Lynn Yao

TCS Engineer

December 03, 2015

Have you selected the right stopper for your freeze-dried drug product?

Lyophilization is widely used for pharmaceuticals to help preserve parenteral drugs that are unstable in liquid formulation, particularly biologics. Lyophilized drugs have many advantages like prolonged shelf life, easy dissolution and good stability. However, a suitable container closure system is necessary to ensure the successful lyophilization of pharmaceutical products while maintaining product quality.
Therefore, the selection of suitable container closure components for a lyophilized drug application is an important consideration, especially the primary elastomer component—a stopper.

Container closure integrity (CCI) is crucial for maintaining the stability and sterility of the drug throughout its shelf life. The dimensions and the fit within the vial could have an impact on the CCI of the system. During the manufacturing of a lyophilized drug, immediately after the freeze-drying process is completed, the stopper acts as the only seal to protect the drug during its transportation from the lyophilization chamber to the crimping station. The initial seal is provided by the interference fit (typically 2–10%) of the stopper plug in the vial bore and the stopper should fit well with the vial1. If the plug diameter of the stopper is too big, it can be difficult to insert the stopper into the vial or even create a pop-up if not well-seated. On the other hand, if the plug diameter of the stopper is too small, it can create leak paths between the stopper plug and vial neck. Either way, the seal integrity is compromised. The long-term seal is formed by the aluminum crimp compressing the bottom of the stopper flange to the top surface of the vial crown (see  Fig. a. Sealed Vial1). Optimal initial seal and long-term seal are critical to achieve container closure integrity.

The stoppers commonly used for lyophilized drug are typically vented – igloo, 2-legged or 3-legged designs. During the lyophilization process, after the drug product is frozen, the ice crystals sublimate via the vent(s) in the stopper. It was observed that the rate of moisture transfer from the vial increased as the cross-sectional area of the vent was increased. However, this increase tapered off as the area of the vent approached approximately 6 mm2 and 10 mm2 when the temperature in the lyophilization chamber was at 0°C and 25°C respectively 2. As a result, it is conclusive that under normal conditions as mentioned above, the number of vents on a stopper does not have an impact on the rate of sublimation, since the size of a vent is typically already greater than 10 mm2. In regards to configuration, the igloo design (single vent) is usually preferred. The igloo designed stoppers tend to be more stable when placed on vials before and after the lyophilization process. These stoppers also have good machinability properties during filling operation with reduced incidences of intertwining.

The rubber stopper is one of the primary packaging components that come into contact or close proximity with the drug product throughout the shelf life of the drug. Therefore, drug to closure compatibility is a critical consideration during the selection of a suitable closure. Rubber formulations are complex in nature. The extractables present in the stoppers used could contaminate the product during lyophilization (under high vacuum) or long-term storage 3. Therefore, pharmaceutical companies need to evaluate the stopper to determine its compatibility with drug. In some instances, a barrier lamination may be recommended to improve the drug-closure compatibility.

To maintain the moisture level in the lyophilized drug product cake during shelf life, rubber formulations with low moisture vapor transmission rates should be selected to prevent moisture ingress, and sufficient drying of the closure after steam sterilization is necessary.