In the latest post in our series P.E.R.F.E.C.T.-ing the Pharmaceutical Packaging Selection Process, we evaluate Container Closure Integrity, an important measure of a container closure system's operability.
Container Closure Integrity (CCI) can be defined as “the prevention of transfer of material into or out of a container closure system”. In a system with good CCI, potential contaminates will not be able to enter the system, and pharmacological material will not be able to exit. Each of the three systems below (vial, syringe, cartridge) should be able to achieve CCI once the rubber component has been added and should be maintained throughout the shelf life of a system. This is achieved in different ways for each configuration.
There are two circumstances in which a vial’s CCI must be evaluated. The first includes only the vial and the stopper; the second also includes a capped seal. Once a vial has been stoppered, nothing should be able to enter or exit the system. However, this is much easier to guarantee once a seal has been capped onto the system.
When a vial is stoppered, it is possible that it will not be capped immediately. In this case, CCI must be ensured until a seal can be properly capped onto the system. When considering only a stopper and vial, two important areas of contact include the “Land Seal” (below, yellow) and the “Valve Seal” (below, blue). The land seal is the area on the bottom of the stopper flange that meets the top of the vial lip. The valve seal is the area of the stopper plug that meets the inner neck of the vial.
Interference fit is measured in the valve seal area and can provide information as to expected CCI performance. To evaluate interference fit, the dimensions of the stopper plug and the inner vial neck must be known. Comparing these two numbers, it is possible to determine how much the stopper will need to compress to fit into the vial. A value of 3-8% is typically considered desirable, though the range of potential fits is likely to exceed this (in either direction) in most combinations. Too much required compression can result in the stopper not fitting in the vial, or “popping out”, which can result in loss of CCI. Too little compression, and CCI may not be achieved at all.
Once a seal has been capped onto the system, the pressure applied to the stopper helps to guarantee CCI is maintained at the land seal as well. However, this is only true if a proper fit between seal, stopper, and vial is achieved. To evaluate “stack-up”, or the dimensional compatibility of these three components, the height of the vial lip, the height of the stopper flange, and the length of the seal skirt are needed. This, together with the expected percent compression of the stopper flange, can determine whether a proper fit is found.
As seals are secondary closure components (they should have no direct contact with drug products) they are often the easiest factor to change if the system is not working well. If the system is too large for a given seal skirt (or if the skirt is too short) then CCI may be risked, since the capping will be incomplete. If the seal skirt is too long (or the system is too small), wrinkling can occur at the bottom of the crimped skirt. This can raise suspicions about CCI, regardless of if CCI is maintained or not, resulting in disposal of otherwise-good product and a potential loss of trust in the brand.
Syringes and cartridges both utilize rubber plungers to obtain CCI after filling with drug product. As with vials, interference fit is an important criterion for assessing whether a given system is expected to work well. For syringes and cartridges, the important dimensions include the inner diameter of the barrel and the outer diameter of the plunger. As the rubber plunger compresses in the barrel, the percent of interference can be assessed.
The size of the plunger is critical to the function of the syringe or cartridge system. If the plunger is too small, CCI may not be achieved. If the plunger is too large, it may not fit in the barrel, or may cause excessively high break-loose forces. Syringes and cartridges also have closure elements, such as combiseals or needle shields/tip caps, that will need to be assessed to ensure that CCI is maintained. This will ensure a thorough CCI evaluation for syringe and cartridge systems.
CCI can be evaluated using methods considered either “deterministic” or “probabilistic”. Deterministic methods are more repeatable and predictable. Probabilistic methods, while popular historically, incorporate some level of randomness. USP <1207> states that “deterministic leak test methods are preferred over probabilistic methods”. Examples of each type of method are below:
Deterministic Methods
Probabilistic Methods
Compendia
The following compendia are important to understand when investigating CCI:
Overall, Container Closure Integrity must be well-understood and well-tested before a drug product can be made available on the market. The prevention of transfer of materials is crucial to the safety and efficacy of a product. In the creation of life-saving drugs, life-threatening risks must be mitigated. Though choosing appropriate elastomeric components can be difficult, Datwyler is available to help guide our clients through the selection process.
Look for the next post in the P.E.R.F.E.C.T.-ing series, in which the concept of Total Quality will be explained.
Sources:
https://www.futuremarketinsights.com/reports/injectable-drugs-market