Choosing Overkill Cycle Parameters

Conventionally, the term “overkill cycle" in validation of a steam-sterilization autoclave process is understood to mean that all items were steamed beyond all hope of anything surviving a grossly exaggerated load cycle. This cavalier approach to sterilization validation, however, is no longer enough to satisfy most regulatory inspectors, who have grown accustomed to control strategies based on risk assessment and scientific rational for the mitigation of the identified risks. A more robust, quality-by-design philosophy based in sound science and process understanding is more appropriate and defendable.

A key component when presenting any autoclave validation package is to be able to clearly defend how the requirement to correlate biologic and physical lethality data from the validation reports is satisfied (1). Fulfilling this requirement can provide sound justification for autoclave critical process parameters (CPPs) and how they were validated.

Development work to justify load parameters
When claiming overkill sterilization, one must be careful to have a good scientific rationale for the choice of cycle parameters. Just choosing the time and temperature on a cycle without detailed assessment does nothing to demonstrate control or knowledge of the critical operating parameters of the autoclave cycle or how those are affecting your particular load conditions. Theoretical values cannot be assured throughout a load before mapping with thermocouples is done to assure air removal and equilibration times support these assumptions.

It is necessary to compare theoretical F₀s (i.e., lethality levels) with the actual F₀s delivered in an actual cycle. This real development testing will give a good idea of performance and capability of the autoclave and allow for realistic program-parameter settings.

It may be appropriate to add some time or temperature as a safety factor to account for all of the variables inherent to autoclaving items needed in a manufacturing process. Unknown incoming bioburden load is a reasonable driver to choose an overkill sterilization cycle. However, gross overage indicates a lack of control of the process and a lack of understanding of the appropriate lethality being delivered to load items. Delivered lethality should be well understood from development runs and applied judiciously, even in overkill cycles, in order for validation to be a credible assurance of process functionality.

Fractional cycles as a method of validating overkill cycles
Once actual F₀s throughout loads have been determined in development studies, program parameters may be defined for the autoclave cycles. At this stage, it may be appropriate to use fractional validation load programs, for which the validation cycle program delivers an F₀ close to values needed to inactivate the BIs. The successful completion of this fractional cycle then gives a baseline to which a rational overage may be added for routine manufacturing cycles and justifies the term overkill (2).

By defining a fractional (i.e., partial) cycle time and temperature for validation loads based on an understanding of the autoclave capabilities in conjunction with particular load limitations, an excellent rationale can be made, and manufacturing cycles can be programmed as overkill cycles. The overkill compensates for deviations in time or temperature caused by calibration faults in controlling thermocouples, chamber leaks, variability in packaging and assembling components, or other production events.

Conclusion
Any autoclave validation, for either overkill or product-specific load cycles, must demonstrate the delivered lethality to the most difficult locations using biological and physical data. More than being just a “dead or alive” reading, the bioindicator (BI) does enumerate delivered lethality when assessed appropriately. By knowing the D value of the BIs used and setting the fractional validation cycle to accommodate this value, inactivation can be achieved in the BIs and correlated to the thermocouple readouts. This validated cycle can then be appropriately increased to account for minor process variations to support a robust, validated process. This validation method, firmly based in the accepted tenets of sterilization science and a rational scientific approach, will provide a sound basis for an autoclave sterilization program.

References

1. FDA, Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice, Section IX C 1 (Rockville, MD, Sept. 2004).
2. USP, General Chapter  <1211> "Sterilization and Sterility Assurance of Compendial Articles" (US Pharmacopeial Convention, Rockville, MD, 2013).

—John Anderson is a quality assurance and validation professional with years of inspection experience. He can be reached at johnnyred32@gmail.com.

This article is excerpted from an article on defining and presenting overkill cycle validation, which will appear in the Troubleshooting column of the November 2013 issue of Pharmaceutical Technology.