Filter integrity tests – principles and influencing variables
Sterile filters are of great importance during aseptic production of drugs and medical products. It’s their task to retain germs and particles from gasses and liquids so that they don’t contaminate the manufactured product. According to the GMP guidelines and the requirements by the American health authority (FDA), manufacturers are obligated to test the filter for integrity before and after the production cycle. By performing a filter integrity test it’s proved that the filter is fully functional and that no unwanted components did pass. In practice, there are destructive and non-destructive tests. Since non-destructive tests are of a higher significance from a financial standpoint alone, we exclusively want to discuss this group here and explain the individual tests as well as their differences.
1. Bubble point test
The so-called bubble point test is one of the mostly used test methods in the pharmaceutical industry as well as in medical engineering. The test is simple and cost-efficient and is supposed to show that the pores of the filter are impermeable for germs and particles of a specific size. The process takes advantage of capillary forces as well as surface tension of a liquid applied to the filter. That’s why a suitable liquid needs to be added to the filter before the beginning of the test. This can be water or an alcohol-water-mix, depending on the filter composition. It’s important to moisten the filter surface completely. Afterwards, pressure is applied to the filter and increased gradually. If the pressure exceeds a certain value, characteristic bubbles appear on the other side of the filter. This means that the liquid has been pushed through the filter and overcome the capillary forces retaining it. The value of the pressure is determined and documented. If the pressure is below a certain limit value (depending on the wetting liquid, this is either specified by the filter supplier or it was determined product-specifically during filter validation), it’s a sign that the filter doesn’t work properly anymore. In this case, the filter can’t be used in production anymore and has to be replaced.
2. Diffusion test (forward flow test and pressure hold test)
The diffusion test takes advantage of the natural diffusion of gas molecules according to Fick’s law. The filter needs to be moistened with a liquid just like in the bubble point test. Afterwards, pressure is applied that equates to roughly 80% of the specified bubble point pressure. The gas molecules diffuse through the water-filled pores of the filter because of the effort to maintain a concentration balance. The higher the pressure and the larger the filter surface, the larger is the diffused gas quantity. In case of the so-called forward flow test, the system replaces the gas quantity measured on the side of the filter continually by supplying the same gas quantity on the non-sterile side. This way, the differential pressure is constant during the entire duration of the test and only smaller drops in pressure are measured. In case of the pressure hold test, also known as pressure decay test, the device doesn’t supply any further gas. The testing device measures the entire pressure drop only once instead. For both tests, there are reference values for the filters according to their surface and pore size. If the calculated flow rate is higher than the approved limit value, a filter damaged is likely. It’s important to mention at this point that it’s crucial to pay attention to the correct environmental conditions and test settings during the test. Otherwise it’s possible that measuring errors occur in case of strong temperature fluctuations or non-compliance with testing times.
3. Water flow test
The water flow test is used for hydrophobic filters that are unsuitable for the first two measuring methods due to the nature of the liquid to be used for wetting. The water-repellent characteristics of the filter are taken advantage of instead. Water is applied to the filter during the performance of the test and the pressure is increased. The water enters into the pores of the filter in the so-called intrusion area, but doesn’t permeate it because the hydrophobic forces are too strong. The water flow increases exponentially above a certain pressure value and penetrates the filter. The pressure value, measured at the moment the water leaks out, is to be determined and compared to the approved values provided by the filter manufacturer.