Page 45 - Assurance of Sterility for Sensitive Combination Products and Materials

Terminal sterilization 33

3.2.3.3 BI approach
The third method for validating a terminal sterilization process is the BI ap-
proach, also known as the overkill method. This method uses a BI challenge
to validate the sterilization process, like the combined BI/bioburden-based
approach. Unlike the combination approach, the overkill method uses a
high population of resistance organisms on the BI. This extreme population
of highly resistant organisms will result in actual SALs in excess of the de-
sired SAL.
A relationship between the product bioburden and the PCD must be es-
tablished such that the PCD presents a greater challenge to the sterilization
process. In many cases, the population of the BI used in the PCD is several
6
logs greater than the product bioburden (e.g., 10 vs 10 [3]). The compar-
ative resistance is established by exposing the PCD and product samples
to a fractional sterilization process, where both are tested for sterility. In
this study, as the PCD must be more resistant than the product samples, all
product samples must be negative for growth and some portion of the PCD
samples should be positive for growth from the sterility test results.
After the PCD is proven to be more resistant to the sterilization process
than the bioburden, the validation of the sterilization process begins. The
PCD is exposed to conditions where all PCD challenges are negative for
growth. Once this endpoint is found, the exposure time (typically) is mul-
tiplied accordingly (typically doubled) to reach the required SAL. Again,
this approach is very conservative and will result in a sterilization process
that far exceeds the required conditions needed for the product SAL. The
sensitivity of product components and active ingredients adds challenges to
using the overkill approach for validation.

3.2.4 Validation overview
Terminal sterilization inactivates microorganisms as opposed to aseptic pro-
cessing which involves preventing contamination of sterile materials. The
validation of the sterilization process starts with understanding the impact
of the sterilization modality to the product performance, at the highest
sterilization conditions, as well as the ability to inactivate the microbial
organisms at the lowest conditions. Because of this fundamental difference,
and inherent safety factors therein, regulatory agencies prefer terminal ster-
ilization process evaluation before the use of aseptic processing whenever
possible [27].
There are multiple modalities for terminally sterilizing products. The
selection of the modality is based on the compatibility of the device with a