Process optimization to remove immunoglobulin A, immunoglobulin M and prekallikrein activator for intravenous immunoglobulin G production

Abstract Background and Objectives The demand for intravenous immunoglobulin (IVIG) is increasing, but supply is limited. Some residual protein contaminants such as prekallikrein activator (PKA) and immunoglobulin A (IgA) can cause severe adverse effects, necessitating a more efficient purification process with high recovery and fewer impurities. Materials and Methods We used IVIG intermediate from caprylic acid precipitation as the starting material. Diatomite adsorption and two‐step anion exchange chromatography (AEX) were employed to remove PKA, Factor XII, prekallikrein and kallikrein. Three resins for the second‐step flow‐through mode AEX were evaluated, and the loading conditions were optimized by Design of Experiments (DoE) and high‐throughput screening experiments to better remove IgA and immunoglobulin M (IgM). Pilot‐scale experiments validated the feasibility of the optimized process. Results Diatomite adsorption (300 g/kg, 1 h) and two‐step AEX could remove PKA, Factor XII, prekallikrein and kallikrein to below the limit of detection. The best AEX resin and optimal loading condition (pH 6.0 with 3.0 mS/cm conductivity) to remove IgA and IgM were obtained. As a result, IgA and IgM could be reduced to 3.83 and 10.70 μg/mL, respectively, with the immunoglobulin G (IgG) recovery over 86.9%. The 800‐L pilot‐scale results demonstrated successful process scale‐up, achieving robust IgG recovery and effective impurity removal for IVIG production. Conclusion The combination of diatomite absorption and optimized two‐step AEX resulted in IVIG preparation with enhanced purity and high recovery.