Improving the Integrity Test Assurance of Multiround Housings Assessments - Pharmaceutical Technology

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Improving the Integrity Test Assurance of Multiround Housings Assessments
The authors describe a novel approach for the integrity testing of large sterile filter systems such as multiround housings and describe a multipoint diffusion test capable of detecting minor failures.


Pharmaceutical Technology


Summary


Figure 6: Multipoint diffusion test on cartridges A, B, C, D, and E. (ALL FIGURES ARE COURTESY OF THE AUTHORS.)
The trials showed that the traditional single-point diffusion test was not accurate enough for multiround housing integrity testing. Subtracting more than 40% from the cumulative individual maximum diffusion values would have detected the failing high-diffusion cartridge (cartridge H), but it also would have increased the risk for getting false-failure test results. Single-point diffusion testing also was incapable of detecting the bubble-point failing cartridge even when the maximum value was reduced by almost 50%.


Figure 7: Multipoint diffusion test on cartridges A, B, C, D, F, and G. (ALL FIGURES ARE COURTESY OF THE AUTHORS.)
The bubble-point test, however, was capable of detecting the bubble-point failing cartridge. If the multiround setup contained the high-diffusion cartridge as the only failing cartridge, the bubble point was incapable of detecting this flawed filter because the high diffusion cartridge did not have a clearly defined bubble-point value below the minimum bubble point. The difference between the expected bubble-point value and the measured bubble point was ≤50 mbar (0.73 psi).


Figure 8: Multipoint diffusion test on cartridges A,B, C, D, F, and H. (ALL FIGURES ARE COURTESY OF THE AUTHORS.)
The multipoint diffusion test was capable of detecting the flawed high diffusive flow filter element respectively low bubble-point filter element. The difference between expected diffusion values and measured diffusion values on the multiround housing was less than 5% (see Figures 6–8).

Discussion

The integrity test of sterilizing filters is a fundamental element in performance and retentivity assurance. Only a test procedure capable of detecting minor failures fulfills the requirements for high-quality assurance. No integrity test would be able to detect an infinite number of small membrane failures. Nevertheless, the production release testing of filter manufacturers and the process validation minimize the risk of those shortcomings.

The described trials were performed with cartridges rejected by the manufacturers' release criteria. Such minor failures are unlikely to happen after production release and could thus represent worst-case conditions.

The tests were performed with polyethersulfone (Sartopore 2) 0.2 m only. Other sterilizing-grade membrane filter cartridges may require different parameters, depending on membrane type, design, and polymer.

Increased safety margins will be required to ensure the same degree of integrity-test reliability for multiround housings larger than 5 x 30 in. Using the simulating approach discussed in this article, one can see that to detect a single failing 10-in. element in an 8 x 30 in. multiround housing, the maximum allowable diffusive flow must be lowered by 37%, instead of 33%

In the future, the authors will perform additional trials using the same type of cartridge to increase the statistical background. Different cartridges will also be tested to determine whether other membrane types and membrane configurations may be tested with the same accuracy.

Pascal Martin* is a project manager at Merial SAS, Lyon, France, tel. +33 4 72 72 39 61, fax +33 4 72 72 34 93,
Magnus Stering is head of Application Services South Europe Filtration, Sartorius Stedim Biotech SA, Aubagne, France. Maik W. Jornitz is vice-president of product management FT/FRT, Sartorius Stedim North America Inc., Edgewood, NY. Jens Meyer is a product manager of integrity testing at Sartorius Stedim Biotech GmbH, Goettingen, Germany.

*To whom all correspondence should be addressed.


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