ABSTRACT
Multidose formulations have patient-centric advantages over single-dose formats. A major challenge in developing multidose formulations is the prevention of microbial growth that can potentially be introduced during multiple drawings. The incorporation of antimicrobial preservatives (APs) is a common approach to inhibit this microbial growth. Selection of the right preservative while maintaining drug product stability is often challenging. We explored the effects of three APs, 1.1 % (w/v) benzyl alcohol, 0.62 % (w/v) phenol, and 0.42 % (w/v) m-cresol, on a model immunoglobulin G1 monoclonal antibody, termed the "NIST mAb." As measured by hydrogen exchange-mass spectrometry (HX-MS) and differential scanning calorimetry, conformational stability was decreased in the presence of APs. Specifically, flexibility (faster HX) was significantly increased in the CH2 domain (HC 238-255) across all APs. The addition of phenol caused the greatest conformational destabilization, followed by m-cresol and benzyl alcohol. Storage stability studies conducted by subvisible particle (SVP) analysis at 40 °C over 4 weeks further revealed an increase in SVPs in the presence of phenol and m-cresol but not in the presence of benzyl alcohol. However, as monitored by size exclusion chromatography, there was neither a significant change in the monomeric content nor an accumulation of soluble aggregate in the presence of APs.
