Container Closure Integrity
Container Closure Integrity (CCI) testing is performed in order to determine whether sterile product packaging forms an integral seal during the manufacturing process and maintains that seal over time. In fact, the FDA Guidance (Guidance for Industry: Container and Closure System Integrity Testing in Lieu of Sterility Testing as a Component of the Stability Protocol for Sterile Products, U.S. Food and Drug Administration, February 2008) states CCI tests “may be more useful than sterility testing in demonstrating the potential for product contamination over the product’s shelf life or dating period.” Scientists at Avista Pharma have been performing Container Closure Integrity testing for over 15 years, and in the process, validating methods for dozens of drug products utilizing traditional methods as well the newest technologies available.
Avista Pharma has experience with the following CCI methods:
Laser-based Headspace Analysis
Avista utilizes a Lighthouse FMS-III Headspace Oxygen Analyzer for determining the oxygen content in optically clear vials and syringes. The laser used in the system is optically tuned to be able to detect and accurately measure oxygen. Since the method is non-destructive, changes in oxygen levels over time can be monitored and correlated to leak size. Headspace analysis can easily detect defects smaller than 1 micron in size in products packaged in a low-oxygen headspace (for example, lyophilized samples or those containing nitrogen or argon overlays).
Dye Ingress Testing
Avista utilizes a dye ingress test to evaluate the container closure integrity of vials, syringes and bottles. The dye ingress test involves performing a vacuum and pressure challenge on the test samples while they are submerged in methylene blue dye. After the challenge the samples are visually evaluated and then measured on a UV-Vis spectrophotometer at the specific wavelength of methylene blue dye. The absorbance measured from the samples is compared to a limit standard in order to determine whether a leak is present. The Avista Pharma dye ingress test is able to detect leaks as small as 5 microns in size. Validation is recommended to ensure the drug product is compatible with the methylene blue dye, that the detection limit is adequate and that the vacuum and pressure conditions are suitable for the container configuration.
Microbial Immersion Testing
Avista Pharma can perform a microbial immersion CCI test upon client request. The test involves performing a vacuum and pressure challenge on media-filled samples while they are submerged in a microbial broth. Following the challenge the samples are incubated and observed for the presence of growth. If growth is observed, the organism is identified to determine whether it is the challenge organism, and if found to be so, a leak is confirmed.