Filter Integrity Testing and Process Application

The performance of any sterilizing filter directly associates with the retention of bacteria sized below 0.22 µm. Therefore, filters of different sizes are used in sequence to reduce the load on a single small-sized filter. The first filter has a 0.45 µm size followed by 0.22 µm. Afterward, they get sterilized with steam for another batch process, read about steam sterilization. These filters require filter integrity testing both before and after use if tested non-destructive.

The primary purpose of the Filter Integrity unit includes testing of the filter membrane, disc filters, capsules, and/or cartridge. The device used to test the integrity of filters commonly known as Filter Integrity Machine. This machine requires compliance to Class B, Digital Device, under Part 15 of FCC regulations. The equipment performs on the principle of differential pressure both online and offline. The testing unit facilitates a data description management unit, which enables data management internally with the help of HMI.

Two cases exist for performing the filter integrity testing

1. New Filter
2. Filters that requires re-use

In the first case, filter manufacturers themselves perform the testing along with proper certificates and documentation. Hence, not mandatory for drug makers, yet it is better to conduct testing prior to application. Meanwhile, the second case often requires testing to check the intactness of the pore size of the membrane. Testing the differential pressure, a means by which one can assure the integrity of the filter. Agar plates often help to re-check that no bacteria crossed the 0.22 µm filter.

Classification of Filter Integrity Testing

FDA set-forth guidelines and requirements for testing the integrity of filters, along with attaching the related documentation to batch records. Filter integrity testing classified into two categories:

1. Destructive Testing
2. Non-Destructive Testing

Destructive Testing

Destructive Testing carried out at filter manufacturers from each lot as per the pre-defined sampling plan. Destruction of filters takes place to assure that no bacteria can pass through the membrane. Simply put, filters retain bacteria. This testing complies according to the method outlined in ASTM F838-83, Standard Test Method for Determining Bacterial Retention Of Membrane Filters Utilized For Liquid Filtration. Also, filters test in-house using a suitable bacterial medium containing around 10³ per m².

Non-Destructive Testing

Re-using the filters for the next batch involves risk especially when filter integrity is in question. Filters used in the previous batch may get damaged or distorted questioning their integrity for the previous and upcoming batch. Next, if filter integrity testing fails, the previous batch may need re-processing or suitable corrective action immediately.

The non-destructive filter integrity testing involves different test methods mentioned below;

• Bubble Point Test
• Diffusion Test
• Pressure Drop Test
• Water Intrusion Test

These tests ensure physically the filter integrity and a cartridge. Each test has its own significance and principle of operation dictated further.

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 applied to measure the diameter of a pore. The minimum amount of pressure required to remove the liquid out from the pores helps in measuring the pore size.

Nowadays testing units come up with pre-loaded automatic test sequences for each test. The bubble point test includes the following activities:

1. Filter wetted with suitable solvent uniformly (Water for hydrophilic filters and Water + Alcohol for hydrophobic filters).
2. Pressure applied upstream of the filter. Amount of minimum pressure expected from the recommendation provided by filter manufacturers.
3. Pressure increased slowly till bubbling occurs at downstream.

If bubbling appears at a lower pressure than the set pressure, the test considered as fail. The pressure at which bubbling occurs the downstream of filter termed as Bubble Point. Reasons for failure include but not limited to;

• Incorrect installation of the filter inside the housing
• Filter wetting is non-uniform
• The in-appropriate solvent used for wetting the filter causing compatibility issues due to different surface tension than recommended or;
• Filter failed integrity because of deformation

Once we get the pressure at which bubbling occurred, we then can calculate the diameter of the pore size with the help of the following equation;

where,
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

Application of units require uniformity in common standards, refer here.

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 surface area. Unlike the Bubble Point test, here effectiveness measurement basis includes downstream gas flow-rate instead of pressure. Typically, the pressure used to perform this test is 75-80% of the bubble point of that membrane. The manufacturer provides requirement specifications for this test.

Procedure goes like this:

1. Filter wetted uniformly with a suitable solvent.
2. Pressure applied upstream of the membrane and gradually increased up to the recommended value and allowed for the stabilization.
3. Measure the downstream gas flowrate with the help of a suitable flow-meter for 60 seconds.

If the value of gas flow-rate comes higher than the recommendation, the test failed either or all because of the below conditions;

• Incomplete wetted membrane
• Insufficient stabilization
• Filter failed integrity because of damaged pore size

To test and compare the outcome following formula may help

where;
Q – Diffusional flow
A – Membrane surface area
L – Effective Length
ΔP – Differential Pressure
Φ – Porosity of the membrane
k – Diffusivity

Equally important, unit balance in common standards required for the valued outcome. This test recommended when handling high-surface-area systems starting from 1.5 sq. m onwards.

Pressure Drop Test

While dealing with different housing arrangements, bubble point or diffusion tests becomes ineffective. Hence, Pressure Drop Tests perform on automated testing units for defining filter integrity. As this process performs at the upstream of the assembly, the downstream manual operations get eliminated. Manufacturers do not specify the requirements and hence calculated based 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 calculated as per the following formula.

where;
D – Rate of Diffusion
P_atm – Atmospheric Pressure
V – Volume of system at upstream
t – time
ΔP – Pressure Drop or Decay

Water Intrusion Test

This test typically performed to detect the quality of defects of hydrophobic filters. These filters installed as air vent filters. Water with pressure penetrated inside the filter upstream to compare the outcomes with the manufacturer’s specification limits.

Typical Arrangement

The following diagram shows a typical arrangement of filter integrity testing along with allied accessories.

Ensuring inlet and outlet pressure tubing connected properly is important prior to starting the test sequence. As per the test recipe program, steps and parameter values are preset. Generally, a tester has the following components installed on it including Housing, HMI, Printer, Tubings, Keyboard, Alarms, TC Clamp connections, etc.

Automation Aspects for Filter Integrity Units

The reliability of the components of a testing unit depends on their MoC. Hence, compatibility with the laboratories and commercial manufacturing environments becomes necessary. The manufacturer takes care of that part, including automation hardware. Suitable safety measures including alarms and interlocks must prevent mishandling the system in emergency conditions. Proper PLC and HMI configuration would serve the purpose of automation of the testing unit. Communication methods may involve the use of Ethernet or serial bus protocols. The entire system may integrate with Manufacturing Execution System as well.

The user interface includes HMI for process visualization. Also, it facilitates proper levels with password protection including Admin, Engineer, Supervisor, and Operator at minimum. 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.

Apart from the mentioned above, secure back-up and restore procedures also included in the automation package.

GxP Requirement for Filter Integrity Units

• 21 CFR Part 11, Electronic Records, and Signatures
• GAMP 5 A Risk-based Approach to compliant GxP Computerized Systems
• BS EN 60204-1, Safety Guidance and Recommendations on Electrical Equipment
• Certificate of Compliance

Some test units produce paper-based records storing no data electronically. Such units don’t fall under the requirements of 21 CFR Part 11. Also, the application of such units not designed for cGMP regulated environments.

For testing units requiring compliance with FDA 21 CFR Part 11, the validation plan should cover procedural and technological control. Consider the following points while complying with 21 CFR Part 11.

• Generation, Modification, and Maintenance of Electronic Records
• Audit Trails for all the Electronic Records
• Equipment Qualification and Test Method Validation
• Training of Concerned Personnel for 21 CFR Part 11
• Electronic Signatures
• User Management
• Data Export in the format suggested by FDA
• Human Readability for defined retention time

Filter Integrity Test: FAQs