Container/Closure Integrity Testing and the Identification of a Suitable Vial/Stopper Combination for Low-Temperature Storage at -80  C

Abstract

After storage of a live viral vaccine at -80 °C in glass vials closed with rubber stoppers, overpressure in some of the vials was observed, posing a serious safety problem for medical personnel as well as for the product. A working hypothesis to explain this phenomenon involved a possible container closure integrity issue at these low temperatures. The glass transition temperatures (T(g)) of many rubber stopper formulations are in the range -55 to -70 °C. At storage temperatures below T(g), the rubber stopper loses its elastic properties, resulting in compromised seal integrity of the vial and ingress of cold dense gas into the vial headspace. Upon thawing, the rubber stoppers regain their elastic properties and the vials quickly reseal, thereby trapping the ingressed gas, which leads to overpressure in the vial headspace. Nondestructive, laser-based headspace analysis, which is able to detect changes in headspace pressure and gas composition, was used to investigate the maintenance of container closure integrity. Changes in the vial headspace composition and/or pressure are a clear marker for vials that have lost container closure integrity.