Challenges and developments in the manufacturing of high-concentration biotherapeutic monoclonal antibodies

The past two decades have witnessed the rise of biotherapeutics as safe and effective solutions for curing or managing a spectrum of hard-to-treat diseases. Monoclonal antibodies (mAbs) form one of those most successful subclasses of biotherapeutics due to their exceptional precision and superior safety profile. Unlike other biotherapeutics, mAbs are characterized by high dosage amount and these have led to development of high concentration mAb (HC-mAb) formulations, driven by the desire to transition the treatment from prolonged intravenous infusion in a hospital to a relatively simpler subcutaneous injection at home. While this is convenient for the patient, mAbs are ultimately proteins and are vulnerable to a variety of degradation pathways including aggregation, most of which accelerate at higher concentration. In addition, HC-mAbs are also likely to exhibit elevated viscosity, posing a challenge during manufacturing of the drug product and its analytical characterisation. This review offers an in-depth discussion on how solution properties of HC-mAbs, such as elevated viscosity and aggregation propensity, are altered due to significant protein-protein interactions. Next, a detailed analysis of the consequential late-stage manufacturing challenges that are encountered during critical unit operations like ultrafiltration/diafiltration and fill/finish is presented. The last section deals with the role of advanced analytical characterisation in monitoring product quality of HC-mAbs during formulation and process development. The review focuses on major developments in the last 5 years (2019-2025).