# Presentation: 528516

## Limiting Batch Size: Effects of Batch Size on Risk ofContamination with Infectious Agents

***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 CommitteeGaithersburg, MDJune 26, 2002

- 301-738-2028301-738-9012 (fax) tlynch@clearant.com

## 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

## 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?

## 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_).

## 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.

## 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**

**600,000**

**- 1:60,000**

**-   1:250,000**

**-   1:1,000,000**

**-   1:500,000**

**0 - 10%**

**10 - 20%**

**20 - 70%**

**> 70%**

## 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

## 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**

**0 - 0.1%**

**0.1 - 0.2%**

**0.2 - 0.4%**

**> 0.4%**

## 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**

**0.0001 - 0.001%**

**0.001 - 0.01%**

**0.01 - 0.1%**

**> 0.1%**

## 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%**

**1**

**10**

**100**

**Pool Size, donors**

**Risk of Contaminating Pool**

**1:1,000,000**

**1:250,000**

**1:60,000**

**1:15,000**

**Prevalence of Agent**

## 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