Abstract
Biopharmaceutical manufacturers and engineers are implementing filter integrity testing procedures that incorporate single-use
systems both upstream and downstream in the manufacturing process to improve their processes and reduce risks associated with
product contamination. This article addresses how single-use components can be incorporated into manufacturers' filter integrity
testing procedures. Specific examples include post filtration integrity testing for a media and buffer, a pre-filtration addition
point (application), and filtrations between purification and formulation steps.
Sartorius Stedim Biotech
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Biopharmaceutical manufacturers are striving to improve processes, increase production efficiencies, and launch new products
faster. One way manufacturers can do this is to conduct filter integrity testing. Process fluids during testing and also throughout
the bioprocess, from upstream culture media and buffer preparation to purification, formulation, and final fill, bioprocess
fluids are filtered to achieve and maintain sterility. Testing the condition of these filters both before and after key production
steps allows manufacturers to identify potential breaches in sterility and re-run a batch process if necessary to minimize
product loss.
Introducing single-use components into these filter integrity test systems reduces the risk of contaminating in addition to
improves process flexibility. This implementation is aided through the incorporation of single-use connection technologies.
Overview of Filter Integrity Tests
Filter integrity testing verifies that the filters used in a bioprocess are functioning properly and are capable of removing
a minimum particle size from filtrate. These tests can be conducted pre- or post-filtration, or both, and are primarily non-destructive.
The standard non-destructive testing methods are bubble-point, gas diffusion, and pressure decay tests.
The first step in all three tests requires that the filter membrane be thoroughly wetted with a flush solution. During testing,
the filter inlet is sealed while controlled pressure, typically in the form of compressed air or other gas, is applied to
the proximal side of the filter membrane. Excess filtrate is allowed to exit the filter outlet to a flush bag or collection
vessel.
In the bubble-point test, pressure is gradually increased until bubbles are observed exiting the filter outlet. The pressure
at which the bubbles are observed indicates whether or not the filter is functioning correctly. This is the simplest test
to perform and requires the highest pressure.
The gas diffusion test uses lower pressure and measures gas as it diffuses through a filter membrane to determine integrity.
During the test, a calibrated gas flow meter is attached to the filter outlet, potentially compromising sterility. Both the
bubble-point and gas diffusion tests typically are conducted post-filtration.
Pressure decay tests do not compromise sterility, are performed at low pressure, and are widely used for in-process testing.
A calibrated pressure gauge is used on the proximal side of the filter rather than using visual observations or an outlet
flow meter as in the other tests. Filter integrity is determined by the rate of pressure decay across the filter; excessive
pressure decay indicates failure.
In addition to non-destructive testing, destructive testing can be conducted post-filtration for the final formulation and
fill process. Rigorous bacterial challenge testing passes a known quantity of challenge bacterium into a filter. The resulting
filtrate is aseptically transferred to growth-promoting medium to confirm that all bacterial cells were retained in the filter.
Bacterial growth indicates filter failure.
