Pre-Use/Post-Sterilization Integrity Testing (PUPSIT) continues to be a much-discussed topic in the manufacture of sterile pharmaceutical and biopharmaceutical products. This article summarizes the outputs of a multi-year consortium between BioPhorum and the Parenteral Drug Association (PDA) on the topic.
It is generally recognized that post-use filter integrity testing is sufficient to detect filter failure and ensure patient safety unless there is a possibility that a filter passing the post-use test could have allowed bacterial penetration during filtration. This possibility is the phenomenon referred to as filter “flaw masking”, hypothesized to occur when, for example, a filter is damaged during sterilization such that it allows bacterial penetration, but that the damage becomes plugged during the filtration process to such an extent that it allows the filter to exhibit a passing post-use integrity test result. Two workstreams within the SFQRM consortium were designed specifically to evaluate the risk of this filter flaw masking and to understand in what conditions it might occur: Masking Studies, and Bacterial Challenge Test (BCT) Data Mining.
The objective of the Masking Studies workstream was to determine if the hypothesized masking phenomena can occur and under what conditions. To directly evaluate the possibility of filter flaw masking, this workstream executed tests where marginally flawed filters were challenged with a proteinaceous solution to plug the defects and create a passing post-use integrity test.
The following sets of flawed filters were used for the tests:
- Cartridge filters rejected from filter manufacturing lines due to marginally out-of-specification integrity test results
- Disc filters with intentionally created defects generated by laser-drilling 10 μm holes in 47mm flat disc membranes.
The results of the masking studies workstream show that flaw masking can be made to occur, but it is not likely to occur under typical drug manufacturing conditions. These studies also demonstrate some criteria for evaluating the risk of masking: If companies manufacture products with unusually high foulant concentrations and use filters to levels that approach blockage conditions, then the risk of masking may be relevant. However, if filtration processes use systems that are appropriately sized, experience minimal flow decay and filter blockage, then the risk of flaw-masking will be minimal.
Bacterial Challenge Test (BCT) Data Mining
The consortium identified an additional way to evaluate the risk of flaw masking which doesn’t require finding (or creating) defective filters. Any fluid with a flaw-masking mechanism should also cause an increase in the bubble point value of an integral filter. In other words, the relative movement of a bubble point value between a pre-use test and a post-use test of an integral filter can indicate whether a flawmasking mechanism is present.
The “BCT Data Mining” workstream used this concept to evaluate historical integrity test results from over 2,000 filters used in bacterial challenge tests (the bacterial retention validation performed on sterilizing filters). These historical tests provide an opportunity to evaluate whether a bubble point inflation mechanism (and thus a risk for fl aw masking) exists for any given fluid and filter combination.