GAMP as part of Your Quality System “a collaborative quality program for System Integrators”

1. GAMP as part of Your Quality System“a collaborative quality program for System Integrators” Paul Bennison Industrial Applications Team

2. GAMP as part of Your Quality System • Background • Today, our pharmaceutical customers typically procure automated systems via relatively small local system integrator companies • These companies have widely different capabilities and interpretations of how to comply to cGxP quality requirements • Project execution standards, both in terms of cost control and meeting schedules, vary dramatically for one integrator to another • Large international pharmaceutical companies are looking to off load the burden of managing many small suppliers in disparate locations • A need for a collaborative Quality System program for system integrators exists

3. GAMP as Part of Your Quality System • What is Validation? • Why is Validation of Computer Systems Important? • What is GAMP? And Why was GAMP developed? • How does a Quality System Assist Validation? • Automation System procurement example showing both Equipment Supplier and User Responsibilities • Implementation Challenges • Establishing a Culture of Procedural Change • Document Management / Change Control • Quality System Summary • Benefits of a GAMP based approach • Actual example, ROI measurement with and without GAMP

4. What is Validation? • The FDA has defined Validation as: • “Establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality attributes” • Key Words: • “Documented evidence” • “Pre-determined specifications” • Validation can be re-stated as a means of proving that the requirements for a system have been: • defined in advance, and that the system has been tested to prove that these requirements have been met and proof that each step has been completed by objective evidence in the form of documentation

5. Why is validation of Computer Systems Important? • It can be argued that it is more important to apply the principles of validation to automated systems than to any other aspect of a pharmaceutical process. • Automated systems, especially software components cannot be tested in the same way as a physical product • Software is different, all software programs contain errors. How it is used will determine whether the errors become apparent or not. • Software application complexity can mean that we could not test every permutation of inputs and use cases • Therefore end line testing (while still an important feature of a good quality system) cannot be relied upon on its own to ensure product quality • The FDA believes that the only way to develop validatable software is within a ”Quality Regulated Environment.”

6. What is GAMP and why was it developed? • GAMP - Good Automated Manufacturing Practice • 1990, the UK Pharmaceutical Industry Computer Systems Validation Forum (GAMP Forum) was set up to promote the better understanding of validation of automated systems in pharmaceutical manufacturing • improve understanding of the regulations and their interpretation, to improve communication within the pharmaceutical industry and with its suppliers • Why was GAMP developed? • Each company, and indeed each project team within a company, tended to apply personal preferences rather that a methodology for compliance • To provide suppliers with a universal standard that would meet the requirements of the pharmaceutical industry • An independent standard that can be referenced within commercial contracts, Suppliers can concentrate on quality concepts such as “repeatability”

7. GAMP Guide and Special Interest Groups • Guide releases and publication dates • V 1.0, March 1995 • V 2.0 May 1996 • V 3.0 March 1998 • V 4.0 Dec 2001 • GAMP Organization • Europe and America • 10 Special Interest Groups (SIGs) • JETT and Process Control Source: JETT Consortium

8. How a Quality System assists Validation • FDA believes that companies with effective Quality Systems provide the best environment for developing software • The repeatability and control over events that are essential for the development of validatable systems are best provided by a formal quality system. Systems that regulate: • What Actions are taken on a project • How they are executed, and by Whom • What Steps are to be taken to Confirm that they have been implemented correctly

9. GAMP 4.0 Figure 6.2 Implementation Using GAMP Guidelines • Keys steps involved for suppliers of computer systems to ensure that their products can be successfully validated

10. Functional Specification (traceable to URS) Automated System procurement model User Supplier Master Validation Plan User Audit Equipment Validation Plan Engineering Feasibility Study and Results P.O. • Explanation to Supplier RFQ User Requirements Specification (Living Document) Proposal • Project Plan • Quality & Validation Plan Proposal P.O. Proposal Analysis Approval Detailed Design Documentation (traceable to Functional Specification) Review Functional Specification Approval System Acceptance Test Specifications (IQ/OQ) Review Detailed Design • Hardware • Software Review System Acceptance Test Specifications Approval System Acceptance Testing and Results User Witness Optional Integrate with Validation Documentation as appropriate Maintenance & Support Documentation Source: JETT Consortium

11. User’s Activities • User Requirements Document • Without a well defined Users requirements, all other validation efforts are pointless • Vendor Audits • Prior to awarding a contract the vendor’s quality system and their ability to meet the user requirements need assessment • Specification Review and Approval • Users should review and approve the Validation Strategy, and updates to UR, FS and test specifications • Factory Acceptance Testing • Prior to delivery of a system, the system (SW) should be tested. A User’s representative should witness this

12. User’s Activities • Installation Qualification • Confirms the H/W, electrical system drawings are same a specified and has been installed correctly • “GAMP 4, Documented evidence that the system has been installed according to written and pre-approved specifications” • Operational Qualification • A full functional test of the system prior to its intended use • “GAMP 4, Documented evidence that the system operates in accordance to written pre-approved specifications through the specified operating ranges” • Performance Qualification • Establish documented evidence that the system performs in a repeatable and stable manner over a number of batches or a period of time

13. Quality System Program - Lifecycle • Phase 1. the development of Written Procedures that control each critical phase of the project • review draft quality program with pharmaceutical manufacturers • review draft procedures with system integrators • Release of the Quality System • Quality Policy - QP001 • Issue and Control of Procedures - QP002 • Issue and Control of Documents - QP003 • System Configuration and Change Control - QP004 • Training - QP005 • Project Validation Plans - QP006 • System design and Test Specifications - QPxxx etc..

14. Implementation Using GAMP Guidelines Design Documentation

15. Implementation Using GAMP Guidelines Test Documentation

16. System Design Specification System Test Specification Managing Customer Expectations and Project Deliverables

17. Implementation Challenges • Establishing a Culture of Procedural Control • Variation In Acceptance Standard • Documentation Management and Change Control

18. Implementation Challenges • Establishing a Culture of Procedural Control • Many software developers are resistant to ideas of working within the confines of specifications and procedures developed by others • A well defined quality system should not prohibit creativity or improvements to a product • Undocumented maverick engineering efforts play no part in this industry

19. Implementation Challenges • Documentation Management • Effective documentation management is, arguably, the corner stone of compliance. If doubt is cast over the timeline of data creation or its accuracy, then all the other efforts expended can be rendered worthless. • Follow the document lifecycle from creation, review, approval issue, transmittal, change, re-issue, archival, and withdrawal • The cost of implementing a formal document management software application, that manages e-signatures, security, audit trails is beyond the means of many System Integrators • Lack of a collaborative solutions

20. Implementation Challenges • Variation In Acceptance Standard • Despite GAMP being available since mid 90’s, there is still a wide degree of variation within the pharmaceutical industry to what defines the minimum acceptable standards • It is not uncommon to see projects where documents are created with the “correct” titles: URS, FS etc. However, upon close inspection it becomes clear that the documents were produced only to create the impression of a quality approach, and were not referenced during the development of the system

21. Remote Engineering Teams Lead PM Sales Accounting & Administration OEM Supplier Specialty Engineering Customer System Integrators Implementation Challenges • Collaborative Engineering - Document Management and Change Control

22. Remote Engineering Teams Lead PM Sales Accounting & Administration OEM Supplier Specialty Engineering Customer System Integrators Need to Collaborate • Project/Engineering Infrastructure

23. Implementation Challenges • Collaborative Engineering - Document Management and Change Control • Change control continues to be a problem in the pharmaceutical industry. Even where very high standards were employed during the development of a computer system, experience indicates that the System Development Life Cycle (SDLC) often breaks down as soon as post validation changes are made • SDLC: reference: GAMP 3, Volume1, Part 1, Section 7, Figure 7.3 “The Validation Concept Applied to the Development Life- Cycle of an Automated System”

24. GAMP Methodology ROI Analysis Courtesy of: Dr. David Selby, David Begg Associates, Kirkbymoorside, N. Yorks, UK YO6 6AX

25. Scenario • two equivalent sterile filling lines • Ampoules (pre GAMP) • Vials (post GAMP) • equivalent equipment train • Tunnel sterilizer • Filler • Automatic crack detection • Automatic particulate inspection • Equivalent project cost ($2m)

26. Requirements Specification Minimal Efficiency (Day 1) 0 <30% 100 Not done Design Qualification Pre-Delivery Inspection Installation Qualification Operational Qualification Software Review 0 7 days Now Availability (for production) Wastage Maintainability Retrospective Validation 0 60% 100 5 weeks 0 0 70% 100 0 8-12% 100 Not done Poor Misc. Controls Validation Total Man days (approx.) Not done Significant Documentation 0 100 Adequate 30 days Pre GAMP

27. Comprehensive - 2 weeks (+ several consultations) Requirements Specification Efficiency (Day 1) 0 75% 100 Significant Design Qualification Pre-Delivery Inspection Installation Qualification Operational Qualification Software Review 0 7 days Now Availability (for production) Wastage Maintainability Retrospective Validation 0 90%100 5 weeks 0 0 100 0 1% 100 4 days Good Misc. Controls Validation Total Man days (approx.) Unnecessary Documentation 2 weeks 0 100 Good 90 days Post GAMP

28. Summary • GAMP should be the corner stone of your Quality System • FDA believes that companies with effective Quality Systems provide the best environment for developing software • A Quality System derived from GAMP provides a consistent set of development methods to aide and achieve validation • Collaborative Infrastructure Tools • Provides a geographically distributed project engineering team the means through which consistent development methods (GAMP/QMS) can be deployed “a collaborative quality program for End Users, System Integrators and OEMs”

29. GAMP as part of Your Quality System“a quality program for System Integrators” • Paul Bennison • Schneider Electric - Pharmaceutical Competency Center • Raleigh, NC 919 855 1182 • PAUL.BENNISON@MODICON.COM • GAMP Information sources: • WWW.GAMP.ORG • WWW.JETTCONSORTIUM.COM