Fluid network for volumetric sterile sampling

Abstract

Fluid networks and methods for sterile sampling from a process source are described. The fluid network includes a valve that isolates the valve port that receives the process sample from all other valve ports except when the process sample flows through the valve. The fluidic network also includes a sample processing module having a filter element and a sample preparation element to prepare a process sample for analysis. A positive displacement pump operates to draw the process sample into the fluidic network and push a portion of the collected process sample through the sample processing module prior to dispensing the processed process sample from the fluidic network. A process sample remaining in a process sample supply line from the process source to the process inlet port may be pushed back to the process source via a gas flow to limit a collected process sample volume.

Description

[0001] Related Applications

[0002] This application claims the benefit of an earlier filing date of U.S. Provisional Patent Application Serial No. 63 / 339,746, filed on May 9, 2022, entitled “Fluidic Network for Positive Displacement Aseptic Sampling,” and claims the benefit of an earlier filing date of U.S. Provisional Patent Application Serial No. 63 / 340,538, filed on May 11, 2022, entitled “Fluidic Network for Positive Displacement 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 using positive displacement pumps. 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 the desired volume. If the tip of the syringe is previously in contact with a biological organic material or another contaminant, the process may introduce the contaminant 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.

[0006] Considerable time and effort is often required to perform routine aseptic sampling to avoid problems associated with the introduction of contaminants into the bioreactor, especially when the sampling process is not fully automated. In addition, filtration and purification are often required before the process sample is provided to the analytical instrument.

[0007] Conventional bioprocess sampling techniques can obtain tens of milliliters of sample from a bioreactor to produce a clarified sample for analysis. In some applications, the sample volume that can be collected can be limited. For example, for small volume bioreactors, such as research-scale bioreactors, milliliters of sample volume account for a significant portion of the bioreactor volume. Therefore, the number of samples that can be collected throughout the bioprocess may be limited, thereby limiting the ability to monitor and regulate the bioprocess. Summary of the invention

[0008] In one aspect, a fluid network for aseptic process sampling includes a sampling valve, a sample processing module, a displacement pump, a selection valve, and a valve control module. The sampling valve can be configured to be in at least a first valve state and a second valve state, and includes a process inlet port for receiving a process sample, a process outlet port for providing a process sample, and a plurality of valve channels. The sample processing module includes a filter element and a sample preparation element that are fluidly connected to each other. The selection valve is arranged between the sampling valve and the sample processing module and in a fluid path that is fluidly connected to the sampling valve and the sample processing module. The selection valve is also fluidly connected to the displacement pump. The selection valve can be configured to be in a first valve state, a second valve state, and a third valve state, in which the sampling valve fluid is connected to the displacement pump, in the second valve state, the displacement pump fluid is connected to the sample processing module, and in the third valve state, the sampling valve fluid is connected to the sample processing module. The valve control module is in communication with the sampling valve and the selection valve, and is configured to control the valve states of the two valves. The process sample path is defined between the process inlet port and the process outlet port, and includes at least one valve channel in the sample processing module and the sampling valve. When the sampling valve is in the first valve state and the selector valve is in the first valve state, the section of the process sample path upstream of the sample processing module receives the process sample by aspiration operation of the positive displacement pump. When the sampling valve is in the first valve state and the selector valve is in the second valve state, at least a portion of the process sample received in the section of the process sample path is pushed through the sample processing module by operation of the positive displacement pump.

[0009] The fluid network may also include an injection valve in fluid communication with the process outlet port of the sampling valve.

[0010] The positive displacement pump may be a syringe pump.

[0011] The selection valve may include a first valve fluidly coupled to the displacement pump and a second valve in fluid communication with the sampling valve, the sample processing module, and the first valve. The second valve can be configured to be in a first valve state, in which the sampling valve is fluidly coupled to the first valve, in a second valve state, in which the first valve is fluidly coupled to the sample processing module, and in a third valve state, in which the sampling valve is fluidly coupled to the sample processing module.

[0012] The sample preparation element can be an affinity purification element, a size exclusion element, or an ion exchange element. The filtration element can be a membrane, a syringe filter, or a glass frit.

[0013] The sampling valve may further include a gas inlet port, wherein when the sampling valve is in the second valve state, the gas inlet port is in fluid communication with the process inlet port through one of the valve channels to direct a gas flow received at the gas inlet port into a fluid path between the process inlet port and a process source. The fluid network may further include a gas valve in fluid communication with the gas inlet port and the gas source, wherein the gas valve is configured to control a gas flow entering the gas inlet port.

[0014] The sampling valve may further include a backwash inlet port, and the fluid network may further include a manifold configured to control the flow of multiple fluids and having a manifold outlet port in fluid communication with the backwash inlet port to provide a flow of a selected one of the fluids. The manifold may include a manifold valve having a first inlet port configured to receive a gas flow, a second inlet port configured to receive a first solvent flow, and a manifold outlet port in fluid communication with the backwash inlet port of the sampling valve, wherein the manifold valve can be configured to be in a first valve state, a second valve state, and a closed valve state, in which the backwash gas flow is directed from the first inlet port to the outlet port, in which the first solvent flow is directed from the second inlet port to the outlet port, and in which the first inlet port and the second inlet port are fluidly disconnected from the outlet port. When the manifold valve is in one of the first valve state and the second valve state, the gas flow or the first solvent flow can flow through the sample processing module in a reverse flow direction, respectively. The manifold valve may have a third inlet port configured to receive a second solvent flow, wherein the manifold valve is configurable to be in a third valve state in which the second solvent flow is directed from the third inlet port to the outlet port. When the sampling valve is in the second valve state and the selector valve is in the third valve state, a fluid path may be formed from the manifold valve through a backwash inlet port of the sampling valve, the sample handling module, the selector valve, and at least one of the valve channels of the process sample path.

[0015] The process source may be a bioreactor.

[0016] The filter element and the sample preparation element may be integrated into a single housing.

[0017] The fluid network may also include a solvent selection valve and a plurality of solvent sources. The solvent selection valve has a network port and a plurality of solvent ports, and is in fluid communication with the displacement pump through the network port. Each of the solvent sources is in fluid communication with a corresponding one of the solvent ports. The solvent selection valve can be configured to be in a plurality of valve states, each valve state coupling one of the solvent sources to the displacement pump through the network port fluid.

[0018] In another aspect, a method for aseptic process sampling includes drawing a process sample from a process source into a process sample path including at least one valve channel of a sampling valve and a sample processing module having a filter element and a sample preparation element. At least a portion of the process sample drawn into the process sample path is pushed in a forward direction through the sample processing module to the injection valve, and a portion of the process sample is pushed back toward the process source.

[0019] The method may also include loading at least a portion of the process sample pushed into the injection valve into the sample loop.

[0020] The sample processing module may be a single housing that houses a filtration element and a sample preparation element. The sample preparation element may include one of an affinity purification element, a size exclusion element, and an ion exchange element.

[0021] The method may also include providing at least one of a solvent flow and a gas flow through the sample processing module in a reverse direction. An elution buffer flow may be provided through the sample preparation element in a forward direction to elute the compound of interest. A regeneration buffer flow may be provided through the sample preparation element. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] 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.

[0023] 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.

[0024] Figure 2 is a schematic diagram of an example of a fluid network configured to collect a process sample from a process source.

[0025] Figure 3 A selector valve having a valve state switched to a second valve state is shown. Figure 2 Fluid network.

[0026] Figure 4 yes Figure 3 An alternative implementation of the fluid network is shown and includes additional valves to enable the provision of selected solvents from multiple solvent sources.

[0027] Figure 5 Shows Figure 3A fluid network in which an injection valve is switched to a valve state for loading a process sample from the fluid network into the sample loop.

[0028] Figure 6 Shown according to Figure 5 A fluid network in which an injection valve switches to different valve states to inject a process sample in a sample loop into a liquid chromatography system flow.

[0029] Figure 7 Shows Figure 6 A fluid network is optionally reconfigured to allow a portion of a process sample in a fluid path extending from a process source to be pushed back toward the process source.

[0030] Figure 8 Shows Figure 7 A fluidic network in which the selector valve switches back to its first valve state to allow the syringe pump to return to its original position.

[0031] Fig. 9 Shows Figure 8 A fluid network wherein the selector valve is switched to its second state and wherein the manifold valve is in its first valve state to provide gas flow through the process sample path.

[0032] Fig.10 Shows Fig. 9 A fluid network in which a manifold valve is switched to its second valve state to provide a first solvent through a process sample path.

[0033] Fig.11 Shows Fig.10 A fluid network in which the manifold valve is switched to its third valve state to provide a second solvent through the process sample path.

[0034] Fig.12 Shows Fig.11 A fluid network in which the sampling valve is switched to its first valve state and the metering pump is switched to its first valve state in preparation for collecting another process sample.

[0035] Fig.13 is used Figures 2 to 12 A flow chart representation of an example of a method for performing aseptic process sampling in a fluid network shown in FIG.

[0036] Fig.14 It is used to prepare Figures 2 to 12 The process sample path of the fluid network shown in FIG. 1 is represented by a flow chart of an example of a method of receiving another process sample. DETAILED DESCRIPTION

[0037] 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.

[0038] 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 a sterile 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, flow to a system for analyzing the process sample. The fluid network also includes a sample processing module having a filter element and a sample preparation element to prepare a process sample for analysis. A volumetric pump operates to draw the process sample into the fluid network and pushes a portion of the collected process sample through the sample processing module before distributing the processed process sample from the fluid network. The sample preparation element can provide significant flow restriction. Advantageously, the position of the injection pump in the fluid network enables the process sample to be pushed through the sample preparation element, but based on flow restriction, the prior art of using an upstream pump or aspirating by a sample manager for sample collection is not practical. After dispensing the process sample from the fluid network, the process sample path within the fluid network is cleaned and dried, and the sampling valve is then reconfigured to a valve state for collecting and processing another process sample. "Process sample path" refers to a fluid path in a fluid network through which a process sample received at a process inlet port flows and then leaves the fluid network at a process outlet port. Therefore, 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. In addition, the process sample retained in the process sample supply line leading from the process source to the process inlet port can be pushed back to the process source via a gas flow. This return of the process sample to the process source further limits the total volume of the process sample extracted from the process source, and enables the separation between the process source and the fluid network to be increased for convenience.

[0039] As part of the cleaning process, valve channels and other components (such as sample processing modules) in the process sample path are dried and backwashed. One or more solvents and one or more gases can be used, and the order and duration of the solvent and gas streams can be varied. Advantageously, the ability to extract small volume process samples (e.g., a few hundred microliters or less) prevents significant product losses produced by the bioprocess during process monitoring. This ability to collect small volume process samples makes the fluid network particularly suitable for small volume bioreactors. In addition, the service life of the components in the sample processing module is increased, and maintenance time and cost are correspondingly reduced.

[0040] 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.

[0041] 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.

[0042] Figure 1A and Figure 1B1 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 eight 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 eight stator ports on a stator surface 14 via an internal fluid channel, and the stator surface is adjacent to a 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 transmitted between the stator ports on the external port 12 and the stator surface 14. A pipeline can be connected to the external port 12 using a compression fitting to allow a fluid stream 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 deliver or receive process sample streams to or from other components of the fluid network (e.g., filters, sample separation devices, or both) and external systems, such as process sampler modules of an analytical system (e.g., a liquid chromatography system). The external ports 12 through which the process sample streams pass are determined by the internal valve channel configuration established by the valve state of the valve.

[0043] Figure 2 A to Fig.12 is a schematic diagram of an example of a fluid network that can be used for aseptic sampling. The fluid network includes a plurality of valves, and the different diagrams show the valves configured in corresponding valve states to achieve the desired function of aseptic process sampling. For example, the fluid network can be used to sample an ongoing bioprocess in a bioreactor. See also Fig.13 , which is a flow chart representation of an example of a method 100 for sampling a sterile process that can be practiced using a fluid network. Sampling can be performed in a repeated manner over a period of time to enable monitoring of the process from initiation to completion.

[0044] The fluid network includes a sampling valve 20, a sample processing module 22, a volumetric pump 24, a selection valve 26 and a valve control module (not shown). In the illustrated example, 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 be arranged to provide other valves of similar functionality. The stator includes a plurality of stator ports 28-1 to 28-8 (collectively 28) on the stator surface. The stator channel passing through the stator body couples the external valve port fluid to the corresponding stator port 28. The pipeline can be connected to the external port, for example, using a compression fitting, so that the fluid flow flows into the corresponding stator channel and stator port 28 or flows out from the corresponding stator channel and stator port. The rotor includes a plurality of valve channels 30-1 to 30-4 (collectively 30). As shown in the figure, the valve channel 30 is a curved microchannel formed as a groove on the rotor surface. Each valve passage 30 provides a flow path that can be used to fluidically couple two of the stator ports 28 depending on the configuration of the valve 20 in one of the valve states.

[0045] The sampling valve 20 can be rotated 90° clockwise relative to the stator by the rotor, Figure 2 The first valve state shown is rotated to Figure 7 The second valve state shown switches between valve states. 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.

[0046] The sample processing module 22 includes a filter element that is fluidly connected in series with the sample preparation element. When in use, the process sample first flows through the filter element, which removes large particles and cell agglomerates from the flow to produce a clarified process sample. As a non-limiting example, the filter element can be one or more of a membrane, a syringe filter, a glass material or similar components. The clarified sample can include components in expressed proteins, dead cells, cytoplasm and other solutions. The sample preparation element receives the clarified process sample from the filter element and separates one or more desired target compounds for subsequent processing or analysis. As a non-limiting example, the sample preparation element can be a size exclusion column, an ion exchange column or an affinity purification column. For example, the desired target compound can be a therapeutic protein of interest, such as an antibody. The sample preparation element in the form of an affinity purification column can include a ligand with high affinity for the antibody. When the clarified process sample flows through the column (at a neutral pH), the antibody is retained, while the remaining flow passes through the column and is directed to waste. Subsequently, an elution buffer can be provided by the column to release and flow the antibody from the element. For example, the elution buffer can have a low pH or other characteristics that are conducive to antibody elution. The elution buffer may flow through the column in the forward direction. Antibodies released from the column may be provided to an analytical instrument, such as a liquid chromatography system, for analysis.

[0047] In a preferred implementation, sample processing module 22 is configured to hold the housing of both filter element and sample preparation element. In one example, module 22 can be a disposable cartridge. In some embodiments, module 22 can be regenerated between uses and can be used multiple times before needing to be changed. As described in more detail below, the ability of the reverse solvent flow provided by module 22 enables multiple use before needing to be changed.

[0048] The volumetric pump 24 is connected to the fluid network through a metering valve 32. The metering valve 32 can be a rotary shear seal valve, a linear shear seal valve, or other types of valves suitable for switching between valve states to achieve the desired fluid transfer. In preferred examples (including the examples described herein), the volumetric pump 24 is a syringe pump, although different forms of volumetric pumps can be used in other specific implementations. In all figures, the metering valve 32 is shown as being configured to be in a first valve state, in which the syringe pump 24 fluid is connected to the selection valve 26; however, the metering valve 32 can be configured to be in a second valve state, in which the syringe pump 24 is effectively disconnected from the rest of the fluid network and is instead connected to a waste channel or a channel that can be used to draw solvent from a solvent source (not shown), as described below with respect to Figure 4 In the alternative example of the fluid network shown, the selector valve 26 and the metering valve 32 can be implemented in a single valve that performs the fluid path reconfiguration achieved by the combination of the two valves 26 and 32.

[0049] The selector valve 26 includes three ports and can be operated in at least three valve states. In the first valve state, Figure 2 As shown, the selector valve 26 fluidly couples the stator port 28-2 of the sampling valve 20 to the syringe pump 24 via the metering valve 32. In the second valve state, as shown in FIG. Figure 3 As shown, the selector valve 26 couples the syringe pump 24 fluid to the sample processing module 22 via the metering valve 32. In the third valve state, as shown in FIG. Figure 7 As shown, selector valve 26 fluidly couples stator port 28 - 2 to sample processing module 22 .

[0050] The valve control module is communicated with the sampling valve 20 and the selection valve 26, and these valves can be configured to be in their different valve states. In some embodiments, the valve control module is used to control the additional valves in the fluid network. For example, the fluid network shown also includes a gas valve 38 that is fluidly communicated with the sampling valve 20 through the gas inlet port 28-4. The gas valve 38 can be controlled by the valve module. By way of example, the valve control module can be implemented using an independent processor or as a part of a system processor. The valve control module can be connected to the system controller and can be programmed via a user interface, which also enables the 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).

[0051] In some specific implementations, the fluid network also includes a manifold for supplying and controlling multiple fluid streams. In the illustrated example, the manifold includes a manifold valve 40 having a first inlet port 42-1 for receiving a gas stream from a gas source, a second inlet port 42-2 for receiving a first solvent stream, and a third inlet port 42-3 for receiving a second solvent stream. For example, the inlet ports 42-1 to 42-3 can be configured to be connected to external ports of gas and solvent sources using compression fittings and pipes. The manifold valve 40 has a manifold outlet port 42-4 to provide one of a gas stream or a solvent stream. The manifold outlet port 42-4 is fluidically connected to the backwash inlet port (stator port 28-5) on the sampling valve 20. The manifold outlet port 42-4 can be connected to the sampling valve 20 with compression fittings and pipes to provide a gas stream or a solvent stream. As a non-limiting example, the manifold valve 40 can be a solenoid valve, a rotary shear seal valve, or a linear shear seal valve. In a non-limiting alternative example, the manifold may be implemented as a passive fluid tee coupled to fluid source lines that each have a separate flow control device and / or pressure regulator.

[0052] In the following description, reference is made to a series of drawings that show valves in different valve states to enable aseptic process sampling according to one example. Although described in a specific order, it should be appreciated that some steps in the order may be reordered or omitted according to other examples.

[0053] See again Figure 2 , which shows a fluid network configured to collect a process sample from a process source, and see Fig.131 and 2. An example of a method 100 for aseptic process sampling is depicted in FIG. Sampling valve 20, selector valve 26, and metering valve 32 are each operated in their first valve states such that a continuous fluid path is defined from a process source to syringe pump 24. Syringe pump 24 is operated to draw (aspirate) (step 110) fluid such that a process sample from the process source is drawn through valve channel 30-1 and through selector valve 26 toward metering valve 32 such that the process sample is received in a section of the process sample path upstream of sample processing module 22. The operation of syringe pump 24 can be controlled such that a known volume of the process sample is collected.

[0054] See also Figure 3 , the selector valve 26 is switched to its second valve state so that the syringe pump 24 is in fluid communication with the sample processing module 22. The syringe pump 24 is operated to push (step 120) at least a portion of the process sample received in the section of the process sample path in the forward direction through the sample processing module 22. That is, the pushed process sample flows from the selector valve 26 through the module 22 to the stator port 28-8. However, the reverse flow of gas and solvent (i.e., from right to left in the figure through the sample processing module 22, as further described below) is used to remove the particulate matter and cell agglomerates captured by the filter element or residing in the sample preparation element to waste. The additional flow including the regeneration buffer can be used to regenerate the sample preparation element so that the module 22 is ready for subsequent process samples. Therefore, the process sample received at the sampling valve 20 at the module 22 and the stator port 28-8 is clarified and prepared by the filter and the sample preparation element, respectively.

[0055] In various embodiments, a solvent is supplied to the sample preparation element to provide a process sample in the form of one or more target compounds eluted from the sample preparation element. As shown, the solvent supplied by the syringe pump 24 can be used to elute the target compounds retained by the sample preparation element. In an alternative embodiment, the fluid network can be as follows Figure 4 The modified configuration includes an additional valve (solvent selection valve 44) that enables a positive displacement pump (syringe pump 24) to draw solvent from a solvent source (not shown) fluidically connected through one of fluid lines 46-1 to 46-6 (collectively referred to as 46) to valve 44. The drawn solvent can be discharged toward metering valve 32 through network port 48.

[0056] The solvent selection valve 44 shown can accommodate up to six solvent sources; however, the number of solvent sources can be less, for example, if one or more of the fluid lines 46 is a waste channel. One advantage of the solvent selection valve 44 is the ability to select a solvent with a desired elution characteristic for a specific process sampling application. For example, a solvent can be selected based on the characteristics of the sample preparation element and the target compound. It should be understood that solvent selection valves with different configurations (e.g., different numbers of ports and fluid lines 46) can be used.

[0057] See again Figure 3 , the process sample flows from the process outlet port (stator port 28-7) to the injection valve 34 of the liquid chromatography system. Figure 4 The injection valve 34 is shown switched to a valve state to enable a process sample to be loaded (step 130) into the sample loop 36 to await injection into the mobile phase of the liquid chromatography system. Figure 5 Injection valve 34 is shown being switched to different valve states to inject (step 140) a process sample in sample loop 36 into the liquid chromatography system flow.

[0058] Fluid Networks Figure 7 , optionally configured to allow a process sample in a fluid path from a process source to a process inlet port (stator port 28-1) of sampling valve 20 to be pushed back toward the process source (step 150) and into the process source. The network is similar to Figure 6 Configuration. The gas valve 38 controls the flow of gas from the gas source to the stator port 28-4, where the gas flow continues through the valve channel 30-2 and flows out through the stator port 28-1 toward the process source. As a non-limiting example, the gas can be nitrogen, another non-reactive gas, or oxygen. Therefore, any process sample in the fluid path extending from the stator port 28-1 back to the process source through the corresponding stator channel, the corresponding external port 12 and the fluid path (process pipe) can be partially or completely emptied back into the process source. This backwashing of gas into the process pipe reduces the total volume of the process sample removed from the process source. Therefore, for the bioreactor process source, this gas backwashing retains more of the end products of the bioreaction and / or enables more frequent sample collection to better monitor and control the bioreaction.

[0059] The fluidic network is now ready for subsequent process sample collection. See also Fig.14 , which depicts an example of a method 200 for preparing a process sample path of a fluid network to receive a next process sample.

[0060] exist Figure 8, the selector valve 26 is shown switched back to its first valve state. This configuration allows the liquid in the fluid passage between the syringe pump 24 and the stator port 28-2 to be pushed through the valve passage 30-1 and the stator port 28-3 to the waste until the syringe pump 24 returns (step 210) to its original position. Subsequently, the selector valve 26 is switched to the second valve state, as shown in FIG. Fig. 9 As shown. This establishes a continuous fluid path including the process sample path. More specifically, the continuous fluid path extends from the manifold valve 40 through the valve channel 30-4, the sample processing module 22 and the valve channel 30-1 to the waste. The manifold valve 40 is in its first valve state so that the gas flow at the first inlet port 42-1 flows in the opposite direction through the process sample path. The gas flow is used to dry (step 220) the process sample path, including the valve channels 30-1 and 30-4 and the sample processing module 22. As a non-limiting example, the gas can be nitrogen or another non-reactive gas or can be oxygen. Next, the manifold valve 40 is switched to its second valve state, as Fig.10 , where a strong wash solvent flows in the opposite direction through (step 230) the process sample path to the waste. As used herein, a strong solvent means a solvent that is generally capable of dissolving and removing any material remaining in the sample flow path. Strong solvents may damage the process sample. Examples of strong solvents that may 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. The manifold valve is switched back to its first state ( Fig. 9 ) to dry (step 240) the process sample path and then switch to its third valve state, such as Fig.11 , where the weak solvent flows in the opposite direction through (step 250) the process sample path to waste. The weak solvent can remove any remaining strong solvent in the process sample path that could otherwise pose a risk to the next process sample collection. For example, the weak solvent can be a phosphate buffered saline (PBS) solution, a cell culture medium, or another liquid in which cellular material can remain suspended and easily transported in the liquid stream. The manifold valve 40 is again switched back to its first state ( Fig. 9 ) to perform final drying of the process sample path (step 260). Fig.12 The fluid network is then prepared for the next sample collection by switching the sampling valve 20 to its first valve state and switching the metering pump 26 to its first valve state.

[0061] The duration of the gas and solvent passing through the process sample path can be controlled and can be different from each other. In addition, the gas and solvent flow rates can be different. In an alternative example of preparing the sample path to receive the next process sample, the order of the gas flow and solvent flow can be different. For example, step 240 can be omitted so that a weaker solvent can be used to displace a stronger solvent from the process sample path without any intervening gas flow.

[0062] Although various examples have been shown and described, the description is intended to be illustrative rather than restrictive, and it will be understood by those skilled in the art that various changes may be made in form and detail without departing from the scope of the invention as described in the appended claims. For example, although the sampling valve 20 shown in the drawings and described above includes a stator port 28-4 and a valve channel 30-2, these features may be omitted in a sampling valve for a fluid network that does not push a process sample extracted from a process source back to the process source while still providing other features associated with the fluid network. In another example, the process sample path described above includes two valve channels and a sample preparation module. It should be appreciated that in other embodiments, the number of valve channels defining the process sample path may be different, and additional or alternative components may be present in portions of the process sample path that exist outside the sampling valve.

Claims

1. A fluid network for sampling in a sterile process, the fluid network include: a sampling valve configurable in at least a first valve state and a second valve state and comprising a process inlet port for receiving a process sample, a process outlet port for providing the process sample, and a plurality of valve channels, a sample processing module comprising a filter element and a sample preparation element in fluid communication with each other; Positive displacement pumps; a selector valve disposed in a fluid path between and in fluid communication with the sampling valve and the sample processing module, the selector valve further in fluid communication with the displacement pump, the selector valve being configurable to be in a first valve state in which the sampling valve is fluidly coupled to the displacement pump, a second valve state in which the displacement pump is fluidly coupled to the sample processing module, and a third valve state in which the sampling valve is fluidly coupled to the sample processing module; as well as a valve control module, the valve control module being in communication with the sampling valve and the selection valve and being configured to control valve states of the sampling valve and the selection valve, wherein a process sample path is defined between the process inlet port and the process outlet port and includes the sample processing module and at least one valve channel of the sampling valve, wherein a section of the process sample path upstream of the sample processing module receives the process sample by a suction operation of the volumetric pump when the sampling valve is in the first valve state and the selection valve is in the first valve state, and wherein at least a portion of the process sample received in the section of the process sample path is pushed through the sample processing module by operation of the volumetric pump when the sampling valve is in the first valve state and the selection valve is in the second valve state.

2. The fluid network of claim 1, further comprising an injection valve in fluid communication with the process outlet port of the sampling valve.

3. The fluid network of claim 1, wherein the positive displacement pump is a syringe pump.

4. A fluid network according to claim 1, wherein the selection valve includes a first valve fluidly connected to the volumetric pump and a second valve fluidly connected to the sampling valve, the sample processing module and the first valve, the second valve being configurable to be in a first valve state, a second valve state and a third valve state, in which the sampling valve is fluidly connected to the first valve, in the second valve state, the first valve is fluidly connected to the sample processing module, and in the third valve state, the sampling valve is fluidly connected to the sample processing module.

5. The fluid network of claim 1, wherein the sample preparation element is one of an affinity purification element, a size exclusion element, and an ion exchange element.

6. The fluid network of claim 1, wherein the filter element comprises one of a membrane, a syringe filter, and a frit.

7. The fluid network of claim 1, wherein the sampling valve further comprises a gas inlet port, and in, When the sampling valve is in the second valve state, the gas inlet port is in fluid communication with the process inlet port through one of the valve channels to direct a gas flow received at the gas inlet port into a fluid path between the process inlet port and a process source.

8. The fluid network of claim 7, further comprising a gas valve in fluid communication with the gas inlet port and a gas source, the gas valve being configured to control a flow of gas into the gas inlet port.

9. The fluid network of claim 1 , wherein the sampling valve further comprises a backwash inlet port, the fluid network further comprising a manifold configured to control the flow of a plurality of fluids, the manifold having a manifold outlet port in fluid communication with the backwash inlet port to provide a flow of a selected one of the fluids.

10. The fluid network of claim 9, wherein the manifold comprises 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 a manifold outlet port is in fluid communication with the backwash inlet port of the sampling valve, the manifold valve being configurable to be in a first valve state, in which the backwash gas flow is directed from the first inlet port to the outlet port, a second valve state, and a closed valve state, in which the first valve state the backwash gas flow is directed from the first inlet port to the outlet port, in which the first solvent flow is directed from the second inlet port to the outlet port, and in which the first inlet port and the second inlet port are fluidly disconnected from the outlet port.

11. A fluid network according to claim 10, wherein the manifold valve has a third inlet port configured to receive a second solvent flow, and the manifold valve is configurable to be in a third valve state, in which the second solvent flow is directed from the third inlet port to the outlet port.

12. The fluid network of claim 10 , wherein when the sampling valve is in the second valve state and the selector valve is in the third valve state, a fluid path is formed from the manifold valve through the backwash inlet port of the sampling valve, the sample handling module, the selector valve, and at least one of the valve channels of the process sample path.

13. The fluid network according to claim 12, in, When the manifold valve is in one of the first valve state and the second valve state, the gas flow or the first solvent flow, respectively, flows through the sample processing module in a reverse flow direction.

14. The fluid network of claim 1, wherein the filter element and the sample preparation element are integrated into a single housing.

15. The fluid network according to claim 1, wherein the fluid network further comprises: include: a solvent selection valve having a network port and a plurality of solvent ports and in fluid communication with the positive displacement pump through the network port; and a plurality of solvent sources, each solvent source being in fluid communication with a respective one of the solvent ports, Wherein the solvent selection valve is configurable to be in a plurality of valve states, each valve state fluidly coupling one of the solvent sources to the positive displacement pump via the network port.

16. A method for sampling in a sterile process, the method include: drawing a process sample from a process source into a process sample path including at least one valve channel of a sampling valve and a sample processing module having a filter element and a sample preparation element; pushing at least a portion of the process sample drawn into the process sample path in a forward direction through the sample processing module to an injection valve; as well as A portion of the process sample is pushed back toward the process source.

17. The method of claim 16, further comprising loading at least a portion of the process sample pushed to the injection valve into a sample loop.

18. The method of claim 16, wherein the sample processing module is a single housing that houses the filtration element and the sample preparation element.

19. The method of claim 16, wherein the sample preparation element comprises one of an affinity purification element, a size exclusion element, and an ion exchange element.

20. The method of claim 16, further comprising providing at least one of a solvent flow and a gas flow through the sample processing module in opposite directions.

21. The method of claim 20, further comprising providing a flow of elution buffer through the sample preparation element in a forward direction, thereby eluting the compound of interest.

22. The method of claim 21, further comprising providing a flow of a regeneration buffer through the sample preparation element.

23. The method of claim 16, wherein the process source is a bioreactor.

Images