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Transcript of 1 March 26-28, 2008 Pennsylvania Convention Center James Robinson, PE Vice President, Technical &...
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
2
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
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
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
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
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
+/-
+/-
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
Cryo-electron Microscopy of Pleomorphic VLPs
A/Indo H5N1 VLPs
9
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
10
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
11
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
12
Influenza Vaccine Production
Traditional Flu Vaccine Production*:
Insect Cell Culture-Based Flu Vaccine Production:
Cell Substrate
Preparation
Remove Cells,
Purify VirusInfect &
Incubate
Inactivate
Virus
Infect
Incubate
Candle
Chill
Harvest
13
Influenza Vaccine Production
Traditional Flu Vaccine Production*:
Insect Cell Culture-Based Flu Vaccine Production:
Cell Substrate
Preparation
Remove Cells,
Purify VirusInfect &
Incubate
Inactivate
Virus
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Influenza Vaccine Production
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
15
Influenza Vaccine Production
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
16
Influenza Vaccine Production
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
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
Influenza Vaccine Production
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
19
Influenza Vaccine Production
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
20
Utility Comparison
1.0
0.0
Egg
Bas
ed
VLP E
gg B
ased
VL
P
BuildingUtilities
ProcessUtilities
8%
49%
21
Influenza Vaccine Production
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:
22
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
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 ProductionThe Disposable Approach
Facility $150,000,000
Sq ft 145,000
Facility $40,000,000
Sq ft 55,000
NVAX VLPs
Egg Based
24
Influenza Vaccine ProductionThe 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