Why does PAT need Rapid Microbiology Methods?

1. Why does PAT need Rapid Microbiology Methods? S.Lonardi, P.J.Newby, D.Ribeiro, B.Johnson PAT Subcommittee meeting October 23, 2002

2. Purpose • To consider the interrelation between PAT ideals and the implementation of Rapid Microbiology Methods (RMM) • To outline the current GSK implementation strategy

3. Objectives • To advance dialogue on the implementation of RMM • To outline PAT ideals in terms of RMMimplementation • To understand if the GSK point of view is aligned with agency and industry opinion • Ultimately to facilitate the introduction of new microbial technologies into the pharmaceutical sector

4. Outline • Introduction • PAT & RMM • Barriers to PAT • The current position • Products and processes define the technology • The technologies • ATP bioluminescence • Solid-phase laser cytometry (ScanRDI) • Proposed approach • Advantages of RMM to PAT • Conclusions

5. Proposed PAT definition • Systems for analysis and control of manufacturing processes based on timely measurements, during processing, of critical quality parameters and performance attributes of raw and in-process materials and processes to assure acceptable end product quality at the completion of the process. • ACPS PAT-Subcommittee (Benefits WG) Recommendations (02/02 Meeting)

6. PAT - in relation to RMM • PAT provides an opportunity to move from the current “testing to document quality” paradigm to a “Continuous Quality Assurance” paradigm that can improve our ability to ensure quality was “built-in” or was “by design” - ultimate realization of the true spirit of cGMP! • At/On/In-line measurement of “performance” attributes • Real-time or rapid feedback controls (focus on prevention) • Greater insight and understating of processes • Potential for significant reduction in production (and development) cycle time • Reduce (regulatory) concerns and potential for remote inspection strategies FDA Science Board Meeting, 9 April 2002

7. Options for Introducing PAT A. Currently marketed “robust” products. PAT to improve efficiency (minimal improvement in quality assurance) B. Current marketed products needing improvement. Step wise PAT approach - first improve quality and then improve the efficiency C. New products. PAT used throughout development and scale-up. Lab based tests to ensure shelf-life and/or for establishing “public standards.” Presentation of Ajaz S.Hussain at Pittcon March 22, 2002

8. PAT & RMM • Current GSK manufacture/QA approach is following option A. • Attention is focused on improving • Raw material testing • End product release tests (non-sterile & sterile) • Environmental monitoring • Water testing • In-process bioburden testing • New product introduction follows option C.

9. Barriers to applying PAT • Technical reasons • Current microbial tests require 4-14 days • Overall process optimisation is the recommended approach • Reduced incentive to invest in real time chemical controls when finished products cannot be released • Concurrent development of chemical and microbial release methodologies will assist PAT ideals • Guidance is unclear

10. Barriers to applying PAT (cont’d) • Cultural and organisational reasons • Considering microbial rapid methods as part of a wider design for the release of finished goods under PAT requires: • Spreading the knowledge within the company • Convince local management& regulatory affairs • Co-ordination between sites located in different regional areas • Significant resources required for development and implementation • Unclear/unknown regulatory process - perceived significant risk • Long time to attain the objective/benefits

11. Current GSK position

12. Current Release tests • Non-sterile testing • Microbial Limit Test • Clean liquids/inhaled/topicals • Current test is 5 days - or more • Sterile • Sterility test • All terminally sterilised and aseptically processed products • Current test is 14 days - or more Current methods are potential bottlenecks to product release!

13. In-Process testing • Environmental monitoring • Air • Surfaces • Personnel • Raw material testing • In-process Bioburden • Water testing • All rely on microbial growth • Results take 4 to 5 days Real-time results not possible with current methods!

14. RMM are needed • Because current microbiological methods are…. • Potential bottlenecks to product release • Cannot deliver Real-time results • PAT improvements must encompass all areas of the process to achieve maximum benefits!

15. Sterile Vials Ampoules Syringes Non-sterile Clean liquids Inhalers Topicals Water WFI Purified Environmental monitoring Air/gas Surfaces Personnel Input raw materials In-process bioburdens Products & sample types

16. Products and processes define the technology • Product and process requirements are paramount • The technology must satisfy the product requirements & specifications • Different technologies offer different attributes • Understanding the process and product will dictate the best technology solution • Different technologies will have different implementation requirements • PDA Technical Report 33 identifies different parameters

17. The Technologies

18. ATP bioluminescence Non-sterile products Qualitative & quantitative testing Systems Identified: PallCheck Rapiscreen MicroStar Solid-phase laser cytometry Sterile, non-sterile products Single cell detection Filterable products only System Identified: ScanRDI The technologies

19. ATP Bioluminescence: PallCheck

20. ATP Bioluminescence: Rapiscreen

21. ATP Bioluminescence: MicroStar

22. Bioluminescence: an example 16 14 12 ln (RLU) after 18h 10 8 6 NC Anig Bsub Calb Criso Ecol Mlut Paer Pseud Sabo SAur

23. Solid-Phase Laser Cytometry: ScanRDI

24. 18 Mean ScanRDI 16 Result / ml 14 Mean Plate 12 Count / ml 10 Counts/ml 8 6 4 2 0 28/07/00 03/08/00 07/08/00 27/06/00 04/07/00 10/07/00 12/07/00 18/07/00 20/07/00 09/08/00 Solid-Phase Laser Cytometry: an example

25. RMM implementation • The GSK implementation strategy is mainly based on: • PDA Technical Report 33 • Draft Pharm. Forum Chapter <1223> • Technology choice will be product driven • Implementation will involve an integrated approach for: • Microbiological performance • Instrument qualification • Computer system compliance • Education & training

26. Advantages of RMM to PAT • Increased security of supply to patients • Reduces potential for product stock-outs • Significantly faster than current methods • A step closer to real time results • Increased sensitivity • Potential for in-line testing • Reduces in-process test times • Reduces potential for batch rejections/re-works • Builds quality into product/process • Comparable to duration of chemical methods

27. Conclusions • RMM will have a significant impact for overall PAT • Concurrent development of chemical and microbial release methodologies will assist PAT ideals • GSK is interested in RMM for product testing and in-process control optimisation • ATP bioluminescence (Pallcheck / Rapiscreen / Microstar) & Solid-Phase laser Cytometry (ScanRDI) are main contenders • The GSK implementation strategy is based on PDA TR 33 and Draft Pharm. Forum Chapter <1223>

28. Effective dialogue with regulators and rest of industry is considered essential for success!

29. END OF PRESENTATION