Flebogamma® DIF (intravenous immunoglobulin) purification process effectively eliminates procoagulant activities

• Presence of FXIa in IVIG concentrates may pose a thrombogenic risk.
• Flebogamma® DIF manufacturing process includes fractionation and purification steps.
• After pasteurization there is no residual evidence of procoagulant activity marker.
• Activity remains unquantifiable in the final product concentrated at 5–10% IgG.
• Results are similar regardless of the different IVIG manufacturing facilities.

BackgroundStudies have demonstrated that traces of activated factor XI (FXIa) present in specific brands of intravenous immunoglobulin (IVIG) concentrates may pose a thrombogenic risk.AimTo characterize procoagulant activity during fractionation and the elimination capacity of the Flebogamma® DIF (Grifols' IVIG) manufacturing process.MethodsFlebogamma® DIF fractionation steps included cryoprecipitate supernatant (Cryo/S), Fraction (Fr) I supernatant, and Fr II + III suspension. Purification steps included ultrafiltrate I, acid treatment, and pasteurization. Samples were assessed for total protein, IgG, and procoagulant activation markers.ResultsCryo/S showed no procoagulant activity for prekallikrein activator (PKA), kallikrein-like, and non-activated partial thromboplastin time (NaPTT) with normal (-PPP) or FXI-deficient (-FXI) platelet poor plasma. Thrombin generation test (TGT)-PPP and TGT-FXI were <83–148 and <53–197 nM thrombin, respectively. Shortened NaPTTs (100–296 s), high PKA (51–119 IU/mL), kallikrein-like activities (0.043–0.075 ΔAU/min), positive TGTs (98–298 nM), and FXIa (9.5–14.0 ng/mL) were detected in Fr II + III. After pasteurization, no residual evidence of any procoagulant activity marker was observed, including the final IVIG concentrate at 5% or 10% protein. Results were similar in Fr II + III from different IVIG manufacturing facilities.ConclusionsThe Flebogamma® DIF production process is capable of eliminating procoagulant activity because of its purification steps.