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

Figure 4
As the PES-based membranes exhibit binding of the protein along the membrane surface when the membrane is exposed to the protein at high TMPs, the transmissibility across the membrane increases and is noticeably higher for the PES-based 8 kDa device. The transmissibilities are even higher at the high protein concentration levels (Figure 4). Data show less transmissibility for the 5 kDa devices, particularly the regenerated cellulose 5 kDa, for which data suggest zero transmissibility. The nonpositive values were the result of the online ultraviolet (UV) meter not being zero-adjusted to provide the correct absorbance baseline for the process buffer solution; however, the trend differences are significant among the devices. The higher the transmissibility, the higher the risk of product loss across the membrane during full concentration–diafiltration processes. As the data show, PES-based 5 kDa membranes are also favorable in terms of product retention capability; however, for our application, historical data have established that PES-based devices pose cleaning and reuse challenges because of their high protein binding. This excessive polarization of PES-based membranes is discussed in detail in the following section of this article.


Small-scale concentration–diafiltration runs were executed to test membrane performance in accordance with operating parameter data from the JF-versus-TMP tests. Based on the JF-versus-TMP trials, crossflow rates and TMP parameter values can be assessed to perform small-scale concentration–diafiltration runs. For the PES-based devices, crossflow rates of 3.0 LPM/m2 at a TMP of 20 psig were selected. For the regenerated cellulose runs, crossflow rates of 2.0 and 3.0 LPM/m2 were selected along with TMPs of 20 and 25 psig. Product load levels of 25, 34, and 51 g/m2 were initially tested to provide a range of the expected protein load to the system. When combining all these options into the experimental design, it is important to note the expected outcomes in terms of process cycle times and large-scale system capacity, because processing at 3.0 LPM/m2 at a TMP of 25 psig may not be possible at large scale if pressure drops are extreme in a large-scale skid. The size and capacity of the large-scale pump should also be considered.

Product recovery schemes are also of critical importance when designing and conducting small-scale model experiments. The initial transfer out of concentrated bulk material from the system was the first step, as it should be for every recovery scheme. A single flush or a series of flushes with the appropriate buffer solution followed the initial transfer out of the runs. Some of the flushes were circulated for times ranging from 5 to 15 minutes at no TMP to allow sweeping of the membrane and release of additional material. Careful attention should be given not to overshoot the final target concentration (if specified) when performing the flushes.

The cassettes used in the scale-down models had membrane areas of 50 cm2 and 0.1 m2. The large-scale commercial process is based on 20 m2 total area; therefore, scale-down factors of 4,000 and 200 were used. The amount of diluted protein material was fixed to provide target product loads of 25, 34, and 51 g/m2 for each case. The benchtop TFF processes were performed with an äKTA crossflow system equipped with Unicorn software to collect and analyze process data. The quality attributes of the final product were verified by analytical methods designed to assess purity, identity, and potential byproducts such as dimers and aggregates. Verification of these attributes is important to investigate potential detrimental effects of the membranes or of the process on the nature of the final product.

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