Radiation sterilization of aseptically manufactured products

This paper discusses an approach for establishing a sterilization dose for an aseptically processed product after the product is in its final packaged state, in other words, terminal sterilization. It applies to aseptic processes where the fill/finish operation is conducted in a closed system using isolator or restricted access barrier technology, that is, no human intervention. The example that is given in this paper uses gamma radiation as the sterilizing agent. Other forms of radiation such as high-energy electrons or X-rays also could serve as the sterilizing agent. The proposed approach involves irradiation of the aseptically processed product at very low doses of radiation, which is possible due to the extremely low levels of bioburden that may be present on the product following a fill/finish operation. Rather than sacrificing a large number of product units that may be required to obtain a statistically significant sampling of the product for bioburden analysis and other test purposes, the test unit is a surrogate consisting of actual pharmaceutical product that was inoculated with a highly radiation-resistant micro-organism. Selection of the microorganism was based on analysis of a library of environmental monitoring data taken from the aseptic area. Because of microbial diversity between different aseptic processing facilities, selection of the test microorganism would depend on the aseptic area under study. The approach that is discussed in this paper addresses selection and preparation of the surrogate, test of sterility of the surrogate following irradiation, determination of the radiation resistance of the test microorganism, and application of the approach to calculate a sterilization dose that is less than 10 kGy. At this low dose, it may be possible to terminally sterilize radiation-sensitive pharmaceutical products, for example, those in liquid form. Additional studies are warranted to determine the general applicability of the proposed approach.