Evaluation of Container Closure System Integrity for Storage of Frozen Drug Products: Impact of Capping Force and Transportation

Abstract

Frozen-state storage and cold-chain transport are key operations in the development and commercialization of biopharmaceuticals. Today, several marketed drug products are stored (and/or shipped) under frozen conditions to ensure sufficient stability, particularly for live viral vaccines. When these products are stored in glass vials with stoppers, the elastomer of the stopper needs to be flexible enough to seal the vial at the target's lowest temperature to ensure container closure integrity and thus both sterility and safety of the drug product. The container closure integrity assessment in the frozen state (e.g., −20°C, −80°C) should include container closure integrity (CCI) of the container closure system (CCS) itself, impact of processing (e.g., capping process on CCI), and impact of shipment and movement on CCI in the frozen state. The objective of this work was to evaluate the impact of processing and shipment on CCI of a CCS in the frozen state. The impact on other quality attributes was not investigated. In this light, the ThermCCI method was applied to evaluate the impact of shipping stress and variable capping force on CCI of frozen vials and to evaluate the temperature limits of rubber stoppers. In conclusion, retaining CCI during cold storage is mostly a function of vial–stopper combination, and temperatures below −40°C may pose a risk to the CCI of a frozen drug product. Variable capping force may have an influence on the CCI of a frozen drug product if not appropriately assessed. Regarding the impact of shipment on the CCI of glass vials, no indication was given at room temperature, −20°C, or −75°C when compared with static storage at such temperatures.

LAY ABSTRACT: Today, several marketed products are stored (and/or shipped) under frozen conditions to ensure sufficient stability. When these products are stored in glass vials with stoppers, the elastomer of the stopper needs to be flexible enough to seal the vial and ensure container closure integrity and thus both sterility and safety of the drug product. The impact of processing and shipment on the container closure integrity (CCI) of a container closure system (vial, stopper, and flip-off cap) in the frozen state is assessed. A helium-leakage test at low temperature (ThermCCI) was used to evaluate the impact of shipping stress and variable capping force on CCI of frozen vials as well as the temperature limits of rubber stoppers. In conclusion, it was found that retaining CCI during cold storage is mostly a function of vial–stopper combination and that temperatures below −40°C may pose a risk to the CCI of a frozen drug product. Variable capping force may have an influence on the CCI of a frozen drug product if not appropriately assessed. Additionally, it was observed that the shipment of the frozen glass vials did not affect the CCI.