Reducing time to market and total cost of ownership are two critical areas that pharmaceutical manufacturers can focus on heavily to be successful in a market launch for a new drug. While a tremendous amount of work goes into the discovery and manufacturing of new drugs, it is important to protect those drugs from when they are made to when they are used by a patient.

One of the key areas that must be considered in this crucial preservation stage is container closure integrity. Failure to maintain an integral packaging system risks danger to the patient, and can thus affect a number of areas within a company including revenue generation, equipment efficiency, and reputation.

Since the publishing of USP <1207>, the pharmaceutical industry now has a guidance document that can aid in decision making in relation to packaging and component selection, as well as how to monitor for container closure integrity over the entire product lifecycle.

This guidance chapter can be broken down further to gain a comprehensive understanding of how to monitor container closure integrity, and mitigate drug shortages by effectively preserving products from end to end with a well manufactured and assembled package or delivery system.

When breaking it down container closure integrity into manageable parts, there are six key areas to consider that, when accounted for effectively, give a thorough understanding of where the greatest risk to container closure integrity failures are present.

Those six areas are materials, equipment, process, environment, people, and measurement.

• Materials: When selecting packaging components for a drug, it is important to understand the design and intended fit of those components. In vial systems, blowback features and inner neck diameters are two crucial factors that need to be considered when evaluating proper fit for purpose. Certain stopper designs work most effectively with certain vial designs, so it is important to look at these relationships and select a package system that best protects the drug product inside. In the case of pre-filled syringes, barrel length, lubrication, and plunger rib radius are all factors that come into play when selecting a proper container system for drugs that will be administered via a pre-filled syringe.
   
• Equipment: Capping equipment for vial systems play a significant role in ensuring that container closure integrity has been created from the moment the system is sealed off from the rest of the environment. Understanding the compatibility with different aluminum seals and vial systems in relation to the capping equipment can help reduce the risk of a breach in container closure integrity at the very beginning of the sealing process.
   
• Process: Once the equipment for sealing has been considered, understanding the effect that equipment has on the process will provide continuous evaluation of intended sealing conditions. From here, it now is possible to look at quantifiable characteristics that will help to form a basis of understanding that the materials and equipment are fit for their intended purpose. Some of these quantifiable areas are percent compression, residual seal force, and container closure integrity itself.

• Environment and People: As data is gathered to support the fit-for-purpose claim in regard to the materials and equipment, other external driving forces are introduced into the total process: environment and people. It is important to understand that the environment can significantly impact the container closure integrity of a sterile packaging system, even if the materials and equipment have been effectively selected. Conditions during the storing and distribution phases can present multiple risks in maintaining container closure integrity. In the environment, process controls around cleaning and ensuring sterile products are of critical importance, as this is a phase where contamination on the surface of components or in any part of the equipment could create an entry for microorganisms and thus a breach in sterility. People also have a significant effect on the process. People often carry with them a number of sources that can cause contamination, including clothing fibers, hair, and other solvents or materials. Ensuring that there is no contamination throughout the material and equipment handling process is an area that requires a great deal of attention to mitigate risks to container closure integrity.
   
• Measurement: In the last stage of ensuring a sterile product package system, measurement techniques are used to draw conclusions around the other areas of consideration and how they interact and rely on one another. It is important to note that measurement techniques also can be used to verify and provide quantifiable information around each of the previously discussed areas exclusively. In this stage, container closure integrity techniques and technologies are employed that will provide information regarding whether container closure integrity has been established and maintained throughout the entire process. USP <1207> states the preference to use deterministic methods over probabilistic methods; however, both are still discussed and recognized in the chapter. Some of the more popular deterministic methods include helium leak mass spectrometry, high voltage leak detection, headspace analysis, and vacuum decay. Historical container closure integrity methods like microbial and dye ingress also are discussed as less favorable, probabilistic methods.

New deterministic technologies have been, and still are, being developed to provide an effective, quantitative route for characterizing container closure integrity. A number of these new technologies also are nondestructive, which allows for a single container system to be used for a number of assays. This, in turn, may help to reduce the total cost of product needed to fulfill a necessary set of testing. These technologies also introduce objectivity into the measurement techniques, which reduces the risk imposed on the process by people influences.

The careful consideration of all six of these key areas, and the in-depth knowledge of how advances in technology can create a more reliable foundation for generating objective, accurate, and quantifiable container closure integrity data, will better allow pharmaceutical manufacturers to reduce total cost of developing products.

In addition, attention to these issues may help to mitigate drug shortages by attempting to remove error and reduce risk. Finally, knowledge of problematic leaks, and how to reduce high-risk processes in packaging, may enable pharmaceutical manufacturers to avoid supply chain disruptions—helping to ensure that drug products reach the patients who need them.

About the Author

Christopher J. Barnes is Technology Manager of the Container Closure Integrity Lab at West Pharmaceutical Services, Inc.
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This story also can be found in the November/December 2018 issue of  Pharmaceutical Processing.

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