、经验有限，学科配套不齐全 Abundant,experienc
21、ed,complete disciplines，high-cost 数量充足，经验丰富，学科齐全,费用昂贵Organization机构Temporal,project based,lately involve 临时、基于项目、后期介入Standing,multi-projects,life-cycle involved 常设，多项目，全程Implementation执行Random,no strict procedure,absent or overlapping随意，无严格程序，漏项或重叠Normative,strict procedure,integrity 规范、程序严格、过程完整Doc
22、umentation文件Poor integrity,irregular,non-real-time，reference absent 完整性差，不规范，非实时，引用失缺 Good integrity,normative,real-time,complete reference,credible完整性好，规范，实时，引用齐全可信Approach 方法Partly follows ISPE Baseline Guide 5仅部分参照ISPE调试与确认指南ASTM E2500 07+ISPE Baseline Guide+GAMP52012 ISPE CHINA ANNUAL CONFERENCE
23、Definition 定义定义Commissioning&qualification services integrated into the pharmaceutical project 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,installat
24、ion,operation,performance of facilities,systems,and equipments,and finally the process 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 o
25、peration and maintenance.与与制制药药工工程程项项目目全全过过程程相相整整合合的的调调试试与与确确认认服服务务(I-C&Q(I-C&Q服服务务）系由专业调试与确认咨询商提供有价值的咨询服务，应用GEP、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&QI-C&Q服务的定义与内容服务的定义与内容Defini
26、tion(cont.)定义（续）定义（续）When Does Commissioning Occur?调试的时机调试的时机Commissioning can begin during pre-design,design,construction or 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
27、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调试与确认的整合调试与确认的整合Commissioning can support qualification if performed 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
28、 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。13Definition and Contents of I-C&Q Services I-C&QI-C&Q服务的定义与内容服务的定义与内容Test&BalanceStart-up TestingDefinition(cont.)-Commissioning Span of Control 定义定义(续续)-)-调试跨度的控制调试跨度的控制Commissioning 设计前调试开车测试设计施工开车运行及维护测
29、试及平衡Source（来源）:D.Colburn et al.(2003)I-C&QC&QRisk Management 风险管理管理Design Review 设计审核核Change Management 变更管理更管理Product Knowledge生产知识Regulatory法规 Company Quality公司质量Process Knowledge工艺知识Good Engineering Practice良好工程良好工程规范范Requirements需求Specification&Design规格与设计Verification确认Acceptance&Release验收与放行Ope
30、rations&CI运行及持续改进ASTM E2500-07:Standards for Specification,Design&Verification of Pharmaceutical&Biopharmaceutical Manufacturing Systems&EquipmentDefinition(cont.)-Flexible Approach ASTM E2500 定义定义(续续)-ASTM E2500-07)-ASTM E2500-07柔性方法柔性方法15ISPE Baseline Guide 5 Design Inputs设计输入 Impact Assessment 影响
31、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 Management刚性的变更管理ASTM E2500 Design Inputs设计输入 Design Re
32、view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 Safety工艺，产品质量和病人安全 Quality by Design,Design Space and Continuou
33、s 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&QI-C&Q服务的定义与内容服务的定义与内容Definition(cont.)定义（续）定义（续）Source（来源）:IT Pharma Validation Europe(2008)162012 ISPE CHINA ANNUAL CONFERENCEContents服务内容服务内容Represents“owner“as an objective advocate 作为目标宣传者代表业主Guides the development of F-
34、URS,URS 指导编制设施URS及系统URSOrganizes 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 and Contents of I-C&Q Services I-C&QI-C&Q服务的定义与内容服务的定义与内容20
35、12 ISPE CHINA ANNUAL CONFERENCEContents(cont.)服务内容（续）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 process 指导调试、确认全过程Ensures implementation of selec
36、ted 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&QI-C&Q服务的定义与内容服务的定义与内容2012 ISPE CHINA ANNUAL CONFERENCEContents(cont.)服务内容（续）服务内容（续）Guides Computer System Validat
37、ion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 operator training 协调系统测试和操作人员培训Definition
38、and Contents of I-C&Q Services I-C&QI-C&Q服务的定义与内容服务的定义与内容2012 ISPE CHINA ANNUAL CONFERENCE Service Packets Breakdown 服务工作包分解服务工作包分解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 Plan development 系统影响评估与验证总计划编制Quality system prog
39、ram 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&QI-C&Q服务的定义与内容服务的定义与内容2012 ISPE CHINA ANNUAL CONFERENCE Service Packets Breakdown(cont.)服务工作包分解服务工作包分解 （续）（续）Risk Analysis and S-E/URS SOP,VP development guidance 风险分析及设备/系统用户需求、验证计划编制指导Comm
40、issioning 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&QI-C&Q服务的定义与内容服务的定义与内容20
41、12 ISPE CHINA ANNUAL CONFERENCE Service Packets Breakdown(cont.)服务工作包分解服务工作包分解 （续）（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-
42、C&Q Services I-C&QI-C&Q服务的定义与内容服务的定义与内容2012 ISPE CHINA ANNUAL CONFERENCEServices Provider and Stakeholders 服务提供商及相关方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 profe
43、ssional in individual field;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 CONFERENCEServices Provider and Stakeholde
44、rs 服务提供商及相关方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）合格的服务团队人员构成（续）Including but not limited to,包括但不限于，pTeam leader 团队领导pCompliance and regulatory expert 合规和法规专家pMechanical C&Q engineer(HVAC,utilities)机械调试与确认工程师（暖通、公用）pProcess equipment/system C&Q engineer 工艺设备、工艺系统调试与确认工程师2
45、012 ISPE CHINA ANNUAL CONFERENCEServices Provider and Stakeholders 服务提供商及相关方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）合格的服务团队人员构成（续）pComputer system validation engineer(software and hardware)计算机系统验证工程师pAMV engineer and process validation engineer 分析方法验证工程师及工艺验证工程师pCleaning，st
46、erilization,and fumigation validation engineer 清洁，灭菌，熏蒸验证工程师pDocument coordinator and technical writer文件协调控制员及技术文件编制人员 2012 ISPE CHINA ANNUAL CONFERENCEServices Provider and Stakeholders 服务提供商及相关方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）合格的服务团队人员构成（续）pOutsource support subje
47、ct matter experts of compliance and regulatory,mechanical(HVAC,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 CONFERENCEOther Project Parties 其它项目参与方其它项目参与方p A/E consultants 工程设计pProcurement 采购pCon
48、struction 施工pProject management 项目管理pCommissioning leaders or coordinator from contractors and owner 承包商、业主调试负责人或协调员 pOperations/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服务提供商及相关方2012 I
49、SPE CHINA ANNUAL CONFERENCEThe Authorities 监管部门监管部门pFood&Drug Administration食品药品监督部门 pMunicipal planning&construction administration规划、建设管理部门pEnvironmental Protection环保部门pFire authority消防部门pSafety Supervision Administration安全监督部门pLabor Protection 劳动保护部门pQuality Supervision 质量监督部门 Services Provider a
50、nd Stakeholders 服务提供商及相关方服务提供商及相关方2012 ISPE CHINA ANNUAL CONFERENCERegulatory Requirements 法规要求法规要求 Necessity必要性必要性Source（来源）:R.E.Chew and D.Petko(2007)pEU 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。pRelationship of ASTM Stand