Container Closure Integrity of Rubber-stoppered Glass and Plastic Vials Stored at -80°C and in Dry Ice

Patrick Curran¹, Vinod Vilivalam¹, Suzanne Kuiper² and Derek Duncan^2
1West Pharmaceutical Services, Inc. and ²Lighthouse Instruments B.V.

An increasing number of pharmaceuticals including vaccines, stem cells and proteins require cold storage to maintain efficacy prior to use. However, the ability to maintain container closure integrity (CCI) during cold storage is not completely understood.

Concerns about CCI failure have been raised for the storage and shipment of pharmaceutical products in rubber-stoppered vials under cold conditions (e.g. -80°C or dry ice). Commonly used butyl stoppers are believed to lose their elastic properties below their glass transition temperature (Tg) posing a risk to sealability [1], [2]. The temporary loss of CCI under cold conditions can allow cold, dense gas from the surrounding low-temperature storage environment to leak into the stored vial. The ingress of the gas can contribute to loss of efficacy of the stored drug product due to interaction with the gas as well as overpressurization of the vial. Overpressurization occurs when cold, dense gas becomes trapped within the vial as the rubber stopper warms to a temperature above its Tg after it is removed from the cold storage conditions. After the rubber stopper has regained its elastic properties and reseals the vial, the headspace pressure of the vial increases as the cold, dense gas warms to room temperature.

Conclusions

The rubber stoppers tested in this study are suitable for use with glass and Daikyo Crystal Zenith® polymer vials for cold temperature storage (-80°C or dry ice) and for transport in dry ice. Rubber-stoppered glass vials and Crystal Zenith polymer vials demonstrated CCI at temperatures as low as -80°C, well below the Tg’s of the rubber stoppers (between -60°C and -65°C).

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Daikyo Crystal Zenith® is a registered trademark of Daikyo Seiko, Ltd.
Daikyo Crystal Zenith® technology is licensed from Daikyo Seiko, Ltd.