Computational fluid dynamic modeling of alternating tangential flow filtration for perfusion cell culture

Abstract

Alternating tangential flow (ATF) filtration has been successfully adopted as a low shear cell separation device in many perfusion‐based processes. The reverse flow per cycle is used to minimize fouling compared with tangential flow filtration. Currently, modeling of the ATF system is based on empirically derived formulas, leading to oversimplification of model parameters. In this study, an experimentally validated porous computational fluid dynamic (CFD) model was used to predict localized fluid behavior and pressure profiles in the ATF membrane for both water and supernatant solutions. The results provided numerical evidence of Starling flow phenomena that has been theorized but not previously proven for the current operating parameters. Additionally, feed cross flow velocity was shown to significantly impact the localized flux distribution; higher feed cross flow rates lead to an increased localized permeate flux as well as irreversible and reversible fouling resistance. Further, the small average permeate flux values of 2 L·m−2·h−1 traditionally used in perfusion bioreactor membranes lead to approximately 50% of the membrane length utilized for permeate flow during each pressure and exhaust phase, leading to a full membrane utilization during one ATF cycle. Our preliminary CFD results demonstrate that local flux and resistance distribution further elucidate the dynamics of ATF membrane fouling in a perfusion‐based system.

Reduction of medium consumption in perfusion mammalian cell cultures using a perfusion rate equivalent concentrated nutrient feed

“…Contrary to runs 1 and 2, the concentration of the product was not equal in the bioreactor and in the harvest stream. This gradient is referred to as sieving and occurs when the membrane permeability is decreasing 38,39 . High cell densities or addition of antifoam agents are suspected to largely contribute to this effect.…”

“…This gradient is referred to as sieving and occurs when the membrane permeability is decreasing. 38,39 High cell densities or addition of antifoam agents are suspected to largely contribute to this effect. Figure 8 summarizes the different performances that were obtained in this study.…”

Modulation of transmembrane pressure in manufacturing scale tangential flow filtration N‐1 perfusion seed culture

“…Critically, the cell culture performance was not compromised despite the reduced permeate rate. The importance of minimizing filter fouling is relevant not only in perfusion seed cultures, but also production processes to maintain the desired product retention 27,28 . Kim et al demonstrated the need to control the TMP of hollow fiber filters to reasonable levels in order to enhance FVIII yield of their perfusion culture 5 .…”

“…23 We demonstrated through experimentation at small scale that the high TMP observed in our perfusion process is predominantly driven by reversible fouling that is likely an but also production processes to maintain the desired product retention. 27,28 Kim et al demonstrated the need to control the TMP of hollow fiber filters to reasonable levels in order to enhance FVIII yield of their perfusion culture. 5 The reduction in the permeate flow rate at manufacturing scale also resulted in an overall savings of 15% of the perfusion medium required to maintain the 5 days N-1 operation.…”

Virus harvesting in perfusion culture: Choosing the right type of hollow fiber membrane

“…Likewise, fast inversions of the feed flow direction, as described for ATF systems, can be applied. Thereby, membrane sections along the fiber change periodically the flow direction across the membrane facilitating continuous backflushing with each pump cycle (Radoniqi, Zhang, Bardliving, Shamlou, & Coffman, 2018;Figure 1). Although these hydraulic cleaning methods can be effective, they may increase the shear stress on cells and reduce the net flux.…”