Abstract
This paper presents a new theoretical integrated modeling approach with practical case studies for calculating container closure integrity (CCI) that concurrently accounts for both diffusion and mass/volumetric flow in real time. For pharmaceutical, biological, cell, and gene therapies, container closure systems (CCSs) must ensure drug sterility and stability by safeguarding against microbial contamination and gaseous ingress (e.g., oxygen, carbon dioxide, moisture, etc.) according to product requirements. In addition to the testing approach for evaluating CCI performance, a modeling approach can be an important part of CCI control strategy. Modeling is a powerful tool that provides information in situations where testing is not feasible, technically impossible, too time-consuming, or too expensive. Previously published models have lacked a systematic approach, or the versatility needed to coherently and concurrently integrate both diffusion and effusion to solve problems arising in field applications. The new integrated modeling approach described in this paper applies a robust numerical method to real world applications. The model is based on the law of conservation and continuity for molecular flow, Fick′s law of diffusion, and Darcy-Weisbach theory of frictional mass/volumetric flow. This new integrated modeling approach handles time-dependent diffusion and effusion by combining diffusion and mass/volumetric flow seamlessly in real time. For CCS under vacuum filled with nitrogen, this new modeling approach is able to reveal that oxygen ingress into CCS through a leak path will enter in two phases, starting with effusion and continuously followed by diffusion in a seamless transition. Our integrated modeling approach is capable to calculate and capture exact timing of the phase transition point providing unique understanding of complicated CCS problems. Using the finite difference method, all modeling results are numerically solved from governing equations along with initial and boundary conditions for each individual cases. The modeling results were precise and consistent with previously published testing results. This new integrated modeling approach displayed its capability and versatility to handle complicated leakage scenarios in practical applications. As a part of CCI control strategy, the modeling approach is a powerful tool for evaluating leaks, gauging their leak sizes, determining whether the CCS conforms to product requirements, and making informed decisions accordingly. While additional studies are to be carried out to fully develop the potential of this model, the applications hold great promise and in addition, to providing insight into container closure integrity may also provide a solid foundation for CCIT, and providing a solid foundation for CCI testing method development and validation for CCI performance.
- Darcy-Weisbach equation
- Ficks law
- container closure integrity (CCI)
- container closure system (CCS)
- diffusion
- mass and volumetric flow
- Received September 14, 2020.
- Accepted March 15, 2021.
- Copyright © 2021, Parenteral Drug Association
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