Proposed single-use process solution: design considerations
Figure 1: Utilisation sequence options for single-use redundant filtration assemblies. F1 is the first liquid filter. F2
is the second liquid filter.
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Many biopharmaceutical companies already use variations of SURF assemblies for final and bulk fill operations. However, preparation
and utilisation sequences may differ across processes and geographies because of differing national guidelines.
This study reviewed different redundant filtration assembly designs and operating sequences, and proposes a new SURF assembly
that has greater operational robustness and minimises the risk of product contamination. Below are the major design considerations
for the assembly (see Figure 1):
- A barrier filter (0.2 µm, EMD Millipore) was included in the design as a combined liquid and gas outlet. The barrier filter
contains both hydrophilic and hydrophobic sterilising-grade PVDF membrane, which can exhaust both air and water from the assembly.
As a result, it can be used as the initial filter flush outlet and as a sterile air outlet during integrity testing and the
filter drying step. Such a filter further solves the problem of flush volume constraints imposed by the catch bag/tank size.
The assembly can be wetted and tested for integrity multiple times without breaching the sterile envelope.
- Catch bags were attached to the vents of the liquid filters to collect liquid during venting.
- Gamma stable vent filters were attached to the bags to enable passage of air during venting.
- A hydrophobic PVDF filter was added on the air inlet line to ensure sterility of the air coming into the assembly for integrity
testing.
- Single-use sterile connectors were used at the assembly's inlet and outlet to assure sterile connections during operation.
- In-line liquid filter capsules were selected (as opposed to T-line capsules) to reduce the hold-up volume.
- The assembly was used in the vertical orientation to achieve better draining after wetting and during product recovery after
filtration.
The catch bag on the first liquid filter is primarily in place to avoid the liquid spill that can occur during venting for
water flush and product filtration. With some minor modifications, the catch bags on both the first and second liquid filters
can also be used for in-process sampling. The catch bag on first liquid filter and the separate air inlet line (with an air
filter near the feed inlet) are additional features that are incorporated to ensure cleanliness and ease of operation.
Pre-use, post-sterilisation integrity testing of a redundant filtration setup can be challenging. With either stainless steel
or a singleuse assembly, it is critical to maintain setup sterility during every step. The efficiency of the filter wetting
step is also important to avoid false negative integrity test results. For highvalue products, the drying step after integrity
testing is crucial to minimise product dilution. Figure 1 outlines the utilisation sequence for SURF assembly before use. Along with the points mentioned above, operator convenience
and regulatory compliance were also considered.
Figure 2: Total organic carbon (TOC) and conductivity (µS/cm) versus flush volume (mL).
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A flushing test was conducted to record the reduction of total organic carbon (TOC) and conductivity with flush volume. The
filters and assembly were flushed with deionised (DI) water at a flow rate of 250 mL/min for a total of 20 L. The assembly
effluent was sampled at 1 L intervals and tested for conductivity and TOC. Analytical results for flush filtrate samples are
summarised in Figure 2. At the end of 20 L reverse osmosis (RO)/DI water flush, TOC and conductivity were 0.231 ppm and1.1 µS/cm, respectively.
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