Time Temperature Superposition Evaluation and Modeling for Container Closure System′s Seal Performance at Low Temperatures

Abstract Container closure integrity (CCI) is essential for parenteral packaging. CCI performance must be maintained throughout the entire time temperature transition cycle of a sealed drug′s product lifespan. Prior publications have lacked systematic considerations for the impact of dynamic temperature transition coupled with time dependent transition on sealing performance associated with the viscoelastic characteristics of rubber stoppers used in container closure system (CCS). This paper demonstrates that sealing performance changes inherently and is fundamentally both time- and temperature- dependent. Our research results display this critical time temperature transition impact on CCS sealing performance by applying compression stress relaxation (CSR) on a rubber stopper for experimental data collection and modeling evaluation. The experimental results agree with modeling evaluation following Maxwell-Wiechert theory and the time temperature superposition based on the Arrhenius and Williams-Landel-Ferry methods. Both testing and modeling data show good consistency, demonstrating that the sealing force inevitably changes over time together with temperature transition because of the viscoelastic nature of the rubber stoppers. Our results show that compression seal force decreases quickly as temperature decreases. The significant loss of rubber stopper sealing force at lower temperature transitions could contribute significant risk to CCI at low storage and transport temperatures. By employing both experimental testing and modeling evaluation, an in-depth understanding of the time- and temperature- dependent nature of rubber stopper sealing force was developed. The nonlinearity of CSR is quantitatively predictable, deriving from the viscoelastic characteristics of the rubber stopper material coupled with the time temperature superposition. Modeling evaluation, with a powerful capability to handle actual testing data, can be employed as a predictive tool to evaluate the time- and temperature- dependent sealing force throughout the entire sealed drug product lifespan. The present study is only applicable before reaching the rubber glass transition temperature Tg - a critical transition phase that can′t be skipped/separated from real time temperature transition, and it will further determine the CCS sealing performance while approaching cryogenic temperature. There has been a growing interest in recent years in the assessment of container closure systems for cold storage and shipment. The present work provides a new, integrated methodology framework and some fresh insights to the parenteral packaging industry for practically and proactively considering, designing, setting up, controlling, and managing stopper sealing performance throughout the entire sealed drug product lifespan. Particularly, CCS seal performance at lower temperature needs to be properly addressed, evaluated, calculated, simulated, predicted, tested, and assessed through an integrated system approach for critical data-driven risk management.