Qiang Liu, PhD, Research and Development Supervisor

The container closure system for a drug product provides critical protection for stability and sterility. Contaminants (such as microorganisms and reactive substances) could potentially cross through defective container closures putting the drug product and patients at risk. USP chapter <1207> defines the concept of container closure integrity as "encompassing the absence of all package leaks that risk product quality". FDA also introduced container and closure system integrity testing in lieu of sterility testing as a component of a stability protocol for sterile products.

Among a variety of CCIT tests, dye ingress testing is one of most commonly used methodologies. During the test, the container closure test articles are put into an empty vacuum chamber to introduce negative pressure to the articles. This vacuum removes air inside the container/closure system. The vacuum is then released and methylene blue hydrate solution enters the chamber until it reaches atmospheric pressure. The articles are removed from the chamber, rinsed, patted dry, and examined for the presence of methylene blue through visual inspection or spectrometry. To pass the test, there must be no detectable methylene blue inside any of the tested container closure systems. ARL provides CCIT services for a variety of container types and compounds including colored compounds such as Methylcobalamin, Cyanocobalamin, and Mitomycin.

The sensitivity and applicability of CCIT methodologies varies based on container type, size, fill volume, and compounded drug product. ARL recommends and provides CCIT method validation services for clients' specific container closure system.