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


A scientifically ideal procedure would be to place bacterial endospores during cycle development at worst-case positions. The inactivation characteristics of the spores at that position could then be correlated to the inactivation of the same spore preparation achieved at a reference position. For such studies in theory, it is vital that the worst-case positions are well defined and bacterial endospores are correctly positioned without alteration of worst-case conditions. Most sterilization processes, however, are not easily amenable to such an analysis. Worst-case positions tend not to be freely accessible or easily inoculated with endospores, and it can be difficult to recover endospores from worst-case positions. In addition, such studies must be performed in production autoclaves or production equipment because various large-scale sterilization processes cannot be simulated with a biological indicator evaluator resistometer (BIER) vessel. Production autoclaves do not deliver heat with square-wave characteristics and, therefore, precise quantitative studies of D-values are not feasible therein.

To evaluate the biological effect of large-scale sterilization processes, test pieces with a defined number of microorganisms and defined resistance to saturated-steam exposure (D-value) should be exposed to actual or simulated worst-case conditions. Test pieces can be paper strips inoculated with resistant spores, units of inoculated product, vials with inoculated stoppers inserted, or pieces of tubing of a length simulating a worst-case exposure. The inactivation characteristics of the test pieces under reference conditions should be determined in a laboratory using a BIER-vessel. The requirements for manufacturing quality control of such test pieces (confectioned BI) are standardized in ISO 11138 (12).

Unfortunately, the definition of true worst-case positions at which BIs are to be exposed is not well understood by many users. The necessary availability of saturated steam or any possible influence of the microenvironment of spores are neglected. Standard paper strips or self-contained BIs are frequently used to simulate various worst-case conditions, and the coldest position measured in a temperature-mapping study of a load is often assumed to be the worst-case position, although this is not necessarily a valid assumption.

To correctly validate a sterilization cycle, it is necessary to use data gathered during product or process development to identify the conditions or positions where inactivation of spores is most difficult to achieve. These conditions should be simulated as closely as possible by suitable BIs. Whether this can be achieved by using a spore preparation on paper strips or a self-contained BI must be decided in each case. In many cases, a better simulation will be achieved with a customized BI that uses units or assembled parts of the product to be sterilized.

Cycle monitoring. Although using BIs as an additional means of monitoring autoclave cycles is recommended in hospitals, this practice is not common in the manufacture of pharmaceuticals or medical devices. Once a sterilization cycle has been validated for standardized defined loads, manufacturers typically rely on physical measurements for cycle control.

Again, the approach taken should be governed by what is intended with the process. In a hospital setting it is impossible to define reproducible loads and, thus, by convention a defined pack of tissue is considered the standard worst-case position. Defined loads are common practice in the manufacture of medicinal products. A pack of tissue would not be a good representation of a worst-case for typical pharmaceutical sterilization processes for the reasons discussed previously.

The situation may again be different in pharmaceutical laboratories engaged in development or quality work, where standardized sterilizer loads also are difficult to define. The less defined a sterilization process is with regard to worst-case positions, the higher the advantage of arriving at a conventional definition of a standard worst-case model. For production processes governed by the rules of good manufacturing practices (GMP), validation of load-specific cycles is generally required, and reliance on standard worst-case models is not accepted in most cases.

Properties and quality of bacterial endospore preparations and biological indicators

D-value of biological indicators. An important prerequisite for the suitability of endospore preparations is their D-value in correlation with the theoretical effectiveness of the process. When BIs are used to validate a sterilization cycle, the normal expectation is that all BIs exposed during the cycle are completely inactivated at the end of the exposure time. For quantitative determination of the sterilizing effect, it is necessary to apply reduced-exposure conditions that leave a fraction of viable endospores that can be quantified. The resistance of the endospore preparations used must be such that meaningful exposure times can be applied to obtain fraction-negative results. Graded fraction-negative conditions typically are used to evaluate the resistance of BIs.


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