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

Page 1 Global Manufacturing and Supply Purpose To consider the interrelation between PAT ideals and the implementation of Rapid Microbiology Methods (RMM) To outline the current GSK implementation strategy

Page 2 Global Manufacturing and Supply Objectives To advance dialogue on the implementation of RMM To outline PAT ideals in terms of RMM implementation 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

Page 3 Global Manufacturing and Supply 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

Page 4 Global Manufacturing and Supply 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)

Page 5 Global Manufacturing and Supply 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

Page 6 Global Manufacturing and Supply 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

Page 7 Global Manufacturing and Supply 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.

Page 8 Global Manufacturing and Supply 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

Page 9 Global Manufacturing and Supply 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: S preading 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

Page 10 Global Manufacturing and Supply Current GSK position

Page 11 Global Manufacturing and Supply 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!

Page 12 Global Manufacturing and Supply 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!

Page 13 Global Manufacturing and Supply 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!

Page 14 Global Manufacturing and Supply Products & sample types 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

Page 15 Global Manufacturing and Supply 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

Page 16 Global Manufacturing and Supply The Technologies

Page 17 Global Manufacturing and Supply The technologies 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

Page 18 Global Manufacturing and Supply ATP Bioluminescence: PallCheck

Page 19 Global Manufacturing and Supply ATP Bioluminescence: Rapiscreen

Page 20 Global Manufacturing and Supply ATP Bioluminescence: MicroStar

Page 21 Global Manufacturing and Supply Bioluminescence: an example NCAnigBsubCalbCrisoEcolMlutPaerPseudSaboSAur ln (RLU) after 18h

Page 22 Global Manufacturing and Supply Solid-Phase Laser Cytometry: ScanRDI

Page 23 Global Manufacturing and Supply Solid-Phase Laser Cytometry: an example

Page 24 Global Manufacturing and Supply RMM implementation The GSK implementation strategy is mainly based on: PDA Technical Report 33 Draft Pharm. Forum Chapter Technology choice will be product driven Implementation will involve an integrated approach for: Microbiological performance Instrument qualification Computer system compliance Education & training

Page 25 Global Manufacturing and Supply 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

Page 26 Global Manufacturing and Supply 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

Page 27 Global Manufacturing and Supply Effective dialogue with regulators and rest of industry is considered essential for success!

Page 28 Global Manufacturing and Supply END OF PRESENTATION