Improving Tangential Flow Filtration Yield

How to maximize product yield and membrane lifetime to enhance a tangential flow filtration process.
Jul 01, 2008
Volume 21, Issue 7


Selection and sizing of membrane flat-sheet cassette devices are critical to a successful tangential flow filtration (TFF) process. To maximize return on investment, the devices should boost product yields while offering cleaning and reuse results that provide superior membrane lifetime cost benefits. In this case, small-scale models were developed and executed to test and evaluate selected membrane devices for a protein concentration–diafiltration application, in which the current device delivered unacceptable product recovery and cleaning and reuse results. The application involved the last purification step of a recombinant bacterial protein. Characterization and optimization of operating process parameters were followed by performance verification at the pilot plant, and by full commercial-scale use of the device selected.

Millipore Corporation
Optimization of tangential flow filtration (TFF) processes and membrane lifetime studies have been previously reported in detail.1–3 However, the application to a final purification step involving a bacterial protein for product yield and membrane lifetime enhancements requires an evaluation based on the nature of the feedstock and the purpose of the purification step. Wang, et al., proposed a 10-cycle lifetime for membranes used in a primary recovery TFF process.2 However, that TFF process was designed to handle human monoclonal antibody (HuMab) cell culture harvest material at the start of purification. In a separate review, Rathore, et al., affirmed the importance of reusing membrane filters for multiple cycles before replacing them, and these researchers provided a basis for conducting validation activities for up to 100 cycles of high-volume monoclonal antibody product.3 To improve a TFF process economically, product yield and membrane lifetime should be maximized.

The commercial-scale process for the application in question did not previously have a reuse strategy in place, and product recovery was not maximized. Historical data for the application showed average product yields of approximately 94% with the current polyethersulfone-based (PES-based) membrane. The PES-based membrane was also too difficult to clean to the required normalized clean water permeability (NCWP) standards to implement a satisfactory reuse strategy. In the current study, selected membrane types were tested in laboratory models and their performances were assessed based on product yields and NCWP recoveries. Laboratory studies demonstrated that regenerated cellulose membranes offer better yields and better reuse potential than PES-based membranes for this application. Optimization of the operating parameters focused on product load per surface area, crossflow rate, and transmembrane pressure (TMP). The combination of selecting a new membrane type and optimizing operating parameters led to significant increases in yield. The regenerated cellulose membranes and the new process delivered up to 100% yields in the laboratory and 99% yields at the pilot-plant scale. The low protein-binding nature of the regenerated cellulose membranes also facilitated simple caustic cleaning regimens and stable NCWP values.

In the end, laboratory-scale membrane lifetime studies of the characterized regenerated cellulose membrane processes showed sustained product yields and satisfactory performance over 30 use cycles. The development, characterization strategy, and summary of results are presented here.


The molecular weight cut-off (MWCO) of a membrane is crucial to the retention capability of the target molecule. The recommended choice is generally a membrane with an MWCO rating of less than 1/3 the size of the molecule to recover.4 Following this rule allows the process characterization to proceed efficiently to select the best operating parameter ranges and to optimize for large-scale trials. In the current study, the existing application used a PES-based membrane with an MWCO of 8 kDa, which is greater than 1/3 the size of the molecule to recover. The new membranes tested had MWCO ratings of 1/3 or less of the size of the molecule of interest.

To demonstrate reproducibility of the laboratory model to the commercial process, the commercial TFF process of interest was scaled down to the appropriate laboratory scale and process conditions. The product load per surface area is a critical parameter to consider when designing the proper small-scale model. Conducting experiments at various loads per surface area is important for studying membrane performance over different product-load ranges and its effects on process cycle times.

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