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


For sealed containers, it is important to verify during the development of the sterilization cycle that sterilizing conditions are achieved in all parts of the containers when they reach the sterilization temperature.

In cases in which porous goods are sterilized with the direct access of steam, it is important to verify full penetration of the steam through the pores of the product. Because sterilization conditions in this case are achieved by the direct action of the steam, steam saturation is a critical parameter.

Penetration of steam also can be notoriously difficult to achieve, for example, with filling equipment that has pipes or tubing that is sterilized in place (SIP). Even in processes where air is removed by evacuation, complete air removal may be difficult.

There also may be positions in a load to be steam sterilized that are occluded from the access of steam; for example, the space between the barrel and piston of a filling pump, or the interface between elastomeric stoppers and the necks of glass vials.

Effect of the microenvironment on sterilization efficiency. In addition, the effect of sterilizing conditions can be strongly modulated by the microenvironment encountered by bacterial endospores during sterilization. The decimal reduction time (D-value) of a spore preparation is notoriously different when the spores are presented on a paper strip, suspended in water, or attached to a polymeric surface (1). D-values of spores in solutions can depend on the composition of the solution (2–4). For example, the presence of divalent cations has significant influence on endospore resistance, and D-values are lower in solutions containing high concentrations of glucose (5). Thus, spore inactivation is not dependent solely on the conditions in the autoclave. There are additional chemical and possibly other surface effects that may strongly influence the D-values of suspended or attached endospores.

Such influences of the microenvironment cannot be measured by any physical probes. Using BIs is the only method to directly measure the sterilizing effect, and, therefore, an ideal BI should indicate any effect of product and microenvironment.

Definition of the worst-case position in a sterilizer load. The sterilization effect is achieved as a result of the combined influence of temperature, heat transfer, surface hydration, and all other protecting or inactivating factors that influence endospores during the sterilization process. Therefore, the most difficult-to-sterilize position (the worst-case position) in a sterilizer load should be defined as the position where the sum of all influences on microorganisms results in minimal inactivation.

The relevance of the worst-case position to product safety also should be considered. Although there may be occluded positions in a piece of SIP equipment that are never reached by steam during the sterilization process, such positions also may never come in contact with product. As long as there is no potential to jeopardize the sterility of any product manufactured with that equipment, there would be no good reason why the position should be sterilized. This, however, can be correctly judged only with a thorough understanding of the equipment and the process.

The effect of steam sterilization on microorganisms trapped between the polymeric stopper and the vial in terminally sterilized pharmaceuticals has been discussed (6). The relevance of that position to the sterility of the contents of the vial is critical for the decision of whether that is, in fact, the worst-case position of the load. As long as deformation of elastomeric stoppers during the cooling phase of autoclaves cannot be excluded, such a position certainly would have to be considered as relevant for the sterilization effect.

Overkill processes. The necessary sterilization assurance is described in United States Pharmacopeia: "A sterilization process must result in a biologically verified lethality sufficient to achieve a probability of obtaining a nonsterile unit that is less than one in a million" (7).

In cases in which the product to be sterilized is very heat resistant, sterilization processes are usually designed to achieve inactivation of microorganisms by a wide margin of safety. Such overkill processes are frequently defined on the basis of their ability to inactivate a given number of microorganisms. Overkill processes are defined in USP 30 as follows:


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