Packaging CCIT is critical in
ensuring pharmaceutical packaging remains leak- free, protecting products from contamination and ensuring patient safety.
Deterministic test methods rely on physicochemical technologies. In contrast, results of most probabilistic tests are visually assessed, so any variation in the skills of the technician can impart bias. In a dye test, for example, which relies on seeing a colour, the human eye may not provide consistent results. “Methods providing a qualitative output are inferior to quantitative methods“, adds Proff. “This is like measuring people’s height as under or over 170cm, compared to measuring and noting everyone’s height individually to get a representative sample and seeing the complete height distribution. Knowing the distribution enables me to better judge how many units I need to test and how good they have to be in order to suggest a whole batch is defect-free.”
Pros and cons
Choice of test clearly depends on the drug and the container. For a drug substance that is sensitive to oxygen, gas tightness is a key issue. “Everything depends on the formulation, so you have to consider the content,” says Proff. “There are some techniques that are more practical for increased sensitivity levels, such as headspace analysis, but you might have to wait longer with exposure to the tracer gas to see smaller defects.”
Headspace analysis is a non-destructive, laser-based, and fully automated inspection method for sealed drug delivery solutions. By assessing the partial pressure of a given gas molecule in the area inside the container that does not contain the product itself – the headspace – it measures the quantity of specific gases and how their composition changes over time. This determines whether a gas can permeate the CCS. Helium leak testing is another common CCIT method. It involves either adding helium inside the container before closure or purging the container with helium on the atmospheric side of the test with leakage being
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detected on the vacuum side by an increased helium signal. One advantage is that it is highly sensitive and can detect even the smallest of leaks. Also, it has essentially the same test duration no matter the size of the defect of interest.
“Helium is an ideal tracer gas, as it is a noble gas, which will not react with any matter in the container and therefore lead to immediate detection upon leakage,” says Proff. “There are very low levels of helium in the atmosphere – around 5ppm – so you can be sure that the helium you introduce to the test system is generating most of the signal. That would not be the case with oxygen, carbon dioxide, or water under normal circumstances.” Nevertheless, helium is not everyone’s preferred choice. Its use can be more cumbersome to automate than other substances, and there is scope for false positives. Laser-based headspace scores higher when it comes to ease of use. Another complicating factor is that the limited global supply of helium makes it expensive. High voltage leak detection (HVLD), also known as the conductivity and capacitance test, is another technique for leak detection in non-porous, rigid or flexible packaging containing liquids. Using the principle of electrical conductivity and resistance, voltage and detection probes are positioned on either side of a rotating sample to scan the geometry of the package. In a non-leaking package, the current emitted by the voltage probe will register as a low voltage in the detection probe. If there is a leak, capacitance on one side of the packaging will be eliminated, so a higher voltage will register.
Every process for CCIT also has to contend with the fact that drug containment and delivery systems are increasingly complex and intricate, often consisting of many components and a variety of materials. The need to ensure that all components are rigorously tested is a complicating factor.
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