Senior Scientist Regeneron Pharmaceuticals Elmsford, New York
This work addresses a critical gap in formulation science by revealing how surfactant requirements identified in simplified mAb systems fail to translate to multi-excipient formulations, uncovering an excipient-dependent aggregation risk that is otherwise missed during early development.
• Formulation scientists • Protein stability scientists • Biopharmaceutical development teams • CMC formulation scientists • Process development scientists • Analytical development scientists • Platform formulation teams
Surfactants and stabilizing excipients are routinely employed to mitigate aggregation in monoclonal antibody (mAb) formulations; however, surfactant requirements are often established using simplified screening systems that may not reflect realistic, multi-excipient formulations. This presentation describes a stepwise formulation strategy used to evaluate the combined effects of surfactant concentration, protein concentration, and common stabilizing excipients on mAb aggregation behavior. Initial surfactant screening was conducted in a histidine-buffered mAb formulation (pH 6.0) and identified a surfactant concentration sufficient to suppress aggregation in the absence of additional excipients. When this surfactant level was subsequently applied within a multivariate design of experiments (DOE) incorporating sucrose and arginine, all formulations containing the predetermined surfactant concentration exhibited elevated high-molecular-weight (HMW) species, with aggregation severity dependent on excipient composition and protein concentration. In contrast, formulations containing a six-fold higher surfactant concentration consistently suppressed HMW formation across all tested conditions. Systematic excipient isolation revealed that arginine-containing formulations were particularly susceptible to aggregation at sub-threshold surfactant levels, whereas sucrose-containing formulations remained stable. Orthogonal analytical techniques, including size-exclusion chromatography, micro-flow imaging, and colloidal stability measurements, were used to confirm aggregation trends across molecular and particulate scales. This talk will highlight how multivariate analytical approaches can uncover excipient-dependent aggregation risks that are masked during early screening and discuss the implications of these findings for risk-informed formulation design. Collectively, this work demonstrates the limitations of extrapolating surfactant requirements from minimal systems and provides practical guidance for developing robust mAb formulations under realistic, multi-excipient conditions.
Learning Objectives:
Recognize how excipient composition can alter surfactant effectiveness and lead to aggregation risks that are not detected during simplified monoclonal antibody formulation screening.
Apply multivariate design of experiments (DOE) and orthogonal analytical techniques to identify excipient-dependent aggregation risks and critical surfactant thresholds in protein formulations.
Incorporate risk-informed formulation strategies to avoid extrapolating surfactant requirements from minimal systems and improve formulation robustness across development and lifecycle stages.
