Sterilization specification, lethality

The range of sterilization specifications calculable by these various approaches is summarized in Table 2. It is apparent that very brief sterilization specifications (on the order of 2-3 min holding time at 121°C) are obtainable when the microbiological contamination is completely characterized in terms of numbers and thermal resistances. In practice, such limits on hold times could be difficult to control precisely, are probably insignificant in terms of thermal lethality compared with heat-up and cool-down times, and could prove difficult to sell to regulators. Without complete thermal characterization of thermal resistances, specifications calculable by the bioburden approach are hardly significantly shorter than overkill specifications. Thus, it probably makes practical sense in most cases to choose only between overkill cycles for thermally resistant products and aseptic manufacture for heat-sensitive products. 

The performance qualification (PQ) phase of validation follows the development of the sterilization specifications and of the sterilizer parameters which will deliver them. The purpose of PQ in steam sterilization of pharmaceutical products, equipment, laboratory media, and SIP systems is to confirm that the sterilization specification consistently achieves its intended purpose. The process is run using the parameters derived from process development on (usually) three separate occasions and tested for compliance with a variety of predetermined acceptance criteria. As a subset of PQ, the purpose of bio-validation is to confirm that the lethality expected from the process does not significantly deviate from what is expected. Biovalidation is a test of consistency. If the acceptance criteria are not achieved, there may be need for more process development. 

Bio-validation is usually done against a sterilization specification which delivers less lethality than the lower limit of lethality allowed by the sterilization specification defined for the material being sterilized. It is clearly intellectually flawed to choose to validate something different to that which is ever to be used in practice. So what is the reasoning behind this practice ... 

Bio-validation cycles are therefore designed to ensure that no more lethality is delivered than that specified by the lower limits of lethality of the sterilization specification used in routine practice. Ideally this is... 

In the European Pharmacopoeia PhEur), a specification of 121°C for 15min is given as the reference condition for overkill sterilization of aqueous preparations. The United States Pharmacopeia (USP) defines a lethality input of 12D. These specifications merit some examination in detail. 

Hundreds of loci are involved in the barley chlorophyll mutation system (Gustafsson, 1955), and tests for sterility in barley, embryonic lethals in Arabidopsis, or quantitative traits in different species probably respond to mutations in thousands of loci. These tests record forward mutation independently of locus specificities inferred from variations in phenotype spectra and from mutabilities of individual genes cf. Ehrenberg et al., 1956 Lundqvist et al., 1968). 

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