Quality control is hugely important in the pharmaceutical industry, meaning thorough testing is required. This applies not only of the drug itself but also to its packaging. Defects in blisters, vials and syringes put the safety of the patient and the effectiveness of the drug at risk and must be tested for using appropriate leak detection methods. New guideline developments, such as the United States Pharmacopeia 2016 USP 1207, have led to a change in leak testing methods for container closure integrity testing, especially for sterile packaging. Deterministic and non-destructive leak tests are now recommended over widely used probabilistic leak test methods. Pfeiffer Vacuum offers a complete range of products to support these applications and constantly strives for innovation to further improve the safety and quality of pharmaceutical products.

Pharmaceutical Technology spoke to Lukas Engel, Application Engineer for Leak Detection, Pfeiffer Vacuum, to find out more.

Who is Pfeiffer Vacuum and what are its key markets?

Pfeiffer Vacuum is one of the leading suppliers and manufacturers of vacuum and leak testing solutions. We offer a wide range of products, including vacuum pumps, measurement gauges, gas analysers, leak testing solutions, chambers and components. The company stands for innovative solutions and high-tech products in the analytical, industrial, research & development, semiconductor and future technologies markets. For pharmaceutical customers, we offer freeze-drying solutions and container closure integrity testing (CCIT), focusing on deterministic and non-destructive leak testing methods.

What is container closure integrity testing (CCIT)?

CCIT is the leak testing of primary packaging containers, such as blisters, glass vials, and syringes. Pfeiffer Vacuum has a dedicated portfolio for CCIT. The quality and effectiveness of drugs depends significantly on their proper packaging, and sterile products and moisture- or oxygen-sensitive drugs require a high-quality barrier between them and the environment throughout their shelf life, which may be up to a couple of years. This barrier protects them from biological contamination, water and oxygen ingress, which can have serious consequences.

Historically, the pharmaceutical industry has primarily used probabilistic test methods like blue dye or microbiological ingress testing. Nowadays, those methods are being replaced by deterministic methods which reduce the need for sample preparation and validation and detect leaks and defects more reliably.

What different CCIT technologies has Pfeiffer Vacuum developed?

There is no one-size-fits-all solution, and Pfeiffer Vacuum offers three different leak testing technologies for CCIT in order to address the multitude of challenges manufacturers face. All Pfeiffer Vacuum technologies are applicable to non-porous packaging such as glass or plastic vials, syringes, blisters, cartridges and others.

Helium mass spectrometry is a deterministic method which has been established as the gold standard for its sensitivity and versatility. Pfeiffer Vacuum has developed a comprehensive solution, in which the container is filled with helium and any helium leakage is detected by highly sensitive equipment. The automatic charging module controls the filling process, guaranteeing sensitive and reliable measurement.

Our patented Mass Extraction Technology works on the principle of rarefied gas flow. This test method is very sensitive to moisture and allows the detection of defects as small as 1 µm. During the test, the test unit is placed in a vacuum chamber and the chamber is evacuated. The leakage rate of the test unit is determined by the flow from the test unit to the vacuum reservoir.

The third technology is our new optical emission spectroscopy (OES), which does not require any specific tracer gas and instead uses the gas mixture present in the container. A multi-gas sensor is used to independently track the different gases, including argon, nitrogen, CO2 and humidity, escaping from a leaky container exposed to vacuum. Standard OES is able to detect defects as small as 0.4 µm, making it much more sensitive than other conventional methods.

At what stage in production do companies use these technologies?

CCIT is required at three main stages. The first is the research and development phase, during which new products are developed, new packaging is tested and processes are validated. Highly sensitive testing, such as helium mass spectrometry, is often required in this phase.

Leak tests are also performed during production as part of process control. A certain percentage of the batch is tested for integrity. For this step, technologies like our Mass Extraction or OES are ideal.

Last but not least, CCIT is also important as part of quality control. At this stage, we test whether the integrity of the packaging is guaranteed, even after long storage. This is often tested at different points in the shelf-life of a product.

Why are these solutions superior to previous methods, such as the blue dye ingress test?

The blue dye ingress test is quite a simple test. You put the samples in a vacuum chamber, add a blue dye solution and evacuate the chamber. After air is evacuated, you vent the chamber again and put the samples under atmospheric or even overpressure. Due to the pressure difference, the blue dye will penetrate through leaks in the container. An operator will inspect the container to determine whether there is blue dye inside. Compared to Pfeiffer Vacuum’s methods, this test is probabilistic, meaning the outcome is random, based on probability, leading to a subjective and qualitative test result. The blue dye test is also operator-dependent. An experienced, trained operator will draw different conclusions to a less trained or tired operator, especially for a sample at the lower sensitivity limit of the test.

With deterministic measures like ours, the test relies on the measurement of a physical or chemical endpoint. This gives objective and quantitative results. For example, you can directly correlate the measured gas flow to the size of the defect. The blue dye test only tells you whether a sample is leaky or not.

Our methods are also much more sensitive, which means you can detect much smaller defects. Another big advantage is that our deterministic methods are non-destructive, which is usually not the case for the blue dye test.  Our methods could therefore be used to test a higher number of samples. It is even possible to test 100% of samples, which is sometimes required by pharmaceutical companies.

Why is it important for pharmaceutical companies to use effective leak detection, and are there any regulations in this area?

The most important concern is patient safety. If the packaging has faults, the product can be contaminated. In general, three main problems can arise: oxygen ingress, moisture ingress and contamination of sterile products. Packaging defects can also impact the effectiveness of the drug.

The recommendations for pharmaceutical companies have undergone a recent shift. The main driver of this has been USP 1207, which came into force in 2016. It encourages companies to move from probabilistic methods like dye ingress or microbial ingress tests towards deterministic methods like helium leak testing, Mass Extraction and OES. Helium leak testing and Mass Extraction are specifically mentioned in USP 1207. OES, as an emerging technology, also complies with its requirements.

Good manufacturing practice (GMP) guidance requires more validation data, produced by an objective testing method. The upcoming revision of the EU GMP Annex 1 regulation that containers closed by fusion have to be 100% tested by an integrity testing method.

With this kind of regulation coming into force, pharmaceutical companies must find non-destructive methods that provide quantitative, statistical data they can rely on.

How are the Pfeiffer Vacuum solutions in this area better than the competition?

CCIT is a broad field of technologies. There is no one-size-fits-all solution, nor a single technology that can overcome all the challenges. In general, Pfeiffer Vacuum technologies are more sensitive than most other common CCIT technologies. Moreover, Pfeiffer Vacuum can support manufacturers throughout the CCIT process. We also provide GMP support for IQ/OQ (installation qualification/operational qualification), including providing the necessary documentation for all our test methods.

Our technologies are highly versatile. We are able to test almost any kind of non-porous containers. Our equipment tooling can be easily exchanged, allowing you to test a variety of container types, from blister packaging and glass vials to syringes and infusion bags, on the same device.