In an effort to maintain product quality attributes of increasingly complex and delicate formulations, life science companies continue to drive toward deeper cold storage. These products, often cell or gene therapies, or proteinaceous in nature, often require storage at temperatures below -20°C, and are involved in storage and distribution environments incorporating dry ice (~-78.5°C), or even liquid nitrogen (~-200°C). Most people are now aware of these challenges as they pertain to the distribution of COVID-19 vaccines. However, the same challenges are faced by all drugs requiring storage at these conditions.

While the products demanding such intense cold storage may be complex, oftentimes, the package systems in which the products are placed are rather traditional in nature, such as a threaded closure or crimp top vial. However, many of the materials used in these package systems and responsible for maintaining package integrity are not typically intended for or assessed at these temperatures. When exposed to deep-cold or ultra-cold temperatures, physical changes to elastomeric components in particular can occur as materials reach or exceed their glass transition state, creating leaks at low temperatures that would otherwise not be observed while at room temperature. This type of leakage is typically observed at primary seal areas, such as that between an elastomeric closure and glass vial being used below -60C. Having a means to test container closure integrity at these low temperatures enables manufacturers to gain insight into optimal package choice and design, as well as assembly parameters, to minimize leakage and demonstrate robust understanding of a package system’s performance in accordance with USP <1207>.

The team at CS Analytical has first-hand experience designing these types of studies to evaluate fine leakage at cold temperatures incorporating different technologies, such as laser-based headspace analysis and helium leak detection. The appropriate technology and general study approach is considered on a product-to-product basis, taking into account intended storage and shipment conditions, gas sensitivities, and lifecycle stage of analysis.