Protein Fouling of Virus Filtration Membranes: Effects of Membrane Orientation and Operating Conditions

Abstract

The capacity of virus filters used in the purification of therapeutic proteins is determined by the rate and extent of membrane fouling. Current virus filtration membranes have a complex multilayer structure that can be used with either the skin-side up or with the skin-side facing away from the feed, but there is currently no quantitative understanding of the effects of membrane orientation or operating conditions on the filtration performance. Experiments were performed using Millipore's Viresolve 180 membrane under both constant pressure and constant flux operation with sulfhydryl-modified BSA used as a model protein. The capacity with the skin-side up was greater during operation with constant flux and at low transmembrane pressures, with the flux decline or pressure rise due primarily to osmotic pressure effects. In contrast, data obtained with the skin-side down showed a slower, steady increase in total resistance with the cumulative filtrate volume, with minimal contribution from osmotic pressure. The capacity with the skin-side down was significantly greater than that with the skin-side up, reflecting the different fouling mechanisms in the different membrane orientations. These results provide important insights for the design and operation of virus filtration membranes.

Effect of solution pH on protein transmission and membrane capacity during virus filtration

“…Similar results were reported during filtration of bovine serum albumin (BSA) solutions (Higuchi et al, 2004). Syedain et al (2006) examined the effect of operating conditions and membrane orientation on BSA fouling during virus filtration. The capacity for the Viresolve 180 membrane with the skin-side up increased with decreasing pressure and when operated at low flux (for constant flux experiments).…”

“…The large values of the observed sieving coefficient (S o ¼ C f /C b ) are consistent with the high degree of internal concentration polarization within the membrane substructure that occurs when the membrane is operated in the skin-side down orientation. This type of internal polarization has been discussed previously by Syedain et al (2006).…”

“…Current applications of virus filtration use disposable normal flow filters, with the more open side of the membrane facing the feed stream (Brough et al, 2002). This orientation provides greater capacity than obtained with the skin-side up, which is usually attributed to the capture of protein aggregates and other large foulants within the macroporous substructure thereby protecting the virus-retentive skin layer (Syedain et al, 2006).…”

Plasma surface modification of polypropylene microfiltration membranes and fouling by BSA dispersion

“…Membrane filtration is increasingly used for the separation and purification of protein-containing dispersions [1][2][3]. But fouling is one of the critical factors determining the effectiveness of the membrane process [4,5].…”

Dextran sieving test for characterization of virus filtration membranes

“…Although liquid-liquid porosimetry could be used to study the entire pore size distribution by obtaining data for the intrusion fluid flow rate over a wide range of trans-membrane pressures, these data can be difficult to interpret due to uncertainties in the surface tension, the contact angle, and the detailed pore geometry. In addition, liquid-liquid porosimetry provides data on the narrowest throat in a given flow path through the membrane; it gives no information on the anisotropic pore structure found in most virus filtration membranes, which can have a critical effect on the permeability and fouling characteristics of the virus filter [9]. The net result is that there are currently no methods available that can provide data on the overall retention and pore size characteristics of virus filtration membranes.…”