Advancements in Low-Cost, non-Conventional Bioprocessing Methods for Therapeutic Proteins

Abstract

Protein-based drugs are becoming increasingly important both therapeutically and economically. However, these drugs are complex and costly to manufacture, making them difficult to access for many patients and not feasible for disease indications requiring large volumes and low costs. Therefore, advances are needed in protein drug manufacturing and especially in downstream processing, which represents the greatest bottleneck in modern protein drug processes. Here, we present a range of new protein purification methods as well as critical analyses of existing methods, focusing on separations that exploit changes in chemical phase as a low-cost alternative to chromatography. First, we develop a low-cost and highly scalable purification method for the clinical-stage antiviral Griffithsin. We show that the method dramatically improves upon the current process for production of clinical trial material. Second, we extend the Griffithsin purification method by scaling it up and integrating it with an auto-inducible cell lysis method, increasing purification performance enough to enable a complete clinical-quality process without any conventional chromatography. Finally, we conduct a meta-analysis of phase change-based protein purification methods. We show that, contrary to the common assumption in the field, the major barrier to adoption of these methods is cost rather than purification performance, and we identify for the first time the key factors driving purification costs across a wide range of such methods.