Cell culture based vaccine production : Engineering Bottlenecks Etienne Malhaize, Director of Technical Service – Process Biotech. NAE/IOMConference April 10 th, Vaccine production : Potential Engineering Approach to a Pandemic

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

Product streams Classical flu vaccine: egg derived Classical flu vaccine: adjuvanted formulation Tissue Culture Pandemic Flu approach in GSK Biological

Hamilton Rixensart Shanghai Singapore Dresden Egypt Gödöllö Moscow St. Amand les Eaux Nashik Brazil Marietta (Asia Pac) Wavre Alliances JV’s Affiliates Quebec Montreal GSK Biologicals Global Industrial Operations Network

Improved Flu Vaccine for elderly using adjuvant Build egg-based critical mass: Dresden (60 m doses) ID Biomedical (75 m doses) Introducing a new cell-culture based production (~2010) GSK Positioned to be a Flu Vaccine Leader Extensive preparations for pandemic flu Developing new delivery systems

Introduction Typical vaccine production process : PACKAGING FORMULATION BULK Antigen 1 Antigen 2 Antigen 3 Adjuvant FILLING

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 knows…and 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 Learning 1 : We need to build before clinical results are completed Risk : Potential impact: - -Capacities - -Budget - -Timing

µ-carriers  Cells are anchorage dependent and are growing on µ -beads  High antigen yields (Y=5)  Typical size : 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 (Y=1)  Typical size : L  Major challenges –Bigger volumes –Longer cell culture lead time. The context : Cell culture : µ-carriers or free suspension ?   Question 3 : « What will be the impact of cell culture technology on design ?»

The context : Impact of cell culture on equipment and facility design µ-carriers cell cultureFree cell suspension culture Tank (CIP/SIP) 1x 3000L Media Tank (in use) 1x 3000L Footprint unit in Media Prep. Area Fermented 1x1000L Fermented 1x1000L Fermented = Harvest tank 1x5000L Harvest tank 1x3000L Footprint unit in Cell Culture room Media Tank (in use or in SIP/CIP) 1x 1000L Media Tank (in use or in SIP/CIP) 1x 5000L

µ-carriersFree cell suspension 6 Footprint (in unit for one train) ~4m Ceiling height (in meters) ~3m ~6m Learning 2 : Depending on the cell culture technology, the equipment and facility design can dramatically change…then, build very flexible ! The context : Impact of cell culture on equipment and facility design Media Prep. Area Cell Culture room 2 x 3000L Media tank (by train) Fermented (by train) Harvest tank (by train) 1 x 1000L 1x1000L + 1x5000L 1 x 3000LNA

  µ-carriers   Free cell suspension From design… Fermenters (1000L) 10 months Fermenters (5000L) 10 to 14 (*) months (*) Special facility construction design if >5000 L...to Delivery The context : Impact of cell culture on equipment and facility design 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)

The context : GMP and Biosafety in BL3 Personnel Flow Clean Equipment/Material Flow Waste Flow Process Flow MAL IN MAL OUT PAL 1 PAL 3 PAL 2 Typical BSL 3 process viral contained area Sterile corridor Waste corridor Room pressure (Pa) Connection to Biokill

GEP Control (Engineering steps) GMP Control (Qualification steps) Process Validation & Continuous Validation User Requirement Brief Basic Design Specification Phase System Build System Level Impact Assessment Validation Master Plan Design QualificationStart Detailed Design URS Design Phase Construction Phase Production Continuous Validation (Maintenance) Process Validation Post-Commissioning Installation Qualification Operational Qualification Performance Qualification Installation & Operational Phases Performance Phase Design QualificationComplete Pre-Commissioning Commissioning GSOPBIO VAL The context : “ Never compromise with Quality…”

Standard timing for «Greenfield » project Standard timing for «Greenfield » project

The opportunities : System Level Impact Assessment

The opportunities: Parallel Commissioning Learning 5: A strong and rational qualification approach helps to reduce timing

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 »)  all GMP and BSL 3  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…)

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) 6/ When possible, chose renovation to speed small scales units. 3/ Anticipate purchasing of long lead equipments 4/ Use new innovative technologies 5/ Have a strong and rationale validation approach

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