# US 12,110,483 B2 · Perfusion bioreactor with filtration systems

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- Number: US 12,110,483 B2
- Document ID: US12110483B2
- Status: Granted
- Kind: B2
- Application number: 18/308,870
- Filed: 2023-04-28
- Published: 2023-10-26
- Granted: 2024-10-08
- Earliest claimed: 2018-05-04
- Assignees: Genzyme Corporation
- Applicants: Genzyme Corporation
- Inventors: Jiuyi Lu; Jason Walther; Jonathan Wang; Kevin Victor Chen
- Web page: https://patentgrep.com/patent/US12110483B2

## CPC

- C12M 41/48: {Automatic or computerized control (automatic analysis G01N35/00)}
- B01D 15/102: {Process control, e.g. determination or optimization of process parameters; Programmable logic control [PLC]}
- B01D 15/1807: {using counter-currents, e.g. fluidised beds}
- B01D 61/18: Apparatus therefor
- B01D 61/22: Controlling or regulating
- C12M 29/00: {Means for introduction, extraction or recirculation of materials, e.g. pumps (pumps per se F04B)}
- C12M 29/04: {Filters; Permeable or porous membranes or plates, e.g. dialysis}
- C12M 29/10: {Perfusion}
- C12M 33/14: {with filters, sieves or membranes}
- C12M 41/40: {of pressure}
- C12M 47/10: {Separation or concentration of fermentation products (bioreactors combined with means for distillation or extraction of liquid fuel C12M43/02)}
- B01D 2311/2626: Absorption or adsorption
- B01D 2311/2688: Biological processes
- B01D 2313/243: Pumps
- B01D 2315/10: Cross-flow filtration
- B01D 2317/04: Elements in parallel
- B01D 2317/06: Use of membrane modules of the same kind
- C12M: APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; {APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS}
- B01D: SEPARATION (separating solids from solids by wet methods B03B, B03D; by pneumatic jigs or tables B03B; by other dry methods B07; magnetic or electrostatic separation of solid materials from solid materials or fluids, separation by high-voltage electric fields B03C; centrifuges, vortex apparatus B04; presses per se for squeezing-out liquid from liquid-containing material B30B9/02; treatment of water C02F, e.g. softening by ion-exchange C02F1/42; {arrangements of air intake cleaners in gas turbine plants F02C7/05} ; arrangements or mounting of filters in air-conditioning, air-humidification or ventilation F24F13/28)

## Abstract

The disclosure provides a filtration system for a cell culture apparatus and a method of cell culture. The filtration system comprises a bioreactor vessel and two or more alternating tangential flow (ATF) filters connected in parallel. A failure in either filter is detected by an in-line sensor, and an automated response system functions to sequester the malfunctioning filter by stopping the flow of liquid media through the filter. Media flow through the remaining operable filters can be increased so that the rate of perfusion through the bioreactor remains relatively unchanged. Such a system may prevent issues that arise from ATF filter failures in conventional perfusion bioreactors, thereby improving the long-term viability of cell cultures.

## Claims

### Claim 1

A perfusion cell culture apparatus comprising:
(a) a bioreactor vessel configured to receive liquid media comprising a cell culture;
(b) a first filtration assembly in fluid communication with the bioreactor vessel, wherein the first filtration assembly comprises:
(1) a first filtration system;
(ii) a first harvest pump connected in series with the first filtration system, wherein the first harvest pump is configured to pump the liquid media from the bioreactor vessel through the first filtration system; and
(iii) a sensor, wherein the sensor is configured to interact with the liquid media inside the first filtration assembly; and
(c) a second filtration assembly configured to operate in parallel with the first filtration assembly, wherein the second filtration assembly is in fluid communication with the bioreactor vessel, and wherein the second filtration assembly comprises:
(i) a second filtration system; and
(ii) a second harvest pump connected in series with the second filtration system, wherein the second harvest pump is configured to pump the liquid media from the bioreactor vessel through the second filtration system; and
(d) a controller, wherein the controller executes operations comprising:
(i) receiving, from the sensor, information indicative of changes in cell density in the first filtration system;
(ii) determining, based on at least the received information from the sensor, changes in cell density in the first filtration system;
(iii) responsive to a determination that of changes in cell density in the first filtration system, causing the first harvest pump to stop pumping liquid media through the first filtration system; and
(iv) responsive to the determination of changes in cell density in the first filtration system, causing the second harvest pump to increase a flow rate of liquid media through the second filtration system.

### Claim 2 (depends on 1)

The perfusion cell culture apparatus of claim 1, wherein at least one of the first filtration system and the second filtration system comprises an alternating tangential flow filter.

### Claim 3 (depends on 1)

The perfusion cell culture apparatus of claim 1, wherein at least one of the first filtration system and the second filtration system comprises a tangential flow filter.

### Claim 4 (depends on 1)

The perfusion cell culture apparatus of claim 1, wherein each of the first filtration system and the second filtration system comprise a filter membrane comprising a pore size of about 0.1 micron to about 1 micron.

### Claim 5 (depends on 1)

The perfusion cell culture apparatus of claim 1, wherein the sensor comprises an optical sensor, and wherein the determining of changes in cell density in the first filtration system comprises determining that cell density in the first filtration assembly is outside of a predetermined threshold range.

### Claim 6 (depends on 1)

The perfusion cell culture apparatus of claim 1, wherein the sensor detects an increase in cell density in the first filtration system.

### Claim 7 (depends on 1)

The perfusion cell culture apparatus of claim 1, wherein the sensor detects a decrease in cell density in the first filtration system.

### Claim 8 (depends on 1)

The perfusion cell culture apparatus of claim 1, wherein causing the second harvest pump to increase the flow rate of liquid media through the second filtration system comprises approximately doubling the flow rate.

### Claim 9 (depends on 1)

The perfusion cell culture apparatus of claim 1, wherein the controller is further configured to:
responsive to the determination of changes in cell density in the first filtration system, output a notification.

### Claim 10 (depends on 9)

The perfusion cell culture apparatus of claim 9, wherein the notification comprises a visual alert or an auditory alert.

### Claim 11 (depends on 1)

The perfusion cell culture apparatus of claim 1, further comprising an isolation valve connected in series with the first filtration assembly, wherein the valve is configured to control the flow of liquid media through the first filtration assembly, and wherein the controller is further configured to:
responsive to the determination of changes in cell density in the first filtration system, close the isolation valve.

### Claim 12 (depends on 1)

The perfusion cell culture apparatus of claim 1, wherein the first filtration assembly further comprises a guard filter connected in series with the first filtration system, wherein the guard filter is connected downstream of the first filtration system and the sensor.

### Claim 13 (depends on 12)

The perfusion cell culture apparatus of claim 12, wherein the guard filter comprises a pore size of about 0.1 micron to about 1 micron.

### Claim 14 (depends on 1)

The perfusion cell culture apparatus of claim 1, further comprising a capture operation configured to collect product from the liquid media, wherein the capture operation is in fluid communication with the bioreactor vessel by way of at least the first filtration assembly, wherein the capture operation comprises a multi-column chromatography (MCC).