On-site leak detection test of high-efficiency filters in the pharmaceutical production plant
An efficient filter (HEPA) generally refers to a filter with a particle capture efficiency of 99.97% or higher for particles with a diameter of 0.3um or larger. It is usually used as the final filtration device in the clean rooms of pharmaceutical enterprises to provide clean air. Whether a clean room can achieve and maintain the designed cleanliness level to a certain extent is related to the performance of the efficient filter and its installation. Therefore, conducting leak testing on the efficient filters in the clean room to ensure they meet the requirements is one of the important means to ensure the clean environment of the workshop.
The FDA also points out in the guidelines for the production of sterile drugs that leak testing should be conducted after the installation of the efficient filter to check the sealing performance of the filter gasket, frame, and filter material, etc. For sterile agent production workshops, leak testing of the efficient filter should be carried out regularly.
一、The purpose of leak detection for high-efficiency filters
The filtration efficiency of the high-efficiency filter itself is generally tested by the manufacturer. When the filter leaves the factory, it comes with a filter filtration efficiency report and a certificate of conformity. For pharmaceutical enterprises, the leak detection of high-efficiency filters refers to the on-site leak detection after the installation of the high-efficiency filter and its related system. The main purpose is to check for small pinholes and other damages in the filter material, such as frame sealing, gasket sealing, and cracks on the filter structure. The purpose of leak detection is to check the sealing performance of the connection parts between the high-efficiency filter and its installation frame, so as to promptly discover defects in the high-efficiency filter itself and its installation, and take corresponding remedial measures to ensure the cleanliness of the area.
二、The principle of DOP leak detection method
The leak detection of high-efficiency filters is usually carried out by using a PAO generator to deposit dust upstream of the filter. A photometer is then used to measure the concentration of aerosols upstream and downstream of the filter to determine if there is any leakage. The purpose of dust deposition is that the dust concentration upstream of the high-efficiency filter is relatively low, and it is difficult to detect leakage using a particle counter without dust deposition. Therefore, dust deposition is necessary to clearly and easily detect the leakage.
The artificial aerosol DOP has a history of 40 years. For some time, due to suspicion of causing cancer in humans, DOS (Dioctylsebaeate), also known as DEHS (Di(2-ethylexyl)Sebacate) and PAO (Polyaphaolefin) have been used as alternatives instead. However, the test method is still conventionally referred to as the "DOP method". Atmospheric dust, due to its concentration varying with location and time, sometimes being large and sometimes small, is generally not used for leak detection. The FDA (Food and Drug Administration) points out that when conducting leak detection, the selected aerosol should meet certain physical and chemical requirements and should not use aerosols that cause microbial contamination and microbial proliferation.
PAO generators can be divided into two types: thermal generators and cold generators. The thermal generator uses the principle of evaporation and condensation. The atomized aerosol particles are evaporated by a heater and condensed into tiny droplets under specific conditions, leaving a fog-like DOP with a particle size of about 0.3 um to enter the duct. The particle size distribution is 0.1 - 0.3 um. The cold generator refers to the use of compressed air to create bubbles in the liquid and generate fog-like multi-phase DOP aerosol through a Laskin nozzle. The maximum particle size is about 0.65 um. For leak detection of high-efficiency air outlets that require cold detection, a dust deposition ring needs to be equipped inside the air outlet.
When scanning for leak detection of filters, there are two types of cold DOP detection instruments commonly used: one is an aerosol photometer, and the other is a particle counter. The commonly used detection instrument for leak detection of high-efficiency filters is the aerosol photometer (hereinafter referred to as the photometer), which is a forward scattering linear photometer. It consists of a vacuum pump, a light scattering chamber, a photomultiplier tube, a signal processing converter, and a microprocessor.
The working principle of the photometer is: when the airflow is pumped to the light scattering chamber by the vacuum pump, the particles in it scatter light to the photomultiplier tube. In the photomultiplier tube, the light is converted into an electrical signal, which is amplified and digitized and analyzed by the microprocessor, thereby determining the intensity of the scattered light. By comparing the signal generated by the reference substance, the mass concentration of the particles can be directly measured, so its application is very wide. While the particle counter, its test value reflects the concentration of particle numbers in the airflow! It also specifies the particle size range, has high sensitivity, is applicable to all dust source aerosols, and has a large selection range, but is less used in leak detection of high-efficiency filters. The test results of the two instruments are difficult to quantitatively compare.
To determine whether the high-efficiency filter itself and its installation have any obvious leaks, tests must be conducted at the following locations on-site: the filter material; the internal connection between the filter material and the filter frame; the sealing gasket of the filter frame and the frame supporting the filter; the support frame and the wall or ceiling.
The DOP leak detection materials and instruments include: dust source (PAO solvent), aerosol generator, aerosol photometer.
The commonly used aerosol generator is the ATI TDA-6C handheld Laskin nozzle type aerosol generator. It directly uses air without the need for compressed air as the power source. At a working pressure of 20Pa, with an airflow speed of 50-2025FPM (Feet Per Minute), it can generate multi-dispersed submicron-sized oil dust aerosol with a concentration of 10-100ug/ml. The used aerosol photometer is the ATI 2H type photometer, with a dynamic measurement range of 0.00005-120ug/L and a sampling flow rate of 1ft3/min (28.3L/min).
3.1 Introduce PAO aerosol on the upstream side of the test HEPA
For HEPA in the purification air conditioning system, in order to ensure uniform concentration of the aerosol when it reaches the HEPA, the aerosol can be directly introduced from the negative pressure side of the system fan. If it needs to be introduced from the duct, it should be introduced at a distance of at least 10 times the duct diameter from the HEPA, and the number of bends should be minimized (according to the US IEST standard). Generally, as long as the aerosol at the upstream side of the HEPA reaches the required concentration and the concentration fluctuation is within a certain range, it is acceptable. For HEPA on a clean bench, the aerosol is directly introduced from the negative pressure side of the system fan.
3.2 Initialization and setting of aerosol photometer: Set the reference standard values at 100% and 0%
Follow the operation requirements of the aerosol photometer to initialize and set the alarm values. Connect the upstream sampling tube to the upstream sampling port to measure the concentration of the upstream aerosol. Adjust the concentration of the generated aerosol according to the operation requirements of the aerosol generator to make the concentration of the upstream aerosol reach 10-20 ug/ml.
3.3 Leak Detection by Scanning
Remove the diffuser plate of the HEPA. Scan the entire air outlet surface of the filter, the gap between the filter sheet and the frame, the joint between the frame and the frame, and the gap between the frame and the static pressure box. The sampling head should be 1 inch (25.4mm) away from the filter surface during the scanning. The scanning speed should not exceed 5 cm/s. The scanning should be carried out in a straight line, back and forth, with overlapping lines. If there is an alarm sound (i.e., the leakage rate exceeds 0.01%), it indicates a leak. After sealing the leak with silica gel or tightening it, conduct the scanning inspection again. It takes approximately 5 minutes to inspect one filter. During the testing process, it is necessary to frequently confirm the concentration of the aerosol upstream and pay attention to wearing protective masks and goggles during the detection.
四、Result determination and handling
The leakage rate of the high-efficiency filter should be less than or equal to 0.01%. If during the testing process of the HEPA, the %Leakage% at all points does not exceed 0.01%, then the HEPA is deemed qualified. If any point exceeds 0.01%, it is judged as unqualified and that point should be marked. It needs to be repaired or replaced. The leakage area of the filter material of the high-efficiency filter can be repaired with special glue, but the area of a single leakage point cannot exceed 1% of the total area, and the total area of all leakage points cannot exceed 5% of the total area. Otherwise, replacement is necessary.
五、The leak detection cycle for high-efficiency filters
The FDA recommends conducting leak detection in sterile drug production facilities once every six months. In China's GMP inspection guidelines, it is suggested to do so once a year. According to ISO14644, for leak detection in facilities already equipped with HEPA filters, the recommended maximum time interval is 24 months. However, ISO does not only apply to pharmaceutical cleanrooms, so the scope is broader. Leak detection with DOP should be conducted after the installation or replacement of HEPA filters. When environmental testing shows a deterioration in air quality, or when the sterility test of the product is不合格， or when the simulation filling test of the culture medium fails, leak detection can be carried out as part of a deviation. Filters that require leak detection tests also include HEPA filters used in drying tunnels and dry ovens.
