Fran DeGrazio, chief scientific officer, West Pharmaceutical Services, discusses container closure integrity (CCI), and how it’s a fundamental requirement of sterile packaging.
Container closure integrity (CCI) is a fundamental requirement of every sterile package regardless of whether the package holds a drug product or a medical device.
There are several common standards used by industry for characterising acceptable package integrity for sterile barrier packaging systems commonly used for medical devices, such as:
- ASTM F1929 Standard Test Method for Detecting Seal Leaks in Porous Medical Packaging by Dye Penetration; and
- ASTM F2096 Standard Test Method for Detecting Gross Leaks in Packaging by Internal Pressurisation (Bubble Test)
Proving container closure integrity of a drug package, however, is not as simple as following some historic standards when proving the integrity of a drug container.
Several years ago, a new standard was introduced into the United States Pharmacopeia (USP), entitled, Chapter <1207> Packaging Integrity Evaluation-Sterile Products. (1) This chapter introduces the concept that container closure integrity is proven when a package meets its specific maximum allowable leakage limit (MALL) established to maintain product quality attributes for sterility and physiochemical stability throughout expiry. (2)
The most common sterile drug package formats are vial systems and prefilled syringe/cartridge systems.
Proving integrity of these systems is more complex than often expected. An understanding of the MALL as a starting point and choosing the appropriate test method for the application are critical. There should be documented criteria supporting why a particular method is chosen to assure integrity, especially since selection of the wrong methodology could result in a risk to patient safety.
USP <1207> strongly endorses the use of deterministic methods whenever possible (e.g., tracer gas leak detection, high-voltage leak detection, laser-based headspace analysis). Additionally, CCI testing throughout the product lifecycle is recommended. Historic test methods, such as blue dye, are seen as probabilistic and, although they may have their use in certain circumstances, are not recommended for characterising the integrity of a drug packaging system from a best practice standpoint.
Even standard test methods may require optimisation for each drug product package to ensure that the selected leak test method is able to meet all relevant leak detection performance criteria specific for the test product-package system. Validation of the final methods is also required to demonstrate test method detection and precision along with other relevant criteria.
Optimisation of the packaging system for integrity is not only dependent on choosing the right test method but understanding all the various risks that could have an impact on CCI. Critical to this understanding is the form, fit and function of the components that comprise the system being used. Not all components are co-designed to fit together in an integral fashion, whether speaking of a vial, syringe, or cartridge primary package. An understanding of the component’s characteristics, drug filling and sealing factors along with the intricacies of the test methods themselves are necessary. The primary package may also be paired with a medical device to form a drug device combination product. This leads to a more complex challenge in meeting the regulatory expectation that the use of the device with the drug primary package has no negative effect on the integrity of the system.
Container closure package integrity is a complex yet necessary requirement to assure patient safety. Manufacturers should collaborate with experts in this field to minimise risks from regulatory and clinical perspectives.
References
- United States Pharmacopeia and National Formulary. Rockville, MD: United States Pharmacopeial Convention; 2016. https://www.uspnf.com/ Accessed August 25, 2020.
- DeGrazio FL. Holistic Considerations in Optimizing a Sterile Product Package to Ensure Container Closure Integrity. PDA J Pharm Sci Technol. 2018;72(1):15-34. doi:10.5731/pdajpst.2017.007658
