Antibody‐enhanced hepatitis E virus nanofiltration during the manufacture of human immunoglobulin

Abstract

Background: Circulation of hepatitis E virus (HEV) in areas where plasma is sourced for the manufacture of plasma-derived medicinal products (PDMPs) has prompted verification of HEV clearance. HEV exists as quasi lipid-enveloped (LE) and non-lipid-enveloped (NLE) forms, which might be of relevance for HEV clearance from manufacturing processes of antibody-containing PDMPs with solvent/detergent (S/D) treatment upstream of further clearance steps. Study Design and Methods: Presence of different HEV particles in stocks used in clearance studies was investigated, with nanofilters graded around the assumed HEV particle sizes and by gradient centrifugation. HEV removal by 35-nm nanofiltration was investigated in the presence or absence of HEV antibodies, in buffer as well as in immunoglobulin (IG) manufacturing process intermediates. Results: HEV particles consistent with LE, NLE, and an "intermediate" (IM) phenotype, obtained after S/D treatment, were seen in different HEV stocks. In the absence of HEV antibodies, log reduction factors (LRFs) of 4.0 and 2.5 were obtained by 35-nm nanofiltration of LE and IM HEV, consistent with the larger and smaller sizes of these phenotypes. Addition of HEV antibodies enhanced IM HEV removal around 1000-fold (LRF, 5.6). Effective (LRF, >4.8 and >4.0) HEV removal was obtained for the nanofiltration processing step for IG intermediates with varying HEV antibody content. Conclusion: HEV spikes used in clearance studies should be carefully selected, as differences in physicochemical properties might affect HEV clearance. Antibody-mediated enhancement of HEV nanofiltration was

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“…Properties of virus particles enlarging their size, for example, quasi-enveloped HEV 25 as well as antibody/virus particle complexes [23][24][25] enhancing considerably the virus removal capacity of virus retentive filters; therefore, it has to be assessed carefully whether these properties exist under defined feed stream conditions, for example, solvent/detergent treatment prior to virus filtration step and concentration of antibodies specifically reacting with viruses.…”

Filter made of cuprammonium regenerated cellulose for virus removal: a mini-review

“…Several virus clearance studies with emerging viruses were conducted. These results showed that Planova could remove emerging viruses independent of the characters of viruses (Blümel et al 2017 ; Yue et al 2019 ; Kapsch et al 2020 ). As a result, the robust virus removability of Planova was confirmed.…”

“…Subsequently, the secondary particles contact each other to form a gel membrane, which undergoes regeneration and drying to become a dry membrane. A highly interconnected pore structure is formed due to the aggregation of the nodules, i.e., the secondary particles (Kesting 1985(Kesting , 1990Kamide 1990;Kamide et al 1993;van de Witte et al 1996). A membrane formed under v p 0-\ v p c has non-circular pores.…”

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