The increased number of biological products coming to the market and the need to extend product shelf life has driven the growth of lyophilization. Lyophilization is a complex, multi-step process that present many manufacturing challenges, one of which is maintaining and monitoring container closure integrity of the finished package. Concerns over customer complaints, the cost of investigations, and the cost of product recalls is resulting in revised regulatory guidelines.
A lyophilization chamber is backfilled to a gas pressure that is specified for the vial headspace prior to sealing finished vials at the end of secondary drying. A specified headspace pressure varies from product to product. Freeze dried products are either at full vacuum (0 mbar absolute headspace pressure) or partial vacuum (typically 800 mbar absolute headspace pressure). The vacuum level serves the practical purpose of helping to seat the stopper and to facilitate reconstitution.
The shelves are lowered to seat stoppers into the vials once the gas pressure in the vial headspace matches the chamber pressure. At this point, the vial closure integrity is established but not considered complete until the aluminum overseal 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 the unloading and capping to occur. It is possible during this time for stoppers to pop-up allowing gas ingress to the vial headspace. Stoppers can pop up for 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 physical properties of the headspace (gas pressure and/or composition) will change because gas from the ambient environment outside the vial will ingress to the vial headspace. A) If the vial is exposed to nitrogen atmosphere, for example prior to unloading from the freeze dryer, then nitrogen gas will enter the headspace causing the pressure to rise. If the vial is exposed to an air atmosphere, either because the chamber was vented with sterile air or the vial was exposed to room air prior to capping, then air will ingress into the vial causing both the pressure to rise and the oxygen concentration to rise. The practical implications of lost seal integrity are threefold. First, the headspace pressure rises, which may impact the ability to reconstitute the product. Second, if the product is oxygen sensitive then air ingress will result in oxygen exposure and potentially impact the product stability. Third, if container closure integrity is breached then sterility can no longer be assured.
Laser absorption spectroscopy is used for monitoring changes in the headspace gas composition and pressure in each vial. In-process monitoring systems are validated and routinely used for checking closure integrity in freeze dried products, addressing the stopper pop-up issue.