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The FDA set forth guidelines and requirements to conduct and document filter integrity testing. The testing is classified into two categories:
A. Destructive Testing
B. Non-Destructive Testing
A. Destructive Testing
Destructive Testing is by and large carried out at the filter manufacturer’s location from each lot as per their pre-defined sampling plan. Destruction of filters takes place to ensure that no bacteria can pass through the membrane. Simply put, filters retain bacteria.
This testing complies according to the method outlined in ASTM F838-05 (formerly ASTM F838-83), Standard Test Method for Determining Bacterial Retention of Membrane Filters Utilized for Liquid Filtration. Both Health Industry Manufacturer’s Association (HIMA) and FDA have defined the retention of the challenge bacteria level to be 107 per cm².
B. Non-Destructive Testing
Filters used in the previous batch may be damaged or distorted ultimately posing questions on their integrity for the past and coming batch. Reusing a filter adopts non-destructive testing where it is checked for its intactness and quality for the next batch. If filter integrity testing fails, the previous batch may need re-testing/processing as per suitable immediate corrective action. The filter also becomes useless and hence discarded.
The following are the different methods for non-destructive filter integrity testing:
– Bubble Point Test
– Diffusion Test
– Pressure Drop Test
– Water Intrusion Test
1. Bubble Point Test:
This test works on the principle of capillary action and surface tension. Liquid when passed through the filter pores fills inside the pores with the help of surface tension and capillary action. Pressure is applied to measure the diameter of a pore. The minimum amount of pressure required to remove the liquid from the pores helps in measuring the pore size. Nowadays testing units have pre-loaded automated sequences for each test.
The bubble point test goes like this:
l. Filter is wetted with suitable solvent (‘water for hydrophilic filters’ and ‘water+alcohol for hydrophobic filters’) uniformly.
ll. Pressure is applied to the upstream of the filter. The amount of minimum pressure expected from the recommendations provided by filter manufacturers.
lll. Pressure increases slowly until bubbling occurs downstream.
If bubbling appears at a lower pressure than the set pressure, the test is considered a fail. The pressure at which bubbling occurs downstream of the filter is its Bubble Point.
– Possible reasons for failure:
– Incorrect installation of the filter inside the housing
– Filter wetting is non-uniform.
The unsuitable solvent used for wetting the filter is causing compatibility issues due to different surface tension than recommended or;
Filter failed integrity due to deformation
Once we get the bubbling point, the diameter of the pore is calculated by:
P – min. pressure when bubbling occurred
d – Pore dia.
θ – Contact angle between solid and liquid (this angle formed because of surface tension and capillarity)
s – correction factor
σ – surface tension
2. Diffusion Test:
This test works on the principle of Fick’s Law of Diffusion, where the rate of diffusion is directly proportional to the membrane’s surface area. The effectiveness of the diffusion test depends on the downstream gas flow rate, unlike the bubble point test where pressure was the key aspect.
Typically, the pressure used to perform this test is 75-80% of the bubble point of that membrane. The manufacturer provides requirements/specifications for this test.
The procedure goes like this:
l. Filter is wetted uniformly with a suitable solvent.
ll. Pressure is applied upstream of the membrane, gradually increased up to the recommended value and allowed for stabilization.
lll. Downstream gas flowrate is measured with the help of a suitable flow meter for 60 seconds.
If the value of the gas flowrate comes higher than the recommendation, the test failed.
Possible reasons for failure:
– Incomplete wetted membrane
– Insufficient stabilization
– Filter failed integrity due to damaged pore size
Verification of the test is done by using:
where;
Q – Diffusional flow
A – Membrane surface area
L – Effective Length
ΔP – Differential Pressure
Φ – Porosity of the membrane
k – Diffusivity
Again, don’t forget to maintain unit consistency. This test is recommended when handling high-surface-area systems starting from 1.5 m² onwards.
3. Pressure Drop Test:
While dealing with different housing arrangements, bubble point or diffusion tests becomes ineffective. Then, pressure drop tests are performed on the automated filter integrity testing units. Because this test is performed upstream of the assembly, the downstream manual operations get eliminated.
As manufacturers do not specify the exact test requirements, this test relies on system volume data. They measure changes in upstream pressure because of diffusion via the application of an appropriate and accurate pressure gauge.
Maximum allowed pressure drop:
where;
D – Rate of Diffusion
Patm – Atmospheric Pressure
V – Volume of system upstream
t – time
ΔP – Pressure Drop or Decay
4. Water Intrusion Test
This test is typically performed to detect the quality of defects of hydrophobic filters. These filters are installed as air vent filters.
Typical Arrangement:
Filter Integrity Testing Connection with Pressure Sensor and Internal Vent. Generally, common components installed on the testing unit are housing, HMI, printer, tubings, alarms, TC Clamp connections, etc. Proper connections at the inlet and outlet prior to starting the test sequence must be checked before initiating. Check the proper recipe is set, loaded, and ready to execute.
Automation Aspects for Filter Integrity Units:
The reliability of the testing unit components depends on their MoC. Hence, compatibility with the laboratories and commercial manufacturing environments is important. The manufacturer takes care of that part, including automation hardware.
To prevent mishandling during emergency conditions, alarms and interlocks should be considered. The system prevents any unauthorized access to recipe modification, start and stop sequence, and other functions.
An audit trail is another requirement that captures all the activities any user performs. Secure backup and restore procedures are also included in the automation package.
What does a 0.22 micron filter remove?
The diameter or size of the pore is uniformly maintained on the filter membrane. We consider this size one of the smallest in the industry to eliminate the finest-sized particles. This is effective in removing bacteria and not viruses.
