Reinhard Baumfalk, Ph.D
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Integrating filtration steps into an aseptic pharmaceutical process has some unusual complications. Various factors, such
as particle load, fluctuations in pressure and temperature, and cleaning steps (which may have high temperatures or severe
changes in pH), can cause wear to the filter elements.
Continued performance of the filter elements becomes one of the critical process parameters that must be controlled.1,2,3 Using a filter in a process can lead to various damage phenomena such as irreparable blockage of the filter membrane and
cracks or changes to the membrane or pore structure. While blockage can be easily detected during the process run, cracks
or changes in pore structure cannot be detected that easily.4
There is a method for checking these filter element properties throughout the course of the process—the filter integrity test.
A typical four-step integrity test procedure (algorithm) is Figure 1.5 We will delve first into the test methods and then we will describe how to ease the burden by automating the entire cycle.
Many industry-specific terms are defined in the glossary at the end of this article.
INTEGRITY TEST METHOD
The four integrity test steps are implemented upstream and downstream of the filtration unit in order to be able to detect
any possible changes in filter element properties and thereby supply positive results to confirm the success of the filtration
step. The diffusion test and the bubble point test are established, non-destructive test methods. To determine validity, compare
the test results to the filter manufacturer's tolerance data. The bases of the tolerance data are validation processes conducted
by the manufacturer. These are used to determine tolerances by correlating absolute, destructive test methods (bacteria challenge
test) with filter integrity tests. Both test methods rely on a procedure of wetting the filter membrane with a pre-defined
medium (typically ultrapure water, but also customer-specific liquids).4
To start the automatic filter test, the filtration housing is disconnected from the actual process, or the filter is installed
in a separate test housing. In this procedure, the filter element is pressurized at a specific value on the upstream (non-sterile)
side. At this test pressure, the diffusion through the filter membrane is determined for values starting at 0.1 mL/min. By
contrast, when the bubble point test is carried out, the applied test pressure is raised successively and the diffusion measured
in parallel is monitored to determine any disproportionate increase. This increase in diffusion is caused by the wetting medium
being pressed out of the pores of the filter membrane, which initially occurs in the largest pores, thereby providing information
about the upper limit of the pore size distribution. Typical bubble point values for microfilters range between 3,000 mbar
and 4,000 mbar and, in ultrafiltration, can go up as high as 8,000 mbar. These methods also allow reliable detection of cracks
or blockage.
Air filtration also needs a filter integrity test method to guarantee the sterility of critical parameters. Applications for
these filter elements include pharmaceutical and biotechnological production systems. Unlike liquid filtration, air filtration
elements are based on hydrophobic membranes, which prohibit the test methods previously mentioned (membrane wetting with ultrapure
water).
In this context, an alternate, non-destructive method—the water intrusion test (WIT)6 —is an established test. During the WIT test, or the very similar water flow test (WFT), the penetration of water into the
hydrophobic membrane is measured under pressure and evaluated by comparing the results to a limit value. Additionally, this
filter type can be tested by a diffusion test after wetting the membrane by liquids with low surface tension such as isopropanol
or mixtures of WFI and isopropanol.
