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• USP equipment outdated – 6 months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