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


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

One of the most challenging phases when scaling up TFF processes is the product recovery phase. This phase is highly dependent on proper TFF large-scale system skid design; therefore, the system piping and geometric arrangement must be carefully studied before implementing any of the recovery methods developed at the bench or pilot scales.

A disadvantage of the current system was the location of the dispensing port. The port was located at a high point downstream from the membranes on the retentate return line. To take advantage of gravity effects and to maximize yields, researchers recommended dispensing from the lowest possible point in the system, in this case upstream from the membranes on the feed line. The dispensing port was relocated to the low point, and the recovery strategy was modified to include reverse plug flow rinses of the membrane and to take advantage of gravity effects. Special care was taken to avoid excessive foaming of the bulk protein solution during the various transfer phases of the recovery process, especially when using air-displacement methods. Excessive foaming of the bulk solution could result in aggregation of the protein.

In the end, the full-scale concentration–diafiltration process was completed according to expectations. Final yields were slightly below bench-and pilot-scale results at 97.5%; however, continued fine-tuning of the recovery phase could increase final yields. The flux profiles continued their stable trends between 12.5 and 14.0 LMH, and process cycle times were within expectations. On post-process cleaning of the membranes, a 101.9% NCWP recovery was obtained, which was very similar to data observed during small-scale studies. All analytical testing performed on the samples collected showed satisfactory results, with identity, purity, and quality attributes meeting the established acceptance criteria.


Table 4. Performance summary for the regenerated cellulose 5 kDa membrane devices, from benchtop development to large-scale engineering runs
As summarized in Table 4, the laboratory-scale development, pilot-plant trials, and cleaning and reuse runs provided a solid baseline for a major process improvement involving the change from a PES-based 8 kDa membrane to a regenerated cellulose 5 kDa device. Large-scale engineering runs provided reassurance of all the previous development work results.

The cleaning and reuse capacity of the new membranes was demonstrated, and this fact will allow the commercial operation to develop and implement a new reuse strategy. Once the new membranes are fully implemented, substantial financial benefits are expected, as a result of the projected 3% product yield increase and the reuse strategy.

Carlos A. Dominguez and Esteban Rivera are senior engineers, Carlos Escobar is a principal engineer, and James Weidner is a director, all at bulk process development, Amgen Manufacturing, Ltd., Juncos, PR, 787.916.6909,


1. Rathore AS, Wang A, Menon M, Martin J, Campbell J, Goodrich E, et al. Optimization, scale-up, and validation issues in filtration of biopharmaceuticals, part 2. BioPharm Int 2004;17(9):42–50.

2. Wang J, Diehl T, Watkins-Fischl M, Perkins D, Aguiar D, Arunakmari A. Optimizing the primary recovery step in nonaffinity purification schemes for HuMAbs. BioPharm Int. 2008;3(suppl):4–10

3. Rathore AS, Samavedam R, Morrison R, Kichefski T, Cote S. Lifetime studies for membrane reuse: principles and case studies. BioPharm Int. 2007;20(9):48–54.

4. Protein concentration and diafiltration by tangential flow filtration. Technical brief. Billerica (MA): Millipore Corporation; 2003. Millipore Technical Brief: TB032.

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