Failures in the integrity of single-use systems during commercial manufacturing can cause a number of serious problems for biomanufacturers. A loss of system integrity during processing can allow environmental contaminants that can be dangerous for patients (e.g., microbes) to enter a process. Biopharmaceuticals and their intermediates can be highly potent or even infectious agents, so an integrity failure can jeopardize the safety of operators. In severe cases when biomanufacturers cannot ensure the quality of drug products for fear of a contamination, the supply of life-saving medicines to patients can be restricted. Finally, significant costs can be associated with product losses and quality investigations that arise because of leaks within systems.
It is perhaps unsurprising that single-use container–closures are coming under increasing scrutiny from regulators. At many industry meetings, participants from suppliers, end users, and regulators discuss the topic.
For example, the US Food and Drug Administration (FDA) and the American Society for Testing and Materials (ASTM) ran a workshop in 2016 exploring issues relating to using single-use systems in fill–finish applications. The outcomes of that workshop reflected much discussion happening more broadly such as the recommendation that development of physical integrity tests should be correlated to microbial ingress. Suppliers and biomanufacturers must share the responsibility for container–closure integrity assurance. Reflecting that shared responsibility, workshop participants concluded that packaging integrity validation is needed at both the supplier site and (following shipment and installation) at the biomanufacturing location. It was also proposed that defect sizes that could allow bacterial ingress under process conditions into the critical flow path downstream of sterilizing-grade filters should be identified by microbial challenge testing — thereby allowing a physical integrity test to be developed.