EP-4739424-A1 - SYSTEMS AND METHODS FOR HIGH-THROUGHPUT PROCESSING OF MULTIPLE SAMPLES

Abstract

The present invention discloses a tangential flow filtration (TFF) chip featuring a chip substrate assembly with a closed fluid channel, and a membrane assembly including a concentration or filtration membrane, a low volume pathway, and a standard volume pathway. Integrated transfer tubing and one or more diaphragm/valve complexes on a valve insert are interposed along the closed fluid channel. The closed fluid channel is in valve-controlled, fluid communication with the low volume pathway and the standard volume pathway, enabling efficient and controlled filtration processes within a compact and integrated TFF chip design.

Inventors

• MCKNIGHT, Nicholas
• MATTY, Gray
• HILLMAN, Noah
• BELL, ADRIAN
• STEVENSON, JEREMY
• JOHNSON, CHRISTOPHER

Assignees

• Formulatrix International Holding Ltd

Dates

Publication Date

20260513

Application Date

20240708

Claims (20)

1. 1. A tangential flow filtration (TFF) chip comprising: a. a chip substrate assembly defining a closed fluid channel; b. a membrane assembly comprising: i. a concentration or filtration membrane; ii. a low volume pathway; and iii. a standard volume pathway; c. integrated transfer tubing; and d. one or more diaphragm/valve complexes, on a valve insert, interposed along the closed fluid channel; wherein the closed fluid channel is in valve-controlled, fluid communication with the low volume pathway and the standard volume pathway.
2. 2. The TFF chip of claim 1, wherein each of the one or more diaphragm/valve complexes comprises one diaphragm pump and three individually-controllable elastomeric valves.
3. 3. The TFF chip of claim 2, wherein one of the three individually-controllable elastomeric valves is a first source input valve.
4. 4. The TFF chip of claim 2, wherein one of the three individually-controllable elastomeric valves is a second source input valve.
5. 5. The TFF chip of claim 2, wherein one of the three individually-controllable elastomeric valves is a diaphragm output valve.
6. 6. The TFF chip of claim 1, wherein the valve insert further comprises a third source input valve.
7. 7. The TFF chip of claim 1, wherein the valve insert further comprises a first source return valve, and wherein the first source return valve operates as a restriction point such that, when the first source return valve is closed, backpressure on flow over the concentration or filtration membrane drives faster concentration.
8. 8. The TFF chip of claim 1, wherein the valve insert further comprises a second source return valve, and wherein the second source return valve operates as a restriction point such that, when the second source return valve is closed, backpressure on flow over the concentration or filtration membrane drives faster concentration.
9. 9. The TFF chip of claim 1, wherein the valve insert further comprises a low volume pathway input valve and a low volume pathway return valve.
10. 10. The TFF chip of claim 1, wherein the valve insert further comprises a standard volume pathway input valve and a standard pathway return valve.
11. 11. The TFF chip of claim 1, further comprising a purge valve.
12. 12. A high-throughput, automated, multi-sample processing system comprising: a. a base unit; b. a tangential flow filtration (TFF) chip configured to operate with the base unit, the TFF chip comprising: i. a chip substrate assembly defining a closed fluid channel; ii. a membrane assembly comprising: I. a concentration or filtration membrane; II. a low volume pathway; and III. a standard volume pathway; iii. integrated transfer tubing; and iv. one or more diaphragm/valve complexes interposed along the closed fluid channel; c. an automation sub-system for engaging with the TFF chip; and d. a housing defining an envelope for the system.
13. 13. The system of claim 12, further comprising a chip rack in an automation bay for holding one or more chips.
14. 14. The system of claim 12, further comprising a tube rack in an automation bay.
15. 15. The system of claim 12, further comprising a cleaning sub-system in an automation bay.
16. 16. The system of claim 12, wherein the automation sub-system comprising a gantry and robotic gripper.
17. 17. The system of claim 16, wherein the automation sub-system is configured to move above the envelope of the housing.
18. 18. The system of claim 17, wherein the gantry is a mobilized gantry.
19. 19. The system of claim 18, wherein the mobilized gantry is configured to move side to side within the envelope of the housing or up and down within the envelope of the housing, and wherein the mobilized gantry is configured such that a pivot point for the robotic gripper moves up and down or side to side within the envelope of the housing.
20. 0. The system of claim 12, wherein the base unit comprises a first taring sub-system and a second taring sub-system, and wherein the second taring sub-system is a higher- accuracy taring sub-system as compared to the first taring sub-system.

Description

SYSTEMS AND METHODS FOR HIGH-THROUGHPUT PROCESSING OF MULTIPLE SAMPLES CROSS-REFERENCE TO RELATED APPLICATIONS [1] This application claims priority under to U.S. Provisional Patent Application, U.S. 63/525,503, which was filed on July 7, 2023, and which is incorporated by reference herein in its entirety. FIELD [2] This disclosure relates to systems and methods for the high-throughput, automated processing of multiple samples and, in particular, to high-throughput automated sample concentration, high-throughput automated diafiltration, or high-throughput automated tangential flow filtration of multiple samples. BACKGROUND [3] Sample concentration, diafiltration, and tangential flow filtration (TFF) are related processes commonly used in the field of biotechnology and biochemical engineering for the purification and concentration of biological molecules. Of course, these techniques are used in various other settings and applications. [4] Sample Concentration is a process of increasing the concentration of a specific component (e.g., proteins, nucleic acids) in a solution. It usually involves the removal of solvent (usually water) from the sample to reduce its volume and thus increase the concentration of the desired component. Sample concentration can be achieved through various methods, including evaporation, centrifugation, and membrane-based techniques like ultrafiltration or microfiltration. [5] Diafiltration is a membrane-based process used to remove small molecules or salts from a solution while retaining larger molecules. It usually involves the addition of fresh solvent (buffer) to the sample while simultaneously removing an equivalent volume of permeate through a membrane, effectively washing away the small molecules. Diafiltration can be used for buffer exchange, desalting, or removal of unwanted low-molecular-weight substances from a solution. It is often used after sample concentration to further purify the concentrated sample. [6] TFF is a membrane filtration technique where the feed solution flows tangentially across the surface of a semi-permeable membrane, reducing the fouling of the membrane and allowing for a more continuous operation. In TFF, the differential pressure across the membrane drives the filtration process and allows smaller molecules to pass through (permeate) while retaining larger molecules (retentate). TFF can be used for both concentration and diafiltration processes and it usually allows for large scale batch processing of samples. TFF is a widely used technique for the separation and concentration of biological macromolecules, including proteins and nucleic acids. [7] TFF can be used to concentrate a sample by continuously removing the solvent while retaining the larger molecules. This reduces the sample volume and increases the concentration of the target molecule. Moreover, after the initial concentration step, diafiltration can be performed using the same TFF set-up, by adding fresh buffer to the feed and removing the permeate. This helps to remove salts, exchange buffers, or eliminate small contaminants. In particular, in one example, TFF is first used to concentrate the sample and, once concentrated, diafiltration is performed to further purify the sample by removing unwanted small molecules. In certain examples, both steps can be carried out in the same conventional TFF system by adjusting the process parameters. [8] Therefore, conventional systems and methods exist that accomplish one or more of the above; however, conventional systems and methods suffer from several issues, deficiencies, limitations, and problems. [9] Spin column concentrators, like those from Amicon, are commonly used for sample concentration in molecular biology and protein research applications. Spin column concentrators utilize centrifugal force(s) to drive the concentration process. Spin column concentrators typically consist of a filter membrane inside a plastic column that is placed within a centrifuge tube. The sample, usually no more than about 15.0 milliliters maximum, is loaded onto the column, and centrifugation is applied to remove excess solvent or buffer, resulting in a concentrated sample in the column. Unfortunately, spin column concentrators require a significant amount of user touch time, and they have no process control. Moreover, use of spin column concentrators cannot be scaled for large scale batch processing or for continuous flow processing of samples. [10] The Slide-A-Lyzer™ by Thermo Fisher Scientific is a dialysis device used for buffer exchange and sample purification. It utilizes dialysis membranes to allow small molecules and salts to diffuse out of the sample while retaining larger biomolecules. The Slide-A-Lyzer™, in one example, merely provides a manual, moderately scalable method for basic laboratory tasks, and is a more passive technique suited for smaller volumes/batches and simpler applications. [11] The Minimate™ System by Pall is a benchtop TFF system