Why does PAT need Rapid Microbiology Methods

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Why does PAT need Rapid Microbiology Methods?

• S.Lonardi, P.J.Newby, D.Ribeiro, B.Johnson
• PAT Subcommittee meeting October 23, 2002

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Purpose

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

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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

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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

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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)

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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
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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
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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.

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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

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Barriers to applying PAT (contd)

• 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

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Current GSK position
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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!

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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!

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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!

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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

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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

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The Technologies
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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

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ATP Bioluminescence PallCheck
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ATP Bioluminescence Rapiscreen
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ATP Bioluminescence MicroStar
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Bioluminescence an example
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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
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Solid-Phase Laser Cytometry an example
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RMM implementation

• The GSK implementation strategy is mainly based
  on
• PDA Technical Report 33
• Draft Pharm. Forum Chapter lt1223gt
• Technology choice will be product driven
• Implementation will involve an integrated
  approach for
• Microbiological performance
• Instrument qualification
• Computer system compliance
• Education training

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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

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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 lt1223gt

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Effective dialogue with regulators and rest of
industry is considered essential for success!
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END OF PRESENTATION