Fluid network for sterile sampling

Abstract

Fluid networks and methods for sterile process sampling are described. The fluid network includes a sampling valve, a filter, a manifold, and a valve control module. A process sample path in the fluid network includes one or more valve passages and a filter in fluid communication with the sampling valve. The sampling valve can be configured to be in a first valve state to receive a process sample from a process source into the process sample path, and can be configured to be in a second valve state, a gas stream and a solvent stream may be provided through the process sample path to clean and dry the process sample path to prepare for collection of another process sample.

Description

[0001] Related Applications

[0002] This application claims the benefit of an earlier filing date of U.S. Provisional Patent Application Serial No. 63 / 339,679, filed on May 9, 2022, entitled “Fluidic Network for Aseptic Sampling,” and claims the benefit of an earlier filing date of U.S. Provisional Patent Application Serial No. 63 / 340,534, filed on May 11, 2022, entitled “Fluidic Network for Aseptic Sampling,” the entire contents of which are incorporated herein by reference. Technical Field

[0003] The disclosed technology generally relates to fluid networks for bioprocess sampling applications. More specifically, the technology relates to fluid networks and methods for aseptic process sampling. Background Art

[0004] Bioprocesses may take many days to complete, and it may be desirable to sample daily or more frequently to properly monitor and control the process. Bioprocess monitoring often requires sample clarification to interface with analytical instrumentation. The efficiency of the bioprocess can be monitored and the quality of the bioprocess product determined. In some cases, monitoring is used for feedback to make process adjustments.

[0005] In order to receive samples from a bioprocess source (such as a bioreactor), careful procedures should be followed to protect the bioprocess source from contamination. The bioreactor may contain a culture medium that supports the biological growth of one or more desired product materials. Sampling may include introducing a syringe into the reaction vessel to extract a sample of a desired volume. If the tip of the syringe is previously in contact with a biological organic material or another contaminant, the process may introduce contaminants into the reactor. As a result of contamination, the desired output of the bioprocess may be adversely affected or terminated. For example, bacteria, viruses, molds or spores that may be unintentionally introduced into the bioreactor by the sampling process may prevent the desired bioprocess from being carried out. It is usually necessary to have considerable time and energy to carry out conventional aseptic sampling to avoid problems associated with introducing contaminants into the bioreactor. Summary of the invention

[0006] In one aspect, a fluid network for aseptic process sampling includes a sampling valve, a filter, a manifold, and a valve control module. The sampling valve has a plurality of ports and a plurality of valve channels, and can be configured to be in at least a first valve state and a second valve state. One of the ports is a process inlet port configured to receive a process sample, and another port in the port is a process outlet port configured to distribute a process sample. The filter is in fluid communication with the sampling valve. The manifold is configured to supply and control the flow of a variety of fluids. The manifold has a manifold outlet port to provide a flow of a selected fluid in the fluid. The manifold outlet port is in fluid communication with a port in the port of the sampling valve. The valve control module is in communication with the sampling valve and the manifold. The process sample path is defined between the process inlet port and the process outlet port, and includes at least one of the filter and the valve channel. When the sampling valve is in the first valve state, the process sample path can receive the process sample, and when the sampling valve is in the second state, the flow of a selected fluid from the fluid of the manifold outlet port can pass through the process sample path.

[0007] The manifold may be controllable to provide a selected one of a solvent flow and a gas flow to the process sample path. When the sampling valve is in the second valve state and the manifold provides the gas flow, the gas flow is directed through the process sample path. When the sampling valve is in the second valve state and the manifold provides the solvent flow, the solvent flow is directed through the process sample path. The gas flow and the solvent flow may be in reverse directions relative to the process sample flow through the process sample path.

[0008] The manifold may include a manifold valve having a first inlet port configured to receive a gas flow and a second inlet port configured to receive a first solvent flow, and wherein the manifold valve is configurable to be in a first valve state, a second valve state, and a closed valve state, in which the gas flow is directed from the first inlet port to the manifold outlet port, in which the first solvent flow is directed from the second inlet port to the manifold outlet port, and in which the first inlet port and the second inlet port are fluidly disconnected from the manifold outlet port.

[0009] The valve control module may be configured to regulate a time period for at least one of a gas flow and a solvent flow through the process sample path.

[0010] The sampling valve may be a rotary shear seal valve or a linear shear seal valve. The filter may be formed of a porous material.

[0011] In another aspect, a method for aseptic process sampling includes providing a process sample flow through a process sample path in a fluid network, providing a first gas flow through the process sample path after the process sample flow, providing a first solvent flow through the sample path after the first gas flow, and providing a second gas flow through the process sample after the first solvent flow.

[0012] The process sample path may include a filter and at least one valve channel.

[0013] The duration that each of the first and second gas flows and the first solvent flow passes through the process sample path may be predetermined.

[0014] A second solvent flow may be provided through the process sample path after the second gas flow. The second solvent flow may include one of a phosphate buffered saline flow and a cell culture medium solution flow. A third gas flow may be provided through the sample process path after the second solvent flow.

[0015] A second solvent flow may be provided through the process sample path after the first solvent flow and before the second gas flow. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] The above advantages and other advantages of the present invention can be better understood by referring to the following description in conjunction with the accompanying drawings, in which the same reference numerals indicate the same structural elements and features in each of the accompanying drawings. For clarity, not every element is marked in every drawing. The accompanying drawings are not necessarily drawn to scale, but the emphasis is on illustrating the principles of the present invention.

[0017] Figure 1A and Figure 1B are diagrams showing the front and back sides, respectively, of a stator for a rotary shear seal valve that may be used as part of a fluid network for aseptic process sampling.

[0018] FIG. 2A to FIG. 2D is a schematic diagram of an example of a fluid network that can be used for sampling in a sterile process, wherein the figure shows a sequential configuration according to different valve states.

[0019] Figure 3 is a flow chart representation of an example of a method for aseptic process sampling.

[0020] Figure 4 is a flow chart representation of another example of a method for aseptic process sampling. DETAILED DESCRIPTION

[0021] Reference to an "embodiment" or "example" in this specification indicates that a particular feature, structure, or characteristic described in conjunction with the embodiment or example is included in at least one embodiment or example of the present teachings. References to a particular embodiment or example within this specification do not necessarily refer to the same embodiment or example.

[0022] In a brief overview, embodiments and examples disclosed herein relate to a fluid network that enables a sample to be collected from a process source (e.g., a reactor, batch processing, perfusion, or flow) in an aseptic manner. The fluid network includes a valve that isolates a valve port (i.e., a "process inlet port") that receives a process sample from all other valve ports, except when the process sample flows through the valve. The fluid network also includes a process outlet port that distributes the process sample from the valve to, for example, a process sampler. After collecting the process sample, any valve channel and external fluid path that guides the process sample are cleaned and dried, and then the valve is reconfigured to a valve state in which the valve channel is arranged to guide another process sample received at the process inlet port. In this way, the process inlet port is never connected to an unsterilized valve channel, thereby significantly reducing or eliminating the possibility of introducing contaminants into the reactor. Other elements in the process sample path, such as filters that provide sample clarification, are similarly dried and washed. Drying and washing times can be programmed to ensure cleanliness between sample collections.

[0023] Advantageously, the ability to extract small volume process samples (e.g., a few hundred microliters or less) prevents significant product loss produced by the bioprocess during process monitoring. This ability to collect small volume process samples makes the fluidic network particularly suitable for small volume bioreactors. In addition, the useful life of the filter is increased, and maintenance time and costs are correspondingly reduced.

[0024] This teaching will now be described in detail with reference to the exemplary embodiments or examples of this teaching as shown in the accompanying drawings. Although this teaching has been described in conjunction with various embodiments and examples, this teaching is not intended to be limited to such embodiments and examples. In contrast, this teaching encompasses various substitutions, modifications and equivalents, as will be understood by those skilled in the art. Those of ordinary skill who have the right to use the teachings of this article will recognize additional specific implementations, modifications and embodiments within the scope of this disclosure as described herein, as well as other areas of use.

[0025] Unless otherwise specified herein, the description of the value range herein is not intended to be limiting, but refers to any and all values ​​falling within the range individually, and each individual value within such a range is incorporated into the specification as if it were individually described herein. When accompanied by numerical values, the words "about", "approximately", etc. should be interpreted as indicating deviations as those of ordinary skill in the art will understand to operate satisfactorily for the intended purpose. Similarly, when used with reference to physical properties, approximate words such as "approximately" or "substantially" should be understood to take into account the deviation ranges that those of ordinary skill in the art will understand to operate satisfactorily for the corresponding purposes, functions, purposes, etc. The range of values ​​and / or numerical values ​​is provided herein only as an example, and does not constitute a limitation on the scope of the described embodiments. In the case of providing a value range, they are also intended to include each value within the range, as if set forth individually, unless otherwise explicitly stated. Otherwise, the use of any and all examples or exemplary languages ​​("for example", "such as", etc.) provided herein is intended only to better illustrate the embodiments, and does not limit the scope of the embodiments. The language in the specification should not be interpreted as indicating that any unclaimed element is necessary for the practice of the embodiments.

[0026] Figure 1A and Figure 1B 1 is an illustration of the front and rear sides of a stator 10 for a rotary shear seal valve, which can be used as a part of a fluid network for sampling in a sterile process. The stator 10 includes seven external ports 12 that can be used to receive or discharge a fluid stream. Each external port 12 is connected to a corresponding stator port in the seven stator ports on a stator surface 14 via an internal fluid channel, and the stator surface is adjacent to the rotor surface (not shown) in the assembled valve. In a specific implementation, the stator is formed using a diffusion bonding process that enables the internal fluid channel to be effectively routed between the stator ports on the external port 12 and the stator surface 14. The pipeline can be connected to the external port 12, for example, using a compression fitting, to allow fluid to flow into or out of the valve. In the example of the fluid network described below, one of the external ports 12 receives a process sample stream. Other external ports 12 can be used to pass the process sample stream to other components (e.g., filters) and external systems of the fluid network, such as a process sampler module of an analytical system (e.g., a liquid chromatography system), or receive the process sample stream from other components and external systems of the fluid network. External port 12 through which the process sample flow passes is determined by the internal valve channel configuration established by the valve state of the valve.

[0027] FIG. 2A to FIG. 2D is a schematic diagram of an example of a fluidic network that can be used for sterile sampling. For example, the fluidic network can be used to sample an ongoing biological process in a bioreactor. See also Figure 3, which shows a flow chart representation of an example of a method 100 for sampling a sterile process. Sampling can be performed in a repeated manner over a period of time, for example, to enable monitoring of a bioprocess from initiation to completion.

[0028] The fluid network includes a sampling valve 20 and a manifold for supplying and controlling multiple fluid streams. The manifold is shown as a manifold valve 22 implementation, which is connected to various fluid sources to provide and control one of a gas stream, a first solvent stream, and a second solvent stream at a manifold outlet port 30-4. In a non-limiting alternative example, the manifold can be implemented as a passive fluid tee connected to a fluid line, each of which has a separate flow control device or a pressure regulator. As shown, the sampling valve 20 is a rotary shear seal valve, which includes a rotor with a rotor surface and a stator with a stator surface adjacent to the rotor surface. In an alternative specific implementation, the sampling valve 20 can be a linear shear seal valve or can be configured to provide other valve types of similar functionality. The stator channel extends through the body of the stator to couple the external valve port fluid to the stator ports 24-1 to 24-7 (usually 24) on the stator surface. The tubing can be coupled to the external port using compression fittings so that the fluid flows into or out of the corresponding stator channel and stator port 24. The rotor includes a plurality of valve channels 26-1 to 26-3 (generally 26) for establishing fluid communication between the stator ports 24. In some embodiments, the valve channels 26 are microchannels formed as grooves on the surface of the rotor. Each valve channel 26 provides a flow path that can be used to fluidically couple two of the stator ports 24 according to the configuration of the sampling valve 20 in one of the valve states.

[0029] The sampling valve 20 rotates the rotor 90° clockwise relative to the stator, and Figure 2A The first valve state shown is rotated to Figure 2B Conversely, the sampling valve 20 can be changed from the second valve state to the first valve state by rotating the rotor 90° counterclockwise relative to the stator.

[0030] The manifold valve 22 has a first inlet port 30-1 for receiving a gas flow from a gas source, a second inlet port 30-2 for receiving a first solvent flow, and a third inlet port 30-3 for receiving a second solvent flow. For example, the inlet ports 30-1 to 30-3 can be connected to a gas source and a solvent source using compression fittings and tubing. The manifold valve 22 provides a selected gas flow or solvent flow at a manifold outlet port 30-4. The outlet port 30-4 is connected to one of the external ports 12 of the sampling valve 20 with a compression fitting and tubing to provide a gas flow or a solvent flow. As a non-limiting example, the manifold valve 22 can be a rotary shear seal valve or can be an arrangement of one or more solenoid valves.

[0031] The manifold valve 22 can be configured to be in three open valve states: a first valve state in which a gas received at the first inlet port 30-1 is passed to the manifold outlet port 30-4, a second valve state in which a first solvent flow received at the second inlet 30-2 is passed to the manifold outlet port 30-4, a third valve state in which a second solvent flow received at the third inlet 30-3 is passed to the manifold outlet port 30-4, and a closed valve state in which the three inlet ports 30-1 to 30-3 are fluidly disconnected from the outlet port 30-4 to prevent fluid from flowing from the manifold outlet port 30-4. In other embodiments, the number of inlet ports on the manifold valve 22 can be different. For example, there may be only two inlet ports, such as when only one solvent is utilized, or there may be additional inlet ports if more solvents and / or gases are utilized.

[0032] The valve states of the two valves 20 and 22 are controlled by respective valve control signals. In some specific implementations, the valve control signals are provided by a valve control module. By way of example, the valve control module can be implemented using a standalone processor or as part of a system processor. The valve control module can be connected to the system controller and can be programmed via a user interface that also enables an operator to control other system parameters and functions, such as the operation of a process sample source (e.g., a bioreactor) and / or an analytical instrument (e.g., a liquid chromatography system).

[0033] As used herein, "process sample path" means a fluid path in a fluid network through which a process sample received at process inlet port 24-1 flows and then exits the fluid network at process outlet port 24-4. In the illustrated example described herein, the process sample path is defined by the fluid path beginning at process inlet port 24-1. More specifically, the process sample path includes valve channel 26-1, filter 32, and valve channel 26-3.

[0034] According to Method 100 and reference Figure 2A, when in the first valve state, the process sample stream received at the process inlet port 24-1 of the sampling valve 20 is provided through the valve channel 26-1 (step 110), and exits through the port 24-2 before passing through the filter 32 having a filter inlet 34-1 and a filter outlet 34-2. The filter 32 removes undesirable particulate matter and components from the process sample stream. For example, an ongoing biological process may include materials (e.g., cell materials) that may block downstream components and analytical equipment. Such materials are removed from the process sample stream and collected by the filter 32. In some embodiments, the filter 32 is formed of a porous material having a pore size distribution selected to remove undesirable components exceeding a predetermined size in the process sample stream. The filtered process sample stream continues from the filter outlet 34-2 through the valve channel 26-3, then leaves the sampling valve 20 at the process outlet port 24-4 and flows to the process sampler. By way of non-limiting example, the process sampler may include a syringe to extract a known volume of process sample from the stream leaving the sampling valve 20. The collected process sample can then be injected into the analysis system using a syringe. The remaining valve channel 26-2 is connected to the manifold valve 22 or gas at one end at the stator port 24-5 and the other end at the stator port 24-6. In the illustrated configuration, the manifold valve 22 is preferably maintained in a closed valve state; however, if the manifold valve 22 is configured to be in one of its open valve states, a gas flow or solvent flow can be provided through the valve channel 26-2 and discharged at the port 24-6.

[0035] Subsequently, the sampling valve 20 is switched to its second valve state, and the manifold valve 22 is configured to be in its first valve state, such as Figure 2B As shown. With this arrangement, the process sample source is disconnected at port 24-1 and isolated from other valve ports 24 and all valve channels 26. The sampling valve 20 then provides (step 120) a gas flow through the process sample path received from the manifold valve 22 at port 24-5. More specifically, the gas flow passes through the valve channel 26-3 and the filter 32 in the reverse direction, that is, the gas flow enters the filter 32 at the filter outlet 34-2 and leaves at the filter inlet 34-1. The gas backwash enables the material collected by the filter 32 from the previous sample process flow to be removed from the filter 32 and discharged from the valve 20 by flowing through the valve channel 26-1, and then leaves at port 24-7. The gas flow also removes any liquid remaining in the valve channels 26-1 and 26-3. Non-limiting examples of gases that can be used include nitrogen, another of the rare gases, and oxygen. Independent of the backwash process, the previously collected and filtered process sample can be managed by the process sampler and provided to an analysis system (e.g., a liquid chromatography system).

[0036] The manifold valve 22 is switched to Figure 2C, to provide (step 130) a second valve state similar to Figure 2B , a wash solvent flow is passed through the process sample path of the gas flow shown in . The solvent flow helps to remove organic matter and other foreign matter that may remain in the valve channels 26-1 and 26-3 and the filter 32 after the gas backflush. For example, the remaining foreign matter can be dissolved in the solvent and distributed to the waste from the sampling valve 20. Examples of backflush solvents that can be used are detergents or liquids that can lyse and destroy cells within the process sample path and dissolve cell membrane material in the flow and carry it to the waste. In alternative examples, the solvent is a phosphate buffered saline (PBS) solution, a cell culture medium, or another liquid in which the cellular material can be kept suspended and easily transported in the liquid flow. Subsequently, the manifold valve 22 is switched to its first valve state, as Figure 2D As shown, a gas flow is again provided ( 140 ) to dry the valve passages 26 - 1 and 26 - 3 and the filter 32 .

[0037] The duration of the gas flow and solvent flow through the process sample path can be independently controlled via the valve control module. For example, it may be desirable to provide a longer duration for the gas flow through the process sample path than the time period for the solvent flow through the process sample path to ensure adequate or complete drying. The duration can be set to a predetermined value.

[0038] In an alternative embodiment, two or more solvents are used. FIG. 2A to FIG. 2D Components of the fluid network shown in and further referenced Figure 4 , which is a flowchart representation of another example of a method 200 for aseptic process sampling. A process sample flow is provided (step 210) through a process sample path including valve channels 26-1 and 26-3 and a filter 32, after which a first gas flow is provided through the process sample path (step 220). Subsequently, a first solvent flow ("solvent 1" at port 30-2) is provided through the process sample path (step 230), after which a second gas flow (step 240) is provided through the process sample path. A second solvent flow ("solvent 2" at port 30-4) is then provided (step 250) before a third gas flow (step 260) is provided. The gas flow is used to dry the process sample path so that no solvent remains. In a preferred method example, the first solvent is a detergent or another liquid that can destroy cells in the process sample path, and the second solvent is a "weak solvent" (e.g., a phosphate buffered saline (PBS) solution) that retains and transports any cellular material remaining in the process sample path. In a variation of method 200, the second solvent flow may be provided without an intervening second gas flow. In another alternative example of the method, the first solvent stream may be used both before and after the second solvent stream is used.

[0039] After completing the Figure 3 and Figure 4 After the method 100 or 200, it can be seen that all ports 24 and valve channels 26 in the process sample path and downstream of the process inlet port 24-1 have been sterilized and dried. Therefore, valves 20 and 22 can be reconfigured, for example, as Figure 2A as shown, to enable subsequent process samples to be collected in a sterile manner.

[0040] In the above example, the process sample path includes two valve channels and a filter that couples one of the valve channels to the other valve channel. It should be appreciated that in other embodiments of the fluid network, the number and arrangement of valve channels and components in the process sample path may be different. In such embodiments, modifications to the fluid network configuration described herein will be recognized by those skilled in the art to achieve solvent reflux and gas backflush of the process sample path in a similar manner.

[0041] The fluid network can be implemented using a rotary shear seal valve and a solenoid valve; however, it should be appreciated that in other embodiments, the fluid network can be implemented using other fluid switching devices. For example, a linear shear seal valve can be used to implement the same functional switching and fluid path routing. The illustrated rotary shear seal valve 20 includes seven stator ports on the stator and three valve channels 26 that can be formed, for example, on the surface of the rotor; however, it should be appreciated that other numbers of ports 24 and valve channels 26 are also contemplated. In addition, the location of the port 24 and the shape and length of the valve channel 26 may be different from those described above. In addition, the number of gas backflushes and solvent refluxes may be different from those described above.

[0042] While various examples have been shown and described, the description is intended to be illustrative rather than limiting, and it will be understood by those skilled in the art that various changes in form and details may be made without departing from the scope of the present invention as described in the following claims.

Claims

1. A fluid network for sampling in a sterile process, the fluid network include: a sampling valve having a plurality of ports and a plurality of valve channels and being configurable to be in at least a first valve state and a second valve state, wherein one of the ports is a process inlet port configured to receive a process sample and another of the ports is a process outlet port configured to dispense the process sample; a filter in fluid communication with the sampling valve; a manifold configured to supply and control the flow of a plurality of fluids, the manifold having a manifold outlet port to provide flow of a selected one of the fluids, the manifold outlet port being in fluid communication with one of the ports of the sampling valve; and a valve control module, the valve control module being in communication with the sampling valve and the manifold, wherein a process sample path is defined between the process inlet port and the process outlet port and includes the filter and at least one of the valve passages, wherein the process sample path is capable of receiving the process sample when the sampling valve is in the first valve state, and wherein a flow of a selected one of the fluids from the manifold outlet port is capable of passing through the process sample path when the sampling valve is in the second state. 2 . The fluid network of claim 1 , wherein the manifold is controllable to provide a selected one of a solvent flow and a gas flow to the process sample path.

3. A fluid network according to claim 1, wherein the manifold includes a manifold valve, the manifold valve having a first inlet port configured to receive a gas flow and a second inlet port configured to receive a first solvent flow, and wherein the manifold valve is configurable to be in a first valve state, a second valve state, and a closed valve state, in which the gas flow is directed from the first inlet port to the manifold outlet port, in which the first solvent flow is directed from the second inlet port to the manifold outlet port, and in which the first inlet port and the second inlet port are fluidically disconnected from the manifold outlet port.

4. The fluid network according to claim 2, in, When the sampling valve is in the second valve state and the manifold provides the gas flow, the gas flow is directed through the process sample path, and wherein when the sampling valve is in the second valve state and the manifold provides the solvent flow, the solvent flow is directed through the process sample path.

5. The fluid network of claim 4, wherein the gas flow and the solvent flow are in reverse directions relative to the process sample flow through the process sample path.

6. The fluid network of claim 1, wherein the valve control module is configured to regulate a time period for at least one of the flow of gas and the flow of solvent through the process sample path.

7. The fluid network of claim 1, wherein the sampling valve is a rotary shear seal valve.

8. The fluid network of claim 1, wherein the sampling valve is a linear shear seal valve.

9. The fluid network of claim 1, wherein the filter is formed of a porous material.

10. A method for sampling in a sterile process, the method comprising: include: providing a process sample flow through a process sample path in the fluid network; providing a first gas flow through the process sample path subsequent to the process sample flow; providing a first solvent flow through the process sample path after the first gas flow; as well as A second gas flow is provided through the process sample path subsequent to the first solvent flow.

11. The method of claim 10, wherein the process sample path comprises a filter and at least one valve channel.

12. The method of claim 10, further comprising providing a second solvent flow through the process sample path subsequent to the second gas flow.

13. The method of claim 12, wherein the second solvent stream comprises one of a phosphate buffered saline stream and a cell culture medium solution stream.

14. The method of claim 12, further comprising providing a third gas flow through the process sample path subsequent to the second solvent flow.

15. The method of claim 10, further comprising providing a second solvent flow through the process sample path after the first solvent flow and before the second gas flow.

16. The method of claim 10, wherein a duration for each of the first and second gas flows and the first solvent flow to pass through the process sample path is predetermined.

Images