Understanding vial strain during freezing of aqueous solutions-Part I: A combined approach of experimental strain gauge measurements and computer simulations.

Frozen storage or lyophilization of biopharmaceuticals is often used to stabilize drug products. In most cases, the drug is formulated in an aqueous formulation in glass vials. During freezing, physicochemical changes of the formulation, such as excipient crystallization and differences in the coefficients of thermal expansion between glass and the aqueous phase can induce mechanical strain in the vial wall and ultimately lead to glass vial breakage. To systematically characterize strain formation during freezing and its spatial distribution in the vial walls, we used strain gauge measurements and finite element analysis (FEA) simulations. Strain gauge rosette measurements revealed that the direction of principal strains at the vial walls during strain peaks varied with excipients present in the aqueous phase and sensor position. These findings emphasize that correct alignment of linear strain gauges with the principal strain direction is crucial; misalignment can significantly diminish the measured signal and may lead to incorrect conclusions regarding strain distribution and magnitude. Using linear strain gauges, the influence of the gauge position and the vial size was subsequently investigated using a trehalose-based formulation buffer. The measured strain strongly depended on the position of the strain gauge with respect to the fill level, as strain was not evenly distributed throughout the vial wall. Highest strains occurred just below the fill level of the formulation. This was comparable across different vial sizes. Significantly higher strains were observed depending on the freezing method, with shelf cooling producing greater strain than air circulation cooling due to product temperature gradients along the vertical axis of the vial. While locally elevated strains are generated in colder regions, plug detachment is delayed by warmer regions that mechanically constrain the frozen plug. Also, the chamber pressure inside the lyophilizer affected the strain signal. FEA simulations confirmed that the regions of highest strain can be found just below and at the fill level. With increasing fill heights, additional areas of high strain in the lower third of the vial develop which is attributed to a constraining effect of the vial bottom to radial deformation. Overall, the combination of strain gauge measurements and finite element analysis allows systematic identification of parameters governing vial strain formation during freezing, enabling identification of critical parameters relevant to vial breakage during freezing.