Container Closure Integrity Test Method Development on Vials Stored at −80°C Using Headspace Carbon Dioxide Analysis

Abstract

Maintaining container closure integrity (CCI) is challenging for vials that are packaged at room temperature and stored and/or transported at a colder temperature, such as −80°C. Cold temperatures can affect the sealing mechanisms of the package because of the glass transition temperature (−50°C to −70°C) of the rubber stopper used to seal the vial and the different coefficients of thermal expansion of each of the primary packaging components. Most CCI tests are conducted at room temperature and detect leaks from permanent defects that always exist under all storage conditions. However, previous research shows that temporary leaks that develop during cold storage can reseal when the vials are brought back up to room temperature and, therefore, can no longer be detected. The following study demonstrates two methods for CCI testing that can be performed with product-filled, frozen vials, packaged with unmodified headspace conditions using carbon dioxide ingress as a leak indicator. The two methods utilize different gas flow depending on the storage conditions. The first method generates effusive flow through a leaking defect, whereas the second generates diffusive flow. Experimental data revealed the effusive procedure detected laser-drilled defects ≥2 µm in empty glass vials and microwire defects in empty glass and plastic vials with effective defect sizes ≥0.4 and 0.6 µm, respectively. The diffusive procedure detected laser-drilled defects ≥2 µm in empty glass vials and microwire defects in empty glass and plastic vials with effective defect sizes ≥ 0.8 and 2.6 µm, respectively. Liquid product interactions with the defect as well as length of the storage period were also explored.