Development of a Large Scale Production Process for BAX 855, a PEGylated rFVIII Product with Prolonged Half-Life

Abstract 4362

Baxter and Nektar have developed BAX 855, a PEGylated form of Baxter’s recombinant FVIII (rFVIII) product based on the ADVATE™ manufacturing process. The conjugation process for preparing BAX 855 uses proprietary stable PEGylation from Nektar Therapeutics. Similar Nektar technology has been successfully employed for marked and licensed PEGylated drug products and drugs in clinical use. The manufacturing process for BAX 855 comprises several steps, including chromatographic purification on a MacroCap SP resin, a strong cation exchanger, which allows the fractionation of species with different PEGylation degrees and concentration of the conjugate collected by an ultra- / diafiltration step leading to the pre-formulated bulk drug substance (BDS). Final formulation of the BDS includes a filling and lyophilization step to obtain the final drug product. The process described is suited to manufacture BAX 855 in gram scale and showed a good batch to batch consistency, ensuring an equivalent product quality for each batch. BAX 855 manufactured by this process has a specific activity similar to that of rFVIII in ADVATE™ and PEGylation degrees in the narrow range of 2 to 3 mols PEG / mol rFVIII. SDS-PAGE and Western blot analysis of BAX 855 confirm the stable PEGylation and demonstrate an increase in the molecular weight of the various FVIII domains. PK studies in different species display longer survival of BAX 855 compared to ADVATE™.