Role of membrane structure on the filtrate flux during monoclonal antibody filtration through virus retentive membranes

Virus removal filtration is a critical step in the manufacture of monoclonal antibody products, providing a robust size-based removal of both enveloped and non-enveloped viruses. Many monoclonal antibodies show very large reductions in filtrate flux during virus filtration, with the mechanisms governing this behavior and its dependence on the properties of the virus filter and antibody remaining largely unknown. Experiments were performed using the highly asymmetric Viresolve® Pro and the relatively homogeneous Pegasus™ SV4 virus filters using a highly purified monoclonal antibody. The filtrate flux for a 4 g/L antibody solution through the Viresolve® Pro decreased by about 10-fold when the filter was oriented with the skin side down but by more than 1000-fold when the asymmetric filter orientation was reversed and used with the skin side up. The very large flux decline observed with the skin side up could be eliminated by placing a large pore size prefilter directly on top of the virus filter; this improvement in filtrate flux was not seen when the prefilter was used inline or as a batch prefiltration step. The increase in flux due to the prefilter was not related to the removal of large protein aggregates or to an alteration in the extent of concentration polarization. Instead, the prefilter appears to transiently disrupt reversible associations of the antibodies caused by strong intermolecular attractions. These results provide important insights into the role of membrane morphology and antibody properties on the filtrate flux during virus filtration.

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Work Title Role of membrane structure on the filtrate flux during monoclonal antibody filtration through virus retentive membranes
Access
Open Access
Creators
  1. Matthew Billups
  2. Mirko Minervini
  3. Melissa Holstein
  4. Hasin Feroz
  5. Swarnim Ranjan
  6. Jessica Hung
  7. Haiying Bao
  8. Zheng Jian Li
  9. Sanchayita Ghose
  10. Andrew L. Zydney
Keyword
  1. Virus filtration
  2. Monoclonal antibody
  3. Fouling
  4. Ultrafiltration
  5. Membrane structure
License CC BY-NC-ND 4.0 (Attribution-NonCommercial-NoDerivatives)
Work Type Article
Publisher
  1. Biotechnology Progress
Publication Date March 1, 2022
Publisher Identifier (DOI)
  1. https://doi.org/10.1002/btpr.3231
Deposited July 21, 2022

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Version 1
published

  • Created
  • Added mAb_fouling_filter_morphology.docx
  • Added Creator Matthew Billups
  • Added Creator Mirko Minervini
  • Added Creator Melissa Holstein
  • Added Creator Hasin Feroz
  • Added Creator Swarnim Ranjan
  • Added Creator Jessica Hung
  • Added Creator Haiying Bao
  • Added Creator Zheng Jian Li
  • Added Creator Sanchayita Ghose
  • Added Creator Andrew L. Zydney
  • Published
  • Updated Description Show Changes
    Description
    • Virus removal filtration is a critical step in the manufacture of monoclonal antibody products, providing a robust size-based removal of both enveloped and non-enveloped viruses. Many monoclonal antibodies show very large reductions in filtrate flux during virus filtration, with the mechanisms governing this behavior and its dependence on the properties of the virus filter and antibody remaining largely unknown. Experiments were performed using the highly asymmetric Viresolve® Pro and the relatively homogeneous Pegasus™ SV4 virus filters using a highly purified monoclonal antibody. The filtrate flux for a 4 g/L antibody solution through the Viresolve® Pro decreased by about 10-fold when the filter was oriented with the skin side down but by more than 1000-fold when the asymmetric filter orientation was reversed and used with the skin side up. The very large flux decline observed with the skin side up could be eliminated by placing a large pore size prefilter directly on top of the virus filter; this improvement in filtrate flux was not seen when the prefilter was used inline or as a batch prefiltration step. The increase in flux due to the prefilter was not related to the removal of large protein aggregates or to an alteration in the extent of concentration polarization. Instead, the prefilter appears to transiently disrupt reversible associations of the antibodies caused by strong intermolecular attractions. These results provide important insights into the role of membrane morphology and antibody properties on the filtrate flux during virus filtration.
    • Virus removal filtration is a critical step in the manufacture of monoclonal antibody products, providing a robust size-based removal of both enveloped and non-enveloped viruses. Many monoclonal antibodies show very large reductions in filtrate flux during virus filtration, with the mechanisms governing this behavior and its dependence on the properties of the virus filter and antibody remaining largely unknown. Experiments were performed using the highly asymmetric Viresolve® Pro and the relatively homogeneous Pegasus™ SV4 virus filters using a highly purified monoclonal antibody. The filtrate flux for a 4 g/L antibody solution through the Viresolve® Pro decreased by about 10-fold when the filter was oriented with the skin side down but by more than 1000-fold when the asymmetric filter orientation was reversed and used with the skin side up. The very large flux decline observed with the skin side up could be eliminated by placing a large pore size prefilter directly on top of the virus filter; this improvement in filtrate flux was not seen when the prefilter was used inline or as a batch prefiltration step. The increase in flux due to the prefilter was not related to the removal of large protein aggregates or to an alteration in the extent of concentration polarization. Instead, the prefilter appears to transiently disrupt reversible associations of the antibodies caused by strong intermolecular attractions. These results provide important insights into the role of membrane morphology and antibody properties on the filtrate flux during virus filtration.
  • Updated Work Title, Keyword Show Changes
    Work Title
    • Role of membrane structure on the filtrate flux during monoclonal antibody filtration through virus retentive membranes
    • ! Role of membrane structure on the filtrate flux during monoclonal antibody filtration through virus retentive membranes
    Keyword
    • Virus filtration, Monoclonal antibody, Fouling, Ultrafiltration, Membrane structure
  • Updated Work Title Show Changes
    Work Title
    • ! Role of membrane structure on the filtrate flux during monoclonal antibody filtration through virus retentive membranes
    • Role of membrane structure on the filtrate flux during monoclonal antibody filtration through virus retentive membranes