Container Closure Integrity Studies with Laser Based Headspace Analysis
Container closure integrity plays an important role in maintaining the sterility and stability of parenteral products. Loss of container closure integrity can occur due to component defects (cracks in glass, out-of-specification vial/stopper dimensions, improper vial/stopper combinations) or process defects (stopper pop-up prior to capping, misaligned tooling, rough handling). In the past few years, container closure integrity issues in parenteral products have received extra regulatory attention with new regulations issued related to this topic.
Laser-based headspace analysis enables container closure integrity determination 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 into the headspace. LIGHTHOUSE sensors use spectroscopic techniques to make a non-destructive analytical measurement of the headspace conditions.
The headspace method detects the exchange of gas molecules through a leak defect into the headspace and is therefore a physical closure test. The analytical measurement of gas ingress is more sensitive and more reliable than the traditionally used ingress methods for container closure determination: the blue dye ingress and microbial ingress tests. If a container is initially processed with a modified atmosphere in the headspace (e.g. 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. A container with an air headspace can be stored in a nitrogen purged glove box and a leak detected by the measurement of oxygen egressing from the container.
The headspace method is an analytical method and also straightforward to validate. For these reasons, the main regulatory bodies are advising to move away from non-analytical methods for container closure determination. Regulatory guidance from 2008 also motivates the use of a validated physical container closure method to be used in lieu of sterility testing for stability vials. Headspace analysis can be validated for this purpose, especially for sterile lyo product.
The leak rates that result in pressure rise or change in headspace oxygen levels are dependent on container volume and pressure differential for a given defect size. 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. LIGHTHOUSE has developed a validated headspace leak rate model that can be used in support of container closure validation studies.
The availability of a rapid non-destructive method for quantifying the headspace conditions of leaking containers enables the design of container closure validation studies that give science-based insight into the quality of packaging components as well as into the effects of process upsets on the closure integrity of the finished product containers.
LIGHTHOUSE Container Closure Integrity Testing
