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


Models of sterility assurance. There are several models that can be applied to achieve sterility assurance. In the ISO approach, (mainly applied in hospitals and in the manufacture or treatment of medical devices) conventional worst-case devices are defined. For example, stacks of tissue of defined dimensions or hollow tubes of defined diameter and length are loaded with BIs or chemical indicators of saturated steam. These devices are placed at arbitrary positions in ill-defined sterilizer loads. When BIs are inactivated after a sterilization cycle, the cycle is considered effective.

The approach taken under GMP regulations is different. It is expected that each product-specific sterilization cycle is validated separately. The sterilizer load must be defined and the worst-case position must be characterized for each process. Sterilization effectiveness of the cycle should be correlated to the effect obtained at the true worst-case position and not to the effect obtained in a conventional worst-case device.

A third option seems to be favored by some regulators at present. The product to be sterilized is expected to be manufactured under extremely stringent conditions to ensure an extremely low presterilization bioburden. This is apparently seen as important because of the lack of confidence in the validation of the sterilizing effect obtained under worst-case conditions. The goal of this approach is to minimize the probability of survival at ill-defined worst-case conditions by minimizing the presterilization bioburden.

Definition of worst-case positions and worst-case conditions. The effectiveness of steam sterilization is influenced by a number of critical factors. Sterilization temperature and exposure time are the only factors that are considered in F-value or F0-value calculations of sterilization processes. It must be clear that such calculations are valid only when all other factors that influence the inactivation of microorganisms are duly considered. Steam quality is a critical factor in all cases in which steam comes in direct contact with the product or surface to be sterilized. Steam quality may be of minor significance where steam is used only as a means of heat transfer and where heat exchange is achieved rapidly by conduction or radiation.

The worst-case position in a sterilizer load is where the sum of all the influences on microorganisms, including the effect of the product or the influences of the microenvironment results in minimal inactivation. The conditions achieved at that worst-case position are the worst-case conditions for the sterilization process.

Worst-case positions can be determined only in studies using bacterial endospores during product and process development because the worst-case positions are difficult to predict. The worst-case conditions should be simulated in BI studies as closely as possible and the sterilizer conditions needed to achieve the required effect therein should be reflected in the parameters to be measured when the sterilization process is monitored.

Overkill cycles. The term overkill cycles for highly effective sterilization cycles is misleading and should be abandoned. Following the USP definition, the Ph.Eur. standard cycle for steam sterilization is an overkill cycle. It is sufficient to inactivate 15-log scales of a resistant microorganism with a D-value of 1 min. If the D-value of the BI is 1.5 min (as defined in Ph.Eur.), then the inactivation is only 10 logs, which means that it is just sufficient to deliver the kill time for a BI with 106 viable spores/unit. If the area between the stopper and the glass wall of a vial is taken as the worst-case position, then the cycle might not even kill 6 logs of endospores of the most resistant environmental isolate, and the cycle may qualify for a bioburden-oriented cycle at best.

A sterilization cycle in of itself cannot be considered an overkill cycle unless the effect is related to a given situation in which a given maximum number of organisms of a given maximum resistance under defined worst-case conditions is considered.

A risk-based approach. Worst-case positions of loads or equipment to be sterilized and the worst-case conditions achieved therein must be specified for each sterilization cycle. Because these are the conditions in which the least biological effect is achieved, quantitative studies on inoculated bacterial endospores are needed to investigate and determine the minimal lethal effect achieved by a sterilization cycle.


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