Microbiological Efficacy of the Cycle
Validation studies that demonstrate the efficacy (lethality) of the production cycle need to estabilished. A sterility assurance of 10 or -6 better should be demonstrated for any terminal sterilization process. The level of sterility assurance should be demonstrated for all parts of the drug product (including the container and closure, if applicable), which are claimed to be sterile. The specific type of study and the methods used to carry out the study (or studies) are product and process specific and may vary from manufacturer to manufacturer. In general, the following types of information and data should be provided.
- Identification and Characterization of Bioburden Organisms
Describe the methods and results from studies used to identify and characterize bioburden organisms. The amount and type of information supplied may be dependent on the validation strategy chosen.
For example, more information may be needed for bioburden-based autoclave processes than for overkill processes. Information concerning the number, type, and resistance of bioburden organisms may be necessary, including those organisms associated with the product solution and the container and closure. It may be necessary to identify the most heatresistant bioburden organisms
- Specifications for Bioburden
Specifications (alert and action levels) for bioburden should be provided. A description should be included of the program for routinely monitoring bioburden to ensure that validated and established limits are not exceeded (e.g., frequency of analysis and methods used in bioburden screening). The methods provided should be specific.
- Identification, Resistance, and Stability of Biological Indicators
Information and data concerning the identification, resistance (D and Z values), and stability of biological indicators used in the biological validation of the cycle should be provided. If biological indicators are purchased from a commercial source, it may be necessary to corroborate the microbial count and resistance, and provide performance specifications.
- The Resistance of the Biological Indicator Relative to That of Bioburden
Studies characterizing the resistance of the biological indicator relative to that of bioburden may be necessary. Resistance in or on the product (i.e., in the product solution, or on the surface of container or closure parts or interfaces) should be determined as necessary. If spore carriers are used (e.g., spore strips), the resistance of spores on the carrier relative to that of directly inoculated product should be determined, if necessary.
- Microbiological Challenge Studies
Microbiological validation studies should be submitted that demonstrate the efficacy of the minimum cycle to provide a sterility assurance of 10 or better to the product under the most difficult to -6 sterilize conditions (e.g., the most difficult to sterilize load with biological indicators at microbiological master sites or in master product or both). Use of a microbiological master product or site should be supported by scientific data. Microbiological master sites or solutions are those sites or solutions in which it is most difficult to kill the biological indicator under sterilization cycles that simulate production conditions.