US-12618040-B2 - Product quality attribute measurement

Abstract

Systems for measuring a product quality attribute of an analyte of a biological sample include a first flow control device, a sample purification device, a second flow control device in fluid communication with first and second sample analyzers, where the first sample analyzer includes a first chromatography column, and a control unit configured so that during operation of the system, the control unit adjusts a configuration of the second flow control device to direct a portion of the biological sample to one of the first and second sample analyzers, and determines a product quality attribute of an analyte of the biological sample based on an analysis of the portion of the biological sample by the one of the first and second sample analyzers.

Inventors

• Marina Hincapie
• Victoria Berger

Assignees

• GENZYME CORPORATION

Dates

Publication Date

20260505

Application Date

20200922

Claims (20)

1. 1 . A method for measuring product quality attributes of an analyte of a biological sample, the method comprising: obtaining a biological sample in a biological manufacturing system and delivering the biological sample to a first flow control device, wherein the first flow control device is configured to direct the biological sample either to a second flow control device or to a purification apparatus in fluid communication with the second flow control device; delivering the biological sample to the second flow control device, wherein the second flow control device is configured to receive the biological sample either directly from the first flow control device or from the purification apparatus; directing a first portion of the biological sample to a first sample analyzer via the second flow control device in fluid communication with the first flow control device, the purification apparatus, and the first sample analyzer, and obtaining information about a first product quality attribute of an analyte of the biological sample by analyzing the first portion of the biological sample in the first sample analyzer; directing a second portion of the biological sample to a second sample analyzer in fluid communication with the second flow control device and obtaining information about a second product quality attribute of an analyte of the biological sample by analyzing the second portion of the biological sample in the second sample analyzer, wherein the first and second product quality attributes are different.
2. 2 . The method of claim 1 , wherein the purification apparatus comprises an affinity chromatography column.
3. 3 . The method of claim 1 , wherein the first sample analyzer comprises a first chromatography column.
4. 4 . The method of claim 3 , wherein the first chromatography column comprises at least one member of the group consisting of a cation exchange chromatography column, a size exclusion chromatography column, and a reversed phase chromatograph column.
5. 5 . The method of claim 3 , which comprises a quantification detector in fluid communication with the first chromatography column of the first sample analyzer, the method comprising generating, using the quantification detector, an electrical signal representative of an amount of an analyte in an eluate stream from the first chromatography column.
6. 6 . The method of claim 3 , wherein the second sample analyzer comprises a second chromatography column that is different from the first chromatography column and comprises at least one member selected from the group consisting of a cation exchange chromatography column, a size exclusion chromatography column, a reversed phase chromatography column, and a hydrophilic interaction chromatography column.
7. 7 . The method of claim 1 , wherein the first product quality attribute of the analyte is a concentration of the analyte in the biological sample, a measure of aggregation of the analyte in the biological sample, a measure of charge variants or heterogeneity of the analyte in the biological sample, or a measure of purity or integrity of the analyte in the biological sample.
8. 8 . The method of claim 2 , wherein the affinity chromatography column comprises at least one member selected from the group consisting of a Protein A chromatography column, a Protein G chromatography column, and a receptor binding column.
9. 9 . The method of claim 1 , comprising delivering a buffer solution to the first sample analyzer from a buffer reservoir when the first portion of the biological sample is directed into the first sample analyzer.
10. 10 . The method of claim 9 , wherein the buffer solution has a pH of 4.0 or less.
11. 11 . The method of claim 1 , wherein the analyte comprises a protein in the biological sample.
12. 12 . The method of claim 11 , wherein the protein comprises an antibody in the biological sample.
13. 13 . The method of claim 1 , wherein the biological sample is a harvest medium extracted from the bioreactor.
14. 14 . The method of claim 1 , wherein the biological sample is a portion of a cell culture.
15. 15 . The method of claim 5 , wherein generating an electrical signal representative of an amount of the analyte in the biological sample comprises measuring at least one of absorbance information and fluorescence information corresponding to the analyte.
16. 16 . The method of claim 5 , wherein generating an electrical signal representative of an amount of the analyte in the biological sample comprises measuring ion abundance information corresponding to the analyte.
17. 17 . The method of claim 1 , comprising directing additional portions of the biological sample into additional sample analyzers and obtaining information about at least one additional product quality attribute of the analyte of the biological sample.
18. 18 . The method of claim 17 , wherein the at least one additional product quality attribute is different from the first and second product quality attributes and is selected from the group consisting of a concentration of the analyte in the biological sample, a measure of aggregation of the analyte in the biological sample, a measure of charge variants or heterogeneity of the analyte in the biological sample, or a measure of purity or integrity of the analyte in the biological sample.
19. 19 . The method of claim 1 , which comprises obtaining the biological sample by extracting the biological sample from an operating bioreactor via the first flow control device, wherein the first flow control device is in fluid communication with the bioreactor.
20. 20 . The method of claim 1 , wherein at least one of the first and second product quality attributes comprises a measure of charge variants or heterogeneity of the analyte in the biological sample, a measure of aggregation of the analyte in the biological sample, a measure of purity or integrity of the analyte in the biological sample, or a concentration of the analyte in the biological sample.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application Ser. No. 62/904,682, filed Sep. 23, 2019, the entire contents of this application is herein incorporated by reference. TECHNICAL FIELD This disclosure relates to systems and methods for product quality attribute measurement for samples including harvested samples from continuous bio-manufacturing systems. BACKGROUND Mammalian cells containing a nucleic acid that encodes a recombinant protein are often used to produce therapeutically or commercially important proteins. Integrated, continuous bio-manufacturing is an important aspect of reducing costs associated with therapies based on such proteins. Monitoring systems are used in bio-manufacturing to assess various biological products and process conditions. SUMMARY Integrated, continuous bio-manufacturing of therapeutic protein substances and other biological molecules holds tremendous promise for future production of life-saving drugs and enhancing widespread adoption of therapies that rely on the availability of such biological molecules. Two-column and multi-column chromatography systems in a variety of configurations can be used for bio-manufacturing on an industrial scale. In such systems, analysis of eluents from the chromatography systems can be used to determine a variety of product quality attributes to monitor and adjust a wide variety of bioprocess conditions. This disclosure features methods and systems for determining one or more product quality attributes for analytes in biological samples, including samples harvested from bioreactors and offline samples introduced in series or in parallel into the systems. A variety of product quality attributes can be measured, including but not limited to analyte concentration, analyte charge variants or heterogeneity, analyte aggregation, and analyte integrity or purity. The systems can include sample analyzers with different types of chromatography columns dedicated to the measurement of specific product quality attributes. The measured product quality attributes can be used to provide feedback and control over bio-manufacturing process-related parameters and operations. In one aspect, the disclosure features systems for measuring a product quality attribute of an analyte of a biological sample, the systems featuring a first flow control device, a sample purification device in fluid communication with the first flow control device, a second flow control device in fluid communication with the first flow control device, with the sample purification device, and with first and second sample analyzers, where the first sample analyzer includes a first chromatography column, and a control unit coupled to the first and second flow control devices and configured so that during operation of the system, the control unit: (a) adjusts a configuration of the first flow control device to direct a portion of a biological sample from the first flow control device into either the sample purification device or into the second flow control device, so that the portion of the biological sample is received in the second flow control device; (b) adjusts a configuration of the second flow control device to direct the portion of the biological sample to one of the first and second sample analyzers; and (c) determines a product quality attribute of an analyte of the biological sample based on an analysis of the portion of the biological sample by the one of the first and second sample analyzers. Embodiments of the systems can include any one or more of the following features. The first chromatography column can be a cation exchange chromatography column, a size exclusion chromatography column, or a reversed phase chromatography column. The sample purification device can include an affinity chromatography column. The second sample analyzer can include a quantification detector configured to generate an electrical signal representative of an amount of an analyte in the biological sample. The first chromatography column can be in fluid communication with the quantification detector, and the quantification detector can be configured to generate an electrical signal representative of an amount of the analyte in an eluate stream from the first chromatography column. The first sample analyzer can include a quantification detector in fluid communication with the first chromatography column and configured to generate an electrical signal representative of an amount of an analyte in an eluate stream from the first chromatography column. The second sample analyzer can include a second chromatography column, and the second chromatography column can be different from the first chromatography column and can be one of a cation exchange chromatography column, a size exclusion chromatography column, a reversed phase chromatography column, and a hydrophilic interaction chromatography column. The second flow control device can be in fluid co