With the new version of EU GMP Annex 1 coming into effect on 25 August this year, big changes to the way the pharmaceutical industry approaches container closure integrity testing (CCIT) are in motion. The new guidance mandates the use of a “statistically valid sampling plan”, with visual inspection alone not considered an acceptable test method. In addition, 100% testing is now required for fusion-sealed containers such as ampoules and IV bags.
Companies that were previously reliant on probabilistic methods such as the blue dye test are now looking to implement a more sophisticated and deterministic approach to CCIT. This is also motivated by guidance from the US Pharmacopeial Convention (USP <1207>), which encourages a move away from probabilistic methods (e.g. blue dye ingress, microbial ingress) towards deterministic ones.
While regulations will be a key influence behind the types of CCIT methods that pharma companies deploy, manufacturers must also weigh up their own requirements for efficiency and quality when choosing a system.
The ideal CCIT test is not only deterministic but non-destructive, as this allows for the rigorous testing recommended by EU GMP. The ability to automate the system and perform tests in as little time as possible are key factors affecting the method’s efficiency. The ease and speed with which the test can be set up should also be considered, meanwhile, its compliance with traceability standards will affect its ability to be used in the production environment. Finally, one of the most important attributes of an advanced CCIT method is high sensitivity: can it detect packaging defects as small as 1 micron to provide ultimate assurance of product sterility?
Traditional, probabilistic CCIT methods fail to meet many of these criteria. To take the blue dye ingress test as an example, the method is destructive, non-traceable and non-automatable. Its detection limits are above those of newer test methods by as many as >20 micron and its test duration is much longer.
To improve quality, boost productivity, and comply with shifting regulatory standards, the pharmaceutical industry is now getting ready to move over to the world of deterministic CCIT. Leak detection methods such as Helium Mass Spectrometry, Mass Extraction, and Optical Emission Spectroscopy, which are used widely across industries such as automotive, electronics, energy, and chemical processing, are often considered the future of CCIT too.
These methods satisfy many but not all requirements of an ideal CCIT system. Helium Mass Spectrometry, for example, is high-speed, traceable, and unrivalled in terms of sensitivity. However, the use of helium tracer gas is destructive, making it far better suited to the R&D environment. On the other hand, Mass Extraction and Optical Emission Spectroscopy are non-destructive, traceable, high-speed, and possible to automate, as well as more sensitive than the blue dye ingress test, meaning they are a great option for high-throughput offline and inline testing.
Tips for getting started with a new method
In the recent whitepaper available for download below, CCIT specialists at Pfeiffer Vacuum share tips for getting started with deterministic integrity testing. These include the importance of evaluating the detection limits of your current method, with guidance for how this can be done.
Chuck Davidson, Product Manager Leak Detection, Pfeiffer Vacuum, explains: “First of all, you need to evaluate the sensitivity of your current probabilistic test methods, typically blue dye testing. You want to know what that sensitivity is so that you can address that and make sure that whichever method you’re planning to use is at least as good or hopefully better.”
It is critical to assess the requirements of your packaging system and select the test method that is most appropriate to the product rather than one that is preferable overall. Before choosing a system, it is also important to know the testing strategy you plan to deploy, as certain methods will lend themselves to certain production stages or sampling plans. For example, companies striving for 100% integrity testing can consider Optical Emission Spectroscopy, which is non-destructive, automatable, and can rapidly test multiple articles in the same chamber.
“It’s important to define your test strategy so that you can put the method in production and start reaping the benefits of going to a deterministic and more consistent result,” adds Davidson.
For more information on CCIT tips and a comprehensive scientific study comparing the detection limits of various probabilistic and deterministic test methods, download the whitepaper below.