GMP Inspections – A Global Perspective Auditing of Computerised System Suppliers

1. GMP Inspections – A Global PerspectiveAuditing of Computerised System Suppliers IPCMF & ISPE Conference Global Pharma NetworksTom Farmer 25th June 2004

2. Overview of Presentation • Reasons to Audit Computerised System Suppliers • Outline Procedure for Audit • Case Studies/Examples • Overview of Audit Repository Centre (ARC) • Typical Issues/Observations • Summary and Conclusions

3. Reasons to Audit Suppliers • Business Reasons • Risk Management • Good Practice • Cost/Schedule/Quality Benefits • Regulatory • Requirements and Expectations

4. Business Reasons • Risk Assessment • Regulatory Impact • Data Integrity • Security • Product Quality • Business Risk • Risk To manufacturing/process equipment • Corporate Reputation • Safety Concerns • Patient Safety • Environmental Safety • Supplier Audit is not part of Risk Assessment as such, but an integral part of the overall Project Management process which includes Risk Management.

5. Business Reasons (Cont.) • Good Practice • Communication/Develop Relationships • Helps identify misunderstandings and risks • Set or clarify expectations and intentions with regard to documentation & other deliverables • Identify potential gaps in procedures (eg: change control, configuration management) at an early stage, so they can be addressed with minimal impact. • Cost/Schedule/Quality Benefits • Reduce Rework • On-Time Delivery • Aim for “Right First Time”

6. GMP Regulations • EU Vol 4 Annex 11 • 21 CFR Part 210, 211 (Drugs) • 21 CFR Part 820 (Medical Devices) • 21 CFR Part 11 (Electronic Records & Signatures) • ICH Q7A (Active Pharmaceutical Ingredients)

7. EU Regulations • EC Guide to GMP for Medicinal Products • Vol 4, Annex 11 • “5. The software is a critical component of a computerised system. The user of such softwareshould take all reasonable steps to ensure that it has been produced in accordance with asystem of Quality Assurance.” (emphasis supplied) ICH • Q7A (API Manufacturing) • Not explicit regarding requirement for supplier audits (ie: Supplier audits/assessments not stated as mandatory)

8. FDA Regulations • Do not explicitly mandate computerised system supplier audits, with possible exception for Medical Devices (21 CFR 820) • But note that for Medical Devices, computer system supplier could be providing components that are part of the finished product.

9. FDA Regulations (Cont.) • 21 CFR 820.50 (a) • “Each manufacturer shall establish and maintain procedures to ensure that all purchased or otherwise received product and services conform to specified requirements. (a) Evaluation of suppliers, contractors, and consultants. Each manufacturer shall establish and maintain the requirements, including quality requirements, that must be met by suppliers, contractors, and consultants. • Each manufacturer shall: • (1) Evaluate and select potential suppliers, contractors, and consultants on the basis of their ability to meet specified requirements, including quality requirements. The evaluation shall be documented. (emphasis supplied) • (2) Define the type and extent of control to be exercised over the product, services, suppliers, contractors, and consultants, based on the evaluation results. • (3) Establish and maintain records of acceptable suppliers, contractors, and consultants. “

10. FDA Warning Letter – Oct 2003 • “4. Your firm failed to evaluate and select potential suppliers on the basis of their ability to meet specified requirements, including quality requirements with all evaluations documented as required by 21 CFR 820.50(a)(1). You failed to document supplier audits and your audit procedure (PUR-0200) fails to describe supplier audit procedures [FDA 483, Item #7].”

11. FDA Regulations • 21 CFR Part 11 • Again, not explicit on supplier audits, but implied by the Validation and Training requirements • Need to look to FDA guidance documents

12. FDA Guidelines • For validation, Scope and Application guideline specifically references • FDA’s guidance for industry and FDA staff General Principles of Software Validation (CDRH - Medical Device guidance) • GAMP 4 Guide • Guidance for Industry - Part 11, Electronic Records; Electronic Signatures — Scope and Application • “We recommend that you base your approach on a justified and documented risk assessment and a determination of the potential of the system to affect product quality and safety, and record integrity.” • Convergence in approach to computerised systems across the different regulatory groups (CDER, CBER, CDRH)

13. General Principles of Software Validation; Final Guidance for Industry and FDA Staff (CDRH - Jan 2002) • 6.3. VALIDATION OF OFF-THE-SHELF SOFTWARE AND AUTOMATED EQUIPMENT • Where possible and depending upon the device risk involved, the device manufacturer should consider auditing the vendor’s design and development methodologies(empasis supplied) used in the construction of the OTS software and should assess the development and validation documentation generated for the OTS software. Such audits can be conducted by the device manufacturer or by a qualified third party. The audit should demonstrate that the vendor’s procedures for and results of the verification and validation activities performed the OTS software are appropriate and sufficient for the safety and effectiveness requirements of the medical device to be produced using that software.

14. GAMP Guideline • Section 7.1 - Determining Validation Strategy • “Suppliers should be formally assessed as part of the process of selecting a supplier and planning for validation. The decision whether to perform a Supplier Audit should be documented and based on a Risk Assessment and categorisation of the system components.” • Also highlights role of end-user in assisting and educating suppliers • Appendix M2 – Audit Guideline and Checklist

15. Other Industry Guidelines • PIC/S : GOOD PRACTICES FOR COMPUTERISEDSYSTEMS IN REGULATED “GXP” ENVIRONMENTS (Aug 03) • The assurance of the reliability of a Supplier’s software products is attributable to the quality of the software engineering processes followed during development. This should include design, coding, verification testing, integration, and change control features of the development life cycle, (including after sales support). In order for customers to have confidence in the reliability of the products, they should evaluate the quality methodology of the supplier for the design, construction, supply and maintenance of the software.(emphasis supplied) A formal, extensive review of the history of the Supply Company and the software package may be an option to consider where an additional degree of assurance of the reliability of the software is needed. This should be documented in a Supplier Audit Report.

16. Other Industry Guidelines (Cont.) • PDA TR 32 “Auditing of Suppliers providing Computer Products and Services for Regulated Pharmaceutical Operations” • Includes a very detailed procedure and checklist for supplier audits • Basis of audit procedure for Audit Repository Centre (ARC) shared audits

17. Summary – Reasons to Audit Suppliers • If Predicate Rules do not explicity mandate Supplier Audits, why conduct them? • Business Benefits • Risk Management • Good Practice • Cost/Schedule/Quality • Regulatory expectations • FDA Guidelines & Requirements for System Validation • Implication of Industry Guidelines (GAMP, PIC/S, PDA etc) • Audits are not mandatory but are considered ‘good practice’, and it is for the regulated user to determine any auditing needs, scope and standards. Recommend that the need for supplier audit/assessment be linked to Risk Assessments (and GAMP Categorisation)

18. Summary – Reasons to Audit Suppliers • Organisations are expected to demonstrate control of the processes and systems that affect data integrity, product quality, and patient safety • Quality cannot be inspected or tested into the finished product – it needs to be designed and built in • For software, one method to help achieve this is to follow a formal software development lifecycle (SDLC). • Audit of suppliers helps ensure that a SDLC is in place and is followed.

19. Approach to Supplier Audits

20. Approach to Supplier Audits • Pharma Industry has not yet formally embraced a single standard method for supplier audit, in spite of regulatory expectation to evaluate suppliers as part of the technical acquisition process. • Possible sources • GAMP 4 & VPCS Best Practice Guide • PDA TR32 • PIC/S • ISO 10011 Guidelines for auditing quality systems Part 1: Auditing • Other industry guidelines • Have procedure/SOP in place, and ensure personnel are trained accordingly.

21. Approach to Supplier Audits (Cont.)

23. Approach to Audits - Initiation • Determine Need for Audit • Based on Risk Assessment • System Categorisation • System Scale and Complexity • Define appropriate Audit Type • Document justification for Audit (or otherwise) • As part of Risk Assessment and/or within Validation Master Plan

24. Risk Assessment (GAMP – App M3)

25. GAMP Software Categorisations

26. GAMP – GLP Good Practice Guide

27. Audit types • Postal Audits / Assessments • System Audit / Detailed Audit • Surveillance Audit / Monitoring Audit • Joint Audits • Shared Audits

28. Approach to Audits – Planning • End User inputs • Risk Assessment & System Categorisation • Supplier Audit Procedure and Standard Checklist • Validation Master Plan • System Specifications/User Requirements/Project Brief • Supplier Inputs (If available) • Supplier Profile • Organisation Chart • Product/Service Details • Development Methodology • Proposal/Quotation

29. Approach to Audits – Planning (Cont.) • Preparation • Audit Agenda • Audit Specific Checklist • Contact Supplier • Agree date and timescales with Supplier • Copy Supplier with agenda and checklist • Confirm resource availability with Supplier

30. Approach to Audits - Conduct • Typical Agenda • Introductions • Company Overview Presentation (including Quality System Overview/Workflow Methodology) • Office/Facility Tour • Inspection of selected Audit Areas • Include QMS and Procedures, Project Documentation, Maintenance etc • Review Findings/Observations • Present Findings to Supplier

31. GAMP Company Overview Organisation and Quality Management Planning and Product/Project Management Specifications Implementation Testing Completion and Release Support/Maintenance Supporting Processes and Activities PDA TR 32 Quality System Project Management Methodology Testing Configuration Management Manufacturing Document and Records Management Security Training and Education Maintenance Approach to Audits – Checklist/Audit Areas

32. Comment on use of checklists • Need to be careful with use of standard checklists • Key is in preparation for audit • Tailor audit criteria and checklist based on supplier product and/or services • Try to ensure that audit criteria is suitably descriptive within checklist • When documenting audit execution • Try to avoid simple yes/no type responses • Include comments as appropriate to elaborate on and explain answers and observations • Include objective evidence, by unambiguous reference, or attachment

33. Approach to Audits – Observations • Communicate observations back to Supplier for response • Consider categorisation of observations (eg: Critical, Major, Minor, Comment only) • Helps to set priorities for actions • Helps justification of decision • Highlight positives also – ie: where supplier meets or exceeds industry best practices

34. Approach to Audits – Report • Audit Report to be issued for approval • Include completed “checklist”, not just observations/findings • Include positive observations also • Formal Response on observations required from Supplier

35. Approach to Audits – Follow Up • Need to ensure close out of observations by supplier • Remember, past performance is a good indicator of future performance (but not a guarantee) • Continuous monitoring is important, particularly for larger projects and customised systems • Use audit as an opportunity to establish open dialog and collaboration with your suppliers

36. Case Studies / Examples

37. Case Study/Example # 1 • “Operations” identify need for new automated system • “Projects Group” prepare equipment specification • Projects Group select Vendor/Supplier • Main Criteria Used • Cost (Cheapest!) • Technology • At FAT stage, Projects Group request input from Quality Unit / Validation

38. Case Study/Example # 1 (Cont.) • Assessment/Audit planned & executed • Findings: • No Quality Systems/Procedures in place at supplier • Poor Design Documentation (No Functional Specification, etc) • Poor Change management/configuration management • Planned FAT Testing of limited benefit from Validation perspective – additional testing required.

39. Case Study/Example # 1 (Cont.) • Actions • DQ developed and executed • Develop additional detailed test procedures for FAT, Site testing & qualification • Impact • Project Schedule Impact (Project Delayed) • Cost Impact (Internal costs as well as Supplier)

40. Case Study / Example #2 • Project Group include Quality Unit /Validation at project definition phase. • Postal Assessment of all prospective suppliers, followed by conference call with each supplier (ie: Quality issues addressed as part of bid analysis, as well as technical and commercial issues) • Prefered Supplier agreed by all parties (Operations, Projects, Quality)

41. Case Study / Example #2 (cont.) • Detailed systems audit conducted in selected suppliers premises at start of project • Limited/minor issues only raised at audit • On-going monitoring of supplier during project, up to system delivery to site • On time, within budget – no surprises

42. Case Study / Example #3 • Replacement of Laboratory Analysers • Categorised as GAMP Category 3 (Standard Software), but systems considered GxP critical • Supplier Audit indicated by company SOP • Issues: • Multiple Suppliers (> 6) • Local Supplier location not the same as System Development location.

43. Case Study / Example #3 (Cont.) • Following consultation with end-user, decided on Postal Audit (GAMP VPCS Good Practice Guide used as template). • Review of responses followed up by conference call with supplier to clarify written replies and request additional information • Reserved right to request “face-to-face” detailed audit, if deemed necessary • Main Benefits - Cost Saving. • Also, get involvement/feedback from system development group, as well as local distribution and support groups.

44. Case Study / Example #4 • Manufacturing Control System • Categorised as GAMP 4/5, and system considered GMP Critical • Challenges • Scale of project • Multiple locations involved • Quality Unit an integral part of project process. • Aim to instill a culture of “Right First Time”

45. Case Study / Example #4 (Cont.) • Supplier Audit conducted as part of selection process • Follow-up surveillance audits/reviews during implementation (monthly) to supplement suppliers internal quality group. • Benefits • Identified issues at an earlier stage, and helped minimise impact • Reduced Rework/Retesting on site • Helped ensure overall schedule targets met

46. Shared Audits

47. ARC (Audit Repository Centre) • Centralised repository for audit reports, available to subscribing end-user companies. Not strictly limited to computerised system suppliers. • Statistics (as at June 2004) • Audits Available – 28 • Audits Scheduled - 13 • Audits under consideration – 18 • Links • http://www.auditcenter.com/available.htm • http://www.auditcenter.com/scheduled.htm • http://www.auditcenter.com/consideration.htm

48. ARC (Cont) • Probably more appropriate as part of corporate system selection, may not be fully suitable for local (smaller) system implementations. • Access to ARC report does not absolve end-user from responsibility – need to analyse audit results and observations, and make decision on supplier acceptability. • For project based systems, will still require on-going monitoring of supplier/implementer

49. Typical Issues / Observations

50. Considerations – Client side • Timing of Audit/Assessment • Scope / Intent of Audit • Supplier Preparation (for Audit) • Follow up on Audit Observations/Findings • Overall business benefits of Quality (and Operations) input at the design and procurement stages