Why does PAT need Rapid Microbiology Methods S

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

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

Objectives l To advance dialogue on the implementation of RMM To outline PAT ideals in terms of RMM implementation l To understand if the GSK point of view is aligned with agency and industry opinion l Ultimately to facilitate the introduction of new microbial technologies into the pharmaceutical sector l Global Manufacturing and Supply Page 2

Outline l l Introduction l PAT & RMM l Barriers to PAT The current position l l Products and processes define the technology The technologies l ATP bioluminescence l Solid-phase laser cytometry (Scan. RDI) l Proposed approach l Advantages of RMM to PAT l Conclusions Global Manufacturing and Supply Page 3

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) Global Manufacturing and Supply Page 4

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 c. GMP! l At/On/In-line measurement of “performance” attributes l Real-time or rapid feedback controls (focus on prevention) l Greater insight and understating of processes Potential for significant reduction in production (and development) cycle time l Reduce (regulatory) concerns and potential for remote inspection strategies l FDA Science Board Meeting, 9 April 2002 Global Manufacturing and Supply Page 5

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 Global Manufacturing and Supply Page 6

PAT & RMM Current GSK manufacture/QA approach is following option A. l l l Attention is focused on improving l Raw material testing l End product release tests (non-sterile & sterile) l Environmental monitoring l Water testing l In-process bioburden testing New product introduction follows option C. Global Manufacturing and Supply Page 7

Barriers to applying PAT l Technical reasons l Current microbial tests require 4 -14 days Overall process optimisation is the recommended approach l Reduced incentive to invest in real time chemical controls when finished products cannot be released l Concurrent development of chemical and microbial release methodologies will assist PAT ideals l l Guidance is unclear Global Manufacturing and Supply Page 8

Barriers to applying PAT (cont’d) l Cultural and organisational reasons Considering microbial rapid methods as part of a wider design for the release of finished goods under PAT requires: l l Spreading the knowledge within the company l Convince local management& regulatory affairs Co-ordination between sites located in different regional areas l Significant resources required for development and implementation l Unclear/unknown regulatory process - perceived significant risk l l Long time to attain the objective/benefits Global Manufacturing and Supply Page 9

Current GSK position Global Manufacturing and Supply Page 10

Current Release tests l l Non-sterile testing l Microbial Limit Test l Clean liquids/inhaled/topicals l Current test is 5 days - or more Sterile l Sterility test All terminally sterilised and aseptically processed products l l Current test is 14 days - or more Current methods are potential bottlenecks to product release! Global Manufacturing and Supply Page 11

In-Process testing l Environmental monitoring l Air l Surfaces l Personnel l Raw material testing l In-process Bioburden l Water testing l All rely on microbial growth l Results take 4 to 5 days Real-time results not possible with current methods! Global Manufacturing and Supply Page 12

RMM are needed Because current microbiological methods are…. l l Potential bottlenecks to product release Cannot deliver Real-time results PAT improvements must encompass all areas of the process to achieve maximum benefits! Global Manufacturing and Supply Page 13

Products & sample types l l l Sterile l Environmental monitoring l Vials l Air/gas l Ampoules l Surfaces l Syringes l Personnel Non-sterile l Clean liquids l Inhalers l Topicals l Input raw materials l In-process bioburdens Water l WFI l Purified Global Manufacturing and Supply Page 14

Products and processes define the technology l Product and process requirements are paramount The technology must satisfy the product requirements & specifications l l Different technologies offer different attributes Understanding the process and product will dictate the best technology solution l Different technologies will have different implementation requirements l PDA Technical Report 33 identifies different parameters l Global Manufacturing and Supply Page 15

The Technologies Global Manufacturing and Supply Page 16

The technologies ATP bioluminescence l Non-sterile products Qualitative & quantitative testing l Systems Identified: l Pall. Check l Rapiscreen l Micro. Star Global Manufacturing and Supply Solid-phase laser cytometry l Sterile, non-sterile products l Single cell detection l Filterable products only System Identified: l Scan. RDI Page 17

ATP Bioluminescence: Pall. Check Global Manufacturing and Supply Page 18

ATP Bioluminescence: Rapiscreen Global Manufacturing and Supply Page 19

ATP Bioluminescence: Micro. Star Global Manufacturing and Supply Page 20

12 10 8 6 ln (RLU) after 18 h 14 16 Bioluminescence: an example NC Anig Bsub Calb Criso Ecol Mlut Paer Pseud Sabo SAur Global Manufacturing and Supply Page 21

Solid-Phase Laser Cytometry: Scan. RDI Global Manufacturing and Supply Page 22

Solid-Phase Laser Cytometry: an example 18 Mean Scan. RDI 16 Result / ml 14 Mean Plate Counts/ml 12 Count / ml 10 8 6 4 2 Global Manufacturing and Supply 09 / 08 /0 0 0 /0 08 0 Page 23 07 / /0 08 0 03 / /0 07 0 28 / /0 07 0 20 / /0 07 18 / 12 / 07 /0 0 0 /0 07 0 10 / /0 07 04 / 27 / 06 /0 0 0

RMM implementation l The GSK implementation strategy is mainly based on: l PDA Technical Report 33 l Draft Pharm. Forum Chapter <1223> l Technology choice will be product driven l Implementation will involve an integrated approach for: l Microbiological performance l Instrument qualification l Computer system compliance l Education & training Global Manufacturing and Supply Page 24

Advantages of RMM to PAT l Increased security of supply to patients l Reduces potential for product stock-outs l Significantly faster than current methods l A step closer to real time results l Increased sensitivity l Potential for in-line testing l Reduces in-process test times l Reduces potential for batch rejections/re-works l Builds quality into product/process l Comparable to duration of chemical methods Global Manufacturing and Supply Page 25

Conclusions l RMM will have a significant impact for overall PAT Concurrent development of chemical and microbial release methodologies will assist PAT ideals l GSK is interested in RMM for product testing and in -process control optimisation l ATP bioluminescence (Pallcheck / Rapiscreen / Microstar) & Solid-Phase laser Cytometry (Scan. RDI) are main contenders l The GSK implementation strategy is based on PDA TR 33 and Draft Pharm. Forum Chapter <1223> l Global Manufacturing and Supply Page 26

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

END OF PRESENTATION Global Manufacturing and Supply Page 28