Pre-Use/Post-Sterilization 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 if he has used an integral filter or not. One method used widely to check integrity of a filter is the bubble point test. To confirm that the filter used is integral, post-use integrity test is made obligatory by regulatory bodies. However, Pre-Use/Post-Sterilization 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 consequent possibility of a non integral filter passing post-use integrity testing. The results clearly show an increase in post-use 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, an ophthalmic. The study was conducted with 0.2 micron sterilizing filters from four different manufacturers. It was observed that some fluid streams show a significant increase in the post-use Bubble Point test values over the pre-use Bubble Point values. This establishes the necessity of performing PUPSIT in certain cases based on the post filtration 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.