Accelerated Formulation Development of Monoclonal Antibodies (mAbs) and mAb-Based Modalities: Review of Methods and Tools

Abstract

More therapeutic monoclonal antibodies and antibody-based modalities are in development today than ever before, and a faster and more accurate drug discovery process will ensure that the number of candidates coming to the biopharmaceutical pipeline will increase in the future. The process of drug product development and, specifically, formulation development is a critical bottleneck on the way from candidate selection to fully commercialized medicines. This article reviews the latest advances in methods of formulation screening, which allow not only the high-throughput selection of the most suitable formulation but also the prediction of stability properties under manufacturing and long-term storage conditions. We describe how the combination of automation technologies and high-throughput assays creates the opportunity to streamline the formulation development process starting from early preformulation screening through to commercial formulation development. The application of quality by design (QbD) concepts and modern statistical tools are also shown here to be very effective in accelerated formulation development of both typical antibodies and complex modalities derived from them.

Alteration of Physicochemical Properties for Antibody-Drug Conjugates and Their Impact on Stability

“…One main indicator for colloidal stability is the selfaggregation propensity. 77 The tendency of the molecules to selfinteract arises from their protein structural properties such as net charge, pI, and distribution of local charges 78 or by hydrophobic interaction to exclude water by self-association. 79 Increasing selfinteraction can further trigger other colloidal instabilities, 80 a reduction of solubility and increased viscosity of the formulation.…”

Preferential interactions of trehalose, L-arginine.HCl and sodium chloride with therapeutically relevant IgG1 monoclonal antibodies

“…13,14 Due to the lack of clear mechanistic understanding of excipient-mediated stabilization, current approaches to formulation development involve high-throughput screening of several excipient combinations to identify a formulation that minimizes mAb instability. 15,16 A rational approach to formulation development requires both a detailed understanding of reaction pathways responsible for aggregation and high viscosity of mAb formulations, as well as the impact of protein-excipient interactions on the kinetics and equilibrium of critical reactions within these pathways. Significant work has been undertaken to understand and identify the critical steps involved in mAb aggregation and high viscosity, [17][18][19][20] but detailed understanding of the nature of mAbexcipient interaction is currently lacking.…”

Retracted: Molecular characterization of excipients’ preferential interactions with therapeutic monoclonal antibodies

“…[5] However, developing an acceptable formulation for a given product can be highly challenging. [6][7][8] Aggregation is the most problematic and common stability issue. [9,10] Antibody aggregation affects both the manufacturing yield and the efficacy of the drug.…”