What Limits the Rate of Vaccine Development and Production?

1. What Limits the Rate of Vaccine Development and Production? Alan R. Shaw VaxInnate Corporation

2. 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

3. 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.

4. 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)?

5. 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

6. 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

7. 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

8. 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?

9. 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

11. First Sale RMC Approval Dose Defined Validate In-Process and Product Characterization Assays Transfer Assays Update Spec. Strategy & Rationale Update Spec. Strategy & Rationale Highly Coordinated Effort Product & Process Definition Stage 1A Dose & Scale Definition Stage 1B Proof of Efficacy & Manufacturability Stage 2 WMA Preparation Stage 3 License & Launch Stage 4 Proof of Concept Stage 0 Marketing Statement of Interest (SOI) Marketing Needs Report Pre-Launch Strategy Worldwide Marketing Plan Clinical/Regulatory Process Assessment- Clinicals Proof of Concept Bridging Studies Efficacy Studies Prepare WMA Support WMA & Extend Expiry Proof of Concept- Clinicals Regulatory Assessment Submit IND Dose Ranging Studies Consistency Studies Release WMA Approval Process LPO Product, Process and Formulation Development Process Support and Optimization Scale Defined Product, Process & Formulation Finalized Analytical Assays Validate Potency, Safety & Ster. Assay ID Parameter for POC Clinicals Stage 1 Anal.& Process Plan Validate Raw Material, Stability and Release Assay Evaluate Assay Performance Update Spec. Strategy & Rationale Serology Assays Spec.. Strategy & Rationale Develop & Evaluate High Throughput Serology Assay Kit Vendor Development of Serology Assays Capable of Evaluation Post-Vaccination and Post-Disease Seroconversion Product Definition, Packaging & Stability Final Product & Primary Package Definition Full Scale Lot Stability Studies Pilot Lot Stability Studies Early Research Stability Experiments Probe & Clinical Lot Stability Studies Market Container Stability Studies Launch and Annual Stability Studies Final Secondary Package Definition Preliminary Product & Packaging Definition Filling and Packaging Development Post-Launch Product and Packaging Support Facilities Detail Design Order Equipment Manufacturing Feasibility Studies Economic Feasibility Assessment Mfg.. Strategy Prepare Prelim. Eng.. & Basis of Design Inspection Preparation Build and Validate Facility Supply / Production Prepare Lab Lots for POC Clinicals Prepare Pilot Lots for Dose Ranging Prepare Phase 3 Quality Lots Prepare Consistency Lots Prepare Launch Quantities of Vaccine Start Stage 0 Stage 0 Review Stage 1A Review Stage 1B Review Stage 2 Review Stage 3 Review Stage 4 Review

12. Fermentation Suite

13. 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

14. 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 Two Divergent Examples

15. Varicella Egg safety Sterility Potency (plaque) Suckling mouse Guinea pig Tissue culture Mycoplasma (x2) Residual moisture rDNA influenza Sterility Potency, ELISA Dose, HPLC excipients Divergent Testing

16. First Sale RMC Approval Dose Defined Validate In-Process and Product Characterization Assays Transfer Assays Update Spec. Strategy & Rationale Update Spec. Strategy & Rationale Highly Coordinated Effort Product & Process Definition Stage 1A Dose & Scale Definition Stage 1B Proof of Efficacy & Manufacturability Stage 2 WMA Preparation Stage 3 License & Launch Stage 4 Proof of Concept Stage 0 Marketing Statement of Interest (SOI) Marketing Needs Report Pre-Launch Strategy Worldwide Marketing Plan Clinical/Regulatory Process Assessment- Clinicals Proof of Concept Bridging Studies Efficacy Studies Prepare WMA Support WMA & Extend Expiry Proof of Concept- Clinicals Regulatory Assessment Submit IND Dose Ranging Studies Consistency Studies Release WMA Approval Process LPO Product, Process and Formulation Development Process Support and Optimization Scale Defined Product, Process & Formulation Finalized Analytical Assays Validate Potency, Safety & Ster. Assay ID Parameter for POC Clinicals Stage 1 Anal.& Process Plan Validate Raw Material, Stability and Release Assay Evaluate Assay Performance Update Spec. Strategy & Rationale Serology Assays Spec.. Strategy & Rationale Develop & Evaluate High Throughput Serology Assay Kit Vendor Development of Serology Assays Capable of Evaluation Post-Vaccination and Post-Disease Seroconversion Product Definition, Packaging & Stability Final Product & Primary Package Definition Full Scale Lot Stability Studies Pilot Lot Stability Studies Early Research Stability Experiments Probe & Clinical Lot Stability Studies Market Container Stability Studies Launch and Annual Stability Studies Final Secondary Package Definition Preliminary Product & Packaging Definition Filling and Packaging Development Post-Launch Product and Packaging Support Facilities Detail Design Order Equipment Manufacturing Feasibility Studies Economic Feasibility Assessment Mfg.. Strategy Prepare Prelim. Eng.. & Basis of Design Inspection Preparation Build and Validate Facility Supply / Production Prepare Lab Lots for POC Clinicals Prepare Pilot Lots for Dose Ranging Prepare Phase 3 Quality Lots Prepare Consistency Lots Prepare Launch Quantities of Vaccine Start Stage 0 Stage 0 Review Stage 1A Review Stage 1B Review Stage 2 Review Stage 3 Review Stage 4 Review

17. 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

18. 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!