What Limits the Rate of Vaccine Development and Production? Alan R. Shaw VaxInnate Corporation.
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Transcript of What Limits the Rate of Vaccine Development and Production? Alan R. Shaw VaxInnate Corporation.
![Page 1: What Limits the Rate of Vaccine Development and Production? Alan R. Shaw VaxInnate Corporation.](https://reader035.fdocuments.in/reader035/viewer/2022070409/56649e8e5503460f94b916f3/html5/thumbnails/1.jpg)
What Limits the Rate of Vaccine Development and
Production?
Alan R. Shaw
VaxInnate Corporation
![Page 2: What Limits the Rate of Vaccine Development and Production? Alan R. Shaw VaxInnate Corporation.](https://reader035.fdocuments.in/reader035/viewer/2022070409/56649e8e5503460f94b916f3/html5/thumbnails/2.jpg)
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
![Page 3: What Limits the Rate of Vaccine Development and Production? Alan R. Shaw VaxInnate Corporation.](https://reader035.fdocuments.in/reader035/viewer/2022070409/56649e8e5503460f94b916f3/html5/thumbnails/3.jpg)
Assumptions for today
• Target antigen(s) defined• Method of presentation defined
– 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.
![Page 4: What Limits the Rate of Vaccine Development and Production? Alan R. Shaw VaxInnate Corporation.](https://reader035.fdocuments.in/reader035/viewer/2022070409/56649e8e5503460f94b916f3/html5/thumbnails/4.jpg)
Now that we know what we’re making and how…
• Biggest job is analyzing what you’ve made• Consistency of product among batches
– Potency– Stability– Purity– What aspects of your product and process are
relevant to these attributes?– How much variability is allowable (as opposed to
measurable)?
![Page 5: What Limits the Rate of Vaccine Development and Production? Alan R. Shaw VaxInnate Corporation.](https://reader035.fdocuments.in/reader035/viewer/2022070409/56649e8e5503460f94b916f3/html5/thumbnails/5.jpg)
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
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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
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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
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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?
![Page 9: What Limits the Rate of Vaccine Development and Production? Alan R. Shaw VaxInnate Corporation.](https://reader035.fdocuments.in/reader035/viewer/2022070409/56649e8e5503460f94b916f3/html5/thumbnails/9.jpg)
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
![Page 10: What Limits the Rate of Vaccine Development and Production? Alan R. Shaw VaxInnate Corporation.](https://reader035.fdocuments.in/reader035/viewer/2022070409/56649e8e5503460f94b916f3/html5/thumbnails/10.jpg)
![Page 11: What Limits the Rate of Vaccine Development and Production? Alan R. Shaw VaxInnate Corporation.](https://reader035.fdocuments.in/reader035/viewer/2022070409/56649e8e5503460f94b916f3/html5/thumbnails/11.jpg)
Highly Coordinated Effort
Stage 4 Review
Proof of ConceptStage 0
Product & Process Definition
Stage 1A
Dose &Scale Definition
Stage 1B
Proof of Efficacy &Manufacturability
Stage 2
WMAPreparation
Stage 3
License &LaunchStage 4
Marketing
Clinical/Regulatory
Process
Analytical Assays
Serology Assays
Product Definition,Packaging & Stability
Supply / Production
Marketing Needs Report
Pre-Launch StrategyWorldwideMarketing
Plan
Proof of Concept-Clinicals
Product, Process and Formulation DevelopmentProcess Support
and Optimization
Validate Potency,Safety &
Ster. Assay
Validate Raw Material, Stability and Release Assay
Evaluate AssayPerformance
Develop & Evaluate HighThroughput Serology Assay
ManufacturingFeasibility
Studies
EconomicFeasibilityAssessment
Mfg.. Strategy
Prepare Prelim.Eng.. & Basis of
Design
InspectionPreparation
Prepare LabLots for POC
Clinicals
Prepare Pilot Lots for Dose
Ranging
PreparePhase 3
Quality Lots
PrepareConsistency
LotsPrepare Launch Quantities of Vaccine
Start Stage 0 Stage 0 Review Stage 1A Review Stage 1B Review Stage 2 Review Stage 3 Review
Dose Defined
Regulatory Assessment
Proof of ConceptBridging Studies
Dose RangingStudies
Process Assessment-Clinicals Efficacy Studies
Consistency Studies
Scale Defined
LPO
Submit IND
Prepare WMASupport WMA &
Extend Expiry
First Sale
Release WMA Approval
Product, Process & Formulation Finalized
Kit Vendor Development of Serology Assays Capable of Evaluation Post-Vaccination and Post-Disease Seroconversion
ID Parameterfor POCClinicals
Stage 1Anal.& Process
Plan
Spec.. Strategy & Rationale
Validate In-Process and Product Characterization
AssaysUpdate Spec. Strategy
& Rationale
Transfer Assays
Update Spec. Strategy & Rationale
Update Spec. Strategy & Rationale
Detail Design
OrderEquipment
Build and ValidateFacility
Statement of Interest (SOI)
RMCApproval
Facilities
Early ResearchStability
Experiments Preliminary Product & Packaging Definition
Probe & Clinical Lot Stability StudiesPilot Lot
Stability Studies
Final Product & Primary
Package DefinitionPost-Launch Product and
Packaging SupportFilling and Packaging Development
Launch and AnnualStability Studies
Full Scale Lot Stability Studies
Market Container Stability Studies
Final SecondaryPackage Definition
![Page 12: What Limits the Rate of Vaccine Development and Production? Alan R. Shaw VaxInnate Corporation.](https://reader035.fdocuments.in/reader035/viewer/2022070409/56649e8e5503460f94b916f3/html5/thumbnails/12.jpg)
Fermentation Suite
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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
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Two Divergent Examples
• 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
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Divergent Testing
• Varicella– Egg safety– Sterility– Potency (plaque)– Suckling mouse– Guinea pig– Tissue culture– Mycoplasma (x2)– Residual moisture
• rDNA influenza– Sterility– Potency, ELISA– Dose, HPLC– excipients
![Page 16: What Limits the Rate of Vaccine Development and Production? Alan R. Shaw VaxInnate Corporation.](https://reader035.fdocuments.in/reader035/viewer/2022070409/56649e8e5503460f94b916f3/html5/thumbnails/16.jpg)
Highly Coordinated Effort
Stage 4 Review
Proof of ConceptStage 0
Product & Process Definition
Stage 1A
Dose &Scale Definition
Stage 1B
Proof of Efficacy &Manufacturability
Stage 2
WMAPreparation
Stage 3
License &LaunchStage 4
Marketing
Clinical/Regulatory
Process
Analytical Assays
Serology Assays
Product Definition,Packaging & Stability
Supply / Production
Marketing Needs Report
Pre-Launch StrategyWorldwideMarketing
Plan
Proof of Concept-Clinicals
Product, Process and Formulation DevelopmentProcess Support
and Optimization
Validate Potency,Safety &
Ster. Assay
Validate Raw Material, Stability and Release Assay
Evaluate AssayPerformance
Develop & Evaluate HighThroughput Serology Assay
ManufacturingFeasibility
Studies
EconomicFeasibilityAssessment
Mfg.. Strategy
Prepare Prelim.Eng.. & Basis of
Design
InspectionPreparation
Prepare LabLots for POC
Clinicals
Prepare Pilot Lots for Dose
Ranging
PreparePhase 3
Quality Lots
PrepareConsistency
LotsPrepare Launch Quantities of Vaccine
Start Stage 0 Stage 0 Review Stage 1A Review Stage 1B Review Stage 2 Review Stage 3 Review
Dose Defined
Regulatory Assessment
Proof of ConceptBridging Studies
Dose RangingStudies
Process Assessment-Clinicals Efficacy Studies
Consistency Studies
Scale Defined
LPO
Submit IND
Prepare WMASupport WMA &
Extend Expiry
First Sale
Release WMA Approval
Product, Process & Formulation Finalized
Kit Vendor Development of Serology Assays Capable of Evaluation Post-Vaccination and Post-Disease Seroconversion
ID Parameterfor POCClinicals
Stage 1Anal.& Process
Plan
Spec.. Strategy & Rationale
Validate In-Process and Product Characterization
AssaysUpdate Spec. Strategy
& Rationale
Transfer Assays
Update Spec. Strategy & Rationale
Update Spec. Strategy & Rationale
Detail Design
OrderEquipment
Build and ValidateFacility
Statement of Interest (SOI)
RMCApproval
Facilities
Early ResearchStability
Experiments Preliminary Product & Packaging Definition
Probe & Clinical Lot Stability StudiesPilot Lot
Stability Studies
Final Product & Primary
Package DefinitionPost-Launch Product and
Packaging SupportFilling and Packaging Development
Launch and AnnualStability Studies
Full Scale Lot Stability Studies
Market Container Stability Studies
Final SecondaryPackage Definition
![Page 17: What Limits the Rate of Vaccine Development and Production? Alan R. Shaw VaxInnate Corporation.](https://reader035.fdocuments.in/reader035/viewer/2022070409/56649e8e5503460f94b916f3/html5/thumbnails/17.jpg)
Physical Plant
• 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
![Page 18: What Limits the Rate of Vaccine Development and Production? Alan R. Shaw VaxInnate Corporation.](https://reader035.fdocuments.in/reader035/viewer/2022070409/56649e8e5503460f94b916f3/html5/thumbnails/18.jpg)
Overall Timelines
• 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!
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