Systems and methods for manufacturing biologically-produced products

Patent metadata

Field	Value
Publication number	US-2020224144-A1
Application number	US-201816499780-A
Country	US
Kind code	A1
Filing date	Mar 30, 2018
Priority date	Apr 1, 2017
Publication date	Jul 16, 2020
Grant date	—

Abstract

Aspects of the present disclosure relate to systems and methods for manufacturing biologically-produced pharmaceutical products. Some of the systems described herein comprise an upstream component comprising a bioreactor and at least one filter (e.g., a filter probe) integrated with a downstream component comprising a purification module comprising at least a first partitioning unit and a second partitioning unit. In some embodiments, these integrated biomanufacturing systems may be operated under continuous or conditions and may be capable of efficiently producing pure, high-quality pharmaceutical products.

First claim

What is claimed is:

1 - 14 . (canceled)

15 . A biomanufacturing system, comprising:
a perfusion bioreactor, wherein the perfusion bioreactor comprises:
a reaction chamber configured to receive at least one feed stream comprising at least one cell culture medium;
a suspension comprising the at least one cell culture medium and at least a first type of biological cells configured to express at least one biologically-produced product;
at least one filter probe at least partially submerged in the suspension, wherein the at least one filter probe is configured to produce at least one filtrate stream lean in the first type of biological cells relative to the suspension, wherein the at least one filtrate stream comprises the at least one biologically-produced product;
an adjustment module fluidically connected to the perfusion bioreactor, wherein the adjustment module is configured to adjust one or more properties of the at least one filtrate stream to produce an adjusted filtrate stream; and a purification module fluidically connected to the adjustment module, wherein the purification module is configured to remove at least a first type of impurity and a second type of impurity from the adjusted filtrate stream to produce a purified filtrate stream, wherein the purification module comprises:
a first partitioning unit configured to remove at least the first type of impurity from the adjusted filtrate stream to produce a first partitioned filtrate stream lean in the first type of impurity relative to the adjusted filtrate stream, wherein the first partitioned filtrate stream comprises the at least one biologically-produced product; and
a second partitioning unit configured to remove at least a second type of impurity from the first partitioned filtrate stream to produce a second partitioned filtrate stream lean in the second type of impurity relative to the first partitioned filtrate stream, wherein the second partitioned filtrate stream comprises the at least one biologically-produced product,
wherein the system is configured to be continuously operated.

16 . The biomanufacturing system of claim 15 , further comprising a level sensing system configured to measure a level of the suspension in the reaction chamber of the perfusion bioreactor.

17 . The biomanufacturing system of claim 15 , wherein the first type of biological cell is microbial.

18 . The biomanufacturing system of claim 17 , wherein the microbial cell is a yeast, optionally being Pichia pastoris.

19 . The biomanufacturing system of claim 15 , wherein the biologically-produced product is selected from granulocyte-colony stimulating factor (G-CSF), human growth hormone (hGH), interferon α-2β (IFN), and a single domain antibody.

20 . The biomanufacturing system of claim 19 , wherein the purification module comprises:
a first column comprising a multimodal cation exchange resin; a second column comprising a resin selected from an anion exchange resin and a hydrophobic charge induction chromatography (HCIC) resin; and, optionally, a third column comprising a resin selected from an HCIC resin and a cation exchange resin.

21 . The biomanufacturing system of claim 20 , wherein the purification module is configured to remove a third type of impurity.

22 . The biomanufacturing system of claim 15 , wherein the impurity is a host-related impurity, optionally being a host cell protein (HCP).

23 . A method of producing at least one biologically-produced product, comprising:
supplying at least one feed stream comprising at least one cell culture medium to a perfusion bioreactor at a first flow rate; producing, within the perfusion bioreactor, a suspension comprising the at least one cell culture medium and at least a first type of biological cells expressing the at least one biologically-produced product; causing at least a portion of the suspension to flow through at least one filter probe to produce at least one filtrate stream lean in the first type of biological cells, wherein the at least one filtrate stream comprises the at least one biologically-produced product, wherein the at least one filter probe is at least partially submerged in the suspension; adjusting one or more properties of the at least one filtrate stream to produce an adjusted filtrate stream; removing, within a purification module, at least a first type of impurity and a second type of impurity from the adjusted filtrate stream to produce a purified filtrate stream flowing at a second flow rate, wherein the purified filtrate stream comprises the at least one biologically-produced product and is lean in the first type of impurity and the second type of impurity relative to the adjusted filtrate stream, wherein producing the purified filtrate stream comprises:
removing, within a first partitioning unit, at least the first type of impurity from the adjusted filtrate stream to produce a first partitioned filtrate stream lean in the first type of impurity relative to the adjusted filtrate stream, wherein the first partitioned filtrate stream comprises the at least one biologically-produced product; and
removing, within a second partitioning unit, at least the second type of impurity from the first partitioned filtrate stream to produce a second partitioned filtrate stream lean in the second type of impurity relative to the first partitioned filtrate stream, wherein the second partitioned filtrate stream comprises the at least one biologically-produced product.

24 . The method of claim 23 , further comprising measuring a level of the suspension in a reaction chamber of the perfusion bioreactor using a level sensing system.

25 . The method of claim 23 , wherein the first type of biological cell is microbial.

26 . The method of claim 25 , wherein the microbial cell is a yeast, optionally being Pichia pastoris.

27 . The method of claim 23 , wherein the biologically-produced product is selected from granulocyte-colony stimulating factor (G-CSF), human growth hormone (hGH), interferon α-2β (IFN), and a single domain antibody.

28 . The method of claim 27 , wherein producing the purified filtrate stream further comprises:
flowing the at least one filtrate through a first column comprising a multimodal cation exchange resin; collecting one or more first fractions comprising the biologically-produced product from an outflow of the first column; flowing the one or more first fractions through a second column comprising a resin selected from an anion exchange resin and a hydrophobic charge induction chromatography (HCIC) resin; collecting one or more second fractions comprising the biologically-produced product from an outflow of the second column; and, optionally, flowing the one or more second fractions through a third column comprising a resin selected from an HCIC resin and a cation exchange resin; and, optionally, collecting one or more third fractions comprising the biologically-produced product from an outflow of the third column.

29 . The method of claim 28 , wherein producing the purified filtrate stream comprises removing a third type of impurity.

30 . The method of claim 23 , wherein the impurity is a host-related impurity, optionally being a host cell protein (HCP).

Assignees

• Massachusetts Inst Technology
• Rensselaer Polytech Inst

Inventors

• Love J Christopher
• Love Kerry R
• Crowell Laura
• Stockdale Alan
• Braatz Richard Dean
• Lu Amos Enshen
• Cramer Steven
• Timmick Steven
• Vecchiarello Nicholas
• Goodwine Chaz
• Mascarenhas Craig A

Classifications

• G16B40/00

  ICT specially adapted for biostatistics; ICT specially adapted for bioinformatics-related machine learning or data mining, e.g. knowledge discovery or pattern finding · CPC title

• G01N30/8658

  Optimising operation parameters · CPC title

• G16C20/20

  Identification of molecular entities, parts thereof or of chemical compositions · CPC title

• C07K2317/14

  Specific host cells or culture conditions, e.g. components, pH or temperature · CPC title

• C07K2317/22

  from camelids, e.g. camel, llama or dromedary · CPC title