1. Risk-Based Commissioning & Qualification Benchmarking Educational Track #1

2. Agenda  Part 1 (8:30 – 10:00) ISPE Baseline ® Guide Volume 5: Commissioning & Qualification vs. ASTM E2500 – Mr. Robert Chew Overview of C&Q approaches – Abbott, Lilly, Pfizer  Break – Vendor areas open (10:00 – 10:30)  Part 2 (10:30 – Noon) Panel Q&A  Wrap-up

3. ISPE Baseline Guide Volume 5: Commissioning and Qualification, vs. ASTM E2500 Robert E. Chew, PE President, Commissioning Agents, Inc.

4. My Background in Subject Official trainer for ISPE Baseline Commissioning and Qualification Guide Member of team that wrote ASTM E2500

5. Key Points to Compare Terminology Qualification practices Focusing the effort Roles and responsibilities Managing changes during the project

6. Terminology C&Q Baseline guide Commissioning Qualification ASTM E2500 Verification

7. Qualification Practices C&Q Baseline Guide “To meet the demands of the regulators” ASTM E2500 Not mentioned

8. Focusing the Effort C&Q Baseline Guide Impact assessments Direct impact systems and critical components V-model ASTM E2500 Risk assessment -> critical aspects

9. Roles and Responsibilities C&Q Baseline Guide Quality pre and post approves protocols; quality control role ASTM E2500 Quality involved in process requirements, risk assessments, critical aspects, and acceptance and release Subject matter experts used throughout

10. Managing Change C&Q Baseline Guide QA pre-approved change control implemented at start of IQ/OQ ASTM E2500 QA pre-approved change control implemented at start of manufacture of product for distribution

11. Common Elements Good engineering practices Planning Requirements definition Engineering design reviews Project change management Documented inspections and testing

12. Risk-Based Commissioning & Qualification Approach Abbott Laboratories Global Pharmaceutical Operations Steve Connelly

13. Overview  Where Abbott Is Today  C&Q Approach  Commissioning & Qualification Activities  How We Manage Cost  Lessons Learned

14. Where Abbott is Today Risk Based Maturity Model* *Adapted from 2007 ISPE Tampa Conference Presentation

15. Commissioning & Qualification Approach  C&Q Approach: Application of ISPE Baseline ® Guide Volume 5: Commissioning & Qualification (last 2 years) Little to no implementation of ASTM E2500-07* Level 3 (Risk-based Maturity Model)  Implementation: Corporate policies support Science & Quality Risk Management and includes Good Engineering Practice (GEP) reference Training ( RBA, GEP, ECM. Commissioning, Risk Assessments) Tools and Templates Discretion of the Validation Review Board (VRB) *ASTM E2500-07: A Standard Guide for the Specification, Design, & Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment

16. Science & Quality Risk Management Qualification Process Flow

17. Good Engineering Practices  Formal acknowledgement of GEP in corporate policy  Divisional GEP guideline consists of minimum requirements  Additional divisional guidelines are in development for life- cycle management – Calibration – Maintenance – Engineering change management  Training to aid site support (implementation)

18. Requirements Based On Impact Category *System = equipment, facility, utility  Three methods: –ISPE-Style System* Impact Assessment Questionnaire –Risk Assessment with any standard method (FMEA, HAZOP, etc.) –Technical Evaluation by SMEs Documented and VRB approved Determining impact  to identifying critical elements  Quality Risk Control –Risk Assessment (i.e. FMEA, etc) used to enable: Qualification focus on critical functions and/or components Leverage limited commissioning testing (FAT/SAT) and Eliminate some redundant activities (i.e. alarms, etc)

19. Commissioning  When supporting Qualification, Commissioning must include or address: Engineering Change Management (ECM) –After point commissioning data intended to support Qualification Testing –Methods described in sufficient detail for repeatability –Documentation confirms critical elements met criteria –Acceptance criteria documented prior to execution –Criteria based on User Requirements –Documentation of observed results  Commissioning & Qualification (C&Q) Plans typically contain run rules for project

20. Qualification – Equipment  User requirements Product and Process User Requirement (PURS) General User Requirements (GURS)  Commissioning (in support of qualification) Test it once (or one set of multiple test repetitions, where appropriate); document it correctly Primarily installation activities, operational testing leveraged in some instances (VRB discretion);compile, summarize test results for VRB approval  Qualification When approved, commissioning reports complete the IQ/OQ phase of Qualification with no additional “protocol” testing

21. Qualification – Software (APC/HMI/DCS)  Categorization (based on product quality impact) Managing control issues for critical elements Supplier Assessments for direct impact systems only VRB discretion with technical advisory from Subject Matter Expert  Holistic Approach Integrated Qualification document (IOQ for equipment/controls; as applicable) APC specific qualification requirements –Traceability matrix = Design Qualifications (DQ) –Commissioning = Qualification except critical items

22. Qualification – Facilities  Indirect Impact Facilities - Commission – Design and construction conforming to GEP – Abbott Engineering Standards  Direct Impact Facilities – Commission/Qualify – Meet quality specifications (i.e. Aseptic facility, etc) – Design and construction conforming to GEP – Abbott Engineering Standards

23. Qualification – HVAC  Categorization Interdependent with facility quality attributes – For example: Continuous monitoring for critical environmental aspects; therefore facility and HVAC can be Indirect Impact (HVAC controls would then be qualified) – For example: Temperature, RH, and room pressure differentials typically critical elements which are monitored and recorded continuously, alarming when parameters exceed specifications; VRB discretion as to qualify

24. Qualification – Utilities  Impact Categories - Typically critical or non-critical  Utility systems typically not big source of Validation Change Request (VCR) sources  Only regulatory requirement concern is typically Potable Water feed to purification – Purpose of pretreatment usually to preserve life of purification equipment rather than direct impact of water quality

25. How We Manage Cost… $In 2007, reviewed C&Q costs for several capital projects to: –Establish a baseline –Compare costs for the “traditional, validate everything” C&Q approach versus the risk-based C&Q approach $Cost comparisons across projects difficult because –Inconsistent reporting and project scope varies widely $Drive cost reporting model for capital projects needed to: – Address scope differences, track additional parameters:  Number of Qualification Protocols per project  Number of Qualified Systems  Total Number of Systems – Three parameters documented in C&Q Plan

26. Monthly Capital Project Status Reports are used to track costs and progress There is a wide variation in the tracking systems used by the engineers for the project costs Most project engineers / project managers use spreadsheets of their own design to track costs How We Manage Cost… Commissioning & Qualification Cost Tracking Details

27. Opportunities Identified for Consistent Reporting Engineering/Commissioning/Qualification costs categorized below  Activities not linear, categorization to clarify “gray” areas of cost reporting  Defines appropriate cost “bucket” for consistency across projects How We Manage Cost…

29. Lessons Learned Risk-Based C&Q is an iterative process (one tiny step at a time)  Corporate & divisional policies in place, tools developed, although success for various sites, concern about corporate & regulatory audits  Sites want to maintain autonomy with guidance; common elements, not same approach (i.e. all engineers comply however variations due to specialty)  Application: Site readiness tools - identifying opportunities for closing gaps

30. Lessons Learned Listen, Speak, Deliver. Communication is key.  Quality may wonder: What if engineering doesn’t do its job?;ensure compliance  Engineering may wonder: Quality = police & spell checkers; “right” the first tyme  Application: Regular/frequent communication with VRB & project team

31. Lessons Learned Sustainable Paradigm Shift  Sites: Implementation, accountability & ownership a must for sustainability  Resources: People, time & money, site retaining technical knowledge  Application: Training & support implementation as applicable

32. Thank you! Questions will be addressed during the Panel Q&A session (after break)

33. Eli Lilly & Company Commissioning and Qualification Approach

34. Eli Lilly & Company Approach to Commissioning & Qualification C&Q Delivery Strategy C&Q Metrics C&Q Lessons Learned Improved C&Q Delivery Strategy

35. Recent GFD C&Q Delivery Strategy ~ Baseline Guide approach (’02 – ‘07) Developed procedures governing C&Q activities Fully commissioned all assets ~ GEP Reserved qualification for critical aspects of DI systems only Leveraged commissioning documentation to support qualification – commissioning subject to GDPs Involved Quality at C&Q strategy level In addition, Simulation has been used to commission automation aspects CSV testing has been integrated within C&Q test documents

36. Fundamental C&Q Delivery Strategy ~ for Global Facilities Delivery (GFD) Capital Projects

37. This strategy has resulted in: Earlier resolution of issues Opportunity to understand systems Reduced Qualification time Reduced Qualification costs Fewer Qualification comments/discrepancies C&Q Delivery Strategy ~ Results

38. C&Q Metrics Schedule Metrics Cost Metrics Discrepancy Metrics

39. Typical C&Q Schedule Metrics ~ Durations 10 months from facility mechanical completion to OQ completion Total Commissioning duration: 24 mos. (172 days/system) Total IQ/OQ duration: 6 months FT duration/system: 42 days IQ duration/system: 11 days OQ duration/system: 17 days Average # of days from MC to OQ completion: 227 days Note: Metrics for new powder filling facility consisting of approx. 40 systems

40. C&Q Cost Metrics ~ Historical view No C&Q prog 1998- 2001 Full C&Q prog 2002- pres. Part. C&Q prog 2001-2003 C&Q Cost as % TIC 40% 20% 10% 5% 25% 10% 5% GOAL3%

41. C&Q Budget Metrics ~ capital projects completed in ‘07 Total Installed Cost C&Q Cost (% TIC) $319MM6.0% $186MM1.5% (comm. only) $180MM5.5% $145MM5.7% (incl. non-CQ activities) $14.5MM4.3% $11.6MM4.3% $7.2MM2.2% Average:4.7% (C&Q projects only) C&Q delivery strategy has resulted in a step change in C&Q savings!!

42. Lilly C&Q Work Breakdown Structure Lilly budgets/tracks C&Q expenses via 4 primary WBS categories: Planning & Design Commissioning Qualification Administration New C&Q Cost Data spec recently approved to provide guidance

43. Planning & Design - Subcategory C&Q plans and strategy Initial schedule development Estimating System classification Component classification System C&Q plans Vendor assessments User requirements Design review, spec review, drawing review reviews/tag list Engineering requirements Design Qualification Traceability Matrices

44. Commissioning - Subcategory FAT development FAT execution Receipt Verification development Receipt Verification execution Installation Verification development Installation Verification execution SAT development SAT execution Construction turnover packages Start-up protocol development Start-up protocol execution Functional testing development Functional testing execution Commissioning packages C&Q plan summary reports FAT travel Supporting documents

45. Qualification - Subcategory IQ development IQ execution OQ development OQ execution PQ development PQ execution

46. Administration - Subcategory Training Project management C&Q resource travel Administrative assistance Audits CSV support

47. Typical C&Q Budget Metrics ~ Cost Breakdown (%) Note: Only includes cost data for C&Q contractor

48. C&Q Discrepancy Metrics ~ Philosophy C&Q delivery strategy based on risk mitigation approach DR/DQ reduced risk during Construction/Build, Commissioning, Qualification Construction quality assurance activities reduced Commissioning risks Simulation reduced risk during Commissioning (Startup, SAT, FT) Commissioning (RV, IV, FAT, SAT, FT) reduced risk during subsequent Commissioning activities and Qualification As risk decreased, the number of discrepancies also decreased - resulted in cleaner qualification documentation and better schedule adherence during qualification

49. Typical C&Q Discrepancy Metrics  1230 discrepancies resulting from Construction QA activities  2800 discrepancies during commissioning  130 discrepancies during qualification

50. Typical C&Q Discrepancy Metrics ~ Categories

51. 1.Properly define User Requirements Testable, verifiable, applicable Not too prescriptive, no design details, no guesses Include C&Q engineers in review/approval process 2.Clearly define data and documentation requirements 3.Change management Don’t implement formal change control too soon Don’t confuse change control with version control Ensure commissioning change process is well understood Ensure construction changes are communicated to team Ensure automation changes are reflected in design docs C&Q Lessons Learned

52. Current GFD C&Q Delivery Strategy ~ Enhanced Baseline Guide approach (last 2 years) Conducted several six sigma initiatives to improve C&Q processes Developed additional procedures and best practices pertaining to C&Q GDP SOP Change Management SOP Transfer of Care, Custody and Control SOP Discrepancy Management Best Practice Developed new specifications governing the following Vendor data and documentation FAT/SAT C&Q cost data Defined new project information management role Implementing new requirements definition process based on systems engineering principles Implementing formal Construction QA program

53. Current GFD C&Q Delivery Strategy ~ Enhanced Baseline Guide approach (cont.) Developed Automation Lifecycle Management engineering standard to accommodate integration of CSV and C&Q resulting in: Elimination of duplicate requirements, design reviews, testing Elimination of “all or nothing” approach to software testing Allowance for risk-based delivery strategies Leverage offline or simulation testing to meet requirements Assessing risk in areas beyond product quality to streamline C&Q delivery Vendor risk Technology risk Automation strategy Leveraging vendor testing to support commissioning vs. just using as contractual gate/risk mitigation The resulting C&Q delivery strategy will hopefully be realized as another step change in C&Q savings! Potential C&Q costs as low as 3% of TIC

54. Questions? Q&A

55. Risk Based Commissioning & Qualification Benchmarking Presented by: Nick Andreopoulos Senior Manager/Team leader Pfizer Global Engineering Peapack, NJ Chris Beltz Senior Manager/Team Leader Pfizer Quality Operations Kalamazoo, MI

56. Agenda Basis of C&Q Practices C&Q Program Management Approach C&Q Cost Management Key Lessons

57. Current C&Q Practices Primarily based on C&Q Baseline® Guide 5 Certain sites have streamlined C&Q process C&Q “Lite” version for small projects and minor equipment changes Leveraging of Commissioning tests into IOQ Applying some ASTM concepts – Focusing IOQ on risk to product quality/patient safety Functional Level Impact Assessment - Replacing Component Level Impact Assessment Currently developing and piloting full ASTM E2500 based Verification approach at targeted sites

58. C&Q Program Management C&Q supported jointly by Quality, Engineering and Automation/IT Quality requirements defined in Corporate Quality Standards C&Q Approach defined in Global Practices Sites develop their own procedures and validation master plans based on the global documents

59. C&Q Cost Management C&Q costs that are associated with equipment qualification are included in Project Capital budgets. Process Validation and Cleaning Validation are not included in project budgets C&Q cost managed by Project team

60. Key C&Q Lessons Learned Upfront involvement by key stakeholders in the Assessment steps to define the appropriate scope for qualification IOQ scope should be focused on critical aspects/functions. All other testing is GEP Testing documents should be based on SME execution and leveraged, where possible, from vendors. Level of documentation should be commensurate with risk to product quality/patient safety. Roles/Responsibilities need to be clearly defined at the outset of projects

61. Risk-Based Commissioning & Qualification Benchmarking Educational Track #1 Part 2

62. Agenda  Part 1 (8:30 – 10:00) ISPE Baseline ® Guide Volume 5: Commissioning & Qualification vs. ASTM E2500 – Mr. Robert Chew Overview of C&Q approaches – Abbott, Lilly, Pfizer  Break – Vendor areas open (10:00 – 10:30)  Part 2 (10:30 – Noon) Panel Q&A  Wrap-up

63. Thank You!! Robert Chew, Commissioning Agents Matt Warhover, Commissioning Agents Steve Connelly, Abbott Laboratories Dave Dolgin, Abbott Laboratories Scott Hamm, Eli Lilly Rick Gunyon, Eli Lilly Nick Andreopoulos, Pfizer Chris Beltz, Pfizer Great Lakes Chapter Board and Directors Ron Dunn, GLC Manager