Packaging integrity can be critical to the efficacy of a medication, and compromises can even be fatal. Pfeiffer Vacuum reveals how its groundbreaking technique offers a user-friendly, efficient and effective means of screening for leaks.
Contamination such as humidity, oxygen or microbiological ingress can impact drug stability throughout a product's life cycle. To prevent the risks of stability failure of highly moisture-sensitive drugs (for example, dry powder for inhalation), or the risk of biological ingress of parenteral drugs, highly sensitive integrity tests are required. Most test methods are very challenging in regard to time, effort, complexity or the limitation of sensitivity and detection range.
Pfeiffer Vacuum's patented approach does not require any specific tracer gas. Instead, the mixture present in the container headspace of the primary packaging is used to perform high-sensitivity tests over a large detection range. The Pfeiffer Vacuum method is therefore deterministic, non-destructive, easy to set up and use, and more sensitive than conventional techniques.
The quality and effectiveness of drugs relies on proper packaging, which must be unscathed and of the highest quality, or serious consequences might arise. This was proved in the 1970s, when contaminated intravenous fluids packaged in glass bottles - which were typical at the time for packaging such dosage forms - caused an estimated 2,000- 8,000 episodes of bloodstream infection. About 10% of the affected patients died, triggering a heightened awareness of package integrity.
Dye ingress testing has historically been the container closure integrity test of choice. The detection limit of this method, with a well-trained operator, is around 20µm. Since the test is strictly visual, the detection limit has been experimentally estimated by using orifices of known diameters. As a consequence, tightness criteria in the pharmaceutical industry are usually expressed as an equivalent hole diameter in micrometres. However, an equivalent diameter is not enough to define the tightness criterion of the packaging. Indeed, the flow leak rate only is directly correlated to the quantity of oxygen or moisture you will get inside a leaky packaging.
Depending on the diameter of the hole, the leak path (length) must be considered in order to define a leak rate (atm.cc/s), which corresponds to a tightness criterion. For large diameters (typically >100µm), the leak can be generally considered as orifice (leak path of negligible length) as defined in USP 1207.1, section 3.9. This corresponds to the 'chocked flow' regime, and the leak rate is directly proportional to the surface of the orifice. For smaller diameters, the leak path (wall thickness) also must be considered. The hole diameter is therefore no longer proportional to the leak rate. Moreover, different flow regimes must be considered.
In laminar flow, the viscosity of the gas (depending on the gas temperature) determines gas-to-gas variations of media transfer through the leak.
In the region of smallest diameters, there is another flow transition. In 'molecular flow' regimes, the molecular mass of the gas and its temperature are the driving parameters. As shown in figure 1, above, the difference between the USP 1207 orifice calculation and the real geometry of the leak is very important for holes with very small diameters.
Helium leak detection is still the most sensitive method for container closure integrity testing. However, some limitations are related to the admittance of the tracer gas. It would, then, be desirable to use a method that offered a low detection limit and did not require a specific tracer gas.
Consequently, attempts have been made to quantitatively test integrity without any specific tracer gas. These methods include pressure and force decay, or optical, methods using lasers and cameras to measure the deformation of a cavity's top foil under vacuum. An overview of leak testing methods used for blister integrity testing is shown in table 1, above.
In a new approach, Pfeiffer Vacuum has introduced optical emission spectroscopy as a method with lower detection limits than any other method that uses gas trapped in the cavity. The packaging to be tested is put into a test chamber that also provides a viewport and mechanical support for the package.
The test chamber can thereby be customised according to the needs of the product formats and the quantity of products tested simultaneously.
After loading the sample, the chamber is evacuated. At pressures lower than 10mbar, a plasma is ignited and its optical emission analysed with an optical emission spectrometer. The lowest detectable signal corresponds to an orifice diameter of roughly 0.1µm (according to USP 1207.1). Since the gas amount is restricted by the available headspace volume of the packaging, the maximum detectable pore size is limited in regards to the free headspace respectively the outgassing of the drug itself.
For further coarse leak tests, the AMI sensor technology can be complemented with a second dedicated leak sensor integrated into the same test equipment to extend the upper detection limit up to a few millimetre holes.
The software solutions used in the AMI are compliant with 21 CFR, part 11. Optional software solutions are available for a manufacturing execution system. Trend analysis can be implemented in the software for early indication of drift production and packaging equipment.
This deterministic method is easy to set up and use and yields quantitative - as well as highly repeatable - results. In addition to the information achieved by a simple go/nogo test method, the AMI enables the detection of drifts in sealing parameters in real time. The loss of valuable pharmaceuticals is prevented and production stops for corrective measures are minimised.
The cycle time depends on the desired detection limit. For a leakage rate of 1.0-10-4mbar-L/S (about 1µm, according USP 1207.1), a cycle time of 30 seconds can be expected. Automatic calibration is implemented into the test equipment using certified calibrated leaks.
Thereby, operator-independent calibration and test results are provided. The AMI can be used for different types of packaging and sealed objects such as medical devices and battery cases. Thereby different sample sizes and detection limits are applicable. In regards to blister packages, the AMI can detect holes up to 0.4µm and can test multiple blisters simultaneously.
About the same detection limit is provided for plastic bottles. Here, up to 100 bottles can be tested at the same time. For glass vials, the detection limit goes down to 0.1µm. Also, no sample preparation or storage time is required and the test results will show within about a minute.