# US 11,999,939 B2 · Process and system for propagating cell cultures while preventing lactate accumulation

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- Number: US 11,999,939 B2
- Document ID: US11999939B2
- Status: Granted
- Kind: B2
- Application number: 18/168,084
- Filed: 2023-02-13
- Published: 2023-09-07
- Granted: 2024-06-04
- Earliest claimed: 2017-11-20
- Assignees: Lonza Ltd.
- Applicants: Lonza Ltd
- Inventors: Brandon John Downey; John Michael Schmitt; Jeffrey Francis Breit
- Web page: https://patentgrep.com/patent/US11999939B2

## CPC

- C12M 41/32: {of substances in solution}
- C12M 41/48: {Automatic or computerized control (automatic analysis G01N35/00)}
- 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}

## Abstract

A predictive model is described that can predict parameter concentrations in the future based on initial, measured concentrations and historical data. A plurality of multivariate techniques can be used to construct the predictive model capable of forecasting concentrations over multiple and diverse cell lines. The predictive model is also scalable. In one embodiment, a future lactate concentration trajectory is determined and at least one condition within a bioreactor is changed or modified to maintain lactate concentration within desired ranges.

## Claims

### Claim 1

A process for propagating a cell culture comprising:
determining a concentration of at least one quality attribute in a cell culture;
measuring values of at least two attribute influencing parameters within the cell culture;
sending the concentration of the at least one quality attribute and the values of the attribute influencing parameter measurements to a controller, the controller including a predictive model that is configured to calculate a future concentration of the at least one quality attribute in the cell culture based at least in part on the values of the attribute influencing parameters;
running simulations on an optimizer to calculate future concentrations of the at least one quality attribute based on manipulation of the attribute influencing parameters within the cell culture; and
the controller selectively changing at least one condition within the cell culture based upon the determined future concentration of the at least one quality attribute in the cell culture for maintaining the at least one quality attribute concentration within preset limits.

### Claim 2 (depends on 1)

A process as defined in claim 1, wherein the quality attribute comprises lactate, protein, glycan, a charge variant, an aggregate, disulfide oxidation, or a disulfide shuffling variant.

### Claim 3 (depends on 1)

A process as defined in claim 1, wherein the predictive model determines future concentration using at least two different multivariate methods.

### Claim 4 (depends on 1)

A process as defined in claim 1, wherein the at least one condition is selectively changed by changing a nutrient media being fed to the cell culture.

### Claim 5 (depends on 4)

A process as defined in claim 4, wherein the nutrient media comprises a carbohydrate source, an amino acid source, a vitamin, a lipid, a protein, a peptide, or mixtures thereof.

### Claim 6 (depends on 4)

A process as defined in claim 4, wherein the nutrient media being fed to the cell culture is changed by changing a flow rate of the nutrient media to the cell culture.

### Claim 7 (depends on 4)

A process as defined in claim 4, wherein in addition to changing the nutrient media being fed to the cell culture, a pH of the cell culture is also selectively changed in order to maintain lactate concentration within preset limits.

### Claim 8 (depends on 1)

A process as defined in claim 1, wherein the cell culture has an incubation period prior to being harvested, and wherein the predictive model forecasts a final quality attribute concentration at the end of the incubation period.

### Claim 9 (depends on 1)

A process as defined in claim 1, wherein the process results in an increase in titer concentration of the cell culture.

### Claim 10 (depends on 1)

A process as defined in claim 1, wherein the cell culture contains mammalian cells.

### Claim 11 (depends on 1)

A process as defined in claim 1, wherein the cell culture is propagated in a batch process for from about 12 hours to about 28 days and then harvested.