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Container Closure Integrity Critical for New Biologics

Mar 06, 2017

Drug product package systems, such as vials and prefilled syringes, must provide a barrier that protects drug product stability and sterility throughout the entire shelf life. Manufacturers are required to demonstrate that systems are capable of maintaining microbial barrier integrity. When it comes to biologics, these products may even require that package systems maintain integrity in stringent environmental conditions (such as frozen or cryogenic environments).

The recent industry trend toward combination product development and patient-centered drug delivery has driven increasingly innovative package design using a wide selection of new packaging materials—all this has implications for testing the integrity of microbial barriers. In addition, more package systems are fully integrated with delivery devices. The package systems not only have to meet the traditional requirements of protecting drug product but also need to enable other system requirements such as proper device functionality. These new requirements lead to customized package design with increased system complexity and, in many cases, present a high level of technical risk for maintaining container closure integrity (CCI). Therefore, CCI testing plays an increasingly important role in informing material selection, derisking of system design and verifying CCI performance.

Upon product filling and sealing, package systems experience downstream processes, ranging from device assembling, packaging, storage, and distribution, all the way to patient use. These processes may introduce additional mechanical stresses and expose the containers to unfavorable environmental conditions that may affect CCI. For example, additional mechanical stress that occurs on a sealing component during device assembly may affect its seal quality. Frozen or cryogenic temperatures during transportation and storage may critically affect sealing capability of elastomer components. These processrelated risks to CCI must be assessed and the potential impact on product sterility and stability considered. Appropriate CCI testing should be integrated into process development studies to detect and control the risk of temporary or permanent loss of integrity.

In response to increasing regulatory expectations and industry needs, the pharmaceutical industry has witnessed significant technical advancements in CCI testing technologies. Advanced technologies, such as high voltage leak detection (HVLD) and vacuum decay, have demonstrated improved detection capabilities compared to conventional dye and microbial ingress methods. Many of the technologies have been used for on-line inspection and/or drug product stability testing. Even these advanced technologies, however, have limitations; there is no “one-size-fits-all” solution that can be applied to all product– package configurations and meet all process development CCI testing needs. The recently revised USP <1207> Package Integrity Evaluation—Sterile Products promotes a risk- and science- based approach and uses the package integrity profile database as a tool to ensure CCI throughout the package design and development, validation and routine manufacturing phases. Under this framework, pharmaceutical and packaging industries are experimenting with best practices to de-risk packaging design and verify continued package integrity throughout the product lifecycle.

The upcoming new PDA course, “Container Closure Systems and Integrity Testing,” scheduled to follow the 2017 PDA Annual Meeting, aims to better equip the industry with information about advanced CCI testing technologies as well as practical business approaches to effectively detect, mitigate and control package integrity. First, the course features lectures by industry experts, on-site instrument demonstrations, and hands-on exercises for advanced CCI testing techniques. The combination provides participants with a unique opportunity to not only learn the working principles but also personally experiment with these relatively new technologies and instruments, including tracer gas detection (e.g., helium leak detection), electrical conductivity and capacitance, vacuum decay leak detection, laser-based gas headspace analysis, mass extraction leak testing.

Furthermore, the course introduces a practical and meaningful risk-based methodology to construct a package integrity profile database using appropriate CCI testing methods. Such an approach starts with a thorough understanding of the construction of package materials, system design and manufacturing processes. The CCI failure modes and effects associated with each aspect are identified based on which type of CCI study is needed. In most cases, a series of CCI tests must be applied in concert with product development, including initial design confirmation, machinability studies and product stability testing, to ensure CCI is achieved and well maintained. The comprehensive results from these studies establish the package integrity profile database and inform CCI control strategy development.

Finally, the course uses case studies and group discussions to promote active participation among students, instructors and industry experts. These open-ended discussions should provide insight into the fast-evolving regulatory landscape and novel applications of CCI testing technologies.

Upon completing the course, participants will be able to compare and contrast various CCI testing technologies and understand their applicability, advantages and limitations. Through case studies, participants will become familiar with establishing a package integrity profile database using appropriate test methods in support of new product marketing approval and commercial CCI control strategy development. Furthermore, the best practices for CCI method development and validation will be discussed.

About the Author

Lei Li currently serves as an engineer advisor at Delivery and Device R&D, Eli Lilly and Company. He has nine years of experience in the pharmaceutical and medical device industry, with a focus on developing API and drug product packaging in support of clinical development and product commercialization, and establishing cold chain distribution for biologic products.

Learn more about this and other PDA Education courses following the 2017 PDA Annual Meeting.

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