Tunable protein crystal size distribution via continuous slug-flow crystallization with spatially varying temperature

Abstract

Accompanied with the growth of the biopharmaceuticals market has been the interest in developing processes with increased control of product quality attributes at low manufacturing cost, with one of the approaches being through genuinely continuous manufacturing processes. Part of this interest is in new drug product formulations that extend shelf-life and improve the patient experience. Some of these drug product formulations require the production of protein crystals of controlled size distribution. This article describes a continuous tubular crystallizer in which the size distribution of the produced protein crystals is tuned by controlling the spatial temperature along the tube. Under appropriate buffer and pH conditions, the magnitude and dispersion of product protein crystals are reproducibly manipulated using a fully controlled temperature profile over a residence time of 25 to 30 minutes, and the formation of amorphous precipitates can be achieved under higher supersaturation conditions via the addition of a concentrated precipitant for drug products in which higher solubility is desired. The tunable continuous process for protein crystallization has the potential to become a low-cost platform technology for producing protein crystals for a variety of biologic drug product formulations.