Membrane reactor for continuous and selective protein mono-PEGylation

PEGylated proteins are value-added biopharmaceutical products obtained by conjugating poly (ethylene glycol) or PEG with proteins It is difficult to simultaneously obtain both high selectivity and extent of synthesis of mono-PEGylated protein using a conventional batch reaction. This paper discusses a hollow-fiber membrane reactor (HMR) system suitable for addressing this issue. The HMR system was operated in a continuous mode with the protein being pumped directly into the lumen of the fiber and the PEG reagent being introduced in the hollow-fiber in a distributed manner along its length. The PEG concentration at any location within the reactor thereby was lower than the protein concentration, and thus the synthesis of higher PEGylated by-products was suppressed, leading to an increase in selectivity of mono-PEGylation. An additional factor that contributed towards the enhancement in selectivity was the radial concentration gradient of reactants and product within the hollow-fiber, which resulted in the diffusion of mono-PEGylated protein away from the reaction zone, thus further suppressing the synthesis of the higher PEGylated forms. The extent and selectivity of monoPEGylation obtained with the HMR system were significantly higher than that obtained in equivalent batch reaction. Furthermore, a continuous process is much more desirable than a batch process from a manufacturing point of view. (C) 2013 Elsevier B.V. All rights reserved