A relatively recent advance in biopharmaceutical processing has been the use of single-use disposable technologies. Single-use disposable technologies include tubing, capsule filters, single-use ion exchange membrane chromatography devices, single-use mixers, bioreactors, product holding sterile bags in place of stainless steel vessels (i.e., sterile fluid containment bags), connection devices, and sampling receptacles (1). The drivers for the implementation of such technology include improved sterility assurance, greater flexibility for biopharmaceutical manufacturing processes, reduced processing times, and cost and energy savings associated with the avoidance of washing, drying, and sterilizing stainless-steel equipment (2).
These advantages notwithstanding, the application of single-use sterile disposable technology in the biopharmaceutical industry remains in its infancy and there are several important validation steps to be considered. These steps relate to product compatibility issues (e.g., extractables and leachable) and to sterility assurance. This paper addresses an important aspect of sterility assurance: ensuring that single-use systems are sterile and that the process of rendering single-use systems sterile does not damage the device or cause adulteration of the product.
The primary method for the sterilization of single-use technology is by gamma irradiation. This is because plastics cannot be subjected to heat-based methods of sterilization without damaging the mould (i.e., styrene and other plastics are temperature sensitive) (3). Other alternative methods, such as gaseous sterilization by ethylene oxide, that although used on occasions, can leave unwanted and potentially toxic residuals (e.g., ethylene glycol and ethylene chlorhydrin) post-sterilization (4). Other alternative sterilization methods (e.g., liquid peracetic acid immersion system and plasma sterilization processes) are not sufficiently well established (5). Electronic beam irradiation is an alternative method of radiation to gamma. This is a concentrated, highly-charged stream of electrons generated by the accelera tion and conversion of electricity (6). Electronic beam radiation is not commonly used for single-use disposable systems due to its relatively limited ability to penetrate some types of plastics (7). Therefore, single-use systems are typically sterilized using gamma rays (i.e., electromagnetic wave radiation) (8). Despite the widespread application of the gamma irradiation, the process remains the only primary sterilization method not described in either the European Pharmacopoeia or United States Pharmacopeia (USP).This paper outlines the process of gamma radiation and describes the important aspects of validation. The paper is designed to provide a guide to those wishing to understand more about the process and to offer advice for quality assurance personnel who are required to audit the sterility assurance of gamma radiation.
Single-use disposable technology
Single-use disposable technologies have been used in biopharmaceutical processing since the 1970s on a limited scale. It is only since the 21st century that such technologies are being implemented for large-scale manufacturing (e.g., upstream, downstream, and product filling applications). The forces driving the wider adoption include improving or eliminating cross contamination, sterility assurance, process efficiencies, operator protection, and cost savings.
Single-use disposable technologies are generally manufactured from plastic polymers involving processes of injection molding, extruding, and blow molding. The applications include devices for making aseptic connections, sampling devices, mixing devices, product-hold bags, and disposable manifold systems. Each of these systems is used to process or contain fluids including additives, buffers, bulk intermediates, and final formulations.
Before single-use technologies can be adopted, a number of tests must be performed in relation to design, microbial inhibition, chemical computability, and leachables and extractables (9).