Lyophilization or Freeze-Drying is broadly used for pharmaceuticals to preserve parenteral drugs properties that are unstable in liquid formulation. Lyophilized drugs have many advantages like prolonged shelf life, easy reconstitution and good stability. Therefore, the container closure integrity (CCI) is crucial for maintaining the stability and sterility of the drug throughout its shelf life.
It is a frequent question: what rubber stoppers should be employed for a specific product? Choose the right stopper at the beginning of the product development can save lots of time and money down to the production line.
Let’s analyze 3 specific areas where the selection of the right stopper is essential:
Compatibility with the product
Influence in the lyophilization process
Correct closure integrity
Compatibility of the rubber stopper with the product
The rubber stopper is a crucial packaging component that come into contact or close immediacy of the drug product. Therefore, its compatibility is a critical consideration during the selection of a suitable closure. Rubber formulations are complex in nature: the exception present in the stoppers used could contaminate the product during lyophilization (under high vacuum) or along the shelf-life storage. An assessment on the stopper-drug compatibility is required by pharmaceutical laboratories during the development phase. In some cases, a barrier lamination could improve the drug-closure compatibility.
Influence of the rubber stopper in the lyophilization process
There are a number of different designs of freeze dry rubber stoppers; Common designs are ‘Igloo’ (single vent), ‘two-leg’ (two vent points), and cruciform (four vent-points), although some have even more. The general belief “the more, the better” talking about the vent points it is not applicable in lyophilization case. As long as there is a vent for the vapour to escape then the number of these is irrelevant: in truth, complex shape could act as moisture that could end up degrading the product once the vial is closed.
Regardless the number of vents, during the lyophilization process, after the freezing step, the ice crystals sublimate via the vent(s) in the rubber stopper. It has been observed that the rate of moisture transfer from the vial increases as the cross-sectional area of the vent increase itself. However, this increase goes down as the area of the vent approached approximately 6 mm² and 10 mm² with temperatures in the chamber of 0°C and 25°C respectively. We can then state that the number of stopper vents does not have an impact on the rate of sublimation, since the size of a vent is typically already greater than 10 mm². The most common design found in the pharmaceutical industry is the igloo stopper: it tends to be more steadily positioned on vials before and after the lyophilization process.
Correct rubber stopper closure integrity
Before any consideration on CCI, there is a constant concept that needs to be addressed related to the stoppering device: the concept of “sticky stoppers”. These rubber stoppers are sticking to the compression plate in the freeze dryer chamber when the plate lifts after concluding the cycle. There are many contributing factors as to why the rubber stoppers could be sticking to the compression plate: over-compressing the rubber stopper with the compression plate (probably the most common), the roughness of the bottom side of the shelves and others. The rubber stopper manufacturers have tried to mitigate the issue by implementing raised features on the top of the rubber stoppers, pharmaceutical rubber stoppers also all have some form of lubricant on them (Silicone, B2 cross-linked silicone and other proprietary coatings), these can reduce the likelihood of the rubber stoppers sticking to the compression plate. Another solution is to “play” with the stoppering recipe: once lifted the compression plate, hold it (or move it slightly up and down) and allow the stacked vials to return in their position in the vial pack. Another solution is to adjust the bottom side of the shelves: whether modifying the roughness or applying coating.
Immediately after the freeze-drying process is completed, the rubber stopper acts as the only seal to protect the drug during its transference from the freeze dryers to the crimping station. The initial seal is provided by the interference fit (typically between 2 and 10%) of the rubber stopper plug in the vial bore. If the plug diameter of the rubber stopper is too big, it can be difficult to insert the rubber stopper into the vial or even pop out if not well placed. On the other hand, if the plug diameter of the rubber stopper is too small, it can create leak paths between the rubber stopper plug and vial neck. It is a good practice to run simulation test manually or automated in and out the freeze dryer to ensure the right selection of the rubber stopper, layout, time to crimping etc.