Page 212 - Assurance of Sterility for Sensitive Combination Products and Materials

Risk to the patient—Quantifying assurance of sterility 191

be underestimated. This underestimation will result in the use of a lower
radiation level as part of the verification testing and in the final processes.
The OC curve shown in Fig. 7.8 demonstrates that the verification test-
ing step cannot be expected to detect this 7% underestimation with high
confidence.
This simplified analysis using the low bioburden average of 3.5 CFU
−6
that for some levels of bioburden the UCB of the PNSU* is >1 × 10 .
7.3.4.3 Conclusion—Point estimates and confidence bounds—
Terminal sterilization; bioburden-based approach
The PNSU* provided by ISO 11137-2:2013 Method 1 is dependent on
the level of bioburden. In some cases, the procedure used to estimate the
level of bioburden will result in a result lower than the truth. The verifica-
tion component of the standard is not likely to detect this underestimate.
−6
While the UCB is in the 10 range, this quantifiable aspect of the stan-
dard does not universally result in providing the targeted PNSU* (typically
−6
<1 × 10 ) with high confidence, although it is close. This result is illustrated
in Fig. 7.9. It is noted again that it is compliance with the entirety of the
standard that assures sterility, not merely the bioburden estimates and veri-
fication dose levels.

7.3.5 Point estimates and confidence bounds—Terminal
sterilization; overkill method
This is another terminal sterilization example of point estimates and con-
fidence bounds from quantifiable aspects of the terminal sterilization val-
idation process. As noted in Section 7.3.4, there are many aspects of the
terminal sterilization process in ISO standards to assure sterility. This is only
part of the standards’ procedures; it is the quantifiable part of the ethylene
oxide process definition Overkill Method. The remainder of the standard
cannot be statistically quantified but is the entirety of what assures sterility.
EO sterilization, ISO 11135:2014 Sterilization of health-care products—
Ethylene oxide—Requirements for development, validation and routine control of

Fig. 7.9 The PNSU* and upper confidence bounds for the ISO 11137-2 Method One.