Purifying biopharmaceuticals: knowledge-based chromatographic process development

• We review process development approaches for the chromatographic purification of proteins.
• We present experimental methods for the determination of protein properties and interactions.
• Methods are connected to mathematical models for performance prediction and optimisation.
• A modular process development concept is introduced.

The purification of biopharmaceuticals is commonly considered the bottleneck of the manufacturing process. Increasing product diversity, along with growing regulatory and economic constraints raise the need to adopt new rational, systematic, and generally applicable process development strategies. Liquid chromatography is the key step in most purification processes and a well-understood unit operation, yet this understanding is still rarely effectively utilized during process development. Knowledge of the composition of the mixture, the molecular properties of the solutes and how they interact with the resins are required to rationalise the design choices. Here, we provide an overview of the advances in the determination and measurement of these properties and interactions, and outline their use throughout the different stages of downstream process development.