CCIT Fresh out of the -86°C freezer

Container Closure Integrity Testing (CCIT) plays a vital role in ensuring the safety and efficacy of pharmaceutical products, and keeping a container tight is far more challenging when it undergoes storage at temperatures below -80°C. The importance of CCI became particularly evident during the COVID-19 pandemic, when vaccines needed to be stored and transported at ultra-low temperatures. It was discovered that while containers appeared intact at room temperature, they potentially began leaking when exposed to deep cold environments. But why does this happen?

How Cold Temperatures Impact Container Integrity

One critical factor influencing container integrity at these low temperatures is the glass transition temperature (Tg) of the materials used, particularly rubber stoppers. The glass transition temperature is the point at which a material, such as rubber, transitions from a flexible, elastic state to a brittle, glass-like state. Typical elastomeric materials used for sealing pharmaceutical containers have a Tg in the range of approx. -50°C to -65°C. When exposed to temperatures below this threshold—such as deep cold storage below -80°C—the rubber becomes stiff and less able to maintain a tight seal.

When a tightly sealed container is placed in deep cold storage, the internal pressure decreases as the temperature drops, due to the condensation of gases inside the container. This results in a partial vacuum relative to the higher ambient pressure outside the container.

If a breach in container integrity occurs while the container is at these low temperatures, the higher external ambient pressure forces gases into the container through the breach. This can accelerate gas exchange, allowing external gases such as oxygen or carbon dioxide to ingress, which can affect the stability and quality of the product inside.

Additionally, when the container warms up, the internal pressure increases as the gases expand back to their original volume. This overpressure can pose significant risks, particularly if the container content is taken into a syringe. In such cases, the overpressure in the vial can push the plunger of a syringe back , in extreme cases even cause it to come out of the syringe. This can lead to potential contamination or handling issues, which underscores the importance of maintaining container integrity.

Impact of Extreme Temperatures During Shipment

It’s important to note that while approx. -80°C is commonly considered the temperature for dry ice shippers, actual shipment conditions can sometimes be even more extreme. During the pandemic, temperature loggers in vaccine shippers have recorded temperatures below -100°C. This additional stress can significantly impact container integrity.

At be integral, we have observed that containers which initially maintained integrity at -85°C were subjected to tests at temperatures below -100°C. Many of these containers then exhibited breaches in integrity. This highlights the critical need to account for potential temperature extremes during shipping and to rigorously test containers to ensure they can withstand not only the standard storage temperatures but also the unexpected conditions encountered during transport.

Regulatory Requirements for Container Closure Integrity

The EU Annex 1 guidelines emphasize the importance of Container Closure Integrity Testing (CCIT) in relation to storage and transport conditions. According to these guidelines, performing CCIT studies is a requirement to ensure that containers maintain their integrity throughout the product lifecycle, including during storage and transportation. This regulatory framework underscores the necessity of thorough and rigorous testing to meet compliance and safeguard product quality.

Ensuring Effective Capping Force

One important technology to significantly reduce the risk of leaking vials at low temperatures is to ensure the correct force when capping the vial with the flip-off cap. If the capping force is not optimal, it can compromise the seal, leading to potential leaks. be integral can support this by measuring the Residual Seal Force (RSF), helping to ensure that the vials are capped with the correct force to maintain integrity under low-temperature conditions.

Of course we can also support you in finding the optimal RSF for your primary package components.

Why Choose be integral GmbH for Container Closure Integrity Testing?

At be integral, we draw on extensive experience and deep industry knowledge to ensure robust container closure integrity, especially under challenging conditions. Our approach to testing and validating container integrity at ultra-low temperatures is informed by a strong foundation of expertise and a commitment to delivering reliable results.

Expertise Built on Valuable Experience

During the COVID-19 pandemic, I was involved in addressing the complexities of vaccine storage and transport, gaining valuable insights into the challenges posed by ultra-low temperatures. This experience has been instrumental in shaping our approach at be integral, allowing us to effectively tackle the unique issues associated with extreme temperature environments.

Innovative and Reliable Testing Capabilities

Our testing facilities are designed to meet rigorous standards, providing reliable assessment of container integrity even under demanding conditions. As a startup, we may not have the largest array of technology, but we compensate with our substantial know-how and creativity. We excel in finding out-of-the-box solutions, as demonstrated by our work with unconventional container designs. Our focus is on ensuring that your containers can perform reliably, not only at standard storage temperatures but also in the face of unexpected conditions encountered during transport.

Tailored Solutions for Your Needs

We offer flexible solutions tailored to meet your specific requirements, whether you need standard testing for routine conditions or specialized assessments for more challenging environments. Our team is dedicated to providing thorough and insightful testing to help you ensure the quality and safety of your products.

Why Integrity Matters

Maintaining container closure integrity is crucial for protecting the efficacy and safety of pharmaceutical products. Our services aim to help you avoid potential product failures, ensure regulatory compliance, and uphold customer trust. At be integral, we strive to offer some of the best testing capabilities available, guided by our expertise and dedication to quality.

Get in Touch

To learn more about our container closure integrity testing services and how we can assist you, please contact us. At be integral, we are committed to supporting you with reliable and innovative testing solutions for your product packaging needs.