Transcript What Limits the Rate of Vaccine Development and Production?

What Limits the Rate of
Vaccine Development and
Production?
Alan R. Shaw
VaxInnate Corporation
Vaccine R&D in one slide
• If natural infection results in protection…
– Mimic the natural response as best you
can
• If natural infection is not resolved by the
host immune response…
– Prepare for a long and difficult program
Assumptions for today
• Target antigen(s) defined
• Method of presentation defined
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Live attenuated virus
rDNA VLPs
Vectored gene delivery
Soluble proteins or peptides on arrays
• Biological manufacturing “host” defined
– Mammalian cells, eggs, yeast, insect cells,
prokaryotes, tomatoes, etc.
Now that we know what we’re
making and how…
• Biggest job is analyzing what you’ve made
• Consistency of product among batches
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Potency
Stability
Purity
What aspects of your product and process are
relevant to these attributes?
– How much variability is allowable (as opposed to
measurable)?
Analyticals
• Each test must be validated
– Sensitivity, limits of detection, quantitation
– Reproducibility, inherent variability
– Robustness, reagents, operators, days
• Equipment associated must be
validated
– Software, and hardware
Analyticals Support Process
Development
• Circular, iterative process
• Analytical tools refined as process
evolves
• A good, stable process depends on
good, stable analytical tools
• Selected assays will be used for release
of licensed product
– Internal QC, FDA/CBER release
Similar Analytical Exercise for
Clinical Trial support
• Identify most relevant aspect of immune
response
• Hope that this can be measured in an
accessible sample
• Validate performance of assays and
equipment
• Also applies to detection of pathogen
Impact of Timing
• Assays need to be “ready” in order to
proceed
• This can be a rate-limiting step!!!
• Especially troublesome when assay
result does not tell you what you think
it’s telling you
– Does this track with stability?
– Does this track with potency?
From Pilot Plant to
Manufacturing
• Pilot facilities mimic process flow but not
scale
• Typically, 10X jump from pilot to full-scale
production
• Issues are often heat transfer, oxygen
transfer, nutrient supplies, odd changes in
host cell physiology at scale
• Having Process R&D and Manufacturing in
one place is helpful
Highly Coordinated Effort
Proof of Concept
Stage 0
Product &
Process Definition
Stage 1A
Dose &
Scale Definition
Stage 1B
Proof of Efficacy &
Manufacturability
Stage 2
WMA
Preparation
Stage 3
License &
Launch
Stage 4
Marketing
Statement of
Interest (SOI)
Marketing
Needs Report
Clinical/Regulatory
RMC
Proof of
Approval
ConceptSubmit
Clinicals
IND
Process
Process AssessmentClinicals
Regulatory
Assessment
Proof of Concept
Bridging Studies
Dose Ranging
Studies
Efficacy Studies
Consistency Studies
Product, Process &
Formulation Finalized
Validate Raw Material,
Stability and Release Assay
Spec.. Strategy & Rationale
Preliminary Product &
Packaging Definition
Supply / Production
Prepare Lab
Lots for POC
Clinicals
Start Stage 0
Evaluate Assay
Performance
Update Spec. Strategy
& Rationale
Update Spec. Strategy
& Rationale
Final Product
& Primary
Package Definition
Pilot Lot
Stability Studies
Mfg..
Strategy
Prepare Pilot
Lots for Dose
Ranging
Stage 0 Review
Process Support
and
Optimization
Transfer Assays
Full Scale Lot Stability Studies
Market Container Stability Studies
Stage 1A Review
Prepare Prelim.
Eng.. & Basis of
Design
Detail
Design
Order
Equipment
Inspection
Preparation
Build and Validate
Facility
Prepare
Phase 3
Quality Lots
Stage 1B Review
Launch and Annual
Stability Studies
Post-Launch Product and
Packaging Support
Final Secondary
Package Definition
Filling and Packaging Development
Economic
Feasibility
Assessment
Approval
Kit Vendor Development of Serology Assays Capable of Evaluation Post-Vaccination and Post-Disease Seroconversion
Probe & Clinical Lot Stability Studies
Manufacturing
Feasibility
Studies
LPO
Validate In-Process and
Product Characterization
Assays
Update Spec. Strategy
& Rationale
Product Definition,
Packaging & Stability
Facilities
Release WMA
Scale Defined
Develop & Evaluate High
Throughput Serology Assay
Early Research
Stability
Experiments
First Sale
Support WMA &
Extend Expiry
Prepare WMA
Dose Defined
Product, Process and Formulation Development
Analytical Assays
Validate
ID
Stage 1
Potency, Parameter Anal.&
Safety &
for POC Process
Ster. Assay Clinicals Plan
Serology Assays
Worldwide
Marketing
Plan
Pre-Launch Strategy
Prepare
Consistency
Lots
Prepare Launch Quantities of Vaccine
Stage 2 Review
Stage 3 Review
Stage 4 Review
Fermentation Suite
Biology is Also Rate-Limiting
• Biomass expansion is determined by
doubling time of host cell
• Release testing is limited by physiology
of the test system
Two Divergent Examples
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Varicella vaccine
Attenuated virus
Made in MRC5 cells
24 hour doubling
time
• ~200 doses per
roller bottle
• 48 hour infection
cycle (x2)
• VaxInnate’s flu
vaccine
• Soluble recombinant
protein
• Made in E. coli
• 50 MM doses per
2000L tank
• 20-30 minute
doubling time
Divergent Testing
• Varicella
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Egg safety
Sterility
Potency (plaque)
Suckling mouse
Guinea pig
Tissue culture
Mycoplasma (x2)
Residual moisture
• rDNA influenza
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Sterility
Potency, ELISA
Dose, HPLC
excipients
Highly Coordinated Effort
Proof of Concept
Stage 0
Product &
Process Definition
Stage 1A
Dose &
Scale Definition
Stage 1B
Proof of Efficacy &
Manufacturability
Stage 2
WMA
Preparation
Stage 3
License &
Launch
Stage 4
Marketing
Statement of
Interest (SOI)
Marketing
Needs Report
Clinical/Regulatory
RMC
Proof of
Approval
ConceptSubmit
Clinicals
IND
Process
Process AssessmentClinicals
Regulatory
Assessment
Proof of Concept
Bridging Studies
Dose Ranging
Studies
Efficacy Studies
Consistency Studies
Product, Process &
Formulation Finalized
Validate Raw Material,
Stability and Release Assay
Spec.. Strategy & Rationale
Preliminary Product &
Packaging Definition
Supply / Production
Prepare Lab
Lots for POC
Clinicals
Start Stage 0
Evaluate Assay
Performance
Update Spec. Strategy
& Rationale
Update Spec. Strategy
& Rationale
Final Product
& Primary
Package Definition
Pilot Lot
Stability Studies
Mfg..
Strategy
Prepare Pilot
Lots for Dose
Ranging
Stage 0 Review
Process Support
and
Optimization
Transfer Assays
Full Scale Lot Stability Studies
Market Container Stability Studies
Stage 1A Review
Prepare Prelim.
Eng.. & Basis of
Design
Detail
Design
Order
Equipment
Inspection
Preparation
Build and Validate
Facility
Prepare
Phase 3
Quality Lots
Stage 1B Review
Launch and Annual
Stability Studies
Post-Launch Product and
Packaging Support
Final Secondary
Package Definition
Filling and Packaging Development
Economic
Feasibility
Assessment
Approval
Kit Vendor Development of Serology Assays Capable of Evaluation Post-Vaccination and Post-Disease Seroconversion
Probe & Clinical Lot Stability Studies
Manufacturing
Feasibility
Studies
LPO
Validate In-Process and
Product Characterization
Assays
Update Spec. Strategy
& Rationale
Product Definition,
Packaging & Stability
Facilities
Release WMA
Scale Defined
Develop & Evaluate High
Throughput Serology Assay
Early Research
Stability
Experiments
First Sale
Support WMA &
Extend Expiry
Prepare WMA
Dose Defined
Product, Process and Formulation Development
Analytical Assays
Validate
ID
Stage 1
Potency, Parameter Anal.&
Safety &
for POC Process
Ster. Assay Clinicals Plan
Serology Assays
Worldwide
Marketing
Plan
Pre-Launch Strategy
Prepare
Consistency
Lots
Prepare Launch Quantities of Vaccine
Stage 2 Review
Stage 3 Review
Stage 4 Review
Physical Plant
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Design starts early, at risk
Construction starts in early phase II
Dig-to-validation from 3 to 5+ years
Purpose-built to make one vaccine
Back-up facilities are rare
Accidents, or regulatory action can stop
supply
• Raw material shortages, recalls
• Filling and packaging also fragile
Overall Timelines
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Inception to licensure can span a career
Varicella, 29 years (1966-1995)
MMRV, 23 years (1982-2005)
Shingles, 21 years (1985-2006)
RotaTeq®, 16 years (1990-2006 +)
Gardasil®, 13 years (1993-2006)
Persistence in a necessary element!