Preuse/Poststerilization Integrity Testing (PUPSIT): To Do or Not to Do?

Abstract

In manufacture of heat labile sterile drug products, the final step involves filtration through sterilizing grade filters. It is the drug manufacturer's responsibility to check whether an integral filter has been used. One method used widely to check the integrity of a filter is the bubble point test. To confirm that the filter used is integral, the postuse integrity test is made obligatory by regulatory bodies. However, preuse/poststerilization integrity testing (PUPSIT) of filters remains debatable for the risks associated in its execution. Although PUPSIT is recommended by regulatory bodies, it poses a risk of compromising downstream sterility and involves high costs to mitigate such risks. This study highlights the impact of filter clogging on bubble point values with the consequent possibility of a nonintegral filter passing postuse integrity testing. The results clearly show an increase in postuse bubble point values, which can camouflage a possible flaw in sterilizing filters. The fluid streams 20% dextrose, 0.001% bentonite, paclitaxel, and 0.05% sodium hyaluronate were selected based not only on the commonality of their clogging propensity but also on the different nature of streams that influence the clogging of sterilizing filters. Paclitaxel is an injectable for oncotherapy, and 0.05% sodium hyaluronate is an ophthalmic. The study was conducted with 0.2 μm sterilizing filters from four different manufacturers. It was observed that some fluid streams show a significant increase in the postuse bubble point test values over the preuse bubble point values. This establishes the necessity of performing PUPSIT in certain cases based on the postfiltration shift in bubble point values. As part of the filter validation studies with specific drug products, additional testing should be carried out to establish the need for PUPSIT on a case-by-case basis.

Keywords: Bubble point; Filter validation; PUPSIT; Postuse integrity testing; Preuse integrity test; Specific drug product validation; Sterile drug products; Sterilizing grade filters.