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1 March 26-28, 2008 Pennsylvania Convention Center James Robinson, PE Vice President, Technical & Quality Operations Novavax, Inc. Bob Bader Senior Manager.

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Presentation on theme: "1 March 26-28, 2008 Pennsylvania Convention Center James Robinson, PE Vice President, Technical & Quality Operations Novavax, Inc. Bob Bader Senior Manager."— Presentation transcript:

1 1 March 26-28, 2008 Pennsylvania Convention Center James Robinson, PE Vice President, Technical & Quality Operations Novavax, Inc. Bob Bader Senior Manager Technology - Pharma Bio Jacobs Engineering Disposable Manufacturing System for Rapid Mass Production of Influenza Vaccine

2 2 Influenza Vaccine Manufacturing Today Agenda Todays Flu Vaccines The Ideal Flu Vaccine Virus-Like Particle Flu Vaccine in Insect Cells Advantages of VLP Vaccine Manufacturing Economic Impact of Disposable Manufacturing Systems in Influenza Manufacturing Summary

3 3 Influenza Vaccine Manufacturing Today US Licensed Inactivated influenza vaccines –Whole virion –Split virion Live-attenuated vaccines Approaching Licensure Adjuvanted inactivated vaccines* Recombinant HA vaccine In Development Virus-Like Particles DNA Vaccines Universal Flu Vaccines* some licensed in EU

4 4 Influenza Vaccine Manufacturing Today Vast majority (>90%) of licensed capacity is in egg-based products –Reliable process for seasonal production –Potential loss of supply in an avian flu outbreak –First cell culture facilities are coming on line in Europe Significant investment in new US facilities continues –Egg ($1.5 capital/dose capacity) and cell-culture ($3/dose) Demand promises to grow with supply –Expanded recommendations –Pandemic preparedness –Market shortages globally

5 5 Pandemic Influenza Vaccine Manufacturing Challenges Non-adjuvanted pandemic vaccines to date have required increased doses for a protective HAI response Yield of pandemic vaccine production in eggs is lower than seasonal strains The likelihood of a pandemic event is driving increased capacity and advances in flu technology –Risk of overcapacity for seasonal markets The time required to obtain high-producing non-pathogenic strains challenges a fast delivery of pandemic vaccine once a pandemic is declared Virus mutations could greatly reduce the value of the vaccine stockpiles created.

6 6 Influenza Vaccine Manufacturing Tomorrow Vaccine supply that does not rely on egg-based production High yielding process supporting a robust response with less investment Fast response to an emerging influenza strain Cross-protective product for antigenic drift Flexible facility that supports other products when not producing for a pandemic threat Rapid scale-up Improved stability Available regionally +/-

7 7 Influenza Vaccine Manufacturing in Insect Cells Novavax, Inc. is developing an Influenza Virus-Like Particle (VLP) Vaccine as an alternative to traditional influenza vaccines –The process uses recombinant baculovirus to infect and express VLPs that contain Hemagglutinin (HA), Neuraminidase (NA), and Matrix (M1) Protein –The proteins self-assemble as particles that resemble influenza virus, but do not contain flu RNA –The approach has a number of quality and manufacturing advantages to the traditional influenza manufacturing processes

8 8 Cryo-electron Microscopy of Pleomorphic VLPs A/Indo H5N1 VLPs

9 9 Why Recombinant Influenza VLP Vaccine Speed from strain selection to product release is weeks Exact genetic match Recombinant VLPs are clinically proven (HPV, HBsAg) with a broad immune response –Improved immunogenicity of flu VLPs (vs. split virion vaccine) in preclinical studies No eggs Yields are higher than egg-based production; potential for additional increase in yield No pathogenic virus in manufacturing Controlled cell culture process (Serum-free, Protein-free, Suspension Culture) The use of this approach has allowed Novavax, Inc to develop a process that uses disposable equipment and closed systems for product processing

10 10 Faster Delivery of First Dose Product Availability NOVAVAX Traditional sequence available Cloning & Seed Prep Mfg & Fill 1 st Lot RGpathogenicity Mfg 4 wks 8 wks12 wks16 wks20 wks 9+ week advantage 24 wks28 wks Release & Ship Form/Fill, Release & Ship Wait for Reagents

11 11 Influenza Vaccine Production Traditional Flu Vaccine Production*: Grow, Collect, & Fertilize Eggs Infect with Influenza Virus Incubate Treat with Formaldehyde (subvirion products treated with detergent) LS/HS Centrifugation, Diafiltration, Chromatography Thaw vial from WCB Grow to Mfg Scale Cell Substrate Preparation Remove Cells, Purify Virus Infect & Incubate Inactivate Virus Insect Cell Culture-Based Flu Vaccine Production: Infect with Recombinant Baculovirus, Incubate baculovirus inactivated MF/DF, Chromatography Thaw vial from WCB Grow to Mfg Scale

12 12 Influenza Vaccine Production Traditional Flu Vaccine Production*: Insect Cell Culture-Based Flu Vaccine Production: Cell Substrate Preparation Remove Cells, Purify Virus Infect & Incubate Inactivate Virus Infect Incubate Candle Chill Harvest

13 13 Influenza Vaccine Production Traditional Flu Vaccine Production*: Insect Cell Culture-Based Flu Vaccine Production: Cell Substrate Preparation Remove Cells, Purify Virus Infect & Incubate Inactivate Virus

14 14 Influenza Vaccine Production Relative Influenza Process Yield mcg/dose Relative Yield (Doses/L) egg based current insect cell process cell-based

15 15 Influenza Vaccine Production ProcessEgg BasedInsect Cell Culture Upstream Custom Inoculators Single Use Bioreactors Large Incubators Candling Stations Custom Harvesters Purification Large Fixed TanksSingle Use Bags Low Speed CentrifugesSingle Use Microfiltration Filtration Ultrafiltration SkidsSingle Use Ultrafiltration Ultra Centrifuges Chromatography Buffer PrepSingle Use Buffer Prep Buffer StorageBuffer Bags Sub-micron FiltrationSingle Use Sub-micron Filters Process Equipment Comparison

16 16 Influenza Vaccine Production Support Equipment Comparison SupportEgg BasedInsect Cell Culture Process Large WFI SystemSmall WFI System CIP Skids (Multiple)N/A Clean Steam/SIP SystemsN/A Egg Disposal SystemN/A AutoclavesN/A Parts WashersN/A Containment Decon Autoclave Large Liquid Waste Kill SystemSmall Liquid Waste Kill System BL2+ Facility DesignGLSP Facility Design Class B HVAC SystemsClass C HVAC Systems

17 17 Influenza Vaccine Production Traditional Flu Vaccine Production Capital Costs: Insect Cell Culture-Based Flu Vaccine Production: egg-based facility USA 100M doses/year (600K eggs/day) 140K square feet $150M mammalian cell culture facility USA 100M doses/year 140K square feet $300M Novavax, Inc Insect Cell Culture Rockville, MD Disposable Approach 75M doses/year 55K square feet $40M Benchmark cell culture facility 2 – 5,000L reactors Traditional Approach Fully automated downstream $225M

18 18 Influenza Vaccine Production Comparison of Project Duration Time, yrs Design Construction Commissioning Qualification Validation Egg Based Process Insect Cell Culture Design Construction Commissioning Qualification Validation Time Saved

19 19 Influenza Vaccine Production Comparison of Project Duration Time, yrs Design Construction Commissioning Qualification Validation Egg- Based Process Insect Cell Culture Design Construction Commissioning Qualification Validation Time Saved Earlier Revenue Generation Faster Payback on Smaller Investment

20 20 Utility Comparison Egg Based VLP Egg Based VLP Building Utilities Process Utilities 8% 49%

21 21 Influenza Vaccine Production Traditional Flu Vaccine Production Unit Costs: depreciation utilities materialslabor materialslabor Relative Variable costsRelative Fixed costs Relative Variable costsRelative Fixed costs COGS = unit variable costs + fixed costs units made Lower fixed cost reduces dependence on production volume for low unit cost. Higher yields drive lower variable costs. Egg-based Mammalian cell culture materials labor Insect Cell Culture-Based Flu Vaccine Production Unit Costs:

22 22 Influenza Vaccine Production The Disposable Approach Advantages of Disposable/Closed Manufacturing Approach –Reduced process equipment complexity –Reduced facility complexity and cost –Faster Construction, Commissioning, and Launch –Rapid expansion of capacity –No change-over cleaning/validation between strains/products –LEAN manufacturing approach –Significant reduction in facility/equipment validation (>50%) –Manufacturing cost structure shifted to variable costs Significant reduction in capital equipment costs (>70%) Supports a regional manufacturing approach

23 23 Traditional Flu Vaccine Production: Insect Cell Culture-Based Flu Vaccine Production: Large, central manufacturing facilities Located in developed countries Supported by complex site infrastructure ~100M doses $150 – $300M Facilities Distributed Globally Located where vaccine is needed Requiring little local infrastructure 10 – 20 M doses (75M dose plant for ~$40M) Influenza Vaccine Production The Disposable Approach Facility $150,000,000 Sq ft145,000 Facility $40,000,000 Sq ft 55,000 NVAX VLPs Egg Based

24 24 Influenza Vaccine Production The Disposable Approach Summary Production of Recombinant Influenza VLP Vaccine offers a favorable alternative to traditional manufacturing approaches The elimination of the pathogenic virus in the manufacturing process eliminates containment concerns and allows use of disposable systems Disposable systems provide significant economic benefits to influenza manufacturing –Lower Capital Cost –Faster Facility Start-up –Rapid Expansion of Capacity –Faster Investment Payback These benefits are well aligned with the needs of a global influenza solution for pandemic and seasonal disease


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