question: BACKGROUND: Plasma-derived immunoglobulins (IgG) are essential medicines that are in worldwide shortage, especially in low- and middle-income countries. Optimised manufacturing processes can increase supply. We evaluated various new process steps for IgG fractionation. MATERIAL AND METHODS: A crude, worst-case, IgG intermediate obtained by caprylic acid fractionation of cryoprecipitate-poor plasma was used as starting experimental material. It was processed inline by Fractogel® (Merck) TMAE anion-exchanger to deplete IgA and IgM, Eshmuno® P (Merck) anti-A and anti-B affinity chromatography to remove anti-A and anti-B isoagglutinins, 0.3% TnBP-1% Triton X-100 (S/D) treatment, C18 chromatography for removal of S/D agents, and single-pass tangential flow filtration (SPTFF) concentration to 20%. Quality, safety, and recovery were evaluated at small and pilot scales to assess purity, removal of IgA, IgM isoagglutinins, S/D agents, thrombogenic factors, and lack of toxicity in a cell model. RESULTS: The starting IgG intermediate contained approximately 90% IgG, IgA, and IgM and 10% albumin. Fractogel® TMAE, equilibrated in 25 mM sodium acetate-pH 6.0 and loaded with up to 225 mg of IgG/mL, could remove IgA and IgM, with over 94% IgG recovery with preserved sub-class distribution in the flow-through. Sequential Eshmuno®-P anti-A and anti-B columns efficiently removed isoagglutinins. The C18 packing, used at up to 17 mL of S/D-IgG solution per mL, removed TnBP and Triton X-100 to less than 1 and 2 ppm, respectively. The 20% purified IgG was devoid of activated factor XI and thrombin generation activity. DISCUSSION: This purification sequence yields a >99% pure, 20% (v/v) IgG product, depleted of IgA, isoagglutinins, and thrombogenic markers, and should be implementable on various IgG intermediates to help improve the supply of immunoglobulins.