Investigation for the cause of vial breakage during frozen storage of nucleic acid drug solution and the effect of the internal coating on the vial strain.

Vial breakage has been observed in nucleic acid drug solutions after deep-freezer storage, representing a critical quality concern in pharmaceutical manufacturing. This study aimed to investigate the cause underlying this phenomenon. Visual observation of reference vials revealed the "plugging off" phenomenon, defined as the instantaneous separation of the frozen drug matrix from the vial inner surface, which simultaneously induced vial breakage. Differential scanning calorimetry showed no crystallization peak during the freeze-thaw cycles, indicating that crystallization was not the cause. The thermomechanical analysis revealed that the frozen drug solution underwent volumetric contraction during freezing. Strain-gauge measurements further confirmed that significant mechanical strain developed in the vial wall concurrently with the "plugging off." Collectively, these findings provide a cause explanation for vial breakage in nucleic acid drug formulations, wherein the volumetric contraction of the frozen matrix compared to glass vial generates sufficient mechanical stress to fracture the vial. Additionally, an internal hydrophobic or silicone coating of the vial significantly influenced both the temperature at "plugging off" and suppressed the magnitude of the induced strain, protecting against breakage. This suggested that selecting an appropriate internal coating of the vial could represent one potential strategy for mitigating vial breakage.