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

1

March 26-28, 2008

Pennsylvania Convention Center

James Robinson, PEVice 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

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Influenza Vaccine Manufacturing Today

Agenda Today’s 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

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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

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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

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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.

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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

Supports Distributed Manufacturing

Ease of scale up (Suspension Culture)

Fast Construction & Validation Time

Low Facility Cost (Containment Level)

Low Yield Variation

High Yield

Fast response to new/late strain

Simple/secure of supply chain

Insect cell culture in disposable technology

Mammalian Cell Culture

Egg based

Attribute

Supports Distributed Manufacturing

Ease of scale up (Suspension Culture)

Fast Construction & Validation Time

Low Facility Cost (Containment Level)

Low Yield Variation

High Yield

Fast response to new/late strain

Simple/secure of supply chain

Insect cell culture in disposable technology

Mammalian Cell Culture

Egg based

Attribute

+/-

+/-

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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

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Cryo-electron Microscopy of Pleomorphic VLPs

A/Indo H5N1 VLPs

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Why Recombinant Influenza VLP Vaccine

Speed from strain selection to product release is weeks Exact genetic match Recombinant VLP’s 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

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Faster Delivery of First Dose

Reagent Availability

NOVAVAX

Traditional

sequence available

rHA goat

RG pathogenicity Mfg goat CBER

4 wks 8 wks 12 wks 16 wks 20 wks

9+ week advantage

Product Availability

NOVAVAX

Traditional

sequence available

Cloning &

Seed PrepMfg &

Fill 1st Lot

RG pathogenicity Mfg

4 wks 8 wks 12 wks 16 wks 20 wks

9+ week advantage

24 wks 28 wks

Release

& Ship

Form/Fill,

Release & Ship

Wait for

Reagents

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Influenza Vaccine Production

Traditional Flu Vaccine Production*:

Grow, Collect,

& Fertilize EggsInfect with

Influenza Virus

Incubate

Treat with

Formaldehyde

(subvirion products

treated with detergent)

LS/HS

Centrifugation,

Diafiltration,

ChromatographyThaw vial from WCB

Grow to Mfg Scale

Cell Substrate

Preparation

Remove Cells,

Purify VirusInfect &

Incubate

Inactivate

Virus

Insect Cell Culture-Based Flu Vaccine Production:

Infect with

Recombinant

Baculovirus,

Incubate

baculovirus

inactivatedMF/DF,

Chromatography

Thaw vial from WCB

Grow to Mfg Scale

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Cell Substrate

Preparation

Remove Cells,


Incubate

Inactivate

Virus

Infect

Incubate

Candle

Chill

Harvest

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Cell Substrate

Preparation

Remove Cells,


Incubate

Inactivate

Virus

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Relative Influenza Process Yield

15 30 45 90

mcg/dose

Rel

ativ

e Y

ield

(D

ose

s/L

)

egg based

current insect cell process

cell-based

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Process Egg Based Insect Cell Culture

Upstream

Custom Inoculators

Single Use BioreactorsLarge Incubators

Candling Stations

Custom Harvesters

Purification

Large Fixed Tanks Single Use Bags

Low Speed Centrifuges Single Use Microfiltration

Filtration

Ultrafiltration Skids Single Use Ultrafiltration

Ultra Centrifuges

Chromatography Chromatography

Buffer Prep Single Use Buffer Prep

Buffer Storage Buffer Bags

Sub-micron Filtration Single Use Sub-micron Filters

Process Equipment Comparison

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Support Equipment Comparison

Support Egg Based Insect Cell Culture

Process

Large WFI System Small WFI System

CIP Skids (Multiple) N/A

Clean Steam/SIP Systems N/A

Egg Disposal System N/A

Autoclaves N/A

Parts Washers N/A

Containment

Decon Autoclave Decon Autoclave

Large Liquid Waste Kill System Small Liquid Waste Kill System

BL2+ Facility Design GLSP Facility Design

Class B HVAC Systems Class C HVAC Systems

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Traditional Flu Vaccine Production Capital Costs:


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

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Comparison of Project Duration

Time, yrs

0 1 2 3 4

Design

Construction

Commissioning

QualificationValidation

Egg BasedProcess

InsectCell Culture

Design

Construction

Commissioning

Qualification

Validation

Time Saved

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Comparison of Project Duration

Time, yrs

0 1 2 3 4

Design

Construction

Commissioning

QualificationValidation

Egg-BasedProcess

InsectCell Culture

Design

Construction

Commissioning

Qualification

Validation

Time Saved

Earlier Revenue

Generation

Faster Payback

on Smaller Investment

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Utility Comparison

1.0

0.0

Egg

Bas

ed

VLP E

gg B

ased

VL

P

BuildingUtilities

ProcessUtilities

8%

49%

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Traditional Flu Vaccine Production Unit Costs:

depreciation

depreciation

depreciation

utilities

utilities

utilities

materials labor

materials labor

Relative Variable costs Relative Fixed costs

Relative Variable costs Relative 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:

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Influenza Vaccine ProductionThe 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

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Traditional 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)


Facility $150,000,000

Sq ft 145,000

Facility $40,000,000

Sq ft 55,000

NVAX VLPs

Egg Based

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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

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

Documents

influenza virus

particle flu vaccine

vaccine stockpiles

ideal flu vaccine virus

virus slide

traditional influenza

recombinant ha vaccine

split virion vaccine