Case Study: Risk of re-use
The case study described here highlights an example of the risk of re-use of sterilizing filters without conducting a full
re-use process-scale validation. Specific process details are excluded to maintain confidentiality.
In this case, a pharmaceutical company was using a high-area, pleated, sterilizing grade membrane filter cartridge assembly
to prepare a bulk sterile API antibiotic in a solvent for which the selected filter membrane had some limited compatibility.
The limited capability was deemed acceptable and unrelated. Filters were rinsed with water after each use, followed by cleaning
with a caustic solution. The caustic was rinsed from the filter with water (the degree of removal was not quantified or validated).
The filter was then subjected to an SIP cycle between each batch for which it was re-used. The filter was integrity-tested
before and after each batch and consistently passed its recommended integrity test limit for the maximum number of re-use
cycles specified. Sterility tests of each filtered batch were unremarkable, and there were no reports of product nonsterility.
To supplement the level of confidence provided by the filter integrity tests and batch sterility tests, the drug manufacturer
conducted a bacterial challenge on a filter that had reached its maximum specified re-use life. Following challenge conditions
based on the ASTM Standard Test Method for Determining Bacterial Retention of Membrane Filters Utilized for Liquid Filtration (11), bacterial penetration of the filter was demonstrated. It was determined that the used filter no longer met the definition
of a sterilization grade filter (i.e., 100% retention of B. diminuta bacterial at a challenge level of >107 cfu/cm2 effective filtration area) (4). The bacterial retention test of the reused filter failed despite the fact that the filter
continuing to pass integrity tests correlated to 100% bacterial retention under comparable challenge conditions performed
on previously unused filters by the filter manufacturer.
Several key observations were made from this study. First, after re-use, the filter still showed a high bacterial retention
efficiency, but was no longer capable of meeting its 100% B. diminuta retention claim and the regulatory definition of a sterilizing-grade filter. Second, the controlled low bioburden in the product,
coupled with the reduced but still significant retention properties of the filter, was sufficient to prevent detectable bacterial
penetration in the process, as evidenced by the successful sterility tests and absence of product nonsterility events. Third,
the damage to the filter from the re-use process was not detectable by a standard filter integrity test.
This third observation may seem contradictory to those who believe that filter integrity tests can detect any oversized pores,
leaks, or defects that can compromise sterilizing filter performance. The correlation of such tests as forward flow or bubble
point is based on bacterial challenges of intact filters and those with actual membrane or cartridge damage or defects incurred
during filter manufacturing, handling, and installation. The population of filters subjected to the filter manufacturer's
bacterial retention validation and integrity test correlation studies does not include filters with damage caused by end-user
re-use process incompatibilities. These incompatibilities can occur with unvalidated, cleaning, resterilization, and re-use.