Seal Integrity Testing Using the Tracer Gas Method
Moisture-sensitive drug products are commonly lyophilized to enhance their shelf life and to prepare them for storage and transport. Maintaining a constant moisture level in a lyophilized drug product “cake” ensures product quality. Not only is proper selection of a container closure system (vial, stopper, seal) necessary, but sealing conditions are as well. This is achieved through demonstration of container closure integrity (CCI).
CCI is an essential performance requirement of any container closure system. A holistic approach to achieving this has been published by F. DeGrazio: Holistic Considerations in Optimizing a Sterile Product Package to Ensure Container Closure Integrity. A key element is achieving CCI that meets the specific maximum allowable leakage limit (MALL) for the drug product and closure system.
USP guidance Chapter <1207> Package Integrity Evaluation – Sterile Products presents numerous types of CCI measurement methods with various sensitivities. West's Analytical Lab Services has the facilities, staff, and detailed procedures to perform all of them.
The most sensitive CCI method is tracer gas leak detection with helium. Sealed closure samples are prepared by flooding with 100% helium via a metal cannula inserted through the stopper. After cannula removal, the punctured stoppers are sealed with epoxy. Samples are placed in a vacuum chamber, then vacuum applied continuously, and chamber helium concentration measured by mass spectrometry. Literature has correlated helium leak rates to defect size*. Historically, leak rates lower than 6.0 x 10-6 cm3/s (sometimes called Kirsch level) are considered acceptable. West closure systems typically do far better, with rates lower than 2 x 10-7 cm3/s for 20 mm stoppers, and lower than 7 x 10-8 cm3/s for 13 mm stoppers. This method is also suitable to other container types, such as syringe systems, cartridges and blister packs.