Single-use Systems for Filter Integrity Testing
Bioprocessing facilities historically conducted filter integrity tests using hard-plumbed systems with replaceable filter
elements in stainless steel filter housings that required time consuming set-up, validation, and post-production cleaning.
Modern operations use stand-alone single-use systems or single-use components in combination with stainless steel processing
equipment to reduce costs, maximize production efficiencies, and increase facility flexibility. Extending the use of single-use
components to filter integrity testing is an additional way manufacturers can streamline the bioprocess and get product to
market faster.
Single-use components used in filtration and filter integrity testing include disposable capsule filters, bags, tubing, clamps,
and connectors. Connectors are a vitally important interface between the components in these filter systems. They also provide
quick and easy integration of the subsystem into the larger production process. There is a wide range of connection technologies
available, including:
- standard connections used to quickly connect bioprocess fluid sources to filter assemblies
- aseptic connectors that allow process technicians to connect two or more single-use systems together without introducing contaminants
- aseptic disconnects that feature in-line valves to prevent contaminant ingress and fluid egress on disconnection
- single-use steam-in-place (SIP) connectors that can be used to make sterile connections between single-use systems and stainless
process equipment.
These single-use connections offer engineers flexibility in process design to minimize equipment downtime, and are particularly
beneficial in multi-product facilities.
Post-filtration Testing for Upstream Processes and Buffer Preparation
In traditional stainless steel facilities, the ingredients for culture media or buffer are combined with water and mixed in
a mixing tank. The media or buffer are then pumped through stainless steel filter housings containing sterilizing filter elements
with pore sizes of 0.2–0.1 μm and directly into sterile hold tanks.
Figure 1. Single-use components that can replace some of the stainless steel equipment used in cell culture media and buffer
preparation
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Single-use components and systems can replace some or all of the stainless steel equipment used for culture media and buffer
preparation (Figure 1). Single-use tank liners or specialty mixing bag systems can substitute for fixed mixing tanks. Bag
systems with integrated capsule filters can replace both stainless filter housings and sterile hold tanks.
After the process fluid has been filtered into the sterile hold bag, the filter can be quickly and easily detached for post-filtration
integrity testing using valved quick-disconnect couplings. The resulting aseptic disconnection allows technicians to confidently
remove the filter without the risk of contaminating the contents stored in the holding bag, while also keeping the filter
wetted for integrity testing. After removal, filters may be tested using automated equipment by bubble-point, gas diffusion,
or pressure decay methods. After testing confirms filter integrity, the stored cell culture media may be released for continued
processing.
In-process Pre-filtration Testing Between Purification Steps
Because of the high value of biopharmaceutical proteins, preventing product contamination is crucial when testing during downstream
processes, such as between purification steps. In-process pre-filtration integrity testing verifies that filters are capable
of removing biological contaminants before product filtering begins, allowing replacement of failed filters before processing.
This additional step helps manufacturers avoid costly product loss or reprocessing.
Adopting single-use technology in the pre-filtration testing environment offers many of the same benefits as described in
the post-filtration example. However, designing single-use filtration systems to facilitate pre-filtration testing requires
additional components, including a flush collection bag and an optional flush solution supply bag.
Figure 2. A single-use filter assembly
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Figure 2 illustrates a single-use filter assembly that allows in-process pre-filtration integrity testing. To ensure that
no product is lost during testing, a compatible filter flush solution is used to wet the filter. Opening the flush clamps
allows the solution to enter the tubing line to the filter; the flow clamps remain closed during the pre-filtration testing.
After it is wetted, an automated test system pressurizes the non-sterile side of the filter membrane to verify its integrity
through pressure decay. During testing, excess flush solution is captured in a collection bag.
If the integrity test fails, the entire filter assembly may be replaced before processing. After a successful test, the flush
clamps are clamped off and the filter assembly is connected to the process equipment using standard connections. The filter
is then connected to the sterile hold bag using an aseptic connector. The flow clamps are then opened and filtering can begin.
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