Physicochemical Stability of Monoclonal Antibodies: A Review

Abstract

Monoclonal antibodies (mAbs) are subject to instability issues linked to their protein nature. In this work, we review the different mechanisms that can be linked to monoclonal antibodies instability, the parameters, and conditions affecting their stability (protein structure and concentration, temperature, interfaces, light exposure, excipients and contaminants, and agitation) and the different analytical methods used for appropriate physicochemical stability studies: physical stability assays (aggregation, fragmentation, and primary, secondary, and tertiary structure analysis), chemical stability assays and quantitative assays. Finally, data from different published stability studies of mAbs formulations, either in their reconstituted form, or in diluted ready to administer solutions, was compiled. Overall, the physicochemical stability of mAbs is linked to numerous factors such as formulation, environment, and manipulations, and must be thoroughly investigated using several complementary analytical techniques, each of which allowing specific characterization information to be harvested. Several stability studies have been published, some of them showing possibilities of extended stability. However, those data should be questioned due to potential lacks in study methodology.

Do plasticized polyvinylchloride and polyurethane infusion sets promote infliximab adsorption?

“…Proteins are surface active molecules, and have a tendency to adsorb to hydrophobic surfaces and interfaces: the adsorption phenomenon is especially relevant when the drug is highly diluted, when the contact surface is important, or both [15,16]. Interactions with glass, PVC and polyolefin materials have been reported in laboratory or clinical simulating conditions [17][18][19], but there is scare literature about the behaviour of mAbs during infusions through medical intravenous tubings.…”

Product-Specific Impact of Viscosity Modulating Formulation Excipients During Ultra-High Concentration Biotherapeutics Drug Product Development

“…11,23 Formulation pH has been shown to influence long-range electrostatic interactions by affecting the overall charge on the protein. 24 Protein net charge and therefore nonspecific repulsions are known to increase at pH values further away from the isoelectric point (pI). 25 Salts can also be used to screen electrostatic effects via ions binding to charged residues on the protein surface, thus disrupting electrostatic protein-protein interactions.…”

“…25 Salts can also be used to screen electrostatic effects via ions binding to charged residues on the protein surface, thus disrupting electrostatic protein-protein interactions. 24 Such charge-charge binding, however, can result in changes to protein conformation and may reduce protein stability, 25 and modulating electrostatics by formulations has not been universally found to reduce viscosity. 12,26 Systematically understanding these interactions, both at low and high protein concentrations, and their modulation by formulation parameters is therefore critical to ensuring acceptable viscosity, stability, and processability of protein drug products.…”

Characterization and Modeling of Reversible Antibody Self-Association Provide Insights into Behavior, Prediction, and Correction

“…As of late 2019, 79 commercial monoclonal antibody or antibody-based therapeutics have been approved [1], with several hundred currently being evaluated in clinical development [2]. Central to a therapeutic antibody's selection and success is its developability profile, which is a key driver in pre-clinical and clinical lead nomination [3,4]. Previously, developability flags in therapeutic antibodies have been correlated to overall clinical success, clearly indicating that developability attributes may impact clinical development beyond drug product purity, stability and manufacturability [5].…”