June 1, 2011 (Vol. 31, No. 11)
Wayne M. Garafola
Guidelines on Reducing the Time Needed to Accurately Conduct a Bubble Point Test
Integrity testing filters post-use is a regulatory requirement for products labeled sterile. The bubble point (BP) test is an industry-accepted nondestructive method for testing sterilizing-grade filters for integrity. The BP test is defined as the minimum test pressure at which the liquid within the pore structure of a wetted membrane is forcibly removed from the largest pores by overcoming the capillary forces of those pores. Therefore, the BP depends on the effective diameter of the largest pores. If the observed or measured BP is higher than the validated minimum BP value, then the membrane is within its specification (integral) and sterility of the filtrate is guaranteed.
Small venting hydrophobic filters—like the Midisart® 2000—are utilized on single-use bags, bioreactors, fermenters, and carboys. To ensure the contents of the container remains sterile, a post-use bubble point integrity test is performed on the vent filter. Since the membrane (PTFE) is highly hydrophobic, and not wettable using water only, a low surface tension mixture of isopropanol alcohol (IPA) and water (at a 60/40 ratio) is used as the wetting medium. These small vent filters require ~20 mL of the IPA/water mixture to completely wet the membrane prior to bubble point testing.
Most filters that are post-use integrity tested use an automated instrument (e.g., Sartocheck 4 Plus) to perform BP testing, thereby eliminating the subjectivity associated with human interpretation from the test results. Each automated instrument filter test can take approximately 10–15 minutes to execute. For pharmaceutical sites with large quantities of small area filters, integrity testing can pose a processing bottleneck.
Sartorius Stedim Biotech’s Midisart Test Manifold 10X (Figure 1) enhances productivity by allowing small filter surface area devices to be securely connected in parallel up to 10 ports. It can be wall mounted or placed on a cart.
The use of a filter integrity test manifold that can test up to 10 filters simultaneously, significantly reduces the amount of operator time by ~85% in comparison to individually testing each filter without compromising the accuracy of the test.
To prove the accuracy of using this testing method, individual (0.45 μm and 0.2 μm) filters were each manually wetted with the IPA/water mixture using a syringe and bubble point tested using the integrity test instrument.
Midisart 0.45 μm filters have a minimum bubble point of 0.9 bar, and 0.2 μm filters have a minimum bubble point of 1.4 bar. Figure 2 shows the individual results of the trials where the 0.45 um filter observes a bubble point at ~1.2 bar. The 0.2 μm filters observe bubble point at ~1.65 bar.
Figure 3 observes the ability of the instrument to detect a failure. This can be observed by performing one test using 10 Midisart 2000 0.2 μm filters and then repeating the same test using nine Midisart 0.2 μm filters and one Midisart 0.45 μm filter. The inherently lower BP of the Midisart 0.45 μm filter is used to represent a defective 0.2 μm filter and the integrity test instrument will observe a failed test run with a bubble point of 1.2 bar (passing results >1.4 bar). In Figure 3, the purple colored line shows the test run when nine 0.2 μm filters and one 0.45 μm filter were used on the manifold.
Additionally, small hydrophilic or hydrophobic filter surface areas (5 cm2–300 cm2) were also bubble point tested individually and in parallel using a Sartocheck 4 Plus filter integrity test instrument with similar results. This manifold allows the operator to select how many filters to test at one time using individual ball valves to isolate test and nontest ports.
Once each filter is wetted with an appropriate solvent, the connection to the filter is made securely by inserting the inlet of the filter to the valve port of the manifold. The male connector allows for a secure fit when testing hose barb inlet fittings. Connections are commercially available for a secure fit to other small filter devices that allow the end-user the ability to retrofit various filter assembly fittings (luer lock, 1/2” sanitary, hose barb) to fit securely to this manifold.
Vent filters like Sartorius Stedim Midisart 2000 filters can be wetted with 20 mL of IPA/water mixture (60/40 ratio) using a syringe. Other filter devices can be wetted with the appropriate solvent prior to testing.
To minimize retesting and identify a nonintegral filter, tubing can be attached to the downstream side of each filter set-up and placed within a water reservoir. As the manifold is initially pressurized during the pressure increase phase, non-integral filters will exhibit large gas bubbles flowing out of their individual tubes and the respective ball valve(s) can be turned off allowing the test to continue to the end. Following the completion of the test, these specific nonintegral filters can be rewetted and tested again. Using this setup method can reduce the number of integrity retests.
The use of a manifold allows the end-user flexibility of testing up to 10 filters versus individually integrity testing. This manifold can cut down on an operator’s integrity testing time while accurately measuring filters integrity.
Wayne M. Garafola (firstname.lastname@example.org) is field applications specialist at Sartorius Stedim Biotech.