Pharmaceutical Filtration Integrity Testing of Sterilising–Grade Filters
Filtration – often a necessary step in pharmaceutical processes: Filters keep products reliably on highest safety standards. But who watches the watchmen? Now Sartorius Stedim Biotech has developed new solutions for the testing of sterilizing grade filters...
In the manufacturing of pharmaceuticals, problems encountered during integrity testing of sterilising-grade filters can substantially delay or even entirely prevent a production lot from being released on the market and result in considerable financial damages. Accordingly, the smooth progress of this critical process step to maintain a sterile barrier will gain exceptionally high economic significance.
The use of an integrity test unit over many years requires the highest possible cleanliness during operation of this device in order to prevent it from becoming contaminated. Under specific conditions, the connection between the interior of the integrity test unit and the filter cartridge housing may cause water or even the product or aerosols to flow back through the tubing into the test unit. This article describes the measures that will lead to a substantial increase in safety and reliability during integrity testing.
Preventing Contamination of the Integrity Test Unit
The interior of the test units are not sterile as a rule, and, in certain applications, particles or other contaminants inside the units can penetrate as far as into a filter cartridge housing during testing. Although an integrity test is performed on the non-sterile or upstream side, of the filter, such contamination must be reliably prevented in order to avoid compromising safety during manufacture.
There are two possibilities, in particular, for ensuring that cross-contamination is prevented: Use of a hydrophobic protective filter in the test line. To ensure bidirectional protection, i.e., between the test unit and the filter cartridge, an additional sterile vent filter can be installed directly in the test line between the integrity tester and the filter cartridge housing.
Safety Down to the Last Pore
Such vent filters feature a 0.2 μm sterilsing- grade membrane filter. This means that the test gas is automatically sterile after passing through the filter, which reliability retains particles as well. Another feature is that hydrophobic materials, such as PTFE, are used for these filters. This not only constitutes a sterile barrier, but also at the same time provides reliable protection against the passage of aqueous liquids.
Therefore, this means that the use of such a small air filter enables bidirectional protection in the tubing. However, it must be ensured that this filter in the test line will not adversely affect the test results. Virtually identical integrity test results are yielded both when a small vent filter of the type Midisart 2,000 (0.2 μm PTFE, filter area 20 cm²) is used and when such a protective filter is not installed.
Ultimately, the air filter must be sized so that air flow during the integrity test phase is not impeded. A sterilising-grade filter of the type Sartopore 2 (10’’, 0.2 μm), for instance, has a diffusion limit of 18 mL/min at a test pressure of 2,500 mbar. At a differential pressure of 100 mbar, the Midisart filter permits a flow rate of approximately 8 L/min and, accordingly, does not limit the air flow.
Protective Filters Bring New Challenges
The use of such a protective filter is unproblematic even for carrying out a bubble point test. Although the air flow rate overproportionately increases once the bubble point is attained, the rate still remains well below the critical limit. This can be proven if the same sterilising-grade filter is tested with and without a protective filter in the test line (Fig.1).
The curves with and without a protective filter are nearly congruent, and the integrity test unit measures the same bubble point. This shows that the Midisart filter in the test line doesn’t have any limiting effect, yet simultaneously protects the test unit.
Use of External Vent Valves
For specific applications, it is advisable to use external vent valves. During venting, which is necessary once the test phase has ended, the internal vent valve in the test unit will remain closed and only the external valve will open directly on the housing. As a result, this ensures that the overpressure in the housing can be released only via the external valve and any liquids or aerosols carried along in the air stream cannot flow back into the test unit.
A two-valve solution offers even greater security and reliability. One external valve is installed as a vent valve while a second valve is integrated between the test line and the filter cartridge housing and functions like an isolating valve, which opens only during pressurisation and is closed during both the test and the vent phases.
As the test line is closed off by the isolating valve during the test phase, an external pressure sensor is required in this equipment configuration in order to detect a pressure drop. In either case using automatically takes care of controlling the valves so that the operator does not have to intervene any further.
What Can You Do About Any Contamination of the Integrity Tester?
When integrity test units are operated over the years, even external valves cannot completely prevent particles or similar contaminants from becoming deposited inside the tester. Advanced integrity testers feature specific cleaning functions to enable such contaminants to be completely removed from their interior surfaces or their internal pneumatic components. In this case, the use of compressed air for reliable removal of particles is certainly limited.
Adhesive Contaminants Withstand Cleaning With Pressurised Air
Any contaminants that adhere to the interior surfaces cannot be reliably eliminated alone by pumping in compressed air. However, it is possible to clean the internal lines of the integrity tester using liquids too. Depending on the particular integrity tester model, even aggressive cleaning agents (e.g., up to 1M NaOH) can be used that are then removed by flushing them out with pure water.
After subsequent drying using compressed air, the integrity tester is then ready to operate immediately for regular testing. This option allowing intensive cleaning makes integrity testing more reliable and eliminates the need for expensive servicing. Such preventive cleaning markedly increases the hygiene and microbiological safety during integrity testing.
Integrity Testing of Sterilising–Grade Filters – A Critical Step
Integrity testing of sterilising-grade filters is a critical step in biopharmaceutical manufacturing. Advanced integrity testers enable a number of functions to be used, which make the filter integrity test procedure more efficient, faster and more reliable. Effective measures can be taken that permit integrity test units to be smoothly operated throughout many years. The use of protective filters installed in the test line, as well as of external valves and cleaning functions, provides the highest possible level of safety in integrity testing.