Evaluation of Container Closure System Integrity for Frozen Storage Drug Products.

Sometimes, Drug Product for parenteral administration is stored in frozen state (e.g. -20°C or -80°C), particularly during early stages of development of some biotech molecules in order to provide sufficient stability. Shipment of frozen product could potentially be performed in the frozen state, yet possibly at different temperatures, e.g. using dry ice (-80°C). Container Closure Systems (CCS) of drug products usually consist of a glass vial, rubber stopper and an aluminum crimped cap. In frozen state, the glass transition temperature (Tg) of commonly used rubber stoppers is between -55°C to -65°C. Below their Tg, rubber stoppers are known to lose their elastic properties and become brittle and thus, potentially fail to maintain container closure integrity (CCI) in the frozen state. Leaks during frozen temperature storage and transportation are likely to be transient, yet, can possibly risk CCI and lead to microbial contamination. After thawing, the rubber stopper is supposed to re-seal the CCS. Given the transient nature of the possible impact on CCI in the frozen state, typical CCI testing methods (used at room temperature conditions) are unable to evaluate and thus confirm CCI in the frozen state. Here we present the development of a novel method (ThermCCI) for direct assessment of CCI by a physical method (pCCI) at frozen conditions, using a modified He-leakage test. In this study, different container closure systems were evaluated with regards to pCCI in the frozen state, to assess the suitability of vial/stopper combinations and compared to a gas headspace method. In summary, the ThermCCI He leakage method was more sensitive in detecting pCCI impact than gas headspace and aided identification of an unsuitable CCS.