Transcript Limiting Batch Size: Effects of Batch Size on Risk of

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
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401 Professional Drive
Gaithersburg, MD 20879
301-738-2028
301-738-9012 (fax)
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[email protected]
C L E A R A N T
TSE Advisory Committee
Gaithersburg, MD
June 26, 2002
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
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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?
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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 =
=
=
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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).
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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.
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Risk of Including an Infectious Agent in a Plasma Pool Depends
on the Prevalence of the Agent and the Size of the Pool
- 1:60,000
20 - 70%
10 - 20%
0 - 10%
- 1:250,000
80%
- 1:500,000
60%
Prevalence of
Infectious Agent
> 70%
Risk of Contaminating Pool
100%
- 1:1,000,000
40%
20%
0%
100
1,000
10,000
100,000
600,000
Pool Size, donors
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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
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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
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> 0.4%
0.2 - 0.4%
0.1 - 0.2%
00.1%
Risk of Contaminating Pool
Risk of Including an Infectious Agent in a Tissue Pool Depends
on the Prevalence of the Agent and the Size of the Pool
1.0%
1:15,000
0.8%
0.6%
1:60,000
0.4%
0.2%
Prevalence of
Infectious Agent
1:250,000
0.0%
1
3
10
1:1,000,000
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100
Pool Size, donors
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> 0.1%
0.01 - 0.1%
0.001 - 0.01%
0.0001 0.001
%
Risk of Contaminating Pool
Risk of Including an Infectious Agent in a Tissue Pool Depends
on the Prevalence of the Agent and the Size of the Pool
1%
0.1%
1:15,000
0.01%
1:60,000
0.001%
1:250,000
0.0001%
1
3
Pool Size, units
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1:1,000,000
Prevalence of
Infectious Agent
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Risk of Including an Infectious Agent in a Tissue Pool Depends
on the Prevalence of the Agent and the Size of the Pool
1%
0.1%
1:60,000
1:250,000
0.01%
Prevalence of Agent
Risk of Contaminating Pool
1:15,000
1:1,000,000
0.001%
0.0001%
1
10
100
Pool Size, donors
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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
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