100% Container Closure Integrity Inspection

Container closure integrity plays an important role in maintaining the sterility and stability of lyophilized products and is receiving focused attention from inspectors and recent revised regulatory guidance.  There is a corresponding drive in the industry to implement inspection systems to help ensure the seal integrity of finished product vials.

Loss of container closure integrity can occur due to component defects (e.g. cracks in glass, out of specification stopper dimensions or improper vial/stopper combinations) or process defects (e.g. stopper pop-up prior to capping, misaligned tooling, rough handing ).  Headspace gas analysis enables in-process leak detection by monitoring changes in headspace gas composition or changes in total headspace pressure.

Cracks in glass, displaced stoppers, and dimensional defects in vials and stoppers allow gas flow from outside a container to the inside.  If a container is initially processed with a modified atmosphere in the headspace (purged with an inert gas or evacuated to a reduced pressure) then a total pressure rise or oxygen partial pressure rise can be detected and correlated to a leak rate.  Kirsch (Kirsch 1997a-c and Nguyen 1997) has experimentally demonstrated a correlation between a leak rate and the probability of microbial ingress.  In addition to potential sterility issues, product stability can also be compromised by loss of container closure integrity.   Gas ingress, particularly reactive atmospheric molecules such as oxygen and moisture, can impact product stability and reduce potency through reactions with active ingredients and excipients.

Changes in the headspace gas pressure or gas composition are leak indicators for sterile product packaged under modified atmosphere conditions (headspace conditions other than 1 atmosphere of air).  Examples of products packaged under modified atmospheres are oxygen sensitive liquids that are flame sealed or stoppered under inert atmospheres of nitrogen or argon and lyophilized products that are stoppered under nitrogen, usually at reduced pressure (either full or partial vacuum).  In these cases a container that leaks will exchange gas with the environment outside the container resulting in a total pressure rise (in the case of a vial stoppered under vacuum) or a partial pressure rise in oxygen (in the case of vials and ampoules closed under inert gas blankets).

The leak rates that result in pressure rise or oxygen ingress are dependent on container volume and initial headspace conditions for a given hole size. In general the headspace pressure and oxygen concentration of small volume parenterals packaged under vacuum rise more quickly than the headspace pressure and oxygen concentration of large volume parenterals packaged near atmosphere. Detectable changes in the headspace conditions of a gross leaker occur within minutes. A micro-leak (< 1 micron) will exhibit detectable changes in the headspace after a few hours to a few days depending on the size of the leak and the initial headspace conditions.

Automated laser-based headspace inspections systems are now implemented and validated for 100% container closure inspection of sterile pharmaceutical containers at production speeds. Such implementations give insight into the process, ensure the maintenance of sterility for finished product after capping, and can be seen as a tool for meeting current regulatory guidance.

A Screencast to the LIGHTHOUSE solution for 100% container closure integrity inspection of freeze dried vials

100% Container Closure Integrity Inspection