1、和制藥工程工程全過程相整合調試和確認效勞Agenda議程Introduction 導言Definition and Contents Of I-C&Q Service I-C&Q服務的定義與內容Services Provider and Stakeholders 服務提供商及相關方Necessity必要性Implementation 實施References and Acknowledgements 參考文獻與致謝2012 ISPE CHINA ANNUAL CONFERENCEIntroduction 導言Concepts 概念Good Engineering Practice良好工程規范E

2、stablished engineering methods and standards that are applied throughout the project lifecycle to deliver appropriated cost-effective solution.在項目周期中全程采用已建立的工程方法和標準，以交付合理的、經濟有效的解決方案。Commissioning調試A well planned, documented and managed engineering approach to the start-up and turnover of facilities,

3、 systems, and equipment to the End-User that results in a safe and function environment that meets established design requirements and stakeholder expectations.采用一套良好計劃的、有文件記錄并受管理的工程方法，對工程設施、系統和設備進行試車并交付最終用戶，以建立符合既定設計要求及股東期望的安全、功能良好的環境。2012 ISPE CHINA ANNUAL CONFERENCEIntroduction 導言Concepts (cont.)

4、概念（續）DQ設計確認The documented verification that engineering design of a facility, utility or equipment that can affect product quality adhere to approved User Requirement and design specifications. 對可能影響產品質量的設施、公用工程和設備的工程設計進行有文件記錄的查證，確認與被批準的用戶需求和設計描述一致。IQ安裝確認 The documented verification that all aspects

5、 of a facility, utility or equipment that can affect product quality adhere to approved specifications and are correctly installed. 對設施、公用工程和設備所有可能影響產品質量的方面進行有文件記錄的查證，確認與被批準的描述一致并已得到正確的安裝。 2012 ISPE CHINA ANNUAL CONFERENCEIntroduction 導言Concepts (cont.)概念（續）OQ操作確認The documented verification that all

6、 aspects of a facility, utility, or equipment that can affect product quality operate as intended throughout all anticipated ranges. 對設施、公用工程和設備所有可能影響產品質量的方面進行有文件記錄的查證，確認它們在預期的操作極限內運行正確。PQ性能確認The documented verification that all aspects of facility, utility, or equipment that can affect product qual

7、ity perform as intended meeting predetermined acceptance criteria. 對設施、公用工程和設備所有可能影響產品質量的方面進行有文件記錄的查證，確認其性能符合預先確定的驗收標準。 2012 ISPE CHINA ANNUAL CONFERENCEIntroduction 導言Concepts (cont.)概念（續）PV工藝驗證The process of establishing documented evidence which provides a high degree of assurance that a specific

8、 process will consistently produce a product meeting its pre-determined specifications and quality attributes. 建立文件證據，高度保證在特定生產工藝條件下，可均一地生產符合預定標準和質量屬性的產品的過程。More concepts 更多的概念Risk Based Commensurate with risk 基于風險與風險相適應Science Based CQA, CPPs 基于科學關鍵質量屬性、關鍵工藝參數Quality by Design Verify throughout 質量源

9、于設計全過程的驗證Subject Matter Expert Defined Role 學科問題專家角色定義2012 ISPE CHINA ANNUAL CONFERENCEIntroduction 導言Current Issues Relative to C&Q in Chinese Pharmaceutical Industry 當前中國醫藥工業中調試與確認的相關問題Limited resource and focus on DQ and QBD is not well acknowledged. 投入資源有限，對設計確認、質量源于設計等的重點未充分認識。Very rare profess

10、ional C&Q consultants aligned with international standard and practice. 專業的、與國際標準、規范接軌的調試與確認咨詢服務提供商非常罕見。Lack of local presence of international C&Q consulting expertise and the corresponding local professional engineer supportive team. 國際知名調試與確認專家罕有常駐中國本地，同時缺乏與其配套的本地專業工程師支持團隊。Importance of establish

11、ing a real QMS based on good C&Q practices is not well acknowledged by endorser top management. 以良好的調試與確認實踐為基礎建立一個真正的質量管理體系的重要性并未被企業高層管理人員充分認識。2012 ISPE CHINA ANNUAL CONFERENCEIntroduction 導言Current Issues Relative to C&Q in Chinese Pharmaceutical Industry （cont.） 當前中國醫藥工業中調試與確認的相關問題 （續）Seldom corre

12、ct applications of risk assessment approach and over-interpreting of GMP regulations without understanding their rationales led to overinvestment of the project. 風險分析方法罕有正確應用，未能從基本原理上進行理解，若干GMP法規被過度解讀導致項目過度投資。Seldom systematic planning at the very beginning, most are crash jobs in the final phase of

13、 the project. 鮮有在項目開始即進行系統性的策劃，大部分在項目后期進行突擊。Frequent change orders due to issues exposed in the final C&Q phase led to significant cost of remedy and delay. 因最終調試與確認階段暴露的問題而產生的變更導致可觀的索賠及工期延誤。2012 ISPE CHINA ANNUAL CONFERENCEIntroduction 導言Current Issues Relative to C&Q in Chinese Pharmaceutical Indu

14、stry （cont.） 當前中國醫藥工業中調試與確認的相關問題 （續）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. 不同項目參與方節點不清，溝通不暢導致相當的項目工作重疊或漏項, 罕有調試與確認進行整合。Due to lack of specialized C&

15、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. 由于缺乏專業的調試與確認人員，大部分的調試與確認工作依賴于分包商或供應商，工作質量不可控，而業主或總承包商不得不為每一設備或系統付出額外的費用。2012 ISPE CHINA ANNUAL CONFEREN

16、CEIntroduction 導言Current Issues Relative to C&Q in Chinese Pharmaceutical Industry （cont.） 當前中國醫藥工業中調試與確認的相關問題 （續）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. 盡管有數家確認與驗證咨詢服務提供

17、商，但工作范圍與標準不明確，因而工作的數量與質量都很難評估。 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 conflicts with local codes, e.g. fire fighting or EHS codes. 由于某些專業的

18、專家欠缺，確認與驗證咨詢服務提供商有時僅能揭示項目的某些缺陷，但不能給出相應的經濟有效的解決方案，尤其是在GMP與國內規范，如消防、環保、職業安全衛生規范發生沖突時。2012 ISPE CHINA ANNUAL CONFERENCEIntroduction 導言Gap to Current Good Practices of the International Pharmaceutical Industry 與當前國際醫藥工業良好實踐的差距Aspects 方面China 中國International 國際Marketing Environment市場環境Obvious demand, lim

19、ited investment, development required需求明顯但投入有限，需要培育Regular demand, worth to invest, mature and normative需求一般，認為投入值得，成熟、規范Professionals專業人員Limited quantity, inexperienced, discipline-absent 數量、經驗有限，學科配套不齊全 Abundant, experienced, complete disciplines，high -cost 數量充足，經驗豐富，學科齊全,費用昂貴Organization機構Tempora

20、l, project based, lately involve 臨時、基于項目、后期介入Standing, multi-projects, life-cycle involved 常設，多項目，全程Implementation執行Random, no strict procedure, absent or overlapping隨意，無嚴格程序，漏項或重疊Normative, strict procedure, integrity 規范、程序嚴格、過程完整Documentation文件Poor integrity , irregular, non-real-time，reference ab

21、sent 完整性差，不規范，非實時，引用失缺 Good integrity, normative, real-time, complete reference, credible完整性好，規范，實時，引用齊全可信Approach 方法Partly follows ISPE Baseline Guide 5僅部分參照ISPE調試與確認指南ASTM E2500 07+ISPE Baseline Guide + GAMP52012 ISPE CHINA ANNUAL CONFERENCEDefinition 定義Commissioning & qualification services integ

22、rated 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, installation, operation, performance of facilities, systems, and

23、 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 operation and maintenance. 與制藥工程項目全過程相整合的調試與確認服務(I

24、-C&Q服務）系由專業調試與確認咨詢商提供有價值的咨詢服務，應用GEP、GMP原則和工程經驗，從形成業主項目需求開始擴展到項目交付、直到運行和維護等所有階段，提供有價值的咨詢服務，幫助業主或總承包商完成制藥工程項目中設施、系統、設備的調試以及設計、安裝、運行、性能等一系列確認乃至設施的工藝驗證等。Definition and Contents of I-C&Q Services I-C&Q服務的定義與內容Definition (cont.)定義（續）When Does Commissioning Occur? 調試的時機Commissioning can begin during pre-de

25、sign, 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. 調試可從設計前、設計、施工或開車的時候開始。當從設計前或者設計早期開始時，該過程能產生更大并更經濟有效的效益。 Commissioning integration into qualification調試與確認的整合Commissioning ca

26、n 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 any commissioning or qualification work. 當按確認的制度來進行時，調試可用以支持確認，關鍵是在開展調試與確認工作前，應定義系統測試與查證的所有范圍。13D

27、efinition and Contents of I-C&Q Services I-C&Q服務的定義與內容Pre-DesignDesignConstructionStart-UpOperations &MaintenanceTest &BalanceStart-up TestingDefinition (cont.)-Commissioning Span of Control 定義(續)-調試跨度的控制Commissioning 設計前調試開車測試設計施工開車運行及維護測試及平衡Source（來源）: D. Colburn et al. (2003)I-C&QC&QRisk Manageme

28、nt 風險管理Design Review 設計審核Change Management 變更管理Product Knowledge生產知識Regulatory法規 Company Quality公司質量Process Knowledge工藝知識Good Engineering Practice良好工程規范Requirements需求Specification & Design規格與設計Verification確認Acceptance & Release驗收與放行Operations & CI運行及持續改進ASTM E2500-07: Standards for Specification, De

29、sign & Verification of Pharmaceutical & Biopharmaceutical Manufacturing Systems & EquipmentDefinition (cont.)-Flexible Approach ASTM E2500 定義(續)-ASTM E2500 -07柔性方法15ISPE Baseline Guide 5 Design Inputs設計輸入 Impact Assessment 影響評估 Design Qualification 設計確認 Commissioning 調試 Multiple Trial Runs to Get Th

30、ings Right 多次試運行以達標 IQ, OQ, PQ and Acceptance Criteria IQ,OQ, PQ及接受標準 GEP scope and QA scope overlapped GEP和QA范圍重疊 Focused on Documentation Deliverables 注重關注文件 Rigid Change Management剛性的變更管理ASTM E2500 Design Inputs設計輸入 Design Review設計審核 Risk Mitigation降低風險 Critical Control Parameters Define Acceptan

31、ce Criteria 關鍵控制參數定義接受標準 Verification Testing確認測試 Performance Testing 性能測試 GEP scope and QA scope have clear boundary GEP和QA界限清晰 Process, Product Quality and Patient Safety工藝，產品質量和病人安全 Quality by Design, Design Space and Continuous Improvement質量源于設計，設計空間及持續改進Definition and Contents of I-C&Q Services

32、 I-C&Q服務的定義與內容Definition (cont.)定義（續）Source（來源）: IT Pharma Validation Europe (2008)162012 ISPE CHINA ANNUAL CONFERENCEContents服務內容Represents “owner “ as an objective advocate 作為目標宣傳者代表業主Guides the development of F-URS, URS 指導編制設施URS及系統URSOrganizes or attends gap analysis, impact assessment, risk ass

33、essment and DR or DQ組織或參加偏差分析、影響分析、風險評估以及設計審核或設計確認Reviews standards/strategies early in design 在設計階段審核標準/策略Develops the Cx Plan and VMP編制調試計劃及驗證總計劃Definition and Contents of I-C&Q Services I-C&Q服務的定義與內容2012 ISPE CHINA ANNUAL CONFERENCEContents (cont.) 服務內容（續）Develops Cx contract language for the A/E

34、 & Construction contracts 編制建筑/工程設計及施工合同中的調試條款Guides the Development Quality System Program and Implementation Plan 指導編制質量體系程序及實施方案Guides the total C&Q process 指導調試、確認全過程Ensures implementation of selected measures identified in the OPR 確保業主項目需求中明確的選擇措施的實施Verifies minimum targets have been met 查證最低目標

35、已滿足Completes final C&Q report 完成最終調試、確認報告Definition and Contents of I-C&Q Services I-C&Q服務的定義與內容2012 ISPE CHINA ANNUAL CONFERENCEContents (cont.) 服務內容（續）Guides Computer System Validation指導計算機系統驗證Guides Analytical Instrument Qualification and Analytical Method Analysis指導分析儀器確認與分析方法驗證 Guides Cleaning,

36、 Sterilization, and Fumigation Validation指導清潔、滅菌、熏蒸驗證Guides the PV process, completes PV report 指導工藝驗證過程，完成工藝驗證報告Coordinates system testing and operator training 協調系統測試和操作人員培訓Definition and Contents of I-C&Q Services I-C&Q服務的定義與內容2012 ISPE CHINA ANNUAL CONFERENCE Service Packets Breakdown 服務工作包分解Gap

37、 analysis and URS development guidance偏差分析及設施用戶需求編制指導GMP review GMP審核System Impact Assessment and Validation Master Plan development 系統影響評估與驗證總計劃編制Quality system program and implementation plan development Guidance 質量體系程序及實施方案編制指導Definition and Contents of I-C&Q Services I-C&Q服務的定義與內容2012 ISPE CHINA

38、 ANNUAL CONFERENCE Service Packets Breakdown (cont.) 服務工作包分解 （續）Risk Analysis and S-E/URS SOP, VP development guidance 風險分析及設備/系統用戶需求、驗證計劃編制指導Commissioning Plan and Qualification Protocol development guidance調試計劃和確認方案編制指導Component Impact Assessment, Risk Assessment guidance and DQ 組件影響分析、風險分析指導與設計確認

39、IQ，OP，PQ guidance安裝確認、運行確認、性能確認指導Computer System Validation guidance計算機系統驗證指導Definition and Contents of I-C&Q Services I-C&Q服務的定義與內容2012 ISPE CHINA ANNUAL CONFERENCE Service Packets Breakdown (cont.) 服務工作包分解 （續）Analytical Instrument Qualification and Analytical Method Validation Guide分析儀器確認與分析方法驗證指導

40、Cleaning, Sterilization, and Fumigation Validation guide 清潔、滅菌、熏蒸驗證指導Process Validation guide工藝驗證指導Definition and Contents of I-C&Q Services I-C&Q服務的定義與內容2012 ISPE CHINA ANNUAL CONFERENCEServices Provider and Stakeholders 服務提供商及相關方The Qualified Service Team Structure 合格的服務團隊人員構成Based on the project

41、scope, resource requirements, and the key stakeholders; 取決于項目的范圍、資源需求以及主要相關方;Experienced and professional in individual field; 在相應領域具有經驗和專業素養Need to understand the roles, responsibilities, and levels of authority; 應能理解自身的角色、責任以及權力層次；Have excellent communication, planning, and coordination between di

42、fferent parties.與不同的項目參與方間有很好的溝通、計劃與協調。 2012 ISPE CHINA ANNUAL CONFERENCEServices Provider and Stakeholders 服務提供商及相關方The Qualified Service Team Structure (cont.) 合格的服務團隊人員構成（續）Including but not limited to, 包括但不限于，Team leader 團隊領導Compliance and regulatory expert 合規和法規專家Mechanical C&Q engineer (HVAC,

43、utilities) 機械調試與確認工程師（暖通、公用）Process equipment/system C&Q engineer 工藝設備、工藝系統調試與確認工程師2012 ISPE CHINA ANNUAL CONFERENCEServices Provider and Stakeholders 服務提供商及相關方The Qualified Service Team Structure (cont.) 合格的服務團隊人員構成（續）Computer system validation engineer (software and hardware) 計算機系統驗證工程師AMV enginee

44、r and process validation engineer 分析方法驗證工程師及工藝驗證工程師Cleaning，sterilization, and fumigation validation engineer 清潔，滅菌，熏蒸驗證工程師Document coordinator and technical writer文件協調控制員及技術文件編制人員 2012 ISPE CHINA ANNUAL CONFERENCEServices Provider and Stakeholders 服務提供商及相關方The Qualified Service Team Structure (cont

45、.) 合格的服務團隊人員構成（續）Outsource support subject matter experts of compliance and regulatory, mechanical (HVAC, utilities), process & equipment, clean finishing, operation, QC/QA, QMS etc. 合規和法規、機械（暖通、公用）、工藝與設備、潔凈裝修、運行、質量控制與質量保證、質量管理體系等外部學科問題支持專家。 2012 ISPE CHINA ANNUAL CONFERENCEOther Project Parties 其它項

46、目參與方 A/E consultants 工程設計Procurement 采購Construction 施工Project management 項目管理Commissioning leaders or coordinator from contractors and owner 承包商、業主調試負責人或協調員 Operations/Production, maintenance, R&D, EHS, QC, QA, Qualification &Validation from the owner 業主生產運行、維護、研發、環保及健康安全、QC、QA、確認與驗證等部門Services Prov

47、ider and Stakeholders 服務提供商及相關方2012 ISPE CHINA ANNUAL CONFERENCEThe Authorities 監管部門Food & Drug Administration食品藥品監督部門 Municipal planning & construction administration規劃、建設管理部門Environmental Protection環保部門Fire authority消防部門Safety Supervision Administration安全監督部門Labor Protection 勞動保護部門Quality Supervis

48、ion 質量監督部門 Services Provider and Stakeholders 服務提供商及相關方2012 ISPE CHINA ANNUAL CONFERENCERegulatory Requirements 法規要求 Necessity必要性Source（來源）: R. E. Chew and D. Petko (2007)EU GMP Annex 15 and SFDA GMP Chap. 7 “Qualification and Validation” define the requirements. 歐盟GMP附錄15和中國GMP第七章“確認與驗證”有明確要求。Relat

49、ionship of ASTM Standard to GMP regulations and guidance documentsASTM標準與GMP法規和指南文件的關系日本美國歐盟諸如CFR 211.68 “設備應按書面程序進行校驗、檢查、或核對以確保其恰當性能”等條款是確認的基礎ICH Q9 質量風險管理可用來決定“確認”的范圍指導如何執行ASTM標準的主要原理及基本原則闡明基于風險的查證（或確認）的原理及基本原則Benefits to the Owner 為業主帶來的好處Risk controlled earlier 風險及早得到控制Reduce time and cost to ac

50、hieve and maintain compliance降低項目完成所耗費用與時間并維持項目的合規性Reduce change orders during construction 減少施工過程的變更令Less waste & repetition 更少的浪費與重復Reduce project delays 較少項目推遲Shorten building turnover period 縮短建筑交付周期Validation team and QMS set up 建立驗證團隊和質量管理體系 Earlier released and commercial manufacture 更早地通過認證并

51、投入商業生產 Necessity必要性Benefits to the Owner (cont.) 為業主帶來的好處(續）Cost effective operation and maintenance經濟高效的運行及維護Reduce equipment replacement 減少設備更換Better knowledge, understanding of systems 對系統更好的認識和理解Better trained operations staff 更好地培訓運行團隊Operations and maintenance manuals are complete and submitte

52、d at project turnover. 運行及維護手冊完成并在項目交付時提交Necessity必要性Benefits to the Contractors對承包商的好處Better planning will result in improved installation 更好的計劃可導致安裝的改進More emphasis on quality control on what matters 對質量控制更加強調Quicker resolution of problems (identify problems during QC) 更快地解決問題（在QC過程中界定問題）Increase

53、likelihood of completing project on schedule maximize profit 提高按時完成項目的可能性利潤最大化Reduce post-construction callbacks preserve profit 減少施工后召回保護利潤Necessity必要性Benefits to the Authorities 對監管部門的好處Genuine ,valid and systemic documentations 文件真實、有效、系統Easy of inspection 便于檢查Genuine, credible records and trends

54、 真實可信的記錄與趨勢Easy of supervision 便于監管Clear management programs, integral approvals in manufacturers site 廠商管理程序清晰，審批完整Easy of investigation afterwards便于事后追究Necessity必要性Implementation Flow of Pharmaceutical Project制藥工業項目實施流程Production Start有效投產Feasibility Study可行性研究Concept Design概念設計Procurement采購Constr

55、uction 施工Detail Engineering詳細設計SupportValidation驗證支持 C&Q 調試與確認Decision “GO”客戶決定工程繼續進行Basic + Ext.Basic Engineering基本擴充設計Final investment Decision 客戶做出最終投資決定Cost Estimate造價估算 20%Cost Estimate造價估算 10%Concept Phase 概念階段 Design Phase 設計階段Execution Phase 實施階段 Hand Over交付Validation Phase驗證階段MaintenanceCus

56、tomer Service維修/客戶服務Facility Management設施管理Second Opinion Value Engineering 修改/補充Implementation 實施 Workflow 工作流程Acknowledgement （感謝）: Instruction from Mr. D .W. Vincent F(設施)-URSGA偏差分析BOD設計基礎VMP驗證總計劃RA風險分析E/S(設備/系統)-URSVP驗證計劃CSVFD/FS功能設計/說明DD/DS詳細設計/設計說明CP(FAT, SAT, etc.), Qual.Protocol 調試計劃及確認方案PQ性

57、能確認OQ運行確認IQ安裝確認Commissioning (FAT/SAT, etc.) Exec.調試（工廠/現場驗收測試等）執行DQ設計確認Procurement& Construction采購施工CV清潔驗證Sterilization Validation滅菌驗證PV工藝驗證Medium Fill培養基灌裝Utility Qua/Val公用系統確認/驗證Fumigation Validation熏蒸驗證AIQ分析儀器確認CSV計算機系統驗證CSV計算機系統驗證CSV計算機系統驗證AMV分析方法驗證SIA系統影響評估GMP Rev.GMP審核Implementation 實施 Workfl

58、ow 工作流程 Acknowledgement （感謝）: Instruction from Mr. C.BachofenWorkflowa brief case study (WFI system) 工作流程 簡略的案例分析(注射用水系統）Specify the final users, capacity, standards，etc. to be followed for WFI. system in F-URS 在設施URS中明確注射用水系統的終端用戶、供應能力以及遵循的標準等。Implement GA for the renovated systems. 對改造的系統進行偏差分析。De

59、velop the schematic design of WFI system (e.g. MB, PFD，main equipment list) in the BOD of the facility （design consultant). 在設施的設計基礎中進行 注射用水系統的方案設計（物料平衡、工藝流程圖,主要設備表等）(設計咨詢方）。Implementation 實施 Workflowa brief case study (WFI system)（cont.) 工作流程 簡略的案例分析(注射用水系統）(續）Implement the IA of the WFI system acc

60、ording to the criteria. 按照判據進行注射用水的影響評估 。Specify the level of C&Qs (including CSV) and the rationale of the system in VMP. 在驗證總計劃中闡明調試確認(包括計算機系統驗證）的程度及原因.Develop the URS of the system (including the C&Q requirement), VP based on RA. 在風險分析的基礎上編制系統的URS及驗證計劃.Implementation 實施 Workflowa brief case study