Sterilization processes are designed using one of three basic approaches (including the overkill method), each of which requires some degree of knowledge of the resistance and population of the bioindicator and bioburden (1). The bioburden method requires detailed knowledge and control over the bioburden resistance and population. The bioburden/biological indicator (BB/BI) method relies on the difference in resistance of the bioburden and BI (see Figure 2). With information about and control over the bioburden population and resistance, sterilization cycles requiring less time and temperature (relative to the overkill method) can be used successfully. Both of these methods allow for lower heat input to the materials being processed (an important consideration for terminal sterilization of filled product containers or the sterilization of in-process fluids and laboratory media), provided that increased attention is paid to presterilization bioburden.

The overkill method relies upon the selection of a lethality level known to be adequate to ensure sterilization without routine control over bioburden. A delivered F ₀ of 12 min is an example of an overkill level of lethality. The basis for this level is that if the bioburden on an article were one million and all of that bioburden consisted of resistant spores with a D ₁₂₁ value of 1 min, then a 10^–6 probability of a nonsterile unit (PNSU) would be consistently attained. Obviously, this reflects worst-case assumptions regarding both the bioburden level and resistance, which would in every instance be lower in the real-world condition. The role of the BI would be to prove that there is a strong correlation between a physically determined F ₀ of 12 min and biological lethality at the location of the indicator. A good correlation between biological and physical lethality ensures that an efficient and well-designed cycle with suitable steam penetration and air removal (where necessary) exists.

If understanding of overkill sterilization were all that is needed, this effort would be complete. The difficulty lies in validating overkill sterilization in a manner that is easily defendable to those unfamiliar with sterilization science and realistic in its execution. The first and simplest step is to define the minimum process objective for the sterilization process. The objective is the universal maximum probability of a single nonsterile unit (PNSU) in 10⁶ units (a PNSU of 1 × 10^–6 for any individual item). This is nothing more than an acceptable risk of contamination, whose origin (in the food industry) goes back many years. This criterion is the same for all sterilization processes, regardless of the sterilization method or the cycle approach used. The expectation is that the routine process will achieve the desired PNSU and that the routine process requirement does not apply to the validation effort. If that were not the case, then there would be no difference in the cycle approaches. The intent is always to establish the process such that it provides the same minimum confidence in the sterilized materials regardless of the varying controls defined.

Table I: Definitions of overkill sterilization and assessments of the validation difficulties for each.

What should be immediately evident is that the various definitions of overkill, and thus the validation of overkill sterilization for moist-heat processes, lack consistency. Simply put, demonstration of overkill is variable depending upon the regulatory or compendial expectations. Perhaps most unfortunate of all, none of the definitions include a requirement for nor provide a means to directly support a PNSU of 1 in 10^–6, which is something every sterilization process is expected to achieve.