A Risk-Based Approach to the Use of Biological Indicators in the Development and Control of Steam-Sterilization Processes - Pharmaceutical Technology

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A Risk-Based Approach to the Use of Biological Indicators in the Development and Control of Steam-Sterilization Processes
Validating the sterilization process is extremely important in pharmaceutical manufacturing. The authors explore different types of sterilization processes and discuss the importance of finding the worst-case positions of loads or equipment to be sterilized and the worst-case conditions for each sterilization cycle. Biological indicators (BIs) can be used to simulate worst-case scenarios and determine the effectiveness of a particular sterilization process.

Pharmaceutical Technology

In general, all overkill processes are built upon the assumption that the bioburden is equal to one million organisms and that the organisms are highly resistant. Thus, to achieve the required probability of a nonsterile unit that is less than one in a million, a minimum 12 D process is required. A 12 D process is defined as a process that provides a lethality sufficient to result in a 12 log reduction, which is equivalent to 12 times a D value for organisms with sufficiently higher resistance than the mean resistance of bioburden.

Endless discussions have been led on the number of orders of magnitude by which a resistant spore preparation must be inactivated for a sterilization process to be called an overkill process. Is there a requirement for 12 logs of inactivation as defined in USP or are 8 logs sufficient? And what is the prerequisite D-value of the resistant organisms or BI at 121 C? Is it 1 minute or 1.5 minutes? Or should the definition of an overkill process be based on the theoretical effectiveness of a sterilization process, the F-value, or the standardized F 0-value (8)?

Matters to consider when testing and selecting a BI
The outcome of these discussions can be meaningful only if the subject is precisely defined and clearly understood by everybody. Several points must be clarified that are also not precisely stated in USP (see sidebar "Matters to consider when testing and selecting a BI").

To characterize an overkill sterilization process, the desired (and claimed) effectiveness of the process must be defined. If the overkill effect is defined from inactivation of a large number of resistant spores in a reference position, it is essential to understand how this correlates to the sterilizing effect in worst-case positions. For example, how does the effect seen on paper-strip BIs distributed in the autoclave chamber correlate to the effect on spores in sealed containers or on the surface of polymeric stoppers? How does the effect on paper-strip BIs distributed in easily accessible vessels correlate to the effect on spores on a difficult-to-reach valve in complex SIP equipment?

Bioburden-oriented or combination sterilization processes. Other sterilization processes than overkill processes are targeted to achieve complete inactivation of the bioburden at minimal heat input. This approach is chosen especially to sterilize heat-labile products. Targeted bioburden-oriented or combination processes rely on the experience that presterilization intermediates in pharmaceutical production can be manufactured under stringent precautions to achieve a very low bioburden. In addition, the environmental isolates of heat-resistant microorganisms are, in all experience, far less heat resistant than spores of Geobacillus stearothermophilus, the microorganism whose endospores are most frequently used in BIs.

Commercially available BIs on carriers
For targeted sterilization processes, it is most important to ensure the target bioburden is not higher than expected. It is even more critical for these processes than for overkill processes to characterize the sterilizing effect of the cycle at worst-case positions in the load to be sterilized. BIs containing customized spore preparations (e.g., the most resistant spore preparations harvested from the product or production environment) are sometimes used to demonstrate sterilization effectiveness at worst-case or reference positions.


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