The goal of filter integrity test is to ensure product quality, enhance product performance, and reduce risks. It can generally be divided into two types: destructive tests and non-destructive tests.

Destructive test is typically conducted by manufacturers using statistical samples from each batch of membranes produced, as well as from the production equipment. Simultaneously, manufacturers perform non-destructive test on each sterilizing-grade filter before sale to ensure its integrity. Although products delivered to the end user are inspected for integrity, there is a possibility that the product may become damaged during transportation or supply after it has been released from the manufacturing company. Therefore, it is advisable for the end user to conduct both pre-use and post-use integrity tests to ensure product reliability.

1) Destructive filter integrity detection: Bacterial challenge tests serve as destructive tests. In this assay, a culture medium solution containing bacteria is introduced upstream of the filter to ensure that no organisms are recovered after passing through the filter. This type of test is termed destructive because microbial cultures are intentionally introduced, rendering them unusable afterward; thus, the filter must be destroyed.

2) Non-destructive test: Such detection is performed on the user side both before and after using the filter. Non-destructive test can be categorized into three types: i) Bubble point test, ii) Diffusion flow test, and iii) Water intrusion test (or flow test).

Bubble Point Test

The bubble point refers to the pressure applied to the upstream side of a filter that overcomes the surface tension of the largest pores in the system, thereby forcing water through the membrane while allowing air to flow freely through the pores. This method is commonly employed in small filtration devices and is applicable to both hydrophobic and hydrophilic filters. The procedure can be conducted manually or with automated equipment that measures the minimum bubble point value. This test is based on the principle that liquid is retained in the filter's pores by surface tension and capillary forces. It is used to determine the pore diameter by measuring the minimum pressure required to expel liquid from the membrane pores.

The bubble point is expressed as:

BP= 4*k*γ*cos?/d

Where: k=shape correction factor,

γ = surface tension

? = contact angle

d = pore diameter

The simple procedure for the Bubble Point Test is as follows:

- Wet the filter with a suitable liquid.

- Pressurize the system to 80% of the expected bubble point pressure in the product specifications.

- Slowly increase the pressure until a rapid and continuous bubbling is observed at the outlet.

- The point at which a stream of bubbles is observed is the bubble point for that filter.

Manual Test:

This test can be performed manually, identical to the automatic operation, where a pressure gauge is used to test the housing for a pressure check.

- 80% of the test pressure is manually applied to the upstream side of the filter and allowed to stabilize.

- The outlet is placed in water so a continuous bubbling can be observed.

- Slowly increase the pressure until a stream of bubbles is observed at the outlet.

- The point at which a stream of bubbles is observed is the bubble point for that filter.

The test result is recorded as a pressure measurement (bubble point in mbar). The minimum bubble point is specified by the manufacturer and must be utilized during the development of the test procedure, while the maximum bubble point is determined by the user during the test development process. For instance, in the case of a filter, if the manufacturer specifies a minimum bubble point of 1000 mbar, this value serves as the pass criterion for the filter.

Diffusion Flow Test

The diffusion flow test applies a constant air pressure to the upstream side of a liquid-filled filter and measures the volume of air that diffuses through the filter over time. Under varying air pressures, gas molecules migrate through the water-filled pores of a wetted membrane in accordance with Fick's law of diffusion. The gas diffusion flow rate is proportional to the pressure difference between the upstream and downstream sides of the filter, as well as the total surface area of the filter. The pressure during the diffusion flow test is maintained below the minimum bubble point, allowing the gas dissolved in the liquid to remain in the pores before it begins to diffuse out.

The test method can be performed manually or using automated equipment. The simple operating procedure for the diffusion flow test is as follows:

- Wet the filter with the appropriate liquid.

- Slowly increase the pressure on the upstream side of the filter to the recommended test pressure provided by the manufacturer.

- Allow the system to equilibrate.

- In automated equipment, gas diffusion is measured by the equipment, while manual requires measuring the gas flow rate at the outlet within one minute using an inverted graduated cylinder or flow meter.

The test result is measured in diffusion volume in ml.

Pressure Hold Test/Pressure Decay/Pressure Drop Test: This test is a variant of the diffusion flow test. In this test, the upstream pressure change due to the diffusion of gas through the filter is monitored using a high-precision instrument. The pressure hold value is influenced by the diffusion flow and the upstream volume. It can be calculated using the following equation:

Pressure Hold (Δp) = D*T*Pa/Vh,

Δp = Pressure Drop (bar or psi),

D = Diffusion Rate (ml/min),

T = Time (min),

Pa = Atmospheric Pressure (1 atm or 14.7 psi),

Vh = Upstream Volume of the Device (ml).

Water Intrusion Test

This method is utilized for hydrophobic filters. In this test, the filter is secured within a housing and filled with water (WFI) at ambient temperature . It is allowed to stabilize to remove air bubbles, allowing the water to form a layer on the membrane surface. Test pressure is then applied to the upstream side of the filter, and the pressure drop caused by water vapor passing through the membrane is measured.

The advantages of this method include:

- This test is becoming increasingly popular because it no longer requires the use of solvent-based wetting agents.

- Since the membrane is not wetted during the test, the filter can be reused after draining and minimal drying time, thereby reducing filter downtime.

- It can be performed on filters in sterilization systems because there is no operation occurring on the downstream side of the filter.

Factors Affecting Filter Integrity Test

1) Temperature: Temperature plays a crucial role in integrity testing. Therefore, the ambient temperature of the area, the test gas (air or nitrogen), the filter temperature, the filter housing temperature, and the temperature of the wetting agent or test liquid should all be ambient temperature during the test. Since the water intrusion test relies on the evaporative flow of water across the membrane being tested, any increase in temperature will lead to a higher evaporation rate and, consequently, a greater measured water flow. The test gas should be maintained at room temperature, without any heating or cooling during the process, as this could distort the results. According to the ideal gas law, a uniform temperature change of 1°C within the sample during the diffusion measurement phase can affect the diffusion test results by approximately 25%.

2) Test Gas: The test gas must be clean, dry, and at ambient temperature. When conducting a diffusion flow test, the type of test gas should be taken into account. If no specific gas is indicated, the maximum allowable diffusion value for the filter element is typically provided for air as the test gas. Since nitrogen (N2) has a lower solubility in water compared to air, the diffusion rate for a given filter will be reduced. If nitrogen is used instead of compressed air, the maximum allowable diffusion rate must be adjusted accordingly: nitrogen maximum diffusion = air maximum diffusion × 0.82.

3) Wetting Agent/Test Fluid: The wetting agent specified by the manufacturer in the product specifications must be used. In water intrusion tests, any material that alters the surface tension of water can impact the test results. This includes contaminants, natural oils, and variations in water conductivity, as lower conductivity increases the rate of water evaporation. In bubble point tests and diffusion flow tests, the use of different wetting agents can lead to inaccurate results due to changes in surface tension. Additionally, the filter wetting procedure and the duration of wetting are crucial factors that influence the test outcomes.

4) Test Procedure: Different filters have distinct testing procedures, and the parameters for these procedures should be configured according to the manufacturer's recommendations.

5) Filter Housing: The filter housing must be specific to the type of filter being used, as both the design and volume of the housing will impact the results.

Duoning Integrity Tester (ITPOWER) is a fully automatic filter integrity tester, designed to perform a set of integrity tests on syringe filters, cartridge, capsule filters. Integrity testing is essential step for ensuring product quality and batch release.

User-friendly HMI

?   10-inch color touch screen, supported by Windows system;

?   One-key switching between Chinese and English, and other languages can be made to custom;

?   Real-time test data and process curve display, and whole process monitoring.

User friendly design, precision hardware components, superior performance

?   Independent pipeline setting prevents liquid from flowing back into the tester;

?   Perfect POST (power-on self-test) program, ensure correct operation;

?   Heat dissipation function for both screen and backboard, ensure accurate testing;

?   Accurate algorithm, the measured pressure can be automatically adjusted according to the temperature change of tester, ensure the accuracy of data measurement;

?   St?ubli connection ports, ensures the tightness of the connection and facilitates operation;

?   Festool piezoelectric pressure regulating valve with pressure feedback, provides high precision and sensitive response;

?   Honeywell sensors, comply with FDA requirements, high precision and low fluctuations, no effect on the operation of the amplifier circuit.

Data integrity

?   500 test methods can be pre-edited and saved, and users can also modify and edit methods online;

?   Standard built-in printer, comply with FDA requirements for data records, paper data can be stored for > 10 years;

?   10,000 data records can be stored in system, and supports USB export in PDF format;

?   Provides functions of access management, audit trail, and log query that comply with 21 CFR Part 11.

Optional Accessories

?   Scan code reader (automatically input filter information by scanning code)

?   Expanded Pressure Vessel (Test Large Bubble Point)

Integrity tester can be used to perform following tests:

?   Bubble point

?   Water intrusion

?   Diffusion flow

?   Bubble point + Diffusion flow

Meanwhile, Duoning Biotech provides cartridges and capsule filters with a comprehensive range of pore size specifications and various materials to meet the filtration requirements in the processing of diverse products, including recombinant proteins, antibodies, vaccines, blood products, large infusions, and small injections.