Improving Tangential Flow Filtration Yield - How to maximize product yield and membrane lifetime to enhance a tangential flow filtration process. - BioPharm International

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Improving Tangential Flow Filtration Yield
How to maximize product yield and membrane lifetime to enhance a tangential flow filtration process.


BioPharm International
Volume 21, Issue 7

The ELISA analyses performed on the blank-run samples showed satisfactory clearance of residual protein from the system on completion of the cleaning cycles. These results demonstrated that the regenerated cellulose 5 kDa membranes can be cleaned to the required acceptance criteria with a 0.2 N NaOH solution at 25 C and with processing conditions similar to those used in product processing. The execution of the blank runs spread throughout the 30-cycle schedule (with one at the very end), and their satisfactory results provide justification to support effective clearance and no carryover of product at a 17 g/m2 load for up to 30 run cycles. These results are representative of the projected commercial process load in conjunction with the membrane material to be used; however, these results do not take into account the potential differences introduced by commercial-scale equipment. These differences must be studied using commercial-scale equipment.

COMMERCIAL SCALE-UP

Following completion of all laboratory and pilot-scale development, the process improvement project is introduced to commercial operations. The success of the project requires a collaborative effort among process development, operations, automation, validation, regulatory affairs, quality, analytical sciences, and related support groups. Clear goals must be set, and project planning plays a crucial role in establishing and ensuring the completion of each milestone.


Table 3. Comparative summary of the changes involved with the introduction of the new membranes to commercial large-scale TFF processing
For the current protein application, and based on the development work previously discussed, the changes proposed to the current commercial operation are illustrated in Table 3. The first step was to evaluate, develop, and incorporate the required changes to the automation code to carry out the new operation. Close collaboration with automation was crucial to ensure the introduction of new process parameter setpoints, ranges, and alarms.

Water runs were performed to challenge the new automation code and TFF system performance with the new process parameters. In addition to verification of new code functionality, other tests were performed, such as tests to verify total system hold-up volumes and minimum displacement volumes along piping sections. These tests were useful for designing the appropriate recovery strategy, and for ensuring that the proposed recovery sequence did not overshoot the specified product concentration target. Other tests involving utilities and mechanical elements of the system were executed to verify air pressures, pump capacities, and other functionalities that might be affected because of proposed changes.

Once all automation work was completed and functionality was verified, large-scale engineering runs were scheduled to challenge the new process with product. An important part of the engineering runs was sampling and analytical testing. In addition to the required testing for quality and validation purposes, samples were taken throughout the various phases of the process for mass balance calculations. Protein concentration was determined and, along with process weight data, a detailed mass balance was performed.

Engineering lot preparation activities included all the activities associated with the membrane installation, flushing, cleaning, integrity testing, and equilibration. Because the filtration area was being increased from 20 m2 to 30 m2 and the devices varied, researchers evaluated the removal of the preservative in which the devices are shipped. Samples were collected during the initial water flush phase and were analyzed for preservative concentration. The flushing studies concluded that 600 L of water through both the retentate and permeate sides was enough to clear the preservative solution from the membranes to below the limit of quantification (LOQ) of the analytical method.

Pre-use cleaning and integrity testing included incorporation of the cleaning phases tested at the laboratory and the initial NCWP measurement. Caustic clearance from the system was evaluated by collecting samples during water flushing and rinses until the specified conductivity criteria and neutral pH conditions were achieved. To ensure proper installation of the devices and to verify the integrity of the membranes, air diffusion testing was performed on the cassette assembly, and the diffusion rate was compared to the accepted criteria for the devices. The NCWP measurement and equilibration phases completed the membrane preparation activities to set up the system for processing.


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