Cell culture based vaccine production : Engineering Bottlenecks Etienne Malhaize, Director of Techni

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Cell culture based vaccine production
Engineering BottlenecksEtienne Malhaize,
Director of Technical Service Process Biotech.

NAE/IOMConference April 10 th , Vaccine
production Potential Engineering Approach to a
Pandemic
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Agenda

• GSK Biologicals Flu approach
• Introduction to vaccine manufacturing process
• Engineering approach to a pandemic
• The request
•  Please, build a 100 MM dose/y Flu Pandemic
  facility 
• The context
• Cell culture technologies
• GMP and Biosafety Level 3 (BL3)
• Qualification
• The standard timing for a new vaccine facility
• The opportunities to reduce timing

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Flu approach in GSK Biological

• Product streams
• Classical flu vaccine egg derived
• Classical flu vaccine adjuvanted formulation
• Tissue Culture
• Pandemic

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GSK BiologicalsGlobal Industrial Operations
Network
Dresden
Quebec
Montreal
Hamilton
Gödöllö
Wavre
Moscow
Rixensart
(Asia Pac)
St. Amand les Eaux
Shanghai
Marietta
Nashik
Brazil
Singapore
Egypt
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GSK Positioned to be a Flu Vaccine Leader

• Build egg-based critical
• mass
• Dresden (60 m doses)
• ID Biomedical (75 m doses)

Extensive preparations for pandemic flu
Introducing a new cell-culture basedproduction
(2010)
Improved Flu Vaccine for elderly using adjuvant
Developing new delivery systems
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IntroductionTypical vaccine production process
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The request  Please, build a 100 MM dose/y
facility for Flu-pandemic 

• Question 1 
• What does a  dose  mean ? 
• Is it 100 µg , 10µg, 1 µg?

• Nobody knowsand unfortunately, first clinical
  trials on H5N1 demonstrate poor immune response
  compared with classical seasonal Flu-vaccine.

• Question 2
• How Engineering can help ?

• Design and build Flu facilities as  flexible 
  as possible for both Antigen and Adjuvant Bulk
  production.
• modular design approach

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The context Cell culture µ-carriers or free
suspension ?

• Question 3  What will be the impact of cell
  culture technology on design ?

• µ-carriers
• Cells are anchorage dependent and are growing on
  µ -beads
• High antigen yields (Y5)
• Typical size 1.000 L
• Majors challenges
• Shear stress and mixing
• Sub passages
• Continuous fresh culture media perfusion (often
  3 days)

• Free cell suspension
• Cells are growing on a free suspension
• Low antigen yields (Y1)
• Typical size 5.000 L
• Major challenges
• Bigger volumes
• Longer cell culture lead time.

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The context Impact of cell culture on
equipment and facility design
µ-carriers cell culture
Free cell suspension culture
Footprint unit in Media Prep. Area
Footprint unit in Cell Culture room
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The context Impact of cell culture on
equipment and facility design
µ-carriers
Free cell suspension
Learning 2 Depending on the cell culture
technology , the equipment and facility design
can dramatically changethen, build very flexible
!
Media Prep. Area
Cell Culture room
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The context Impact of cell culture on
equipment and facility design

• Free cell suspension

• µ-carriers

Fermenters (1000L) 10 months
Fermenters (5000L) 10 to 14 () months ()
Special facility construction design if gt5000 L

• Learning 3
• Anticipate purchasing of long lead items (strong
  specifications and long term partnership with
  critical suppliers required)

• Learning 4
• Introduce new technologies (e.g. disposables)

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The context GMP and Biosafety in BL3
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The context Never compromise with Quality

GSOPBIO VAL-1204-30001
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Standard timing for Greenfield  project 
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The opportunities System Level Impact
Assessment
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The opportunities Parallel Commissioning
Learning 5 A strong and rational qualification
approach helps to reduce timing
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The opportunities Renovation of existing
facilities

• Why is renovation a nightmare ? 

• Existing facilities are usually BSL 2 , which is
  much less stringent in Biosafety
• Unexpected  bad surprises  can delay timing
  (when  as build  is unfortunately not  as
  found )
• Commercial scale must comply with all GMP and BSL
  3 requirements (GSK never compromises with
  Quality and Safety).

• When renovation remains attractive ?

• If footprint area remains unchanged, permitting
  procedure with township is much more rapid. Civil
  work and Permitting are on critical path.
• For development and clinical trial (phase
  I,II,III) facilities at a smaller scale (10 L
  80L 600L)

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Conclusions

• How engineering can help to a pandemic approach
  ?

1/ Build before completion of clinical trials
2/ Always build flexible (especially if process
is still under development)
3/ Anticipate purchasing of long lead equipments
4/ Use new innovative technologies
5/ Have a strong and rationale validation approach
6/ When possible, chose renovation to speed small
scales units.
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Thank you for your attention.Etienne Malhaize,
Director of Technical Service Process Biotech.

NAE/IOMConference April 10 th , Vaccine
production Potential Engineering Approach to a
Pandemic