IgA/IgM chromatographic depletion enables efficient 20-nm virus nanofiltration of mini-pool caprylic-acid IgG

Global shortages of human plasma-derived immunoglobulin G (IgG) remain a major challenge for treating primary immunodeficiencies, especially in low- and middle-income countries. Ensuring virus safety is essential, and nanofiltration provides robust removal of small, non-enveloped viruses. 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. Depletion of IgA and IgM increased filtration capacity more than threefold and stabilized flux. Dynamic light scattering confirmed the predominance of monomeric IgG and absence of aggregates after chromatography and nanofiltration. Overall, this process combines two complementary virus reduction steps, caprylic acid treatment and nanofiltration, and provides a practical option for LMICs to convert available domestic plasma into IgG; it could also be adapted to the manufacture of hyperimmune or convalescent IgG preparations.