Screening of Unexplored FDA-approved Inactive Ingredients as Stabilizers for Monoclonal Antibody Products.

PURPOSE: Monoclonal antibodies (mAbs) are susceptible to physical and chemical degradation, which can compromise product quality, efficacy, safety, and shelf life. Although excipients play a critical role in stabilizing mAb formulations, only a limited number are routinely used in marketed products. Therefore, this study aimed to identify underexplored FDA-approved inactive ingredients with the potential to stabilize mAb formulations.

METHODS

Fourteen FDA-approved inactive ingredients were screened using a size-exclusion chromatography (SEC)-based comparative forced-degradation approach. Trastuzumab was used as the model IgG1 antibody and subjected to thermal stress at 70°C and 65°C. Candidate excipients were evaluated through concentration optimization, SEC-HPLC, fluorescence spectroscopy, UV-vis spectroscopy, differential scanning calorimetry, surface plasmon resonance, haemolysis assays, and molecular docking.

RESULTS

Initial screening identified isomalt and myo-inositol as the most effective excipients, reducing high-molecular-weight species by up to 60%, whereas choline chloride produced a smaller but measurable reduction. Optimized concentrations of 400 mM isomalt, 150 mM myo-inositol, and 1.9 mM choline chloride reduced aggregation, preserved monomer content, and improved higher-order structural stability. These formulations retained HER2 and FcRn binding and exhibited haemolysis below 3% compared to PS80 containing mAb sample. Isomalt also improved the thermal stability of adalimumab and rituximab, while molecular docking suggested preferential association with aggregation-prone regions of the trastuzumab Fab domain.

CONCLUSIONS

Underexplored FDA-approved excipients, particularly isomalt and myo-inositol, improved mAb stability under thermal stress and represent promising candidates for further evaluation during therapeutic antibody formulation development.