Container closure integrity (CCI) plays an important role in maintaining the stability and sterility of lyophilized products. Lyophilization is a complex process that presents many manufacturing challenges one of which is maintaining and monitoring container closure integrity.
At the end of the lyophilization process, prior to sealing finished vials at the end of secondary drying, a lyophilization chamber is typically backfilled to a nitrogen gas pressure that is specified for the vial headspace. The specified headspace pressure varies from product to product. Typically, freeze dried products are stoppered at partial vacuum (0.5 to 0.9 atm of nitrogen pressure) – some products can be sealed under full vacuum (0 atm absolute pressure). The vacuum level serves the practical purpose of helping to seat the stopper and to facilitate reconstitution. Once equilibrium is achieved, the gas pressure in the vial headspace matches the chamber pressure and the shelves are lowered to seat the stoppers into the vial. At this point the vial closure integrity is established but not considered complete until the aluminum seal is applied. Once the shelves are raised, the seal integrity must be maintained for a period of time ranging from minutes to hours to possibly days before unloading and capping occur. It is possible during this time for stoppers to “pop-up” allowing gas ingress into the vial headspace. Stoppers can pop up due to a number of reasons including improper seating during shelf lowering, out of specification stopper and/or vial flange dimensions, and stopper coatings.
If seal integrity is lost during this time period then the physical properties of the headspace (gas pressure and/or composition) will change as gas from the ambient environment outside the vial ingresses into the vial headspace. The practical implications of lost seal integrity are threefold. First, the headspace pressure rises which may impact the ability to reconstitute the product and would likely result in a customer complaint. Second, if the product is oxygen and/or moisture sensitive then the ingress of humid air will result in oxygen and moisture exposure, potentially impacting the product stability. Third, if container closure integrity is breached then sterility can no longer be assured.