1. C L E A R A N T TM Limiting Batch Size: Effects of Batch Size on Risk of Contamination with Infectious Agents Thomas J. Lynch, J.D., Ph.D. Senior Vice President, Regulatory and Quality C L E A R A N T 401 Professional Drive Gaithersburg, MD 20879 TSE Advisory Committee Gaithersburg, MD June 26, 2002 301-738-2028 301-738-9012 (fax) tlynch@clearant.com TM

2. C L E A R A N T TM 2 Analysis of Risk Associated with Pooling of Source Materials in the Manufacture of Biologics The dissemination of an infectious agent via a pooled product is potentially greater than by single-donor products. –The inclusion of one or a few units contaminated with an infectious agent may expose all recipients of product made from a pool to that agent. 1995 analysis done in context of: –Pooled Plasma, Solvent/Detergent Treated –Later extended to all Plasma Derivatives

3. C L E A R A N T TM 3 Pool Size in the Manufacture of Plasma Derivatives -- 1995 Analysis Would limiting the size of plasma pools improve the safety of products made from them? –If so, what additional safety margins could be achieved at various manufacturing scales? –Would limiting the size of manufacturing pools be a prudient safety measure? Should any single donor product be converted to a pooled product?

4. C L E A R A N T TM 4 Analysis Simple mathematical models relating: –Prevalence of an infectious agent in the donor population; –Size of the pools from which plasma derivatives are manufactured; –Risk to the recipients. RISK= Risk of exposing a recipient to material made from a pool that included one or more units derived from infected donors (Risk of Exposure). =Proportion of a product that is manufactured from infectious pools (Proportionate Risk). =Probability of including one or more units from infected donors in any single pool (Risk of Contaminating a Pool).

5. C L E A R A N T TM 5 Risk of Exposure is not Risk of Infection Risk of Infection may be much less than Risk of Exposure, and is certainly not greater. Transmission of an agent depends on: –Infectiousness of the agent. –Titer of the agent in the pool. –Distribution of the agent during processing. –Susceptibility of the recipient population. Risk of Exposure is therefore a worst-case estimate of risk.

6. C L E A R A N T TM 6 Risk of Including an Infectious Agent in a Plasma Pool Depends on the Prevalence of the Agent and the Size of the Pool 100 1,000 10,000 100,000 Pool Size, donors 0% 20% 40% 60% 80% 100% Risk of Contaminating Pool Prevalence of Infectious Agent 600,000 - 1:60,000 - 1:250,000 - 1:1,000,000 - 1:500,000 0 - 10% 10 - 20% 20 - 70% > 70%

7. C L E A R A N T TM 7 Plasma Derivatives vs. Tissues RELEVANT No dilution effect –Suggestions that dilution of infectious agent(s) by pooling may reduce infectivity were discounted No neutralization by antibodies –Possibility (discounted) of Ab neutralization not likely for tissues NOT DIRECTLY RELEVANT Large Pools –Thousands to tens of thousands for plasma derivatives –Tissue pooling smaller Repeated exposure –Plasma derivatives often administered repeatedly or life-long –Repeated exposure to tissue unusual/limited

8. C L E A R A N T TM 8 Risk of Including an Infectious Agent in a Tissue Pool Depends on the Prevalence of the Agent and the Size of the Pool 1 3 10 32 100 1:1,000,000 1:250,000 1:60,000 1:15,000 0.0% 0.2% 0.4% 0.6% 0.8% 1.0% Risk of Contaminating Pool Pool Size, donors Prevalence of Infectious Agent 0 - 0.1% 0.1 - 0.2% 0.2 - 0.4% > 0.4%

9. C L E A R A N T TM 9 Risk of Including an Infectious Agent in a Tissue Pool Depends on the Prevalence of the Agent and the Size of the Pool 1 3 10 32 1:1,000,000 1:250,000 1:60,000 1:15,000 0.0001% 0.001% 0.01% 0.1% 1% Risk of Contaminating Pool Pool Size, units Prevalence of Infectious Agent 0.0001 - 0.001 % 0.001 - 0.01% 0.01 - 0.1% > 0.1%

10. C L E A R A N T TM 10 Risk of Including an Infectious Agent in a Tissue Pool Depends on the Prevalence of the Agent and the Size of the Pool 0.0001% 0.001% 0.01% 0.1% 1% 110100 Pool Size, donors Risk of Contaminating Pool 1:1,000,000 1:250,000 1:60,000 1:15,000 Prevalence of Agent

11. C L E A R A N T TM 11 Conclusions For conversion of a Single Donor Product to a Pooled Product, theoretical risk of exposure increases nearly in proportion to pool size for small or moderately sized pools This risk may be mitigated or offset by benefits imparted by processing: –Incorporation of a broadly effective pathogen inactivation method during processing –New therapeutic made possible only by manufacturing of pooled source materials »Risk:benefit can be analyzed only for known infectious agents