Written By BRIAN MULHALL / Chief Executive Officer

As outlined in the USP <1207> General Chapter, Container Closure Integrity Testing (CCIT) is a critical and required step in the evaluation of a container/package system’s ability to create and maintain a sterile barrier, thus ensuring the product contained therein remains safe and efficacious for the end user. Relative to the overall regulatory history of the pharmaceutical and biotechnology industries, deterministic Container Closure Integrity Testing is considered a “new” requirement after a major overhaul to the USP <1207> Guidance chapter became effective in 2016. As a result, the number of “experts” and laboratory-based service providers that have knowledge and experience across the full range of container closure integrity testing requirements may be substantially lower than some other routine and common test methodologies like HPLC or GC testing. Hence, it is important to understand and consider a number of key factors when choosing an advisor or partner laboratory to handle your container closure integrity testing requirements.

Laboratory Capabilities: As outlined in the USP <1207> Container Closure Integrity Testing chapter, there are a number of varying technologies and methods that may be used to evaluate a container/package system. Four critical methods include Laser Based Headspace Analysis, Vacuum Decay, High Voltage Leak Testing and Helium Leak Testing. While at a macro level each of these technologies perform the same function (leak testing), the most ideal technology for your container/product combination depends largely on your overall container closure integrity strategy. This is not a “one technology fits all” approach. The product formulation, package configuration, and specific study goals are critical factors that impact method selection and the way that method is developed and validated. A laboratory that does not have the various technologies and required experience to advise clients lacks the ability to custom-tailor a complete CCI program that best suits a specific product-package configuration or a broader product portfolio.

Quality Requirements: In evaluating any third-party service provider, understanding their approach and stance on quality is a critical element. In many cases, the Container Closure Integrity Testing data that is generated will end up under review at the Food and Drug Administration (FDA) as part of the product approval process. If this is expected to be the case, consideration for using a cGMP laboratory may be a factor especially as it applies to routine sample testing. Other levels of quality may be acceptable for the method development process – ISO 17025 being a good example – other parts of the process may require more stringent quality controls. Understanding and evaluating the quality guidelines your container closure integrity testing program requires is a critical part of the evaluation process.

Use of Positive Controls: Positive controls are container or package systems that have intentionally created “leaks” and play a critical role in the container closure integrity testing process, including demonstrating the method’s limit of detection. Best practices include flow-certified laser drilled holes made at varying sizes and at various locations on the container. For some technologies, different method parameters may be required to find leaks in, say, the vial neck region as opposed to the mid-body. Similarly, demonstrating the ability to find leaks in the headspace region does not inherently imply that defects in contact with liquid product can be readily detected. Positive controls are used to evaluate, and thus optimize, the performance of the method as it will be applied in the real-world. As such, the total number of positive controls used in the development and validation of a container closure integrity test method is crucial. A service provider that is not transparent about the type, quantity, and distribution of positive controls should be approached with skepticism. Understanding the role positive controls play in the overall process should be looked at as a key differentiator when evaluating potential service providers.

Understanding the USP Method Validation Requirements: Developing a container closure integrity testing method is only one part of a successful CCIT strategy. More critical is the validation of that method. Method Validation is the process of performing numerous assessments that are designed to verify that the method being evaluated is suitable and capable of providing consistent analytical data. As outlined in the USP, which is harmonized with ICH Q2R1, there are critical elements of the method validation process that must be addressed. These items include crucial parameters such as Accuracy, Precision, Specificity, Detection Limit, Quantitation Limit, Linearity, Range and Robustness. A cGMP service provider should have these requirements documented as part of an approved quality system procedure. To accomplish the method validation objectives, typically it requires that multiple operators over multiple days and, in some cases, across multiple instruments be completed. Additionally, many of the typical attributes of a validated method need to be considered specifically through the lens of container closure integrity testing. For example, in the case of vacuum decay, Limit of Detection is not necessarily with respect to the analyte (pressure), but rather the ability to detect a certain size leak. A service provider that does not have a clear and documented method validation procedure in place with specific experience in container closure integrity testing should raise immediate warning signs.

Cost & Timing: When evaluating any third-party service provider, cost and timing should always be critical elements in the evaluation process. The same holds true for container closure integrity testing but with a few caveats. Developing and validating an effective (and useable) container closure integrity test method takes time. There is time needed to prepare samples sets and positive controls. Development is a process that requires a number of trial and error steps to define the most effective and reliable approach. Once development is complete and a useable and effective method is developed, it must be “tested” using the validation process. Validation, with a clearly defined plan, tends to be the step in the process that takes the least amount of actual time. But once all of the work is completed, time is needed for report generation and data review. It is best to understand and estimate that a comprehensive container closure integrity testing method development and validation process typically will take 10-12 weeks. A service provider that states that it can be accomplished in less that 10 weeks is most likely cutting corners and not providing the level service required and expected by regulators. With regard to cost, the adage “you get what you pay for” is most appropriate. The service provider that provides a quote that is far less than its competitor should be thoroughly reviewed. In most cases the low-cost approach is not providing the level of detail and attention that is crucial to successful implementation. Key areas to review with regard to cost issues include the number of positive control samples being used, the amount of instrument time dedicated to the development process and the extent of the method validation procedure. When comparing one provider against another, be sure you outline the deliverables and have a full understanding of what you are paying for.

Container closure integrity testing is complicated. As relatively new requirements, the level of marketplace experience and knowledge tends to be much lower that some other test methods that have been in place for decades. Working with advisors and service providers that have experience across multiple technologies, understand the critical elements of method selection, know the regulatory requirements and have published scientific content on multiple aspects of CCIT are some of the key factors that should be considered. Container closure integrity testing takes time and can be costly compared to other qualification testing requirements. Be sure to understand the critical factors in selecting the best partner to help you navigate the process so that you are optimizing the time and expense required.