Page 43 - Assurance of Sterility for Sensitive Combination Products and Materials

Terminal sterilization 31

cycle conditions, such as heat up, temperature, and cool down. The intent is
to determine the resistance level the normal microbial flora present on the
product and packaging has to the sterilization process.
By knowing the bioburden population (count) and relative resistance of
that population from the subprocess studies, an extrapolation can be made
as to the final processing conditions required to deliver the required SAL.
A terminal sterilization process established using the bioburden-based
approach is sensitive to changes in microbial population and resistance. For
this reason, a robust bioburden monitoring program should be implemented
with routine sterilization process checks. In radiation, routine sterilization
process checks are accomplished through the dose audit process. The dose
audit involves exposing product samples to a dose selected based on the
bioburden or established in the incremental studies, which is referred to as
the verification dose. The verification dose is based on the expected resistance
−1
−2
of the bioburden population to deliver an SAL of 10 or 10 (based on the
method used to establish verification dose). The samples are then submitted
for tests of sterility, with the results either supporting continued effectiveness
of the overall sterilization process or indicating that investigation is required
into the validity of the sterilization dose. Similarly, an EO process validated
with the bioburden-based approach should include routine monitoring of
the effectiveness of the sterilization process by exposing the product sam-
ples to fractional process conditions with subsequent product sterility testing.
Heat sterilized product with the bioburden-based approach (probability of
survival approach) should include routine presterilization bioburden moni-
toring to ensure that there has not been a shift in bioburden level or micro-
bial resistance to temperature. The monitoring of key equipment and process
parameters should also be conducted routinely for all sterilization processes.

3.2.3.2 Bioburden and BI-based approach
The bioburden and biological indicator approach introduces a surrogate BI
to validate and routinely monitor the process for EO sterilization. Radiation
validation does not use BIs and focuses only on the bioburden-based
approach.
As with the bioburden-based approach, the bioburden and BI-based
approach requires strong knowledge and control of the product bioburden.
Bioburden fluctuations could have a significant impact on the effectiveness
of the validated sterilization process. The bioburden recovery method and
frequency of monitoring should be effective at detecting shifts in the mi-
crobial flora.