Transcript NVAX CORPORATE

Disposable Manufacturing System for Rapid Mass Production of
Influenza Vaccine
James Robinson, PE
Vice President, Technical & Quality Operations
Novavax, Inc.
Bob Bader
Senior Manager Technology - Pharma Bio
Jacobs Engineering
March 26-28, 2008
Pennsylvania Convention Center
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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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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
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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
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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
Egg
Mammalian
Insect cell culture in
for a pandemic threat Attribute
based
Cell Culture
disposable technology
Simple/secure of supply
chain
 Rapid scale-up
 Improved stability
 Available regionally

+/-
Fast response to new/late
strain

High Yield
Low Yield Variation
Low Facility Cost
(Containment Level)
Fast Construction &
Validation Time
+/-






Ease of scale up (Suspension
Culture)

Supports Distributed
Manufacturing

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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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9+ week advantage
Faster Delivery of First Dose
Product Availability
Cloning &
Seed Prep
Mfg &
Fill 1st Lot
Release
& Ship
NOVAVAX
8 wks
4 wks
12 wks
16 wks
20 wks
Traditional
RG
pathogenicity
Wait for
Reagents
Mfg
Form/Fill,
Release & Ship
sequence available
Reagent Availability
goat
rHA
9+ week advantage
NOVAVAX
4 wks
8 wks
12 wks
16 wks
Traditional
RG
pathogenicity
Mfg
goat
sequence available
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CBER
20 wks
24 wks
28 wks
Influenza Vaccine Production
Cell Substrate
Preparation
Remove Cells,
Purify Virus
Infect &
Incubate
Inactivate
Virus
Traditional Flu Vaccine Production*:
Grow, Collect,
& Fertilize Eggs
Thaw vial from WCB
Grow to Mfg Scale
Infect with
Influenza Virus
Incubate
LS/HS
Centrifugation,
Diafiltration,
Chromatography
Treat with
Formaldehyde
(subvirion products
treated with detergent)
Insect Cell Culture-Based Flu Vaccine Production:
Thaw vial from WCB
Grow to Mfg Scale
Infect with
Recombinant
Baculovirus,
Incubate
MF/DF,
Chromatography
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baculovirus
inactivated
Influenza Vaccine Production
Cell Substrate
Preparation
Infect &
Incubate
Remove Cells,
Purify Virus
Traditional Flu Vaccine Production*:
Infect
Incubate
Candle
Chill
Harvest
Insect Cell Culture-Based Flu Vaccine Production:
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Inactivate
Virus
Influenza Vaccine Production
Cell Substrate
Preparation
Infect &
Incubate
Remove Cells,
Purify Virus
Traditional Flu Vaccine Production*:
Insect Cell Culture-Based Flu Vaccine Production:
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Inactivate
Virus
Influenza Vaccine Production
Relative Yield (Doses/L)
Relative Influenza Process Yield
egg based
current insect cell process
cell-based
15
30
45
90
mcg/dose
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Influenza Vaccine Production
Process Equipment Comparison
Process
Egg Based
Insect Cell Culture
Custom Inoculators
Upstream
Large Incubators
Single Use Bioreactors
Candling Stations
Custom Harvesters
Large Fixed Tanks
Single Use Bags
Low Speed Centrifuges
Single Use Microfiltration
Filtration
Ultrafiltration Skids
Purification
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
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Influenza Vaccine Production
Support Equipment Comparison
Support
Process
Containment
Egg Based
Insect Cell Culture
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
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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Influenza Vaccine Production
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
Insect Cell Culture-Based Flu Vaccine Production:
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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Influenza Vaccine Production
Comparison of Project Duration
Design
Construction
Egg Based
Process
Commissioning
Qualification
Validation
Design
Construction
Commissioning
Insect
Cell Culture
Qualification
Validation
Time Saved
Time, yrs
0
1
2
18
3
4
Influenza Vaccine Production
Comparison of Project Duration
Design
Construction
EggBased
Process
Commissioning
Qualification
Validation
Design
Earlier Revenue
Generation
Construction
Commissioning
Insect
Cell
Culture
Qualification
Faster Payback
on Smaller Investment
Validation
Time Saved
Time, yrs
0
1
2
3
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Utility Comparison
Egg Based
49%
VLP
VLP
Egg Based
1.0
0.0
Process
Utilities
Building
Utilities
20
8%
Influenza Vaccine Production
Traditional Flu Vaccine Production Unit Costs:
Relative Variable costs
Egg-based
Mammalian cell culture
materials
labor
materials
labor
Relative Fixed costs
depreciation utilities
depreciation
utilities
Insect Cell Culture-Based Flu Vaccine Production Unit Costs:
Relative Variable costs
Relative Fixed costs
materials
labor
depreciation
utilities
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.
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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
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Influenza Vaccine Production
The Disposable Approach
Traditional Flu Vaccine Production:
Large, central manufacturing facilities
Located in developed countries
Supported by complex site infrastructure
~100M doses
$150 – $300M
Egg Based
Facility $150,000,000
Sq ft
145,000
Insect Cell Culture-Based Flu Vaccine Production:
Facilities Distributed Globally
Located where vaccine is needed
Requiring little local infrastructure
10 – 20 M doses
(75M dose plant for ~$40M)
NVAX VLPs
Facility
$40,000,000
Sq ft 55,000
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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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