Why Container Closure Integrity is crucial in the pharmaceutical industry

Container Closure Integrity in the pharmaceutical industry

Security and sterility assurance is central when it comes to primary pharmaceutical packaging. Containers and closure mechanisms must function accordingly, and their performance must be tested to prevent leaks and contamination in order to maintain sterile barriers and the shelf life of the product. This not only poses a risk to patients but can also result in financial losses for pharmaceutical companies. Furthermore, poorly sealed containers can lead to regulatory non-compliance and damage the company's reputation. According to USP <1207>, contaminants could include microorganisms, reactive gases or other substances. 

Container closure systems for drug products include all primary packaging components that are required to offer protection and sterility throughout all product life cycle stages. These include rubber stoppers, needle shields, plungers, labels, and secondary materials.

What is Container Closure Integrity Testing (CCIT)?

Container closure integrity testing (CCIT) is a crucial process in the pharmaceutical and biotech industries that ensures the quality and safety of drug products. CCIT refers to the evaluation of the ability of a container’s closure system to maintain its integrity throughout its shelf life. The purpose of CCIT is to prevent contamination from external factors such as air, moisture, and microorganisms.

Previously, CCI tests were carried out only to confirm the sterility of a container, but due to several issues with the testing methods, container and closure integrity tests were developed instead. 

Container closure integrity testing must be carried out following:

• the United States Pharmacopeia (USP) <1207> chapter Package Integrity Evaluation-Sterile Products²
• the FDA Guidance on Container and Closure System Integrity Testing In lieu of Sterility Testing as a Component of the Stability Protocol for Sterile Products³. 
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Container Closure Integrity Testing methods

In pharmaceutical packaging components, defects might not be visible to the naked eye. They can go beyond a broken seal or damaged mechanism and include damage such as microscopic cracks. Other potential issues include whether the product has been packaged according to its requirements, such as freeze-drying products being protected from water vapor4. These are especially relevant to mRNA applications that require low-temperature conditions, as the cold chain conditions and the freeze-thaw cycle can cause issues with container closure integrity and performance. 

Various methods and technologies are available for carrying out Container Closure Integrity Testing (CCIT), as outlined in USP <1207>. The pharmaceutical industry is undergoing significant changes in CCIT approaches due to the new version of EU GMP Annex 1, effective from 2023. This guidance mandates the use of a "statistically valid sampling plan," dismissing visual inspection alone as an acceptable test method.

Companies, once reliant on probabilistic methods like bubble emission, microbial challenge, tracer gas detection, and blue dye ingress, are now transitioning to more sophisticated and deterministic CCIT approaches. This shift is also encouraged by the US Pharmacopeia Convention (USP <1207>), advocating a move away from probabilistic methods toward deterministic ones.

Deterministic methods encompass leak detection, laser-based gas headspace analysis, mass extraction, pressure decay, tracer gas detection, and vacuum decay. The choice of method depends on the manufacturer's specific needs and the type of product being packaged. For a comprehensive overview of all CCIT technologies and CII test methods, refer to USP <1207>.

Headspace analysis

Headspace analysis is a non-destructive, laser-based, and fully automated inspection method designed for sealed drug containment and delivery solutions. This technique measures the quantity of specific gases within the "headspace," which refers to the space inside a hermetically sealed package that is not occupied by the product. The analysis assesses the change in gas composition within sealed containers over time to determine the ability of gas to permeate into the container closure system. 

Helium Leak testing

Helium leak testing is one of the common techniques employed to guarantee container closure integrity. This method entails introducing helium gas into the container and employing a mass spectrometer to identify any leaks. Its high sensitivity enables the detection of minute leaks, as small as 1x10-9 cc/sec. Helium leak testing proves especially valuable for containers that pose challenges in testing through other means. Moreover, it offers an efficient approach to assess the seal integrity of containers that might have been tampered with or damaged.

Obstacles in achieving and maintaining Container Closure Integrity

Addressing and sustaining container closure integrity involves overcoming several hurdles. One primary obstacle is the intricate nature of drug containment solutions and drug delivery systems, which often consist of multiple components and materials. This complexity makes it challenging to ensure the proper sealing of all components and maintain the seal's integrity over the product's shelf life.

Another hurdle lies in the requirement for specialized testing methods to identify leaks and other issues in the container closure system. This necessitates significant investments in both equipment and personnel training.

Lastly, there is the challenge of preserving container closure integrity throughout the entire supply chain, from manufacturing to distribution and eventual use. This demands vigilant monitoring and control of environmental conditions, as well as effective communication and collaboration among all stakeholders engaged in the product's lifecycle.

SCHOTT Pharma’s contribution to CCI Testing

Despite these challenges, it is essential to prioritize container closure integrity to ensure the safety and quality of pharmaceutical products for patients. SCHOTT Pharma provides several solutions to support container closure integrity and product sterility. The analytical services from SCHOTT Pharma provide a robust platform for conducting Container Closure Integrity testing, by focusing on the standards set forth by USP <1207> and 8871-5 Annex D for vials. In addition, for prefilled syringes, we ensure compliance with the guidelines of ISO 11040-4 / -6 Annex H, thereby upholding the integrity and quality assurance in our services for your containers. Moreover, the SCHOTT Pharma Online Shop provides pre-tested and pre-validated sterile, ready-to-use vials with stoppers and seals in smaller batch sizes to accelerate your drug development.