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Testing the integrity of blister packs

Highly sensitive in-line process control system
Testing the integrity of blister packs

Pfeiffer Vacuum’s AMI 120 non-destructive integrity test system conducts highly sensitive, quantitative leak measurements in real time without using any specific tracer gas. Qualified by leading pharmaceutical companies, this in-line process control system for blister packs can measure the leak rate down to 1/10 µm within a cycle time of less than 45 s.

Highly sensitive in-line process control system

Testing the integrity of blister packs
Pfeiffer Vacuum’s AMI 120 non-destructive integrity test system conducts highly sensitive, quantitative leak measurements in real time without using any specific tracer gas. Qualified by leading pharmaceutical companies, this in-line process control system for blister packs can measure the leak rate down to 1/10 µm within a cycle time of less than 45 s.
A list of the various test methods used for package integrity testing was published in the late nineties. The report recommended validating chemico-physical leak test methods by comparing them directly to a microbiological ingress test. This probabilistic test method relies on a series of sequential and/or simultaneous events with random results. The findings are associated with uncertainties that demand large sample sizes and precise test condition controls. Some publications on microbiological ingress tests show that the method detects leakage pathways the size of a single microorganism. On the other hand, several studies have proved that the tests could miss leaks which can compromise product sterility.
It is therefore advisable to apply a deterministic integrity test method, where leakage measurements are based on phenomena that follow a predictable chain of events. One example of this test method is helium leak detection.
Helium leak testing method
Helium leak testing of hermetically sealed parts, such as closed pharmaceutical packages, requires special actions for sample preparation and tracer gas admittance. Helium can be used in various ways. One of these involves sealing the object in a tracer gas containing atmosphere. The method calls for a special atmosphere containing helium during the sealing process. This can be achieved in a sealed station within a production line or in a glove box for batch production. The tracer gas concentration must be monitored precisely during sealing in order to provide quantitative data for the free volume of the part to be tested.
Another method is the so-called bombing test. In the first step, the part to be tested is exposed to helium at high pressure in the bombing chamber. Tracer gas is backfilled into the interior volumes of the sample through the leak channels. The part is subsequently tested in a vacuum chamber connected to a helium leak detector. The theory of this method is well-established and bombing tests are classified as a quantitative test method.
Limitations of helium leak testing
Helium leak detection in hermetically sealed objects has several drawbacks. During the backfilling of the parts in the pressurised chamber, the tracer gas must diffuse through small leaks. The build-up of tracer gas concentration follows an exponential rise curve. The smaller the leak, the slower the process. This method is often too leisurely to cover every single object produced. The helium concentration in the free volume of the part to be tested depends on the bombing pressure, the bombing time and the internal volume of the part. It also varies according to the leak rate, which is unknown prior to performing the test. Following back-pressurisation, the concentration of tracer gas in the internal volume of the sample can only be calculated.
After helium admittance, the part to be tested remains under atmospheric conditions to allow tracer gas to be desorbed from the surface. If a component of the housing acts as a “helium sponge”, the low detection limit will be impacted and the theoretical models used to describe the quantification will fail. During the waiting period, a loss of tracer gas occurs through the leak channels. This means that, once filled, parts cannot be stored infinitely. For any bombing test, therefore, a strict time schedule must be developed. There are regulations defining test procedures for various classes of parts (Table 1). Bombing pressures and exposure times are recommended depending on the part’s internal free volume. The maximum waiting time (dwell time) for all types of product must not exceed one hour.
In short, the lowest detection limit is improved if the dwell time is increased due to the reduction in background signals. The ability to detect coarse leaks decreases because tracer gas is lost from the internal volume of the part.
When testing blister packages, tracer gas can be applied by piercing the aluminium foil of the blister and inserting helium with a syringe. The blister cavity is purged and the gas exchange can take place via a second hole in the foil. During the next test, the two holes are taped. This method is used to pinpoint type leak tests to identify packaging machine failures. It is a destructive method which does not allow one hundred percent testing during production.
When testing large leaks, the tracer gas escapes quickly. During the pump-down of the vacuum chamber, the complete internal volume of the part may be evacuated and the highly sensitive helium leak detection method is unable to detect large leaks. Bombing tests, complemented by gross leak tests, are mainly employed to test fine leaks for this reason. Gross leak tests can be any test method which overlaps with the sensitivity range of the helium fine leak test.
Helium vacuum tests cannot be used if the mechanical stability of the tested part does not tolerate the differential pressure between the gas-filled cavities and the evacuated test chamber. In this case, the part needs to be supported inside the chamber. Food or pharmaceutical packages are typical examples here.
The way to a new sensor technology
Helium leak detection is still the most sensitive method for CCI (container closure integrity) testing. Yet as mentioned earlier, there are certain limitations regarding the admittance of the tracer gas. A method which combines a low detection limit with independence of specific tracer gases would hence be desirable, which is why methods have been developed for measuring leakage rates quantitatively with the gas trapped in a blister cavity, e. g. pressure decay or laser-based gas headspace analytics. An overview of the leak testing methods used in container closure integrity testing is shown in table 2.
Applying an innovative approach, Pfeiffer Vacuum has introduced optical emission spectroscopy. This has lower detection limits than any other method which uses gas trapped in the cavity. The blister package to be tested is placed in a test chamber, which also provides a viewport and mechanical support. The chamber is 150 x 100 x 10 mm in size, in other words large enough for even the biggest blister packages, though adjustments can also be made to tailor the chamber to larger samples.
After loading, the chamber is evacuated with a compact, multi-stage roots pump in the ACP series and a Hipace 80 turbo pump. The ACP series of dry, compact, multi-stage roots pumps creates a clean and dry vacuum without any particle contamination. With its special rotor design, the Hipace 80 achieves a high gas throughput in combination with a very good compression ratio, especially with light gases. This ensures a low residual gas background, which is desirable in leak detection applications, for example.
At pressures lower than 10-2 mbar, plasma is ignited and its optical emission analysed with an external spectrometer. The lowest detectable signal corresponds to an orifice diameter of roughly 0.1 µm. Since the amount of gas is restricted by the free volume of the blister package, the maximum pore size is limited to roughly 200 µm/cm3 of cavity volume.
To extend the dynamic range to even larger leaks, an oxygen sensing method can be integrated into the test equipment. Pore sizes down to 2 mm can then be detected. This method can also be operated independently and provides a deterministic alternative to water bath testing in the same sensitivity range.
The software solutions featured in Pfeiffer Vacuum’s AMI 120 are compliant with 21 CFR Part 11. Optional software is available for a manufacturing execution system. Trend analysis functionality can be integrated in the software to enable early indication of drifts in the production and packaging equipment.
The test system is easy to set up and use. It yields quantitative and highly repeatable results. In addition to the information achieved by a simple go/no-go test method, the new AMI allows realtime detection of drifts in sealing parameters. The loss of valuable pharmaceuticals is prevented and downtime due to corrective measures is minimised. The cycle time depends on the desired detection limit. A cycle time of 30 s can be expected for a leakage rate of 1.0 x 10–4 mbar l/s.
Automatic calibration is implemented in the test equipment by means of certified calibrated leaks, assuring operator-independent calibration and test results.
Future developments of the technology
The AMI sensor technology and test equipment undergo continuous refinements. More applications for this tracer gas-specific sensor technology will soon be supported in various markets. It is rapidly becoming a viable alternative to mass spectrometry with selectivity based on the mass range or optical emission signals. This also includes test stations with specific tracer gases other than helium, offering leak testing and permeation measurements with operational fluids.
www.cpp-net.com search: cpp0315pfeiffer

Dr. Philippe Bunod
Dr. Philippe Bunod
Product Manager Product Integrity Solutions,Pfeiffer Vacuum

Dr. Rudolf Konwitschny
Dr. Rudolf Konwitschny
Technical Support,Pfeiffer Vacuum
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