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

Such studies are difficult because many parameters may influence results, and very little work has been done to develop control procedures to verify the quality of marketed or self-grown spore suspensions or to standardize the procedures for the inoculation of product or equipment, the exposure to sterilization conditions, and the recovery of survivors.

Once the effect of a sterilization process at the worst-case position is known, a sterilization cycle can be defined in consideration of the heat sensitivity of the product, the expected bioburden, and the necessary biological effectiveness to be achieved. It may be that a process that is considered an overkill process in most parts needs special precautions to reduce the bioburden at worst-case positions.

Test pieces that simulate worst-case positions (e.g., vials inoculated between the stopper and the glass) may then be used to verify that the sterilization processes used in the production of pharmaceuticals correctly deliver the conditions needed to achieve the necessary sterilizing effect. Such customized test pieces are product and process oriented but otherwise similar to the conventional worst-case devices used in the ISO approach. Whether commercially available BIs on carriers are suitable to simulate worst-case conditions must be decided for each specific case.

A process characterized and validated with such an approach would then be routinely monitored by physical tests, and the biological effectiveness could be deduced from the measured physical parameters.

Klaus Haberer, PhD,* is the managing director and Korinna Vreden is the head of laboratory, both at Compliance Advice and Services in Microbiology GmbH, Robert-Perthel-Str. 49, D-50739 Cologne, Germany, tel. +49 (0) 221 957457 0, fax +49 (0) 221 957457 25,

*To whom all correspondence should be addressed.

Keywords: sterilization processes, biological indicators, steam sterilization


1. S.L. Rubio and J.E. Moldenhauer, "Effect of Rubber Stopper Composition, Preservative Pretreatment and Rinse Water Temperature on the Moist Heat Resistance of Bacillus stearothermophilus ATCC 12980," PDA J. Pharm. Sci. Technol. 49, 29–31 (1995).

2. I.J. Pflug and G.M. Smith, "Survivor Curves of Bacterial Spores Heated in Parenteral Solutions," in Selected Papers on the Microbiology and Engineering of Sterilization Processes, 5th ed., I.J. Pflug, Ed. (Environmental Sterilization Laboratory, Minneapolis, MN, 1988), pp. 25–65.

3. J.E. Moldenhauer et al., "Heat Resistance of Bacillus coagulans Spores Suspended in Various Parenteral Solutions," PDA J. Pharm. Sci. Technol. 49, 235–38 (1995).

4. K. Sasaki et al., "Effect of Calcium in Assay Medium on D-value of Bacillus stearothermophilus ATCC 7953 Spores," Appl. Environ. Microbiol. 66 (12), 5509–13 (2000).

5. T.C. Penna et al., "The Effect of Media Composition on the Thermal Resistance of Bacillus stearothermophilus," PDA J. Pharm. Sci. Technol. 54, 398–412 (2000).

6. T.J. Berger et al. "The Effect of Closure Processing on the Microbial Inactivation of Biological Indicators at the Closure-Container Interface," PDA J. Pharm. Sci. Technol. 52, 70–75 (1998).

7. The United States Pharmacopeial Convention, Chapter ‹1035›, United States Pharmacopeia 30, CD edition (2007).

8. I.J. Pflug, Microbiology and Engineering of Sterilization Processes, 10th ed. (Environmental Sterilization Laboratory, Minneapolis, MN, 1999), p. 9.6.

9. ISO 18472, "Sterilization of Health Care Products—Biological and Chemical Indicators—Test Equipment," 2005.

10. EMEA, "Decision Trees for the Selection of Sterilisation Methods," Annex to Note for Guidance on Development Pharmaceutics, 2000.

11. European Pharmacopoeia, Chapter 5.1.1 "Methods of Preparation of Sterile Products," 5.7th ed. (Council of Europe, Strasbourg, 2007).


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