IgA/IgM chromatographic depletion enables efficient 20-nm virus nanofiltration of mini-pool caprylic-acid IgG: A proof-of-concept study

Abstract

Shortages of human plasma-derived immunoglobulin G (IgG) in low- and middle-income countries, driven by a lack of local plasma fractionation capacity, represent a serious obstacle to the treatment of primary and secondary immunodeficiencies, as well as other diseases for which IgG therapy is indicated. Ensuring virus safety is essential, and small-pore nanofiltration is widely used as an established virus-reduction step for IgG manufacturing. We examined whether removing immunoglobulin A (IgA) and immunoglobulin M (IgM) by anion-exchange chromatography improves the performance of 20-nm nanofiltration applied to small-pool caprylic acid-purified IgG. Cryo-poor plasma was treated with 5% caprylic acid at pH 5.5, concentrated by ultrafiltration, and processed on Fractogel TMAE to deplete IgA and IgM. The IgG flow-through was filtered sequentially through Planova 35N and 20N (or S20N) filters. Direct nanofiltration of caprylic acid–treated IgG with residual IgA and IgM led to rapid membrane clogging and low throughput. In contrast, depletion of IgA and IgM increased filtration capacity more than threefold and stabilized flux. Dynamic light scattering indicated a predominant monomeric IgG population and absence of aggregates after chromatography and nanofiltration. This proof-of-concept process integrates caprylic acid treatment and small-pore nanofiltration as orthogonal, literature-supported virus-reduction steps; however, process-specific virus validation was not performed in this study. Overall, selective IgA/IgM depletion enables robust 20-nm class nanofiltration of small-pool caprylic acid-purified IgG and supports development of scalable workflows using domestic plasma.