Tortora, Ciro (2025) Experimental and Numerical Simulations of a Cold Storage Process for Pharmaceutical Devices. [Tesi di dottorato]

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Abstract

The growing need for deep-frozen pharmaceutical storage—driven in part by the rise of mRNA-based therapeutics—introduces new challenges for maintaining Container Closure Integrity (CCI) in prefilled syringe sys- tems. This study delivers an in-depth examination of CCI failure mechanisms at cryogenic temperatures, integrating micro-tensile testing, high-fidelity nu- merical simulations, and verification through a modified dye-ingress tech- nique. The study and selection of the material model cannot ignore the characteriza- tion of its mechanical properties. In particular, the response of the elastomer to deformation and temperature variation. The viscoelastic nature of the material was also investigated in depth using frequency rheological tests. A material model was investigated that took into account the viscoelastic ef- fects that emerged, but also the viscoplasticity induced by the glass transition caused by the drop in temperature. The results show that CCI loss consistently occurs at temperatures below the rubber’s glass transition, beginning with the loss of contact at the plunger ribs and eventually leading to full leakage past the trimmed edge. These failure modes exhibit repeatable behaviour, as demonstrated by both experi- mental observations and computational analysis. The root cause is linked to the combined effects of thermal contraction, viscoplastic material response, and progressive loss of contact at the rubber–glass interface, with simula- tions indicating that plastic “locking-in” of deformation is the predominant driver of failure. Overall, the study highlights the need to redesign elastomer formulations and sealing concepts for dependable operation under ultra-low temperature conditions and provides a predictive basis for future CCI evalu- ations.

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