Page 42 - Assurance of Sterility for Sensitive Combination Products and Materials

30 Assurance of sterility for sensitive combination products and materials

A relationship between the product configuration and microorganisms
presented to the sterilization process helps define the approach for valida-
tion. In all sterilization modalities, product test of sterility is conducted at
conditions less than the routine sterilization process to establish characteris-
tics such as the D-value. The validation of the terminal sterilization process
utilizes this information to include safety factors to extrapolate to the de-
sired SAL. The test of sterility, performed as part of development, validation,
or requalification, should not be confused with the test for sterility. The
test for sterility examines microbial growth following routine processing
(aseptic or sterilization). A test for sterility cannot, inherently, extrapolate
to an SAL as the test for sterility can only indicate a sterile or non-sterile
article [26].
There are three approaches to validate the terminal sterilization process:
1. Bioburden-based approach,
2. Bioburden and BI-based approach, and
3. Biological indicator approach (overkill)

3.2.3.1 Bioburden-based approach
The bioburden-based approach to terminal sterilization validation fo-
cuses on the normal microbial flora on the product and can lead to the
development of terminal sterilization processes more gentle or appropri-
ate for combination products. All validation methodologies for radiation
sterilization—Methods 1, 2A, 2B, and VD max SD —are based on the biobur-
den approach. The bioburden-based approach may also be used for gas and
heat sterilization processes (ISO 11137-2:2012, ISO 11135-1: 2014, ISO
14937:2009, and ISO 17665-1:2006).
The bioburden-based approach is executed using unsterilized product
samples that have been manufactured in accordance with routine produc-
tion—this allows for challenging the microbial flora resulting from the pro-
cess and materials, as opposed to samples prepared in a manner different from
the routine manufacturing process. The product samples are typically ex-
posed to subprocess conditions of the terminal sterilization process. In radi-
ation, samples are processed at a low verification dose or at increasing doses,
with samples from each tested for sterility. In EO and other gas-based pro-
cesses, samples could be processed at different exposure times, maintaining
constant humidity and gas concentration, or concentrations can be varied
keeping all other variables constant, or some other combination of variation.
For moist heat, since time is most easily and precisely controlled, the product
is exposed at full temperature for different times while maintaining the other