Impact of Process Loading on Optimization and Scale-Up of TFF Microfiltration

Tangential flow filtration (TFF) microfiltration has been used as one of the choices for clarification of mammalian cell or microbial cell culture in the biopharmaceutical industry. Unlike the ultrafiltration process for protein concentration and the diafiltration application where the feed solution is relatively clean (free of colloids or larger particles after the clarification/purification process), the microfiltration process needs to handle a rather high-fouling feed stream such as cells, cell debris, colloids, etc. In a previously published article, we discussed that a TFF microfiltration step is limited by a maximum throughput or capacity obtainable under a given set of operating conditions.

Some distinct microfiltration characteristics, such as critical permeate flux, permeate flux control, and maximum throughput were explained in that article. The microfiltration process endpoint with permeate flux control is often determined by the decrease of extracellular product or contaminant sieving (increase of rejection), or increase of transmembrane pressure (TMP) to the maximum process limit (with flux held constant). Kubota et al. have also demonstrated higher protein recovery using permeate flux control compared to the standard TFF TMP control, with clear correlation of cake mass resistance related to membrane sieving, both empirically and theoretically. Typically, the permeate flux controlled method is applied to minimize membrane fouling. In the microfiltration process, fouling is assumed to occur first by pore blockage, with a cake formed over the blocked areas of the membrane. However, even with permeate flux control, the pores in the microfiltration membrane are slowly plugged by small colloidal particles when more feed is processed through the membrane.

These solid loading or volumetric loading/throughput (capacity) limits pose constraints in the microfiltration process. There are no general guidelines yet for volumetric or solid loading to microfiltration processes applied across the biopharmaceutical industry. We conducted studies to quantitatively examine the TFF microfiltration process loading limits on the cell and cell lysate clarification (concentration) and the operating parameters that affect the process end points, comparing the plugging models at constant flow. In our article (see the link below) we described experiments, results and future considerations for microfiltration loading challenges. Plugging models for constant flux filtration were investigated with membrane resistance (or transmembrane pressure) profiles. The experimental data analysis corresponded well with the combined cake/complete pore plugging models.

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