Single-use tff system and method incorporating online filter integrity testing

Abstract

The application provides a disposable TFF system integrated with online filter integrity testing and a method, and belongs to the technical field of biopharmaceutical equipment. The application aims to solve the problems of existing technology, such as the need for external equipment for filter integrity testing, high risk of sterility, complicated operation, unreliable data and insufficient compliance. The system comprises: a disposable flow path assembly comprising a TFF filter, a sterile integrity test interface and an isolation valve; a hardware control module integrated with a built-in integrity test module and a sensor array; and a central control unit. The test flow path is physically isolated from the main process flow path through valve isolation. The whole process is automatically controlled through self-detection of the gas source, wetness verification, bidirectional pressure verification and automatic pressure relief, and an electronic report meeting the preset specifications is generated. The application realizes sterile, efficient and reliable online integrity testing, thereby improving production efficiency and compliance.

Description

Technical Field

[0001] This application relates to the field of biopharmaceutical equipment technology, and in particular to a disposable production-type TFF (tangential flow filtration) system and method for downstream biopharmaceutical processes, which integrates online filter integrity testing function. It is suitable for large-scale biopharmaceutical concentration, buffer replacement and other processes, and meets the requirements of pre-use sterilization and post-sterilization integrity testing (PUPSIT) for sterile / virus-free filters. Background Technology

[0002] Tangential flow filtration (TFF) is an indispensable core technology in downstream biopharmaceutical processes, used for the concentration, desalting, and buffer replacement of biomolecules such as proteins, antibodies, and vaccines. With the increasing demands for cross-contamination risk control and compliance in the biopharmaceutical industry, single-use systems (SUS) have gradually replaced traditional stainless steel systems due to their elimination of the need for cleaning validation, avoidance of batch-to-batch contamination, and significant improvement in production efficiency and product safety.

[0003] Filter integrity testing is a critical quality control point in biopharmaceutical processes, especially for sterile or virus-free filters. Their filtration effectiveness must be verified through post-sterilization integrity testing (PUPSIT) to comply with EU GMP Annex 1, FDA, and other regulations. However, existing integrity testing protocols for single-use production TFF systems have several inherent shortcomings:

[0004] High risk of sterility issues: Existing systems often use external, independent devices for integrity testing. During testing, the filter must be manually disconnected from the disposable flow path, connected to an external testing instrument, and then reinstalled after testing. This process takes place in a non-absolutely clean environment, making it highly susceptible to microbial contamination and damage to the sterility barrier.

[0005] The operation is cumbersome and reliant on manual labor: the testing process requires manual completion of steps such as pipe disassembly and assembly, tester connection, parameter setting, and result recording, which is time-consuming (a single test usually takes more than 30 minutes) and highly dependent on the operator's skills and experience, with human risks such as pipe connection errors and parameter setting mistakes.

[0006] Insufficient test prerequisites and data reliability: Whether the filter is sufficiently wetted and whether the pipeline is completely emptied depends solely on manual visual judgment, which cannot be objectively verified and is likely to lead to invalid test results; the test instrument is usually only equipped with a single-point pressure sensor and lacks a data cross-validation mechanism. If the sensor fails, it will directly lead to incorrect test results.

[0007] Safety and compatibility deficiencies: The test flow path lacks reliable physical isolation from the main process flow path, and the test medium may contaminate the process fluid; the residual pressure in the pipeline after the test needs to be manually released, which poses a risk of pressure shock.

[0008] While some manufacturers have attempted to integrate integrity testing functionality in existing technologies (such as the Palltronic® Flowstar series testers and the Sartoflow® Expert SU system), none have resolved core issues in production-grade TFF systems, including physical isolation between the test flow path and the process flow path, fully automated control of the entire process, data cross-validation, and the generation of compliant electronic reports. Therefore, there is an urgent need in this field for an integrated online integrity testing solution specifically designed for production-grade TFF that is aseptic, safe, highly automated, provides reliable data, and complies with regulations. Summary of the Invention

[0009] The purpose of this application is to overcome the shortcomings of existing technologies and provide a disposable TFF system and method for integrated online filter integrity testing. This system deeply integrates the integrity testing module into the main unit, and through innovative valve isolation flow path design, multi-sensor verification, and intelligent control software, achieves one-click, fully automatic, and highly reliable online integrity testing, fundamentally ensuring aseptic safety in production, improving data reliability, and meeting compliance requirements.

[0010] To address the aforementioned issues, this application provides a disposable TFF system with integrated online filter integrity detection, comprising:

[0011] A disposable flow path assembly includes a TFF filter, a process pipeline, a storage bag, a sterility integrity test port, and at least one normally closed isolation valve; the sterility integrity test port is connected to the flow path of the TFF filter via a branch pipeline, and the isolation valve is connected in series with the branch pipeline to isolate the test flow path from the main process flow path;

[0012] The hardware control module includes a system host, a pump, an integrity test module built into the system host, and a sensor array; the sensor array includes: a gas source pressure sensor located in the compressed gas inlet pipeline of the integrity test module, a non-contact air sensor located in the process pipeline, a first pressure sensor integrated inside the integrity test module, and a second pressure sensor located in the main process pipeline near the TFF filter; the test flow path is also equipped with a pressure relief valve;

[0013] The central control unit includes a processor and a non-transitory computer-readable medium storing a control program. When the control program is executed, it controls the hardware control module to work in conjunction with the disposable flow path components to complete online integrity testing and tangential flow filtration processes, and to generate an electronic report that conforms to preset specifications after the online integrity test is completed.

[0014] Based on the above system, optionally, the process piping of the disposable flow path component includes an inlet flow path, a return flow path, and a permeation flow path. The sterility integrity test interface is connected to the upstream or downstream piping of the TFF filter through a branch pipe. The isolation valve is a pneumatic or electric normally closed valve that is only opened during the integrity test.

[0015] Based on the above system, optionally, the hardware control module also includes multiple gas source interfaces and an automatic switching valve. Different gas source interfaces are used to connect to different test gases, and the automatic switching valve is controlled by the central control unit to switch so that the target gas source interface is connected to the test flow path.

[0016] Based on the above system, optionally, the integrity testing module supports one or more testing methods among forward flow, bubble point, and pressure decay, and the integrity testing module has a built-in pressure adjustment unit for controlling the test pressure.

[0017] Optionally, based on the above system, the central control unit is also equipped with a data storage and report generation module, which is used to automatically record sensor data, timestamps, test parameters and judgment results during the test process, and generate electronic reports that meet the requirements of cGMP and FDA 21 CFR Part 11.

[0018] Based on the above system, optionally, the central control unit is configured to: after determining that the pipeline where the non-contact air sensor is located has been emptied based on the signal emitted by the non-contact air sensor, control the opening of the isolation valve to connect the test flow path with the main process flow path.

[0019] Based on the above system, optionally, the central control unit is configured to: compare the readings of the first pressure sensor and the second pressure sensor in real time during the online integrity test; if the difference exceeds the preset tolerance range, determine that the online integrity test has failed and trigger an alarm.

[0020] Secondly, embodiments of this application also provide an intelligent integrity testing method based on the system described in any one of the first aspects, the method comprising the following steps:

[0021] The central control unit controls the pump to operate and delivers wetting liquid to the TFF filter through the process pipeline. After wetting is completed, the purging operation is performed. The non-contact air sensor detects the purging status of the pipeline. If the purging is confirmed to be completed, the next step is performed. Otherwise, the wetting and purging operations are repeated.

[0022] The central control unit controls the opening of the isolation valve and closes the valves in the main process flow path, so that the integrity test module, sterility integrity test interface, TFF filter and branch pipeline form a closed test loop;

[0023] The central control unit activates the integrity test module, injects test gas into the test circuit, and simultaneously reads and compares the readings of the first and second pressure sensors. If the difference in readings is within the preset tolerance range, the test is performed according to the preset test method and the data is recorded. If the difference in readings exceeds the limit, an alarm is triggered and the test is deemed to have failed.

[0024] After the test is completed, the central control unit controls the pressure relief valve to open, releasing the residual pressure in the test circuit to a preset threshold before closing the pressure relief valve.

[0025] The central control unit closes the isolation valve, restores the valve status in the main process flow path, and disconnects the test circuit.

[0026] The central control unit automatically generates an electronic report that conforms to preset specifications, and the system switches to the tangential flow filtration process mode.

[0027] The technical solution provided in this application has at least the following beneficial effects:

[0028] 1. Significantly improved aseptic safety: By using the integrity testing module built into the system host and the valve isolation setting, the test flow path is physically isolated from the main process flow path, eliminating the need to disassemble the pipeline and completely avoiding the risk of microbial contamination caused by external testing, thus achieving the "inherent safety" of PUPSIT.

[0029] 2. High degree of automation: The entire process requires no manual intervention. From self-inspection, wetting, testing to depressurization and report generation, everything is completed automatically by the system. The time for a single test is reduced to 15-20 minutes, which greatly improves testing and production efficiency and reduces the risk of human error.

[0030] 3. Reliable test data: Through triple protection of gas self-inspection, non-contact air sensor wetting verification, and two-way pressure cross-verification, the test premise is ensured to be correct and the data is true and valid, avoiding invalid test results. Attached Figure Description

[0031] The accompanying drawings, which are incorporated in and form part of this specification, illustrate embodiments consistent with this application and, together with the description, serve to explain the principles of this application. Furthermore, these drawings and textual descriptions are not intended to limit the scope of the concept in any way, but rather to illustrate the concepts of this application to those skilled in the art by reference to specific embodiments;

[0032] Figure 1 This is a schematic diagram of the one-time flow path component structure of the system in this application;

[0033] Figure 2 This is a schematic diagram of the overall hardware architecture of the system in this application;

[0034] Figure 3 This is a flowchart illustrating the overall workflow of the system in this application.

[0035] Figure 4 This is a flow diagram of the online integrity testing process for the system in this application.

[0036] Figure 5 This is the pressure relief flow path diagram after the online integrity test of the system in this application is completed.

[0037] Explanation of reference numerals in the attached figures:

[0038] 1-TFF filter; 2-Reservoir bag; 3-Inlet flow path; 4-Return flow path; 5-Permeate flow path; 6-Sterile integrity test interface; 7-Branch line; 8-Isolation valve; 9-Integrity test module; 10-Second pressure sensor; 11-Non-contact air sensor; 12-Pressure relief valve; 13-Compressed gas inlet valve; 14-Central control unit; 15-Pump. Detailed Implementation

[0039] To make the objectives, technical solutions, and advantages of this application clearer, the technical solutions in the embodiments of this application will be clearly and completely described below in conjunction with the embodiments of this application. Obviously, the described embodiments are only some embodiments of this application, not all embodiments. Based on the embodiments of this application, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this application. Unless otherwise specified, the following embodiments and features can be combined with each other.

[0040] Example 1: Specific configuration of system hardware

[0041] Reference Figure 1 and Figure 2 As shown, this embodiment provides a disposable TFF system for integrated online filter integrity detection suitable for antibody drug concentration processes, comprising three main parts:

[0042] 1. Disposable flow path components

[0043] As a core component that comes into direct contact with materials, it features a pre-sterilization design, allowing for direct disposal after use and preventing cross-contamination. Its structure includes:

[0044] 1) Core process components: TFF filter 1 (which can be flat sheet membrane, hollow fiber membrane, etc., referred to as filter), process pipeline and liquid storage bag 2, which constitute a complete tangential flow filtration process flow path; wherein, the process pipeline includes liquid inlet flow path 3, return flow path 4 and permeate flow path 5.

[0045] 2) Dedicated components for integrity testing: including a sterile integrity testing interface 6, a branch line 7, and at least one normally closed isolation valve 8; the sterile integrity testing interface 6 is connected to the upstream or downstream process line of the TFF filter 1 through the branch line 7, forming a test branch with the flow path of the TFF filter 1; the isolation valve 8 is connected in series in the branch line 7 and is normally kept closed to ensure that the test flow path (i.e., the flow path, including the branch line, is only used for online integrity testing) is physically isolated from the main process flow path (i.e., the flow path used to execute the process normally after the test) without any contact, effectively preventing any possible contamination or interference with process parameters. It is only opened by the central control unit 14 during online integrity testing, forming an independent and closed test loop together with the built-in integrity testing module 9.

[0046] 2. Hardware control module

[0047] This module is partially integrated within the system's main cabinet, providing power, detection, and control support for testing and processes, including:

[0048] 1) Power and control components: including a high-precision metering pump 15 (used to drive process fluids and wetting liquids), multiple process valves (controlling the on / off state of the main process flow path), system host (integrating power supply and signal transmission interface), etc. This part is consistent with the existing disposable tangential flow filtration system, so it will not be described in detail.

[0049] 2) Built-in Integrity Test Module 9: Integrated as a standard functional module within the main system cabinet, rather than as an external device, this built-in integrity test module 9 is connected to the system's main controller (i.e., central control unit). Its startup, execution, and judgment are all precisely controlled and time-managed by a unified control system software. The integrity test module 9 includes internal piping and a pressure regulating unit (for controlling test pressure), a gas pressure regulating valve, and a first pressure sensor installed on the internal piping. It can precisely control the pressure and flow rate of the test gas and supports various test methods such as forward flow (diffusion flow), bubble point, and pressure decay.

[0050] 3) The sensor array, in addition to including the first pressure sensor (not shown) integrated inside the integrity test module 9, also includes:

[0051] Gas source pressure sensor (not shown): installed on the compressed gas inlet pipeline, used to monitor the test gas pressure in real time;

[0052] Non-contact air sensor 11: installed in the process pipeline upstream or downstream of TFF filter 1, used to detect whether the pipeline is sufficiently emptied after TFF filter 1 is wetted;

[0053] Second pressure sensor 10: Located on the main process pipeline near TFF filter 1, there can be multiple sensors, forming a bidirectional pressure verification with the first pressure sensor (that is, since the first pressure sensor is located inside the integrity test module near the test gas inlet, and the second pressure sensor is located near the TFF filter, the pressure difference at different locations and in different directions can be reflected by comparing the pressure of the two sensors).

[0054] Pressure relief valve 12: Located at the end of the test flow path ( Figure 2 Specifically, it is configured to connect to the internal piping of the integrity test module 9, and is used to release residual pressure after the test is completed; specifically, the residual pressure in the test pipeline is safely released to a set threshold to ensure operational safety and system stability.

[0055] 4) Gas source adapter components: These include multiple gas source interfaces for connecting different test gases (e.g., compatible with compressed air, nitrogen, etc.), and a compressed gas inlet valve 13 installed on the pipeline at the gas source inlet. This valve is an automatic switching valve, allowing users to select the test gas via software. After the user makes a selection, the automatic switching valve is controlled by the central control unit 14 to connect the target gas source interface with the test flow path, enabling the connection of different gas sources.

[0056] 3. Central control unit

[0057] This part is the "brain" of the system, including an industrial-grade processor (e.g., an Intel Core i5 industrial-grade CPU, 8GB of memory, and 1TB SSD storage), a touchscreen human-machine interface (HMI) (e.g., a 15-inch touchscreen with a resolution of 1920×1080, supporting Chinese / English interface switching), a data storage module and communication interfaces (e.g., including Ethernet ports, RS485 interfaces, and USB interfaces, supporting integration with MES systems), and stores preset control programs (e.g., based on PLC programming), with functions including:

[0058] Process control: Controls the timing of pump 15, various valves, and integrity test module 9 to achieve full automation of self-inspection, wetting, testing, pressure relief, and process switching;

[0059] Data acquisition and processing: Real-time acquisition of detection data from each sensor, comparison and verification of readings from the first and second pressure sensors, and determination of whether the online integrity test has passed;

[0060] Alarm and Interlock: When abnormal situations such as insufficient air source pressure, incomplete pipeline purging, or excessive pressure data deviation occur, an automatic alarm is triggered and measures are taken, such as stopping the process to avoid invalid testing or safety risks. Specifically, the filter wetting and purging operation is only started after the pressure signal received from the air source pressure sensor meets the standard (meets the set pressure requirement for a continuous set time); and / or, the isolation valve 8 is only allowed to open to connect the test flow path and the main process flow path after the pipeline where the non-contact air sensor is located is determined to be purged after receiving a signal from the non-contact air sensor 11; and / or, during the online integrity test, the readings of the first pressure sensor and the second pressure sensor 10 are compared in real time. If the difference in readings exceeds the preset tolerance range, the online integrity test is determined to have failed and an alarm is triggered.

[0061] Report generation: Automatically records timestamps, sensor data, test parameters and judgment results throughout the entire testing process, generating electronic reports that meet preset specifications (such as cGMP and FDA 21 CFR Part 11) requirements, and supports data export, printing and integration with MES systems.

[0062] Example 2: Detailed Process of Integrity Testing

[0063] This embodiment describes the overall process of an intelligent integrity testing method. Using the system from Embodiment 1, a PUPSIT test is performed on a sterilization-grade TFF filter, such as... Figure 3 As shown, the specific steps are as follows:

[0064] Step S1: System Deployment and Configuration: The user installs the pre-sterilized disposable flow path components and ensures that there are no leaks in the connections of the TFF filter, storage bag, and all pipelines; selects the gas source and test method through the HMI, and sets parameters such as test pressure, pressure stabilization time, test duration, and qualified pressure decay threshold.

[0065] For example, by selecting "compressed air" as the air source through HMI, the test method is "pressure decay method", the test pressure is 2.2 bar, the pressure stabilization time is 3 minutes, the test duration is 10 minutes, and the qualified pressure decay threshold is ≤0.03 bar / min.

[0066] Step S2: System self-test: The central control unit controls the gas source pressure sensor to monitor the gas source pressure in real time. If the pressure meets the standard, proceed to the next step; otherwise, an alarm is triggered and the process is terminated.

[0067] For example, if the current gas supply pressure is detected to be 3.0 bar (3.0 bar ≥ preset threshold 2.5 bar), and the HMI displays "Gas supply pressure normal", then proceed to the next step.

[0068] Step S3: Filter wetting and purging: The central control unit controls the pump to operate and delivers wetting liquid to the TFF filter through the process pipeline. After wetting is completed, a purging operation is performed (the wetting liquid is purged). The non-contact air sensor detects the purging status of the pipeline. If purging is confirmed, proceed to the next step; otherwise, the wetting and purging operation is repeated.

[0069] For example, the central control unit controls the opening of the inlet valve on the inlet flow path 3 and the return valve on the return flow path 4, closes the isolation valve, and starts the pump (e.g., a peristaltic pump) to pump the purified water in the storage bag into the TFF filter at a flow rate of 20L / min for 5 minutes.

[0070] After wetting is completed, the pump performs an emptying operation at a flow rate of 15L / min through the waste discharge path (not shown) to discharge the wetting liquid for 2 minutes;

[0071] If the air sensor detects no liquid signal in the pipeline, indicating that it is already filled with gas, the HMI will display "Pipeline emptied" and proceed to the next step.

[0072] Step S4: Test loop construction: The central control unit controls the isolation valve to open and closes the relevant valves in the main process flow path, so that the integrity test module, sterility integrity test interface, TFF filter and branch pipeline form a closed test loop.

[0073] For example, the central control unit controls the inlet valve and return valve to close, the isolation valve to open, and the automatic switching valve to switch to the compressed air interface. At this time, the flow path is: compressed air source → automatic switching valve → integrity test module → first pressure sensor → branch pipeline → isolation valve → second pressure sensor → TFF filter → another second pressure sensor → until discharge, forming a closed test loop.

[0074] Step S5: Perform online integrity test: The central control unit starts the integrity test module, injects test gas into the test circuit, and simultaneously reads and compares the readings of the first and second pressure sensors; if the reading difference is within the preset tolerance range, the test is performed according to the preset test method and the data is recorded; if the reading difference exceeds the limit, an alarm is triggered and the integrity test is determined to have failed. The flow diagram of the online integrity test process is as follows: Figure 4 As shown, Figure 4 In the diagram, the dotted line with arrows indicates the direction of gas flow, and the word "Closed" near the valve indicates that the valve must be closed.

[0075] For example, the integrity test module activates the pressure regulation unit, injects compressed air into the test loop, pressurizes to 2.2 bar within 1 minute, and stabilizes the pressure for 3 minutes;

[0076] During the pressure stabilization period, the central control unit simultaneously collects the readings of the first pressure sensor (2.20 bar) and the second pressure sensor (2.198 bar). The difference is 0.002 bar (0.002 bar ≤ 0.005 bar, i.e. within the preset tolerance range), which determines that the data is reliable.

[0077] The pressure was maintained for 10 minutes, and the system recorded the pressure changes in real time: the pressure decreased by 0.005 bar in the first minute, 0.012 bar in the fifth minute, and a total decrease of 0.02 bar in the tenth minute (i.e., the decrease was 0.002 bar / min). Since 0.002 bar / min ≤ 0.03 bar / min, the filter integrity was deemed qualified.

[0078] Step S6: Automatic Pressure Relief: After the test is completed, the central control unit controls the pressure relief valve to open, releasing the residual pressure in the test circuit to a preset threshold before closing the valve. The flow diagram during the pressure relief process is shown below. Figure 5 As shown, Figure 5 In the diagram, the dotted line with arrows indicates the direction of gas flow, and the word "Closed" near the valve indicates that the valve must be closed.

[0079] For example, after the test is completed, the central control unit stops the gas supply to the control integrity test module, opens the pressure relief valve, and slowly releases the residual pressure in the circuit from 2.2 bar to 0.04 bar (0.04 bar ≤ 0.05 bar) in 30 seconds; after the pressure relief is completed, the pressure relief valve closes.

[0080] Step S7: Flow path restoration and process switching: The central control unit controls the isolation valve to close, restores the state of the relevant valves in the main process flow path, and disconnects the test circuit.

[0081] For example, the central control unit closes the isolation valve, reopens the inlet valve and reflux valve, disconnects the test circuit, and switches the system to the "concentration process" mode; the user starts the concentration program through the HMI, the pump runs at a flow rate of 30L / min, and the TFF filter starts the antibody concentration process.

[0082] Step S8: Electronic report generation: The central control unit automatically generates an electronic report containing data records and conforming to preset specifications.

[0083] For example, after the online integrity test is completed, the system automatically generates an electronic report, with key information as follows:

[0084] Test date: XX / XX / 2025; Test time: 14:30:00-14:55:30;

[0085] Air source type: compressed air; test scheme: pressure holding; test pressure: 2.2 bar; test standard: pressure decay ≤ 0.03 bar / min; test duration: 10 minutes.

[0086] Sensor data: Average reading of the first pressure sensor is 2.20 bar, average reading of the second pressure sensor is 2.199 bar, and the reading difference is 0.001 bar;

[0087] Test results: Pressure decay 0.002 bar / min;

[0088] Judgment result: Qualified;

[0089] Operator: XXX;

[0090] After the report is generated, the user can export the report via USB interface, and the system will automatically upload it to the MES system to complete the audit trail record.

[0091] Example 3: Handling Abnormal Situations

[0092] During the testing process of Example 2, if the following abnormal situation occurs, the system will handle it according to the preset logic:

[0093] Insufficient gas pressure: If the gas pressure is 2.0 bar (<2.5 bar) during self-test, the HMI will display a red alarm "Insufficient gas pressure (2.0 bar), please check the gas supply". The system will stop the process and wait for the user to replenish the gas pressure to ≥2.5 bar.

[0094] Pipeline not purged: If the air sensor detects that the upstream or downstream process pipeline of TFF filter 1 is in a liquid state and not filled with gas, the system will automatically re-perform the purging operation. After 1 minute, it will detect again. If it detects that the pipeline is still in a liquid state and not filled with gas, the HMI will display the alarm "Pipeline purging failed, please check the pipeline connection". The system will stop the process and restart after the user checks the pipeline.

[0095] Pressure data deviation exceeds limits: If, during pressure stabilization, the reading of the first pressure sensor is 2.20 bar and the reading of the second pressure sensor is 2.18 bar, with a reading difference of 0.02 bar (>0.005 bar), the HMI will display an alarm "Pressure data deviation exceeds limits, sensor abnormality". The system will determine that the test is invalid, terminate the process, and prompt the user to calibrate the sensor.

[0096] The specific implementation of this application fully demonstrates the aseptic safety, automation, data reliability, and compliance of the system. Through the built-in testing module, valve isolation settings, multi-sensor verification, and automatic report generation, it effectively solves the core defects of the prior art and provides the biopharmaceutical industry with an efficient, safe, and compliant tangential flow filtration solution.

[0097] It is understood that the same or similar parts in the above embodiments can be referred to each other, and the contents not described in detail in some embodiments can be referred to the same or similar contents in other embodiments.

[0098] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of this application. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples.

[0099] Although embodiments of this application have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting this application. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of this application.

Claims

1. A disposable TFF system integrating online filter integrity detection, characterized in that, include: A disposable flow path assembly includes a TFF filter, a process pipeline, a storage bag, a sterility integrity test port, and at least one normally closed isolation valve; the sterility integrity test port is connected to the flow path of the TFF filter via a branch pipeline, and the isolation valve is connected in series with the branch pipeline to isolate the test flow path from the main process flow path; The hardware control module includes a system host, a pump, an integrity testing module built into the system host, and a sensor array; The sensor array includes: a gas source pressure sensor located in the compressed gas inlet pipeline of the integrity test module; a non-contact air sensor located in the process pipeline; a first pressure sensor integrated inside the integrity test module; and a second pressure sensor located in the main process pipeline near the TFF filter. The test flow path is also equipped with a pressure relief valve. The non-contact air sensor is used to detect whether the pipeline is sufficiently emptied after the TFF filter is wetted. The central control unit includes a processor and a non-transitory computer-readable medium storing a control program. When the control program is executed, it controls the hardware control module to work in conjunction with the disposable flow path components to complete online integrity testing and tangential flow filtration processes, and to generate an electronic report conforming to preset specifications after the online integrity test is completed.

2. The system according to claim 1, characterized in that, The process piping of the disposable flow path assembly includes an inlet flow path, a return flow path, and a permeation flow path. The sterility integrity test interface is connected to the upstream or downstream piping of the TFF filter via a branch line. The isolation valve is a pneumatic or electric normally closed valve that is only opened during the integrity test.

3. The system according to claim 1, characterized in that, The hardware control module also includes multiple gas source interfaces and an automatic switching valve. Different gas source interfaces are used to connect to different test gases. The automatic switching valve is controlled by the central control unit to switch so that the target gas source interface is connected to the test flow path.

4. The system according to claim 1, characterized in that, The integrity testing module supports one or more testing methods, including forward flow, bubble point, and pressure decay, and has a built-in pressure adjustment unit for controlling the test pressure.

5. The system according to claim 1, characterized in that, The central control unit is also equipped with a data storage and report generation module, which is used to automatically record sensor data, timestamps, test parameters and judgment results during the test process, and generate electronic reports that meet the requirements of cGMP and FDA 21 CFR Part 11.

6. The system according to claim 1, characterized in that, The central control unit is configured to: after determining that the pipeline where the non-contact air sensor is located has been emptied based on the signal emitted by the non-contact air sensor, control the opening of the isolation valve to connect the test flow path with the main process flow path.

7. The system according to claim 1, characterized in that, The central control unit is configured to: during the online integrity test, compare the readings of the first pressure sensor and the second pressure sensor in real time; if the difference exceeds the preset tolerance range, determine that the online integrity test has failed and trigger an alarm.

8. A method for testing the intelligent integrity of a system as described in any one of claims 1-7, characterized in that, Includes the following steps: The central control unit controls the gas source pressure sensor to monitor the gas source pressure in real time. If the pressure meets the standard, it proceeds to the next step; otherwise, it alarms and stops the process. The central control unit controls the pump to operate and delivers wetting liquid to the TFF filter through the process pipeline. After wetting is completed, the purging operation is performed. The non-contact air sensor detects the purging status of the pipeline. If the purging is confirmed to be completed, the next step is performed. Otherwise, the wetting and purging operations are repeated. The central control unit controls the opening of the isolation valve and closes the valves in the main process flow path, so that the integrity test module, sterility integrity test interface, TFF filter and branch pipeline form a closed test loop; The central control unit activates the integrity test module, injects test gas into the test circuit, and simultaneously reads and compares the readings of the first and second pressure sensors. If the difference in readings is within the preset tolerance range, the test is performed according to the preset test method and the data is recorded. If the difference in readings exceeds the limit, an alarm is triggered and the test is deemed to have failed. After the test is completed, the central control unit controls the pressure relief valve to open, releasing the residual pressure in the test circuit to a preset threshold before closing the pressure relief valve. The central control unit closes the isolation valve, restores the valve status in the main process flow path, and disconnects the test circuit. The central control unit automatically generates an electronic report that conforms to preset specifications, and the system switches to the tangential flow filtration process mode.

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