Protein aggregation and its impact on product quality

Abstract

Protein pharmaceutical products are typically active as folded monomers that are composed of one or more protein chains, such as the heavy and light chains in monoclonal antibodies that are a mainstay of current drug pipelines. There are numerous possible aggregated states for a given protein, some of which are potentially useful, while most of which are considered deleterious from the perspective of pharmaceutical product quality and performance. This review provides an overview of how and why different aggregated states of proteins occur, how this potentially impacts product quality and performance, fundamental approaches to control aggregate formation, and the practical approaches that are currently used in the pharmaceutical industry.

Figure 1

Schematic overview of a range of different aggregated states that proteins can adopt either as folded molecule or unfolded/partially-unfolded ones. The latter typically result in aggregates that are difficult to dissociate without extreme conditions (high pressure, temperature, and/or denaturant concentration). Images for liquid-liquid and liquid-crystal phase separation (bottom left) are reproduced with permission from Ref. [8], as are those for aggregate phase separation (bottom right) from Ref. [9].