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

– 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

– 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

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

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

• 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– Egg safety– Sterility– Potency (plaque)– Suckling mouse– Guinea pig– Tissue culture– Mycoplasma (x2)– Residual moisture

• rDNA influenza– Sterility– Potency, ELISA– Dose, HPLC– excipients

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

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

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!