FILTER INTEGRITY TEST February 2025

Introduction to Filter Integrity

Table of Contents

Filter integrity test is a critical aspect of filtration systems across various industries. It refers to the ability of a filter to effectively capture and retain particles while allowing the desired components to pass through. Filter integrity testing ensures that the filtered product is contamination-free, ensures the quality and reliability of filtration processes, maintains product purity, and upholds regulatory compliance. The machine used to check the integrity of the filter is known as the Filter-Integrity Machine and basically works on the principle of differential pressure. Manufacturing companies need to comply with Class B and Digital Devices under Part 15 of FCC regulations.

What is Filter Integrity Test?

Filter Integrity Test (FIT) is a Non-destructive physical test used to check the effectiveness and integrity of filters by determining the oversized pores and other defects that comprise the integrity of filters. Particularly used in industries where filtration is critical, such as pharmaceutical manufacturing, biotechnology, food and beverage, and healthcare. The primary purpose of filter integrity testing is to ensure that filters can remove contaminants and maintain product quality.

Classification of Filter Integrity Testing?

Destructive Testing
Non-Destructive testing
Destructive Testing: – Destructive testing methods involve procedures that alter or damage the filter being tested. These methods are not suitable for filters that need to be reused or for situations where preserving the filter’s integrity is essential. Destructive testing may provide detailed information about the filter’s performance but renders the filter unusable after testing. It is carried out manufacturer’s location from each lot as per their pre-defined sampling plan.

Here filter integrity is checked to ensure that no bacteria can pass through the membrane. This testing complies according to the Standard Test Method for Determining Bacterial Retention of Membrane Filters Utilized for Liquid Filtration (Bacterial Challenge Test).

The FDA considers a filter as “Sterile” when it retains the challenge of bacteria Brevundimonas Dimunita (ATCC 19146) at least 1×10⁷ per cm² of filtration area.

Note: – Brevundimonas Dimunita: BCT (Bacterial Challenge Test) Organism.

Diameter: 0.3 – 0.4 µm

Length: up to 1 µm

Concentration Level: Greater than 10⁷CFU/ cm²

For more details about the BCT test comment below.

Non-Destructive Testing: – Non-destructive testing methods are designed to check the integrity, properties, or performance of filters without causing any permanent alteration or damage. Post-batch filters adopt non-destructive testing where it is checked for its intactness and quality for the next batch. If filter integrity testing fails, then the previous batch needs retesting/ processing as per suitable immediate corrective action.

Types of Filter Integrity Testing Methods

Bubble Point Test
Water Intrusion Test
Diffusion Test
Pressure Drop Test
Forward Flow Test
Reverse Flow Test
Air Leak Test

Bubble Point Test (BPT): The Bubble Point Test is a common method used to check the integrity and pore size of filter membranes. In this test, a wetted filter membrane is subjected to increasing gas pressure until a stream of gas bubbles is forced through the smallest pores in the membrane. BPT works on the principle of capillary action and surface tension.

Steps to do Bubble Point Test:

Preparation: The filter membrane is first wetted with a compatible liquid, typically a low-surface-tension fluid like water or alcohol. This ensures that the pores of the filter are filled with the wetting fluid.
Setup: The wetted filter membrane is placed in a testing apparatus (Housing of filter integrity machine), which includes a chamber capable of applying controlled gas pressure to one side of the filter membrane.
Pressure Application: Gas, often air or nitrogen, is gradually introduced to one side of the filter membrane at a controlled rate. The pressure is slowly increased until a steady stream of gas bubbles is observed coming out of the pores of the filter membrane.
Bubble Point Determination: The pressure at which the first steady stream of bubbles is observed is recorded as the bubble point pressure. This pressure indicates the minimum pressure required to force gas through the smallest pores in the filter membrane.
Analysis: The bubble point pressure is analyzed and compared to predetermined specifications or acceptance criteria. If the bubble point pressure falls within the acceptable range, the filter membrane is considered to have passed the test. If the pressure is outside the acceptable range, it may indicate defects in the membrane or improper wetting.

After getting bubbling point, the diameter of the pore is calculated by:

Where:

Pbp is the bubble point pressure,
γ is the surface tension of the wetting fluid,
θ is the contact angle between the wetting fluid and the filter material,
d is the diameter of the pore.

This equation demonstrates that the bubble point pressure is inversely proportional to the diameter of the pore. In other words, smaller pores require higher pressures to overcome the surface tension of the wetting fluid and initiate bubble formation.

Bubble Point Pressure: – The bubble point pressure refers to the minimum pressure required to initiate the formation of gas bubbles in a porous material, such as a filter membrane or a porous medium. It is a critical parameter used in filter integrity testing to check the smallest pore size in the filter membrane.

When conducting a bubble point test, the filter membrane is wetted with a suitable liquid, typically water or another wetting fluid. Then, gas (often air or nitrogen) is applied to one side of the membrane at increasing pressure levels. As the pressure increases, gas begins to penetrate the pores of the membrane. When the pressure reaches a certain threshold known as the bubble point pressure, gas bubbles start to form and are visible on the downstream side (where filtrate comes out) of the membrane.

The bubble point test can be used for both hydrophilic and hydrophobic filters, as long as the appropriate wetting fluid is used to wet the filter membrane before conducting the test.

Hydrophilic Filters: Hydrophilic filters have an affinity for water and are readily wet with aqueous solutions. When conducting the bubble point test on hydrophilic filters, water or other aqueous solutions are typically used as the wetting fluid. The wetting fluid fills the pores of the filter membrane, allowing for accurate measurement of the bubble point pressure.
Hydrophobic Filters: Hydrophobic filters repel water and are typically wetted with non-aqueous fluids, such as alcohol or organic solvents. For hydrophobic filters, the wetting fluid used in the bubble point test should be compatible with the filter material and capable of penetrating the pores to accurately determine the bubble point pressure.

Water Intrusion Test: The Water Intrusion Test is a method commonly employed in filter integrity testing to check the integrity of filter membranes and ensure their effectiveness in retaining particles or microorganisms of specific sizes. In this test, the filter membrane is subjected to controlled conditions where water is applied to one side of the membrane, and the extent of water penetration or intrusion is observed and measured.

WIT test is used to detect the quality of defects of hydrophobic filters. These filters are installed as air vent filters.

Water intrusion test results can be expressed by either water flow or water intrusion.

Water flow is a measure of the actual water volume change at test pressure, which is ~3.5 times lower than water intrusion.

The water intrusion value is determined as the increase in compressed gas volume, because of water flow, normalized to atmospheric pressure.

Here’s how the Water Intrusion Test is typically conducted for filter integrity testing:

Preparation: The filter membrane is securely mounted or placed in a testing apparatus designed specifically for the test.
Wetting: Water, often under controlled pressure or flow rate, is applied to one side of the filter membrane. The water wets the surface of the membrane and begins to penetrate its pores.
Observation and Measurement: The extent of water penetration into the membrane is observed and measured using various techniques. This may involve visual inspection to detect the presence of water droplets or wet spots on the downstream side of the membrane. Alternatively, specialized instruments may be used to quantify water penetration depth or measure changes in pressure.
Analysis: The results of the Water Intrusion Test are analysed to evaluate the integrity and porosity of the filter membrane. Any signs of water penetration beyond acceptable limits may indicate defects, inconsistencies, or variations in pore size that could compromise the filter’s performance.
Interpretation: The observed water intrusion is compared against predetermined acceptance criteria or standards established for the specific application or industry. This helps determine whether the filter membrane meets the required integrity and performance standards.

Water Intrusion Test Formula:

Water intrusion pressure refers to the pressure at which water begins to penetrate or infiltrate into a porous material, such as a filter membrane or a permeable substance. It is a critical parameter used to evaluate the integrity, porosity, and performance characteristics of the material in various applications.

Where:

ΔP represents the pressure difference (in mbar) applied across the porous material during the test.
V is the total volume of water used during the test, measured in milliliters (ml).
T is the duration of the water intrusion test, measured in minutes.
P is the test pressure applied to the material, typically measured in mbar

This formula calculates the rate at which water infiltrates the porous material per unit of time (ml/min) based on the pressure difference, the volume of water used, test duration and test pressure applied. It provides valuable information about the material’s porosity, permeability, and performance characteristics, which is essential for various applications in industries such as filtration, fluid transport, and barrier protection.

3. Diffusion Test:

The diffusion test for filter integrity testing operates on the principle of Fick’s law of diffusion, which states that the rate of diffusion is directly proportional to the membrane’s surface area. This law is a fundamental concept in physics governing the movement of molecules or particles from areas of high concentration to areas of low concentration.

In the context of filter integrity testing, the diffusion test checks the integrity and effectiveness of filter membranes by measuring the rate at which gas molecules diffuse through the membrane. Here’s how the diffusion test aligns with Fick’s law:

Surface Area: According to Fick’s law, the surface area of the membrane directly influences the rate of diffusion. A larger surface area provides more pathways for gas molecules to pass through the membrane, resulting in a higher rate of diffusion.
Pressure Gradient: The diffusion test typically involves applying a pressure gradient across the membrane, with higher pressure on one side and lower pressure on the other. This pressure difference drives the diffusion process, facilitating the movement of gas molecules through the membrane.
Membrane Characteristics: The characteristics of the membrane, including pore size distribution, material composition, and thickness, also impact the rate of diffusion. Membranes with larger pores or higher permeability allow gas molecules to diffuse more rapidly through the membrane.
Time: The duration of the diffusion test also affects the overall rate of diffusion. Longer exposure times provide more time for gas molecules to diffuse through the membrane, leading to increased diffusion rates.

The procedure for the diffusion test in filter integrity testing follows these steps:

Wetting the Filter: The filter is uniformly wetted with an appropriate solvent or wetting fluid. This ensures that the pores of the filter membrane are filled with the wetting fluid, preparing it for the diffusion test.
Applying Pressure: Pressure is applied upstream of the membrane in a gradual manner. The pressure is increased up to the recommended value and allowed to stabilize. This pressure gradient across the membrane facilitates the diffusion of gas molecules through the membrane.
Measuring Gas Flowrate: The flowrate of gas passing through the membrane from the upstream to the downstream side is measured using a suitable flow meter. The measurement is typically conducted for a specified duration, such as 60 seconds.
Checking Test Outcome: If the measured gas flowrate exceeds the recommended value or falls outside of the acceptable range, the test is considered failed. This indicates that the membrane may have defects or breaches that allow excessive gas flow, compromising its integrity and effectiveness in filtration.

Diffusion Formula:

Diffusional flow=LΔP×A×ϕ×D

Where:

ΔP: Represents the differential pressure across the filter membrane during filtration.
A: Denotes the membrane surface area available for gas or fluid passage.
ϕ: Signifies the porosity of the membrane, indicating the fraction of the membrane’s volume that contains pores.
L: Stands for the effective length, which represents the distance gas or fluid must travel through the membrane, accounting for obstacles or pathways.
D: Represents diffusivity, a measure of how easily molecules can move through a substance or medium.

4. Pressure Drop Test: This test evaluates the pressure drop across the filter membrane under controlled conditions, providing insights into the integrity and performance of the membrane in filtration processes.

Pressure Drop Formula: ΔP=P_atm×(Vt×D)

Where,

ΔP: Represents the pressure drop across the filter membrane. It’s the difference in pressure between the upstream side (where the fluid enters the membrane) and the downstream side (where the fluid exits the membrane). The pressure drop is typically measured in units such as Pascals (Pa) or pounds per square inch (psi).
P_atm: Denotes the atmospheric pressure, which is the pressure exerted by the atmosphere at a given location. It serves as a reference pressure for the calculation. Atmospheric pressure is usually expressed in units such as Pascals (Pa) or pounds per square inch (psi).
t: Represents the duration of the pressure drop test, typically measured in seconds. It indicates the time over which the pressure drop is observed and measured.
D: Stands for the dynamic viscosity of the fluid passing through the filter membrane. Dynamic viscosity is a measure of the fluid’s resistance to flow under an applied force. It is typically measured in units such as Pascal-seconds (Pa·s) or centipoise (cP).
V: Denotes the volume of fluid passing through the filter membrane during the test. It’s typically measured in liters (L) or cubic meters (m³).

Factors To Investigate in Case of Failure:

In the event of a failure in a filter integrity test, several factors should be investigated to identify the root cause of the failure and address any issues. Here are the factors to investigate:

Filter (Cartridge) Dryness: Check if the filter cartridge was adequately wetted before the test. Dry filters may not perform effectively during testing.
Pore Size Correctness: Verify if the pore size of the filter membrane matches the specifications required for the application. Incorrect pore sizes can lead to filtration failures.
Leaks in Housings, Connections, and Valves: Inspect the filter housing, connections, and valves for any signs of leaks. Leaks can compromise the integrity of the filtration system.
Damages in Gaskets or O-Rings: Examine gaskets and O-rings for any damages or defects that could cause leaks or improper sealing.
Stabilization Time: Ensure that the system was given sufficient time to stabilize before conducting the integrity test. Inadequate stabilization time can affect test results.
Water Quality and Temperature: Check the quality and temperature of the water used during the test. Poor water quality or extreme temperatures can impact the performance of the filtration system.
Temperature and Pressure: Monitor temperature and pressure conditions during the test. Fluctuations in temperature or pressure beyond acceptable limits can affect filtration efficiency.

Critical Parameters to Validate Filter Integrity Testing:

To validate an automated in situ filter integrity testing system, several critical parameters need to be carefully validated and monitored. Here are the key parameters:

Test Time: The duration of the integrity test, typically set to 10 minutes, ensures sufficient time for the test to capture relevant data and check filter integrity effectively.
Allowed Water Intrusion: Compliance with the water intrusion limits specified by the filter manufacturer ensures that the filter meets performance standards and retains its integrity during operation.
Initial Stabilization and Stabilization Time: Ensuring the system stabilizes adequately before initiating the integrity test is crucial for obtaining accurate and reliable results.
Draining Time and Drying Time: Efficient draining and drying times are essential for preparing the filter system for testing and ensuring consistent testing conditions across trials.
Initial and Final Temperature: Monitoring temperature variations from the beginning to the end of the test helps check the impact of temperature on filter integrity.
Initial and Final Pressure: Tracking pressure changes throughout the test provides insights into the integrity and performance of the filter under different pressure conditions.
Net Volumes: Calculating the net volumes of fluid passing through the filter system ensures accurate measurement and checking of filtration efficiency.
Water Intrusion Value Calculation Formula (Program): Developing and validating the calculation formula used by the automated system ensures accurate determination of water intrusion values and reliable test outcomes.
Maximum Pressurization Loops and Time: Setting maximum limits for pressurization loops and time prevents overloading the filter system and ensures safe and controlled testing conditions.
Maximum Filling Time: Establishing maximum filling time limits prevents excessive fluid loading and potential damage to the filter system.
Residual Moisture Calculation: Calculating residual moisture content, typically based on initial and dried filter weights, helps evaluate filter drying efficiency and overall system performance.

Frequently Asked Questions

1) Why is filter integrity important in bioprocessing?

Filter integrity is crucial in bioprocessing to ensure product quality, safety, and regulatory compliance. It helps prevent contamination and ensures the integrity of the final product.

2) How is filter integrity measured?

Filter integrity can be measured using various methods such as Water intrusion Test, Bubble point testing, diffusion testing, pressure decay testing, and integrity testing using particulate or microbial challenge.

3) What factors can affect filter integrity?

Factors such as operating pressure, temperature, flow rate, filter material, pore size, and the nature of the fluid being filtered can all impact filter integrity.

4) What are some common challenges in maintaining filter integrity?

Common challenges include filter fouling, membrane degradation, improper handling, and inadequate cleaning and sterilization procedures.

5) How often should filter integrity be tested?

Filter integrity testing should be performed regularly, typically before and after each filtration operation, and according to regulatory requirements and industry best practices.

6) What are the consequences of filter integrity failure?

Filter integrity failure can lead to product contamination, compromised product quality, regulatory non-compliance, and potentially costly production delays or recalls.

7) How can filter integrity be optimized?

Optimizing filter integrity involves selecting appropriate filter materials, operating conditions, and implementing robust maintenance and monitoring protocols.

8) Are there specific regulations governing filter integrity in bioprocessing?

Yes, regulatory agencies such as the FDA (Food and Drug Administration) and EMA (European Medicines Agency) provide guidelines and requirements for filter integrity testing and validation in bioprocessing.

9) Why are pressure drop tests performed on automated filter integrity testing units?

Pressure drop tests are performed on automated filter integrity testing units to assess the resistance or obstruction encountered by the filter during the filtration process. This test helps in evaluating the condition of the filter and detecting any potential issues that may affect its performance and integrity.

Here’s why pressure drop tests are important:

Indication of Filter Clogging: Pressure drop tests can detect if the filter is becoming clogged with particulates, microorganisms, or other contaminants during the filtration process. An increase in pressure drop indicates a potential clogging issue, which can impair the filter’s ability to effectively remove contaminants from the fluid.

Monitoring Filter Efficiency: By measuring the pressure drop across the filter, operators can monitor the efficiency of the filtration system. A sudden or significant increase in pressure drop may suggest a decrease in filter integrity, which could lead to compromised filtration performance.

Early Detection of Filter Damage: Pressure drop tests can help in the early detection of filter damage or degradation. If the pressure drop deviates from expected values, it may indicate structural damage to the filter membrane or other components, prompting further investigation and maintenance.

Optimizing Filtration Parameters: Monitoring pressure drop over time allows operators to optimize filtration parameters such as flow rate, pressure, and filter replacement intervals. By understanding how pressure drop changes under different operating conditions, operators can ensure efficient and reliable filtration processes.

Compliance with Regulatory Standards: Many regulatory agencies require monitoring of pressure drop as part of quality control measures in industries such as pharmaceuticals, biotechnology, and food processing. Performing pressure drop tests helps ensure compliance with regulatory standards and guidelines for filter integrity testing.

Overall, pressure drop tests play a crucial role in maintaining the integrity and performance of filtration systems, enabling operators to identify and address issues that could impact product quality, safety, and regulatory compliance.

10) When Does Filter Integrity Testing Become a Consideration?

Filter integrity testing has become a consideration in various industries and applications where the reliability and effectiveness of filtration processes are critical. Here are some situations when filter integrity testing becomes important:

Critical Applications: In industries such as pharmaceuticals, biotechnology, and food and beverage production, where product purity and safety are paramount, filter integrity testing is essential. It ensures that filters effectively remove contaminants and microorganisms without compromising product quality.

Regulatory Compliance: Regulatory agencies such as the FDA (Food and Drug Administration) in the United States and the EMA (European Medicines Agency) in Europe often require filter integrity testing as part of Good Manufacturing Practices (GMP) and quality assurance standards. Compliance with these regulations necessitates regular testing to validate the integrity of filtration processes.

Risk of Contamination: In environments where there is a high risk of contamination, such as in pharmaceutical manufacturing facilities or healthcare settings, filter integrity testing is crucial. It helps prevent the passage of harmful particles, bacteria, or viruses through the filtration system, minimizing the risk of product contamination and ensuring patient safety.

Process Validation: During process validation and qualification activities, filter integrity testing is conducted to verify that the filtration process consistently meets predetermined specifications and performance criteria. This ensures the reliability and reproducibility of the filtration process over time.

Change in Filtration System: Whenever there is a change in filtration equipment, filter type, or operating conditions, filter integrity testing should be considered. This helps assess the impact of changes on filtration efficiency and ensures that the new system meets the required performance standards.

Routine Maintenance: Incorporating filter integrity testing as part of routine maintenance procedures helps identify any issues or degradation in filter performance before they compromise product quality or safety. Regular testing allows for proactive maintenance and ensures optimal performance of filtration systems.

In summary, filter integrity testing becomes a consideration whenever there is a need to ensure product quality, regulatory compliance, and the reliability of filtration processes in critical applications across various industries. It serves as a fundamental tool for maintaining the integrity and effectiveness of filtration systems, safeguarding product quality, and protecting public health.