The primary goal of CCIT is to ensure that the container-closure system is able to maintain the sterility and stability of parenteral products, such as injectables, throughout their shelf life. This is accomplished by verifying that there are no leaks or defects in the container-closure system that could allow ingress of micro-organisms and thus compromise the quality and safety of the drug product.
CCIT of aseptic or sterile products typically involves the testing of the primary container-closure system, which includes the container (such as a vial or syringe) and its closure (such as a stopper or cap). The purpose of CCIT is to ensure that the container-closure system is hermetically sealed and free from leaks.
The USP or Ph.Eur. (pharmacopoeia of the US and Europe) stipulates that containers sealed through thermal fusion such as ampoules and blow-fill-seal containers require 100% testing for each lot. However, for other container types, a statistically valid sampling plan is acceptable.
While regulations, like the recently revised EU Annex 1, prohibit relying solely on visual inspection as a method to evaluate container integrity, performing a visual check for cracks can be included as part of a comprehensive strategy to ensure container integrity. eyetec has rolled out such strategies for several clients in past projects that have been successfully audited by regulatory agencies for approval.
The Different Methods of CCIT Testing in Pharmaceutical Manufacturing
There are several methods for CCIT, including dye ingress, high-voltage leak detection, vacuum decay testing and headspace analysis. Each method has its own advantages and limitations and the choice of method depends on the specific product and container-closure system being tested. Suitable CCIT methods should be developed for each parenteral drug product, both for routine manufacturing and quality control testing.
The process of dye ingress testing is used to identify potential leaks in the container-closure system by utilizing a coloured dye, such as methylene blue. The containers are immersed in the dye and subjected to vacuum pulses. If a leak is present, the dye will penetrate the product upon release of the vacuum, due to the dye being at an overpressure relative to the inside of the container. However, one issue with this method is that interpretation of the results may be subjective, as different analysts may be able to detect varying levels of colour. To mitigate this issue, photometric methods can be developed for a more objective assessment.
High-Voltage Leak Detection (HVLD) and vacuum decay testing are other non-destructive methods that can detect leaks or defects in the container-closure system. These methods involve the application of a vacuum or high voltage to the container. The vacuum decay method applies a vacuum in a chamber that fits a single container. If a leak is present, air from inside the container will flow out and thus a drop in the surrounding vacuum will be registered. High Voltage Leak Detection applies a high-tension field across a section of the container surface. If a crack or leak is present and if the liquid inside the container has sufficiently high conductivity, an electrical current will be recorded as the indication of a leak. The main limitation of HVLD is that it can't be used to detect leaks in the neck region of vials, since the alucap would conduct the current anyway. Additionally, it cannot be used for lyophilized or non-conductive products because they won’t allow current to pass through.
Laser-based technologies, such as laser-induced fluorescence and laser-based headspace analysis, are particularly useful for detecting smaller leaks or defects that may not be detectable with traditional CCIT methods. These techniques are often also used to confirm absence of vapor in freeze-dried products and absence of oxygen in products that require nitrogen overlay. Recent innovation in this field has been to subject the containers to a CO2 atmosphere under overpressure and then measure the CO2 concentration inside the container as an indicator of leakage.
eyetec as a trusted CCIT partner
eyetec is a globally recognized authority in the area of CCIT, with an in-house team of project engineers. Complementary to our consultancy services, our Leak Test Samples (LTS) are specifically created to test and qualify CCIT equipment. eyetec distinguishes itself as one of just three global firms providing certified micrometer Leak Test Samples specifically for the pharmaceutical sector. These samples contain high-precision, laser-drilled pinholes that are certified based on flow measurement. For a perfectly cylindrical pinhole, the measured flow correlates to the pinhole diameter. The Leak Test Samples produced by eyetec are designed and manufactured to serve as a reliable reference sample for leak testing equipment, a critical factor in meeting the compendial requirements for conducting Container Closure Integrity Testing (CCIT).
Depending on the customer's needs, eyetec provides Leak Test Samples in various primary packaging materials and micrometer pinhole sizes. Each sample comes with a certificate that confirms the pinhole size, based on airflow rate. With its centrally located production facilities, eyetec guarantees prompt worldwide delivery of all Leak Test Samples.
Contact us today to learn more about our services and how we can assist you in meeting your CCIT needs.