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Material properties play a role in container closure integrity under frozen or cryogenic storage temperatures.
For biologic drug products that require frozen storage—even down to cryogenic temperatures for some cell and gene therapies—the primary packaging and closure materials and their effect on container closure integrity (CCI) risks should be considered in the system design. Evaluating CCI of the system is crucial because the system needs to maintain integrity throughout the shelf life of the product, which could be two or three years, notes Jennifer Riter, senior director of Business and Technical Operations, Services, and Solutions at West Pharmaceutical Services, which manufactures delivery systems for injectable drugs.
Specifically for low temperatures, CCI testing should evaluate any ingress or egress of gases in the headspace of a container, which could affect product quality by putting the product at risk or affect product stability. “For example, carbon dioxide ingress over time could result in product loss or degradation,” explains Riter.
CCI testing should be based on United States Pharmacopeia (USP) guidelines (1) and should employ quantitative, deterministic testing such as tracer gas analysis or high voltage leak detection, says Riter. She points out that older techniques, such as dye ingress, are to be used as a last resort, only if other methods are not applicable to the system. “The first step is to determine the maximum allowable leak limit (MALL) and identify the risks, such as microbial ingress, ingress of carbon dioxide or loss of headspace, which will be specific to each product and container system,” explains Riter. “The next step is to choose a test for how to examine the MALL and the associated risks. For example, laser-based headspace analysis can check for carbon dioxide ingress.
A best practice is to evaluate CCI on the complete container and closure system during development. CCI is a key part of product testing in Phase III stability studies, notes Riter. Laboratories should perform tests under the cold-storage temperature conditions. Riter says that it is even possible to do testing of systems at cryogenic temperatures, which is important for packaging of cell and gene therapies.
Material properties are another aspect to consider when designing a container system for low-temperature storage conditions. Suppliers for the elastomers used in closures, for example, have evaluated material properties at very low temperatures and can provide appropriate materials for frozen or cryogenic storage, notes Riter.
“Causes for failure could be the material itself or the way the closure is processed or sealed,” says Riter. “It is important to look at how the materials fit together (a ‘stack-up’ analysis) and to identify the appropriate compression of the stopper with the vial, and the seal quality. Different material hardnesses or coatings can affect compression and sealing.”
Modeling tools using historical or supplier data can now be used to predict appropriate compression conditions for a certain type of vial and seal. “In the past, we would seal at low, medium, and high pressures to estimate the right condition. Now, using models, we can dial in more specifically to what compression should be,” explains Riter.
1. USP, USP 40 <1207> “Sterile Product Packaging-Integrity Evaluation” (US Pharmacopeial Convention, Rockville, MD, 2017).