FILTRATION MODULE AND ASSEMBLY FOR FILTERING A PROCESS MEDIUM IN A BIOPROCESS AND METHOD OF SAMPLING DURING A BIOPROCESS

Abstract

A filtration module for filtering a process medium in a bioprocess including a process flow path for a process medium, a filter membrane coupled to the process flow path, and a sampling membrane coupled both to the process flow path and to a sampling flow path for extracting a sample from the process medium. The sampling flow path guides the extracted sample to a sampling outlet of the filtration module or to an analyzer integrated into the filtration module. A filtration assembly including the filtration module and an analyzer coupled to the sampling outlet of the filtration module. A method of sampling during a bioprocess including providing such a filtration module, urging a process medium through the process flow path, filtering the process medium by using the filter membrane, extracting a sample from the process medium by using the sampling membrane, and guiding the extracted sample to a sampling outlet.

Claims

1. A filtration module for filtering a process medium in a bioprocess, the filtration module comprising: a process flow path for a process medium, a filter membrane coupled to the process flow path, and a sampling membrane coupled both to the process flow path and to a sampling flow path for extracting a sample from the process medium, the sampling flow path guiding the extracted sample to a sampling outlet of the filtration module or to an analyzer integrated into the filtration module.

2. The filtration module according to claim 1, characterized in that the sampling membrane forms at least a portion of a boundary between the process medium and the sampling flow path.

3. The filtration module according to claim 1, characterized in that the sampling membrane has a pore size which is smaller than the pore size of the filter membrane.

4. The filtration module according to claim 1, characterized in that at least one further sampling membrane is coupled both to the process flow path and to the sampling flow path, the sampling membranes having different characteristics, including different pore sizes.

5. The filtration module according to claim 4, characterized in that the individual sampling membranes are coupled to different sampling channels of the sampling flow path.

6. The filtration module according to claim 4, characterized in that the individual sampling membranes are coupled to different process channels of the process flow path.

7. The filtration module according to claim 1, characterized in that the sampling membrane is a hollow fiber arranged as a channel in the process flow path.

8. The filtration module according to claim 1, characterized in that the sampling membrane is a capture membrane.

9. The filtration module according to claim 1, characterized in that the sampling membrane is a hydrophilic membrane or a hydrophobic membrane.

10. The filtration module according to claim 1, characterized in that the analyzer is based on at least one of the following techniques: liquid chromatography; liquid chromatography-mass spectrometry; high-performance liquid chromatography; ultra-high-performance liquid chromatography; gas chromatography; gas chromatography-mass spectrometry; matrix-assisted laser desorption/ionization combined with time-of-flight mass spectrometry; enzymatic analysis; spectroscopic analysis; Raman spectroscopy, near-infrared spectroscopy, mid-infrared spectroscopy, ultraviolet-visible spectroscopy, fluorescence spectroscopy; osmometry; pH measurement; conductivity measurement; refractometry; surface plasmon resonance; nuclear magnetic resonance spectroscopy.

11. A filtration assembly for filtering a process medium in a bioprocess, the filtration assembly comprising the filtration module according to claim 1 and an analyzer coupled to the sampling outlet of the filtration module.

12. The filtration assembly according to claim 11, characterized in that the analyzer is based on at least one of the following techniques: liquid chromatography; liquid chromatography-mass spectrometry; high-performance liquid chromatography; ultra-high-performance liquid chromatography; gas chromatography; gas chromatography-mass spectrometry; matrix-assisted laser desorption/ionization combined with time-of-flight mass spectrometry; enzymatic analysis; spectroscopic analysis; Raman spectroscopy, near-infrared spectroscopy, mid-infrared spectroscopy, ultraviolet—visible spectroscopy, fluorescence spectroscopy; osmometry; pH measurement; conductivity measurement; refractometry; surface plasmon resonance; nuclear magnetic resonance spectroscopy.

13. The filtration assembly according to claim 11, characterized by means for urging a transport medium through the sampling flow path.

14. The filtration assembly according to claim 11, characterized by a process control unit configured to receive data from the analyzer and to adjust or to control process components of the bioprocess.

15. (canceled)

16. A method of sampling during a bioprocess, the method comprising the following steps: providing the filtration module according to claim 1; urging the process medium through the process flow path; filtering the process medium by using the filter membrane coupled to the process flow path; extracting the sample from the process medium by using the sampling membrane coupled to both the process flow path and the sampling flow path; and guiding the extracted sample to the sampling outlet of the filtration module or to the analyzer integrated into the filtration module.

17. A computer program comprising instructions to: cause the means for urging the transport medium through the sampling flow path of the filtration assembly according to claim 13 to control the flow of the transport medium.

18. A computer program comprising instructions to control the analyzer of the filtration module according to claim 1 to provide settings and inputs to the analyzer.

19. A computer program comprising instructions to control the analyzer of the filtration assembly according to claim 11 to provide settings and inputs to the analyzer.

20. A computer program comprising instructions to cause a process control unit of the filtration assembly according to claim 11 to evaluate analysis data provided by the analyzer of the filtration module or the analyzer of the filtration assembly, and to adjust or control the bioprocess based on the evaluation.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Further features and advantages of the invention will become apparent from the following description and from the accompanying drawings to which reference is made. In the drawings:

[0040] FIG. 1 schematically shows a sampling technique using two different sampling membranes arranged sequentially;

[0041] FIG. 2a shows a perspective view of a first embodiment of a filtration module according to the invention;

[0042] FIG. 2b shows a view of a first side of the filtration module according to FIG. 2a;

[0043] FIG. 2c shows a section view of the filtration module according to FIG. 2b along sectional plane A-A;

[0044] FIG. 2d shows a view of a second side of the filtration module according to FIG. 2a;

[0045] FIG. 2e shows a section view of the filtration module according to FIG. 2d along sectional plane B-B;

[0046] FIG. 2f shows an enlarged view of detail X according to FIG. 2e;

[0047] FIG. 2g shows a section view of the filtration module according to FIG. 2d along sectional plane C-C;

[0048] FIG. 3a shows a perspective view of a second embodiment of a filtration module according to the invention;

[0049] FIG. 3b shows a view of a first side of the filtration module according to FIG. 3a;

[0050] FIG. 3c shows a section view of the filtration module according to FIG. 3b along sectional plane A-A;

[0051] FIG. 3d shows an enlarged view of detail X according to FIG. 3c;

[0052] FIG. 3e shows a view of a second side of the filtration module according to FIG. 3a;

[0053] FIG. 3f shows a section view of the filtration module according to FIG. 3e along sectional plane B-B

[0054] FIG. 4 schematically shows a multi-channel sampling flow path with two different sampling membranes; and

[0055] FIG. 5 schematically shows a sampling technique using two different sampling membranes in a cascade arrangement.

DETAILED DESCRIPTION

[0056] FIG. 1 schematically illustrates how samples can be taken from a process medium in a filtration module. The upper half of FIG. 1 shows a process medium containing several components. By way of example, three different components of the process medium are represented by different symbols. In this example, large circles represent a plurality of cells 10, medium-sized circles represent a plurality of proteins and/or antibodies 12, and small dots represent a plurality of smaller molecules 14, e.g. glucose and/or lactate molecules.

[0057] A sampling flow path 16 is in direct contact with the process medium. With respect to a flow direction indicated by arrow A, two different sampling membranes 18a, 18b are sequentially arranged in the sampling flow path 16. In particular, each of the sampling membranes 18a, 18b forms a portion of the boundary between the process medium and the sampling flow path 16.

[0058] In the example shown, the first sampling membrane 18a has a smaller pore size (more specifically: a lower molecular weight cut-off (MWCO)) than the second sampling membrane 18b. Therefore, only the smaller molecules 14 can pass through the second membrane into the sampling flow path 16. A first diffusion time can be set, during which a transport medium, typically a buffer or a solvent, is not urged through the sampling flow path 16 in the transport direction A, but halted, to provide sufficient time for the smaller molecules to travel across the first sampling membrane 18a into the sampling flow path 16. The transport medium can then be urged a little further, e.g. up to the second sampling membrane 18b.

[0059] The second sampling membrane 18b has a larger cut-off pore size than the first sampling membrane 18a. Therefore, the medium sized components of the medium can diffuse through the second sampling membrane 18b, especially the proteins and/or antibodies 12. A second diffusion time can be set, during which the transport medium is halted to allow the medium sized molecules to enter into the sampling flow path 16. The transport medium can then be urged further to transport the sample with the molecules collected from the process medium to an analyzer.

[0060] The transport medium can be urged through the sampling flow path 16 by a drive, e.g. a pump, or by gravity. Halting of the transport medium can be effected by stopping the external drive or by other means, e.g. a valve. Alternatively, the transport medium is not halted but constantly urged through the sampling flow path 16 at constant velocity.

[0061] The sampling procedure shown schematically in FIG. 1 allows samples of two different components of the process medium to be taken and analyzed. For example, the concentration of the two components in the process medium can be determined.

[0062] FIGS. 2a to 2f show a first embodiment of a filtration module 20 for filtering a process medium in a bioprocess, in particular in a biopharmaceutical process. In practice, the filtration module 20 is used in a running filtration step of such a process.

[0063] The filtration module 20 is a prefabricated or preassembled unit designed as a cartridge, but could also be designed as a capsule or the like. The whole filtration module 20 is configured as a single-use module, i.e. it is made of materials that can be sterilized, especially by gamma radiation. Preferably, the filtration module 20 is sterilized before it is shipped as a ready-to-use module to a customer.

[0064] The filtration module 20 includes at least one process flow path. Via an inlet connector (not shown) the process medium to be filtered in the filtration module 20 is fed to one filter membrane or a stack of filter membranes 22 (not shown in detail) arranged in the process flow path. Via a corresponding output connector (not shown) the filtered process medium exits the filtration module 20. In case of a cross-flow filtration module, both the retentate and the permeate exit the filtration module 20 via separate output connectors (not shown).

[0065] In addition, the filtration module 20 includes a separate sampling flow path 16. The sampling flow path 16 is formed here as a single channel leading through the filtration module 20 and terminates into an inlet connector 24 and an outlet connector 26, respectively. A transport medium (buffer or solvent) can be urged continuously or intermittently (in a stopped-flow manner) through the sampling flow path 16.

[0066] As can be seen in FIGS. 2c, 2e and 2f, a portion of the sampling flow path 16 is formed by a cylindrical sampling membrane 18. The axial ends of the sampling membrane 18 are pushed on corresponding inner end portions 28 of the inlet and outlet connectors 24, 26, respectively. Thus, the sample membrane 18 forms a portion of a boundary between the process medium and the sampling flow path 16.

[0067] The actual shape and arrangement of the sampling membrane 18 may vary. In any event, the sampling membrane 18 should be coupled both to the process flow path and to the sampling flow path 16 such that selected molecules of the process medium can travel across the sampling membrane 18 into the sampling flow path 16 and form a sample.

[0068] The transport medium in the sampling flow path 16 receives the molecules from the process medium and transports the sample to an analyzer. The analyzer is either integrated into the filtration module 20 or provided as a separate external component of a filtration assembly. In the latter case, the sample is transported via the outlet connector 26 to the external analyzer.

[0069] The integrated or external analyzer can be based on at least one of the following techniques: liquid chromatography (LC); liquid chromatography-mass spectrometry (LC-MS); high-performance liquid chromatography (HPLC); ultra-high-performance liquid chromatography (UHPLC); gas chromatography (GC); gas chromatography-mass spectrometry (GC-MS); matrix-assisted laser desorption/ionization combined with time-of-flight mass spectrometry (MALDI-TOF); enzymatic analysis; spectroscopic analysis, in particular at least one of the following: Raman spectroscopy, near-infrared spectroscopy (NIR), mid-infrared spectroscopy (MIR), ultraviolet-visible spectroscopy (UV-Vis), fluorescence spectroscopy; osmometry; pH measurement; conductivity measurement; optical measurement, in particular refractometry; surface plasmon resonance (SPR); nuclear magnetic resonance spectroscopy (NMR).

[0070] It is generally possible to take samples in the above-described manner from the feed and/or from the retentate and/or from the permeate. The respective sampling membrane 18 has to be coupled both to the respective flow path in the filtration module 20 (feed path, retentate path, permeate path), which is then regarded as part of the process flow path, and to the sampling flow path 16. It may be expedient to provide separate sampling flow paths 16 for each kind of sample (feed, retentate, permeate).

[0071] If different molecules are to be taken as separate samples, a corresponding number of sampling membranes 18 having different characteristics, especially with respect to pore size (MWCO), are provided.

[0072] Depending on the type of analysis, it may be possible to use a regular filter membrane as sampling membrane 18. Accordingly, the sampling membrane 18 allows a relatively large proportion of components of the process medium to permeate through the sampling membrane. In this case, a transport medium in the sampling flow path 16 is not absolutely necessary.

[0073] The connectors of the filtration module 20 are preferably tri-clamp flanges or hose barbs allowing sterile connections. Thus, the filtration module can be easily integrated into a filtration assembly used in a bioprocess. Since the complete filtration module 20 is designed as a single-use module, it can be disposed of as a whole after use and be replaced by a new filtration module 20 for the following application.

[0074] FIGS. 3a to 3f show a second embodiment of the filtration module 20. In the following, only the major differences compared to the first embodiment will be explained.

[0075] In the second embodiment the inlet and outlet connectors 24, 26 are arranged at another side of the filtration module 20, while the sampling flow path 16 is still in direct contact with the process medium. Here, a plurality of sampling membranes 18 are disposed along the sampling flow path 16, each sampling membrane 18 forming a portion of the boundary between the process medium and the sampling flow path 16. In particular, as can be seen in the sectional view of FIG. 3d, the sampling flow path 16 is formed as a single channel with a plurality of openings 30. Each of the openings 30 is covered by a sampling membrane 18. As explained above, the sampling membranes 18 may have different characteristics, especially regarding pore size.

[0076] It is to be understood that the embodiments shown in the Figures are only used to illustrate certain features of the filtration module 20, which may be combined in any suitable manner. Moreover, the sampling membranes 18 may have other shapes, especially in case the filtration module 20 is not configured as a cartridge but as a capsule, for example.

[0077] Especially in cases where it is useful to enrich the analyte before an analysis, a capture membrane can be used as sampling membrane 18. The capture membrane is specifically configured to capture the analyte from the process medium flowing through the process flow path. To this end, the surface of the capture membrane is provided with a specific binding material adapted to the analyte. The accumulated analyte is extracted from the capture membrane by elution on the other side of the membrane, i.e. a solvent is urged through the sampling flow path 16 for washing out the analyte. The solvent is also used as transport medium for guiding the extracted sample to a sampling outlet of the filtration module 20 or to an analyzer integrated into the filtration module 20.

[0078] According to another approach, the sampling membrane 18 is a hydrophilic membrane exhibiting an affinity for water. In general, hydrophilic membranes are capable of filtering such elements as bacteria, viruses, proteins, particulates, and other contaminants. Likewise, it is possible to use a hydrophobic membrane which blocks the passage of water. The choice between a hydrophilic membrane and a hydrophobic membrane depends on the kind of the analyte.

[0079] Irrespective of the general design of the filtration module 20, the process flow path and/or the sampling flow path 16 may be composed of multiple separate channels.

[0080] FIGS. 4 and 5 show two schematic examples of a multi-channel sampling flow path 16 with two individual sampling flow channels 16a, 16b. Each of the sampling flow channels 16a, 16b is provided with a sampling membrane 18a, 18b, respectively. The sampling membranes 18a, 18b may have different characteristics (e.g. MWCO). A transport medium is urged through each sampling flow channel 16a, 16b individually. Thus, the different samples contained in the different sampling flow channels 16a, 16b can be taken to the same analyzer sequentially (one after the other with breaks in between) or to different analyzers (possibly simultaneously).

[0081] In the embodiment shown in FIG. 4 each sampling membrane 18a, 18b is coupled both to the process flow path and to its associated sampling flow channel 16a, 16b, respectively.

[0082] In the embodiment shown in FIG. 5, however, only the first sampling membrane 18a of the first sampling flow channel 16a is coupled to the process flow path, i.e. the second sampling membrane 18b is not coupled to the process flow path. Instead, the second sampling membrane 18b coupled both to the first sampling flow channel 16a and to the second sampling flow channel 16b.

[0083] It is especially expedient if the first sampling membrane 18a has a larger MWCO (pore size) than the second sampling membrane 18b as shown in FIG. 5. With such a cascade arrangement of sampling membranes 18a, 18b it is possible to provide MWCO dependent transport of analytes to the same analyzer or to different analyzers.

[0084] Of course, the cascade arrangement of sampling membranes can be further extended with additional sampling flow channels and sampling membranes interconnecting the individual sampling flow channels.

[0085] A computer program executable on a general-purpose computer can be used to perform or assist performance of any of the method steps described above. In particular, the computer can be configured as a program control unit of the filtration assembly which is adapted to adjust or to control process components of the bioprocess.

LIST OF REFERENCE SIGNS

[0086] 10 cells

[0087] 12 proteins and/or antibodies

[0088] 14 smaller molecules

[0089] 16 sampling flow path

[0090] 16a first sampling flow channel

[0091] 16b second sampling flow channel

[0092] 18a first sampling membrane

[0093] 18b second sampling membrane

[0094] 18 sampling membrane(s)

[0095] 20 filtration module

[0096] 22 filter membranes

[0097] 24 inlet connector

[0098] 26 outlet connector

[0099] 28 end portions

[0100] 30 openings