Bringing innovation to global health
May 2011
Development of enabling technologies to support industrial scale manufacture Marseille, 2011
Alain Pralong
Overview
• Traditional manufacturing capacity
• Evolution of disposable technology
• Starting situation at Crucell
• Shift of paradigm
• Integration at Crucell
• Facility of the future
Traditional manufacturing
• Chemical engineering - stainless steel
• CAPEX intensive – ~350 mEuros
• Labor intensive – 4 to 5 years
• High OPEX – utilities, personnel, raw materials
Traditional manufacturing
• Global fermentation capacity – 450’000 L+
• 2/3 in use planned or other – 1/3 not in use
• Low success rate – ~7 out of 100 leads
• Long development timelines (~12-15yrs)
Evolution of disposables
• Massive development of disposable tools
• Broadening of applications
• Multiple suppliers – market consolidation
• Major progress in regulatory acceptance
First steps
• Traditional 500-L pilot facility
• Adenoviruses on HEK293 for phase III
• In house preparation of glassware
• High contamination risk
First steps
• Replacement of glassware
• Maximal reduction of preparation time
• Maximal reduction of contamination risks
• Massive ergonomic improvement
Development
• CHO multi-step MAb process (Avastin®)
• Old traditional 100-L microbial facility (24yrs)
• USP equipment outdated – 6 months
• Bioreactor upgrade / medium / harvest
Development
Medium and buffer preparation
Development
Medium and buffer dispensing
Development
A
B
Operation and sampling of bioreactors
Development
Small and large scale harvest
Development
• Project setup realized within 5 months
• Minimal CAPEX investment
• Facility always in operation
• 9 months acceleration of transfer project
Start situation at Crucell
• Adenovaccines and monoclonal antibodies
• Per.C6 base platform
• Process intensification
• No manufacturing platform defined
Start situation at Crucell
• Programs at various stages
• Very short timelines to clinics
• No manufacturing capacity available
• Significant market forecasts
Start situation at Crucell
• Small scale in house manufacturing
• Purchase / build new traditional pilot plant
• Outsource / transfer to CMO
• To break new ground
Shift of paradigm
La perfection est atteinte, non pas lorsqu'il n'y a plus rien à ajouter, mais lorsqu'il n'y a plus rien à retirer.
Antoine de Saint-Exupéry
Integration
• Minimal CAPEX investment
• Minimal time for build and commissioning
• Sustainability and efficient resource use
• Significant COGS reduction
Integration
• Standardization as far as applicable
• Limitation of complexity
• Family approach for qualification/validation
• Validation of leachables and extractables
Integration for MAbs and Virus
Product contact only by disposables
Integration for MAbs and Virus
Medium and buffer preparation
Integration for MAbs and Virus
Bioreactor setup
Integration for MAbs and Virus
Bioreactor disassembly
Integration for MAbs and Virus
Bioreactor connections
Integration for MAbs and Virus
Bioreactor harvest
Integration for MAbs and Virus
AIEX chromatography
Integration for MAbs and Virus
Ultra- / Dia-filtration
Integration for MAbs
Mobile clean room concept
Integration for MAbs
Manufacturing platform for clinic and market
Integration for MAbs
Integration for MAbs
• 10 months from order to CTM manufacturing
• First 200-L tox run successful
• 3 USP runs with up to 2.86 g/L
• DSP recoveries between 60 – 70%
• Purity : 97% monomer, all assays ok
Basis for FlexFactory use
• CEMs provide grade C environment and segregation
• DSP process is fully closed
• Only sterile de- / connection technology
• Product always fully protected from operator
Higher quality standard achieved thanwith traditional technology !
Summary for MAbs
• Fully disposable process @ 200-L scale
• Built and operated within 8 months
• Reasonable costs – 6 million US$
• Simple – reduced to the minimum
Conclusion
• Massive development in the last 10 years
• Significant acceleration and cost reduction
• Fulfills GMP requirements
• New DSP technologies needed
Facility of the future
• Traditional = high CAPEX and OPEX cost
• New technologies proved their value
• Merge new technologies and facilities
• Holistic approach – full benefit
Facility of the future
Modular facility within a shell
Facility of the future
• Modular and pre-assembled
• Plug in pre-assembled modules (PAMS)
• Simple building / complex modules
• Key – segregation HVAC from laboratory
• Expansion slots – like computer
Facility of the future
Facility of the future
Facility of the future
Facility of the future
Facility of the future
Crucell conceptual design
Crucell conceptual design
Crucell conceptual design
Other challenges of the future
• Environmental impact management• Increasing expectation level
• Precondition for construction permit
• Sustainable in construction and operation
• Probability of future taxation of environmental impact very high
Sustainability
Sustainability
Sustainability
•How the building fits within the overall built environment
•Links to public transport
•A building that will endure
•Increased quality of life
A positive contribution to society and the built environment
•National climate change scenarios and weather implications
•Identify future cooling and water requirements
•Propose site and building responses
•Adaptable to potential impacts of climate change without recourse to additional energy input
•Able to cope with increased peak weather events
Able to cope with future climate change
•Optimise the façade and building shape/bulk and orientation
•Propose appropriate systems
•Gather energy from the building or define offsite renewable sources
•Reduce energy demands
•Significant reductions in operational energy demand and provision of energy by carbon neutral means
•Development growth without an increase in carbon emissions
Carbon neutral
•Strategy to show how users would control building systems
•How to minimise and recycle waste
•Maintenance and replacement requirements
•Helps reduce energy, waste and water
•Can be monitored
Sustainable in operation
•Identify role of materials in overall energy use
•Design for adaptation measures
•Propose lower impact material options
•Buildings made to be reusable or recyclable
•Material selection
Built using sustainable materials
•Identify site water sources and re-use options
•Reduce potable water demand
•Propose lower water use systems
•Harvest rainwater
•Closed loop water cycle
•Significant reduction in potable water use
•Use of site and location to provide alternative to mains water
•Reduction of energy use from treatment
Collecting and re-use/re-cycling of water
ThemesOutcomesObjective
Top class architecture
Pre-AssembledModules
Pre-AssembledModules
Moving Zone
Shading Louvres
Central Street
Glazed Roof
Grass Roof Construction
Pre-AssembledModules
Pre-AssembledModules
Moving Zone
Solar Heating
Benefits of new facilities
• Simple layout – fast build
• Easy to modify and adapt
• Can grow with with the needs
• Reduction of CAPEX and OPEX
• Prepared for future - sustainable
Summary
• Traditional = high CAPEX and OPEX cost
• Merge new technologies and facilities
• Holistic approach – full benefit
Conclusion
• Think bold
• Holistic approach – process and facility
• Sustainability and prepared for the future
• Maintain flexibility and minimize investments
ISPE Facility of the Year 2009Category Winner ~ Sustainability