Understanding Vial Strain During Freezing of Aqueous Solutions–part II: Identification of Influencing Formulation, Vial and Freezing Parameters and Strain-Mitigating Strategies

Glass vial breakage during freezing and lyophilization processes poses a significant concern, as it can lead to product loss and potential safety hazards. In aqueous formulation buffers containing amorphous excipients, vial breakage has been correlated with the strains associated to the plugging-off of the frozen product from the inner vial surface during freezing. This study aimed to systematically identify parameters influencing this strain and to propose risk-mitigating options. The effects of formulation composition, vial type, and freezing process were investigated. The strain was assessed using strain gauge measurements and simulated via finite element analysis. Our findings show that the formulation composition and vial type had the greatest influence on the generated strains. Thermal contraction of the frozen formulation, and thus strain on the vial, occurred only below Tg'. The presence of a monoclonal antibody in trehalose-based formulation buffer led to an increased strain, with higher strain for higher protein concentrations. The strain was independent of the solid content of the formulation within the range probed in this study. The most effective way to mitigate the strain was to promote an earlier plugging-off, e.g. by modifying the vial surface using a hydrophobic coating (water contact angle > 120°). Bake-on siliconized vials showed the most substantial strain reduction, with a fivefold decrease compared to uncoated vials. In contrast, variation in freezing rate and freezing protocol had only marginal impact on the strain formed, as well as vial wall thickness or material. For formulations containing trehalose and mannitol at mass ratios of 2:1 and 1:2, the incorporation of an annealing step was beneficial due to a decreased plugging-off strain. Overall, this study provides valuable insights into the factors affecting the strain on vials during freezing and offers practical measures to minimize this strain and the associated risk of vial breakage, thereby enhancing the safety of frozen drug products.