Apparatus, System, and Method for Automated Aseptic Sampling

Abstract

To provide a method for sampling a liquid material with a sampling system.SOLUTION: A method according to the present invention includes: providing a sampling system having a gas / liquid separator; and selectively operating a pressure regulation system in the first mode that establishes a first gas pressure condition in a permeate portion of the separation chamber configured to draw a sample of the liquid material from a reservoir through a first flow channel to the retentate portion of the separation chamber and the second mode that establishes a second gas pressure condition in the permeate portion of the separation chamber to push the sample from the retentate portion of the separation chamber through the first flow channel.SELECTED DRAWING: Figure 1A

Description

Background Art

[0001] In the life sciences, cell culture is a common technique. To monitor the growth or characteristics of biological substances, samples are withdrawn from a culture (also referred to as a “bioreactor” and / or “reservoir”) and sent to an analyzer to test or measure the characteristics of the samples. Various systems for delivering a biological sample from a bioreactor to an analyzer are known. Generally, these systems include a flow path, i.e., a tube configured to transport fluids and / or gases, and a pump configured to urge the sample from the bioreactor to the analyzer. To reduce cross-contamination or carry-over from different samples, it is necessary to draw the sample aseptically and clean the flow path. In some cases, the analysis of the sample may require dispensing a precise amount of the sample from the bioreactor.

Summary of the Invention

[0002] According to some embodiments of the present disclosure, a method for sampling a liquid-like material using a sampling system includes providing a sampling system having a gas-liquid separator. The gas-liquid separator includes a separation chamber having a membrane that separates the separation chamber into a retained liquid portion and a permeate liquid portion. The membrane can be gas permeable and liquid impermeable. The gas-liquid separator includes a pressure adjustment system fluidly connected to the permeate liquid portion of the separation chamber. The pressure adjustment system is configured to control the gas pressure in the permeate liquid portion. The method includes selectively operating the pressure adjustment system in a first mode and a second mode. The first mode establishes a first gas pressure condition configured to draw a sample of the liquid-like material from the reservoir through a first flow channel into the retained liquid portion of the separation chamber in the permeate liquid portion of the separation chamber. The second mode establishes a second gas pressure condition for pushing the sample from the retained liquid portion of the separation chamber through the first flow channel towards the reservoir in the permeate liquid portion of the separation chamber.

[0003] According to some embodiments of the present disclosure, a method of sampling a liquid material includes providing a sampling system having a gas-liquid separator. The gas-liquid separator includes a separation chamber having a retained liquid portion separated by a membrane and a permeate port. The membrane is gas permeable and impermeable to the liquid material. The gas-liquid separator includes a pressure adjustment system configured to control the gas pressure in the permeate portion. The method includes providing a first flow channel. The first flow channel fluidly connects the separation chamber to a reservoir containing the liquid material. The method includes operating the pressure adjustment system to apply a negative gas pressure to the permeate portion. The negative gas pressure is effective to draw a sample of the liquid material from the reservoir to the retained liquid portion of the separation chamber. The negative gas pressure in the permeate portion is effective to remove gas from the sample through the membrane.

[0004] According to some embodiments of the present disclosure, a sampling system includes a reservoir containing a liquid material. The sampling system includes a gas-liquid separator having a separation chamber and a pressure adjustment system. The separation chamber includes a retained liquid portion, a permeate portion, and a membrane separating the retained liquid portion and the permeate portion. The membrane is gas permeable and liquid impermeable. The pressure adjustment system is configured to control the gas pressure in the permeate portion. The sampling system includes a first flow channel fluidly connecting the reservoir to the retained liquid portion of the gas-liquid separator. The sampling system includes a multi-port selection valve and a positive displacement pump. A second flow channel fluidly connects the positive displacement pump to the multi-port selection valve. The multi-port selection valve is selectively adjustable among a plurality of positions, and a first position fluidly connects the first flow channel to the second flow channel. The pressure adjustment system is configured to selectively provide a negative pressure to the permeate portion. The negative pressure in the permeate portion is effective to draw a sample of the liquid material from the reservoir to the retained liquid portion of the separation chamber. The pressure adjustment system is configured to selectively provide a positive pressure to the permeate portion. The positive pressure in the permeate portion is effective to push a sample of the liquid material from the retained liquid portion of the separation chamber to the reservoir.

[0005] According to some embodiments, a sampling system includes a sample probe configured to receive a liquid material. The sampling system includes a gas-liquid separator having a separation chamber and a vacuum source fluidly connected to the separation chamber. The sampling system includes a flow path that can fluidly connect the sample probe to the gas-liquid separator. A pressurized air source can be connected to the flow path. The gas-liquid separator is operable under a first condition that creates a negative pressure condition in the flow path to urge the liquid material in a first direction along the flow path.

[0006] According to some embodiments, a method of sampling a liquid material from a reservoir using a sampling system includes providing the sampling system. The sampling system includes a flow path, a gas-liquid separator, a multi-port selection valve having a plurality of ports, and a pressurized air source. The gas-liquid separator is fluidly connected to the flow path to create a negative pressure condition in the flow path. The negative pressure condition urges the liquid material to move in a first direction along the flow path. The pressurized air source is fluidly connected to the flow path to create a positive pressure condition in the flow path. The positive pressure condition urges the liquid material to move in a first direction along the flow path.

[0007] This written disclosure describes exemplary embodiments that are non-limiting and non-exhaustive. Reference is made to the exemplary embodiments shown in the drawings.

Brief Description of the Drawings

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MODE FOR CARRYING OUT THE INVENTION

[0009] The devices, systems, and methods disclosed herein are directed to a sampling system configured to accurately control the amount of sample sent to an analyzer and to minimize sample loss. The system is an aseptic sampling system, i.e., the sample is delivered to the analyzer through a sterilization process, i.e., without contamination or cross - contamination. The aseptic sampling system may include a gas - liquid separator configured to remove gas from a liquid sample material. The gas - liquid separator may include a separation chamber having a gas - permeable and liquid - impermeable membrane. The membrane may divide the separation chamber into a permeate portion and a retentate portion. The separation chamber may be fluidly connected to a pressure - regulating system configured to control the gas pressure of the permeate portion. The pressure - regulating system may be pneumatically connected to the retentate portion of the separation chamber, i.e., the pressure changes caused by the pressure - regulating system may penetrate into the retentate portion through the membrane. The pressure - regulating system may be configured to draw liquid material in a direction towards the separation chamber through a flow path (i.e., channels and / or piping for guiding the flow of fluid) and / or to push liquid material through the flow path (in a direction away from the separation chamber). Pushing and / or pulling the liquid sample material through the gas - liquid separator is beneficial because it enables the sample to be prepared in a first step without the need to connect the flow path to a pump. Since the liquid material can be pushed out of the flow path and back into a reservoir, the gas - liquid separator also enables rapid cleaning or flushing of the flow path and can minimize sample loss.

[0010] The aseptic sampling system can be automated, i.e., a control unit and / or a processor can be configured to control various functions of the system regardless of the presence or absence of simultaneous user input. For example, a set of instructions may be stored in the control unit, and the control unit may output those instructions to the aseptic sampling system (e.g., valve actuation, pump movement, gas pressure control, etc.). In some embodiments, the aseptic sampling system may include a user interface for a user to control functions and / or issue instructions to the aseptic sampling system.

[0011] Figure 1A is a schematic view of a sterile sampling system 100 according to some embodiments. The sterile sampling system 100 includes a pump 102, a multi-port selection valve 106, a gas-liquid separator 110, and a probe 124. The probe 124 can be configured to extend into a reservoir 130 (e.g., a bioreactor, cell culture, or tank) to extract a liquid material 152 (i.e., a sample). The probe 124 can be fluidly connected to the gas-liquid separator 110 through a first flow path 126. In some embodiments, the first flow path 126 is an elongated tube or line. The first flow path 126 can be fixed to the gas-liquid separator 110 at a first port 122. The gas-liquid separator 110 includes a gas-liquid separation module 111 and a pressure adjustment system 160.

[0012] As described hereinafter in this specification, the gas-liquid separator 110 may include any of the features or elements described in U.S. Patent No. 9,381,449, entitled "Carbon Nanotube Composite Membrane," filed June 6, 2013; U.S. Patent No. 9,370,734, entitled "Fluid Degassing Module with Helical Membrane," filed June 13, 2014; U.S. Patent No. 9,656,186, entitled "Fluid Degassing Apparatus," filed May 29, 2015; U.S. Patent No. 9,962,661, entitled "Composite Membrane," filed June 30, 2016; U.S. Patent No. 10,143,942, entitled "Membrane Gas / Liquid Contactor," filed August 29, 2016; and U.S. Patent No. 10,953,348, entitled "Membrane Gas / Liquid Contactor," filed November 30, 2018, which are commonly owned, and the entire contents of which are incorporated herein by reference.

[0013] The gas-liquid separator 110 includes a gas-liquid separation module 111 (further shown in FIG. 3) having a separation chamber and a membrane 350. The membrane 350 can be gas permeable (i.e., allowing gas and air pressure to permeate through the membrane) and can be liquid impermeable. The membrane can divide the separation chamber into a holding liquid portion (also called the retained liquid side) and a permeate liquid portion (also called the permeate side). The holding liquid portion may be directly fluidly connected to the first flow path 126, for example, without passing through the membrane 350. Thus, the holding liquid portion can be configured to receive the liquid material 152 therein. The permeate liquid portion can be directly fluidly connected to the pressure adjustment system 160 of the gas-liquid separator 110 without passing through the membrane 350 in some embodiments. The pressure adjustment system 160 can include a pressurized air source 114, a vacuum source 116, and a pressure adjustment control valve 112. In some embodiments, the pressure adjustment system 160 can operate between a first mode that establishes a first gas pressure condition in the permeate liquid portion of the separation chamber and a second mode that establishes a second gas pressure condition.

[0014] The first mode may include fluidly connecting a vacuum source 116 to the gas-liquid separation module 111 via a pressure regulating control valve 112 and operating the vacuum source 116 to create a low pressure condition (also referred to as a first gas pressure condition and / or a negative gas pressure) in the permeate portion of the separation chamber. The low pressure condition in the permeate portion may create a low pressure condition in the retained liquid portion of the gas-liquid separation module 111. The establishment of the low pressure condition in the retained liquid portion of the gas-liquid separation module 111 is facilitated by a gas environment such as air in the retained liquid portion, and this gas environment may be exhausted through the membrane 350 to leave the low pressure condition. The low pressure condition may provide a suction force to the first flow path 126 and the probe 124. Thus, the liquid material 152 may be drawn from the reservoir 130 and / or the probe 124 to the gas-liquid separation module 111 via the low pressure condition of the pressure regulating system 160. In other words, the pressure regulating system 160 may be in pneumatic communication with the first flow path 126 through the gas-liquid separation module 111 and the membrane 350 of the gas-liquid separator 110. The first mode may be configured to degas the liquid material 152, i.e., to remove gas or bubbles through the gas permeable membrane 350 from the liquid material 152 in the retained liquid portion of the gas-liquid separation module 111. The gas and / or bubbles permeate through the membrane 350 into the permeate portion of the separation chamber. For example, in some embodiments, if the first flow path 126 is filled with a liquid material, the retained liquid portion of the gas-liquid separation module 111 may be filled earlier in time and prevent the liquid material from being drawn from the reservoir 130, so the first flow path 126 may be purged prior to the first mode by filling the first flow path 126 with gas or air.

[0015] The second mode may include fluidly connecting a pressurized air source 114 to the gas-liquid separation module 111 via a pressure regulating control valve 112 and operating the pressurized air source 114 to create a high-pressure condition (also referred to as a second gas pressure condition and / or a positive gas pressure) in the permeate portion of the separation chamber. The high-pressure condition in the permeate portion may permeate through the membrane 350 to create a high-pressure condition in the retained liquid portion of the gas-liquid separation module 111. The high-pressure condition permeating through the membrane 350 may provide a pushing force to the retained liquid portion of the gas-liquid separation module 111 and the first flow path 126. Thus, any liquid material 152 or gas disposed between the retained liquid portion of the gas-liquid separation module 111 and the probe 124 may be pushed out from the first flow path 126, in some embodiments, towards and / or into the reservoir 130. In some embodiments, the liquid material 152 pushed out from the first flow path 126 towards the reservoir may prevent the accumulation of solids in the probe 124 and / or the first flow path 126. For example, in some embodiments, the probe 124 may include a cell-free sampling filter with a microporous membrane, and in some cases, placing the probe 124 in the reservoir 130 may lead to the accumulation of solid materials (e.g., cells, cell debris, and / or other solids) in the filter, which may clog the filter pores. Pushing the liquid material 152 out and back from the probe 124 may remove the solid material from the filter in the form of a "backflush", thereby preventing the accumulation of solids.

[0016] Another advantage of the second mode is to provide a motive pressure source free of particles or microorganisms. Conventional sources of pressurized gas / air for fluid motive in a fluid sampling system are often filtered in an attempt to achieve a sterile environment. However, the best filters typically have a pore size in the range of 0.2 - 5 μm large enough to allow undesirable specific microorganisms and other particles to pass through. The separation membrane of the present invention can be non-porous to prevent the passage of particles and microorganisms. Thus, in the case of the second mode of the pressure regulation system, a completely pure gas can be utilized as the motive force for the flow of fluid through the fluid path of the sterile sampling system 100.

[0017] The gas-liquid separator 110 can be fluidly connected to the multi-port selection valve 106. The degassed liquid material 152 can escape through the second port 118 into the holding liquid portion of the gas-liquid separation module 111. The intermediate flow path 127 can fluidly connect the gas-liquid separator 110 to the multi-port selection valve 106. In some embodiments, the intermediate flow path 127 can include a flow path valve 108 (i.e., a pinch valve) configured to selectively open and close the intermediate flow path 127. The flow path valve 108 can be configured to grip the liquid material 152 in a prepared position in the intermediate flow path 127. In some embodiments, the flow path valve 108 can operate to open only when the sample port 132 is fluidly connected to the pump 102 during pump suction and otherwise to close. In some embodiments, the flow path valve 108 is aseptically shielded. The second flow path 128 positioned between the multi-port selection valve 106 and the pump 102 can be sterilizable by a cleaning agent or other sterilization treatment through the port 138 and thus be "sterile" or substantially free of biological contaminants.

[0018] The multi-port selection valve 106 can be fluidly connected to the pump 102. The pump 102 can include a positive displacement pump, a piston pump, a syringe pump, a peristaltic pump, or any other useful sampling pump. In some embodiments, the pump 102 can be a positive displacement pump to ensure that an accurate sampling volume is sampled from the reservoir. The pump 102 can be fluidly connected to the multi-port selection valve 106 via a second flow path 128. In some embodiments, the second flow path 128 can include a fluid sensor 104 (e.g., a bubble sensor) configured to detect fluid or gas passing through the second flow path 128. The fluid sensor 104 can be configured to detect the presence and / or absence of air bubbles in the liquid material 152. The pump 102 can be configured to suction (i.e., draw air or fluid towards the pump) and discharge (i.e., push air or fluid from the pump).

[0019] The multi-port selection valve 106 can include a plurality of ports including, but not limited to, a sample port 132, a waste port 134, an analyzer port 136, a cleaning agent port 138, a working fluid port 140, and / or an air port 142. The multi-port selection valve 106 can selectively fluidly connect the pump 102 to a plurality of ports (e.g., 132, 134, 136, 138, 140, 142, etc.). For example, FIG. 1A shows a multi-port selection valve 106 that fluidly connects the sample port 132 to the pump 102. The sample port 132 is fluidly connected to an intermediate flow path 127, whereby the sample port 132 fluidly connects the gas-liquid separator 110, the first flow path 126, and the probe 124 to the pump 102. In other words, a sample of the liquid material 152 can be drawn from the reservoir 130 through the sample port 132 to the pump 102.

[0020] Pump 102 can be configured to draw gas or liquid into the second flow path 128 through the first port of the multi-port selection valve 106 and discharge the gas or liquid through the second port. For example, pump 102 can be fluidly connected to sample port 132, and liquid material 152 can be drawn into the second flow path 128. The multi-port selection valve 106 can be actuated to fluidly connect pump 102 to analyzer port 136. Then, pump 102 can discharge liquid material 152 to a downstream analyzer through analyzer port 136. In some embodiments, the multi-port selection valve 106 can be configured to allow the system 100 to dilute, catalyze, or otherwise modify the extracted liquid material 152. For example, pump 102 can be fluidly connected to sample port 132, and thus liquid material 152 can be drawn into the second flow path 128 by pump 102. The multi-port selection valve 106 can be actuated to fluidly connect pump 102 to working fluid port 140, and pump 102 can further draw a working fluid (e.g., a catalyst, an enzyme, a buffer, a calibrant, or other active agent) into the second flow path 128. In some embodiments, the multi-port selection valve 106 can include ports that can be fluidly connected to a downstream analyzer (e.g., a HaLCon™ protein analyzer). In some embodiments, the multi-port selection valve 106 can include ports that can be fluidly connected to a transport container (e.g., a test tube) for analyzing a sample with an unconnected analyzer.

[0021] The plurality of ports shown in FIG. 1A are exemplary embodiments. Various ports can be included in the multi-port selection valve 106 and selectively connected to pump 102. For example, various cleaning agents, various working fluids, various analyzers, additives, calibrants, buffers, and / or outlet ports can be selectively connected to pump 102 via the multi-port selection valve 106.

[0022] In some embodiments, the aseptic sampling system 100 may include a pump 102, a fluid sensor 104, a multi-port selection valve 106, a flow path valve 108, and / or a control system 150 (see FIG. 1B) communicatively connected to a pressure regulation system 160 (including a pressurized air source 114, a vacuum source 116, and a pressure regulation control valve 112). The control system 150 may be configured to control and / or receive data from the components described above. For example, the control system may be configured to selectively open, close, or activate one or more valves, selectively control the pressure in the gas-liquid separation module 111 and / or the flow path, and selectively suction or discharge the pump 102. The control system 150 may be programmed to execute sets or commands or instructions and may be configured to receive input from a user to selectively control one or more functions of the aseptic sampling system 100. The control system 150 may be configured to control one or more elements of the pressure regulation system 160 to select between a first mode (low pressure condition) and a second mode (high pressure condition) in the gas-liquid separation module 111.

[0023] Figures 2A - 2D illustrate an exemplary progression of automated aseptic sampling according to some embodiments. Figure 2A shows a schematic diagram of the aseptic sampling system 100 in a first step of sampling. In some embodiments, the aseptic sampling system 100 can be cleaned, for example, by filling, or ensuring that the first flow path 126, the gas - liquid separation module 111, and the intermediate flow path 127 are filled with air or gas to remove residues from previous procedures, prior to the first step shown in Figure 2A. The first step can include selectively connecting a vacuum source 116 to the gas - liquid separation module 111 via a pressure - regulating control valve 112. The vacuum source 116 can create low gas - pressure conditions in the permeate portion of the gas - liquid separation module 111. The low gas - pressure conditions can act as a suction force to draw the sample 202 from the reservoir 130 through the membrane 350 into the gas - liquid separator 110. As shown in Figure 2A, the sample port 132 is not connected to the pump 102 during this initial operation. The only force acting on the sample 202 to draw the sample 202 from the reservoir 130 into the gas - liquid separator 110 is the low - pressure condition created by the pressure - regulating system 160. The gas - liquid separator 110 can operate to remove gas (e.g., air bubbles) from the sample 202. Under the conditions shown in Figure 2A, the flow - path valve 108 disposed in the intermediate flow path 127 is closed.

[0024] FIG. 2B shows a schematic view of the aseptic sampling system 100 in a second step of sampling according to some embodiments. The sample port 132 of the selection valve 106 is in fluid connection with the pump 102, which draws the sample 202 from the gas-liquid separation module 111 through the intermediate flow path 127 and the multi-port selection valve 106 to the second flow path 128. The vacuum source 116 is in fluid connection with the permeate portion of the gas-liquid separation module 111 to create low pressure conditions for removing gases such as air bubbles through the gas permeable membrane 350. The sample drawn through the gas-liquid separator is preferably degassed (i.e., bubble-free), and thus an accurate sample volume can be aspirated / dispensed. Accurate sample volume delivery is beneficial when used for analytical characterization such as titer measurement. During this second step, the flow path valve 108 disposed in the intermediate flow path 127 is open.

[0025] Figure 2C shows a schematic diagram of the aseptic sampling system 100 in a third step of sampling, according to some embodiments. The sample 202 can be positioned in a second flow path 128 between the pump 102 and the multi-port selection valve 106. The flow path valve 108 disposed in the intermediate flow path 127 is closed in this third step to keep the system aseptic. The multi-port selection valve 106 operates to fluidly connect the pump 102 to an analyzer (not shown) via the analyzer port 136. The pump 102 discharges to dispense the sample 202 towards a downstream analyzer through the analyzer port 136. The pressure regulating control valve 112 operates to fluidly connect the gas-liquid separator 110 to the pressurized air source 114 of the pressure regulating system 160. The pressurized air source 114 creates a high gas pressure condition that permeates through the membrane 350 in the permeate portion of the gas-liquid separation module 111 to push the sample 202 from the gas-liquid separation module 111 through the first flow path 126 towards the reservoir 130. As shown in Figure 2C, since the sample 202 has exited the gas-liquid separation module 111 and been pushed into the reservoir 130, the first flow path 126 does not contain any of the sample 202. This helps to minimize sample loss as the sample 202 disposed between the gas-liquid separator 110 and the reservoir 130 is not discharged to waste but instead is dispensed and returned into the reservoir 130. In the intermediate flow path 127, the sample 202 disposed between the gas-liquid separator 110 and the multi-port selection valve 106 remains. In some embodiments, the intermediate flow path 127 can be minimized (i.e., shortened) to minimize sample loss.

[0026] Figure 2D shows a schematic view of the aseptic sampling system 100 in the fourth step of sampling according to some embodiments. The remaining sample 202 disposed in the intermediate flow path 127 as shown in Figure 2C is aspirated into the second flow path 128 by the operation of the multi-port selection valve 106 that fluidly connects the pump 102 to the sample port 132 with the flow path valve 108 open. Once all of the remaining sample 202 has been aspirated from the intermediate flow path 127 to the path flow path 128 and the flow path valve 108 is closed, the multi-port selection valve 106 then operates to fluidly connect the pump 102 to the waste port 134. The pump 102 can then operate to discharge the sample 202 through the waste port 134 to a waste container (not shown). The clean air from the gas-liquid separator 110 continues to purge through the probe 124 to keep the probe 124 unblocked.

[0027] Figure 3 shows an exploded isometric view of the gas-liquid separation module 111 shown in FIGS. 1A - 2D according to some embodiments. The gas-liquid separation module 111 includes a first plate 342 and a second plate 344, and the first plate 342 and the second plate 344 fit together to form a separation chamber for the gas-liquid separation module 111. In some embodiments, the first plate 342 may include one or more mounting receivers 346 configured to receive one or more mounting tabs 348 positioned on the second plate 344. The gas-liquid separation module may include a gasket 352, a diffusion element 354, and a membrane 350.

[0028] The first plate 342 may define a fluid flow path for contact between the fluid flow and the membrane 350. Alternatively stated, the holding liquid portion of the gas-liquid separation module 111 may be disposed between the first plate 342 and the membrane 350. The second plate 344 may include a pressure regulation port 120 configured to fluidly connect the pressure regulation system 160 to the gas-liquid separation module 111. The permeate portion of the gas-liquid separation module 111 may be disposed between the second plate 344 and the membrane 350. The membrane 350 may be gas permeable such that gas can permeate through the membrane 350. In some embodiments, the membrane 350 may be gas permeable but non-porous. Thus, when low pressure conditions or partial low pressure conditions exist in the permeate portion of the gas-liquid separation module 111, gas will be drawn from the holding liquid portion through the membrane 350 into the permeate portion. The membrane 350 may be impermeable to the liquid material 152, i.e., the liquid material 152 cannot pass through the membrane 350.

[0029] Note that the gas-liquid separation module 111 shown in FIG. 3 is merely one embodiment. The gas-liquid separator 110 used in this aseptic sampling system is described in U.S. Patent No. 9,381,449, entitled "Carbon Nanotube Composite Membrane," filed on June 6, 2013; U.S. Patent No. 9,370,734, entitled "Fluid Degassing Module with Helical Membrane," filed on June 13, 2014; U.S. Patent No. 9,656,186, entitled "Fluid Degassing Apparatus," filed on May 29, 2015; U.S. Patent No. 9,962,661, entitled "Composite Membrane," filed on June 30, 2016; U.S. Patent No. 10,143,942, entitled "Membrane Gas / Liquid Contactor," filed on August 29, 2016; and U.S. Patent No. 10,953,348, entitled "Membrane Gas / Liquid Contactor," filed on November 30, 2018, which are co-owned, and the contents of which are hereby incorporated by reference in their entirety. Further, it should be understood that in the system of the present invention, various embodiments of the gas-liquid separator 110 may be useful. An example of an alternative type of gas-liquid separator useful in the present invention is a hollow fiber silicone rubber type degassing device known in the art.

[0030] FIG. 4 shows a schematic diagram of an exemplary aseptic sampling system 400 that includes a plurality of reservoirs. A single pressure regulating system 160 can be used with a first reservoir 430a and a second reservoir 430b. The pressure regulating system 160 can be fluidly connected to the first reservoir 430a and / or the second reservoir 430b via a reservoir selection valve 404. The first reservoir 430a can be fluidly connected to a first probe 424a, a first gas-liquid separator 410a, and a first flow path valve 408a. The second reservoir 430b can be fluidly connected to a second probe 424b, a second gas-liquid separator 410b, and a second flow path valve 408b. The first reservoir 430a and the second reservoir 430b can be selectively fluidly connected to a pump 102 via a multi-port selection valve 402. The multi-port selection valve 402 can include a first sample port 432a fluidly connected to the first reservoir 430a and a second sample port 432b fluidly connected to the second reservoir 430b. The valve 404 can be selectively operated to fluidly connect to different bioreactors and provide clean air / gas to flush the probes in order to prevent blockage of the probes within the bioreactor.

[0031] Figures 12A - 12C show schematic diagrams of a sterile sampling system 1200 including one or more reservoirs 130a, 130b and a pump 102, according to some embodiments. The sterile sampling system 1200 can include first flow paths 1226a, 1226b fluidly connecting the reservoirs 130a, 130b to respective gas - liquid separation modules 111a, 111b. The gas - liquid separation modules 111a, 111b can be fluidly connected to a pressure regulation system 1260. The pressure regulation system 1260 can include a vacuum source capable of providing a negative pressure to the permeate side of the gas - liquid separation modules 111a, 111b through vacuum lines 1216a, 1216b, and a gas source capable of delivering a gas such as air or providing access to a gas such as air to the permeate side of the gas - liquid separation module 111 through gas lines 1214a, 1214b. In some embodiments, the gas source can deliver a positively pressurized gas, while in other embodiments, the gas source can provide access to a neutral gas (i.e., air having a pressure of about 1 atm).

[0032] The pressure adjustment system 1260 may include pressure adjustment control valves 1212a, 1212b for controlling the fluid connection of the gas source and the vacuum source to each of the gas-liquid separation modules 111a, 111b. In some embodiments, the pressure adjustment control valves 1212a, 1212b may be binary valves having two states. The first state fluidly connects an air source to each of the gas-liquid separation modules 111a, 111b through the respective gas lines 1214a, 1214b, and the second state fluidly connects a vacuum source to each of the gas-liquid separation modules 111a, 111b through the vacuum lines 1216a, 1216b. For example, FIG. 12A shows the pressure adjustment control valves 1212a, 1212b in the first state, where the vacuum source is fluidly disconnected from the gas-liquid separation modules 111a, 111b, and the gas source is fluidly connected to the gas-liquid separation modules 111a, 111b via the gas lines 1214a, 1214b. FIG. 12B shows the first pressure adjustment control valve 1212a in the second state, where the gas source is fluidly disconnected from the first gas-liquid separation module 111a, and the vacuum source is fluidly connected to the first gas-liquid separation module 111a via the vacuum line 1216a. In this state, the fluid from the reservoir 130a can be drawn along the flow path 1226a by the negative pressure established in the gas-liquid separation module 111a through the separation membrane in the module 111a. In some embodiments, the operation of the pressure adjustment control valve 1212a fluidly connects one path (i.e., the air source or the vacuum source) while simultaneously disconnecting the other path.

[0033] The aseptic sampling system 1200 may include intermediate flow paths 1227a, 1227b that fluidly connect the gas-liquid separation modules 111a, 111b to the multi-port selection valve 106. The intermediate flow paths 1227a, 1227b may each include a flow path valve 1208a, 1208b, respectively. The flow path valves 1208a, 1208b may be pinch valves configured to selectively close their respective intermediate flow paths 1227a, 1227b. The multi-port selection valve 106 may include any and / or all of the ports described above with respect to FIGS. 1A-4 for fluidly connecting the intermediate flow paths 1227a, 1227b and / or the secondary flow path 1228 to a plurality of flow paths, reservoirs, downstream analyzers, waste ports, etc.

[0034] The aseptic sampling system 1200 may include a secondary flow path 1228 that fluidly connects the multi-port selection valve 106 to one or more pumps 102. The pump 102 may be a positive displacement pump that includes a piston configured to retract within the cavity (i.e., draw fluid towards the pump) and / or press forward within the cavity (i.e., push fluid out of the pump). In other words, the pump 102 may provide a bi-directional movement of the samples 1252a, 1252b through the composite flow path, with a first direction drawing fluid towards the pump 102 and a second direction pushing fluid out of the pump 102. The secondary flow path 1228 may be configured to store fluid downstream from the multi-port selection valve 106. The multi-port selection valve 106 may operate with the fluid stored within the secondary flow path 1228 to selectively fluidly connect another valve port to the secondary flow path 1228.

[0035] According to some embodiments, the process of aseptic sampling of the sample 1252a using the aseptic sampling system 1200 is described below. The process may begin with the first pressure regulating valve 1212a in a first state (i.e., the vacuum source is fluidly disconnected from the first gas-liquid separation module 111a), the first flow path valve 1208a fully closing the intermediate flow path 1227a, and the multi-port selection valve 106 being disconnected from the intermediate flow path 1227a.

[0036] The pressure regulating valve 1212a can be actuated to fluidly connect a vacuum source to the first gas-liquid separation module 111a. The negative pressure from the vacuum source can permeate through the membrane 350 of the first gas-liquid separation module 111a, and accordingly provide a suction force to the first flow path 1226a. The suction force in the first flow path 1226a can draw the sample 1252a into the first flow path 1226a and the holding liquid portion of the first gas-liquid separation module 111a.

[0037] When the holding liquid portion of the first gas-liquid separation module 111a is at least partially filled, the multi-port selection valve 106 can be actuated to fluidly connect the secondary flow path 1228 to the intermediate flow path 1227a. The first flow path valve 1208a can be actuated to open the intermediate flow path 1227a. The pump 102 can generate a suction force in the flow path (i.e., the piston retracts within the cavity), and thus, the sample 1252a can be drawn from the first gas-liquid separation module 111a into the intermediate flow path 1227a and through the selection valve 106 into the secondary flow path 1228.

[0038] In some embodiments, this step can include an accurate sampling step, where the first flow path valve 1208a is closed and the multi-port selection valve 106 is actuated to fluidly connect the secondary flow path 1228 to the waste port. The pump 102 can generate a positive pressure in the flow path (i.e., the piston extends), and can push any sample located within the secondary flow path 1228 through the waste port. Since the entire intermediate flow path 1227a can be filled with the sample 1252a and the secondary flow path 1228 is not filled with the sample 1252a at all, the amount of the sample 1252a can be accurately controlled. Any pumping of the intermediate flow path 1227a immediately fills the secondary flow path 1228, and thus, the amount of the sample 1252a drawn into the secondary flow path 1228 can be accurately measured / controlled by the pump 102.

[0039] The multi-port selection valve 106 can be operated to fluidly connect the intermediate flow path 1227a to the secondary flow path 1228, and the flow path valve 1208a can be opened. The pump 102 can generate a negative pressure in the composite flow path to urge the sample 1252a into the secondary flow path 1228. After a controlled amount of the sample 1252a has been drawn into the secondary flow path 1228, the flow path valve 1208 can be closed, and the selection valve can be operated to fluidly connect the secondary flow path 1228 to the downstream analyzer port. The pump 102 can generate a positive pressure in the composite flow path to urge the sample 1252a to the downstream analyzer.

[0040] In some embodiments, this step may include a cleaning step. The pressure regulating valve 1212 can be operated to fluidly connect the air source 1214 to the gas-liquid separation module 111. The air source 1214 can urge the sample 1252a located in the first flow path 1226a back towards the reservoir 130. The flow path valve 1208a can be operated to open the intermediate flow path 1227a, and the multi-port selection valve 106 can be operated to fluidly connect the intermediate flow path 1227a to the secondary flow path 1228. The remaining sample 1252a can be drawn from the intermediate flow path 1227a into the secondary flow path 1228 by the pump. The multi-port selection valve 106 can be operated to fluidly connect the secondary flow path 1228 to the waste port, and the remaining sample 1252a can be disposed through the waste port.

[0041] In some embodiments, the above steps can be repeated for a second bioreactor (i.e., the reservoir 130b connected to the first flow path 1226b and the intermediate flow path 1227b). In some embodiments, the second bioreactor can be prepared while the above steps are being performed. For example, FIG. 12C shows a sterile sampling system 1200 with a second bioreactor prepared for sterile sampling of the sample 1252b.

[0042] Figures 13A - 13C show schematic diagrams of a sterile sampling system 1300 including a peristaltic pump 1302 according to some embodiments. The sterile sampling system 1300 may include any or all of the features described above in the sterile sampling system 1200, along with a peristaltic pump 1302, in contrast to one or more pumps 102 in the sterile sampling system 1200. The peristaltic pump 1302 may be unidirectional, i.e., capable of moving fluid in only one direction along the composite flow path. For example, the peristaltic pump 1302 may move fluid from the multi - port selection valve 106 to the secondary flow path 1228, and then through the peristaltic pump 1302 and the downstream flow path 1350.

[0043] According to some embodiments, the process of sterile sampling of a sample 1352a using the sterile sampling system 1300 is described below. This process may start with the pressure regulating valve 1212a in a first state (i.e., the vacuum source is fluidly disconnected from the first gas - liquid separation module 111a), the flow path valve 1208a closing off the intermediate flow path 1227a, and the multi - port selection valve 106 being disconnected from the intermediate flow path 1227a.

[0044] The pressure regulating valve 1212a may be actuated to fluidly connect the vacuum source to the first gas - liquid separation module 111a. The negative pressure from the vacuum source may permeate through the membrane 350 of the first gas - liquid separation module 111a and provide a suction force to the first flow path 1226a. The suction force in the first flow path 1226a can draw the sample 1252a into the first flow path 1226a and into the holding liquid portion of the first gas - liquid separation module 111a.

[0045] When the holding liquid portion of the first gas-liquid separation module 111a is at least partially filled, the multi-port selection valve 106 can be actuated to fluidly connect the secondary flow path 1228 to the intermediate flow path 1227a. The flow path valve 1208a can be actuated to open the intermediate flow path 1227a. The peristaltic pump 1302 can operate to draw the sample 1352a into the intermediate flow path 1227a. The peristaltic pump 1302 can draw the sample 1352a downstream of the multi-port selection valve 106 and at least partially into the secondary flow path 1228.

[0046] In some embodiments, this step may include a sampling step, where the flow path valve 1208a is closed and the multi-port selection valve 106 is actuated to fluidly connect the secondary flow path 1228 to the air port or the cleaning agent port. The peristaltic pump 1302 can draw air or the cleaning agent (either one of which is disposed in the sample 1228 within the secondary flow path 1352a) through the peristaltic pump 1302 and the downstream flow path 1350 to the waste receptacle. Since the entire intermediate flow path 1227a can be filled with the sample 1352a and the secondary flow path 1228 is not filled with the sample 1352a at all, the amount of the sample 1352a can be accurately controlled here. Any pumping of the intermediate flow path 1227a immediately fills the secondary flow path 1228, and in this way, the amount of the sample 1352a drawn into the secondary flow path 1228 can be accurately measured / controlled by the peristaltic pump 1302. For example, FIG. 13B shows the sterile sampling system 1300 in a prepared state.

[0047] The multi-port selection valve 106 can be actuated to fluidly connect the intermediate flow path 1227a to the secondary flow path 1228, and the flow path valve 1208a can be opened. The peristaltic pump 1302 can draw the sample 1352a into the secondary flow path 1228 and through the peristaltic pump 1302 and the downstream flow path 1350 to the downstream analyzer. After a controlled amount of the sample 1352a has been drawn through the multi-port selection valve 106, the flow path valve 1208a can be closed and the multi-port selection valve 106 can be actuated to fluidly connect to the air port. The peristaltic pump 1302 can draw the sample 1352a remaining in the secondary flow path 1228 to the downstream analyzer.

[0048] In some embodiments, the process may include a cleaning step. The pressure regulating valve 1212 can be actuated to fluidly connect an air source to each of the gas-liquid separation modules 111a, 111b. The air source can bias the sample 1352a located in the first flow path 1226a to return towards the reservoir 130a. The flow path valve 1208a can be actuated to open the intermediate flow path 1227a, and the multi-port selection valve 106 can be actuated to fluidly connect the intermediate flow path 1227a to the secondary flow path 1228. The remaining sample 1352a can be drawn out of the intermediate flow path 1227a, into the secondary flow path 1228, and out of the downstream flow path 1350 by the peristaltic pump 1302.

[0049] In some embodiments, the above process can be repeated for a second bioreactor (i.e., the reservoir 130b connected to the first flow path 1226b and the intermediate flow path 1227b). In some embodiments, the second bioreactor can be prepared while the above process is being performed. For example, FIG. 13C shows a sterile sampling system 1300 with a second bioreactor prepared for sterile sampling of the sample 1352b.

[0050] FIG. 5 shows a schematic diagram of an exemplary aseptic sampling system 500 that includes a gas-liquid separator outside the sterile region. An advantage of this embodiment is that it is not necessary to sterilize the gas-liquid separator 110 by autoclaving. The aseptic sampling system 500 can include a T-tube 544 configured to fluidly connect a pressurized gas source 550 to the flow path. The pressurized gas source 550 can be selectively connected and disconnected to the flow path by a valve 548, optionally through a filter 546, to sterilize the pressurized gas supplied to the flow path. The pressure adjustment system can operate the pressurized gas source 550 to push the fluid material back from the T-tube 544 toward the reservoir 130, preferably into the reservoir 130. In the embodiment shown in FIG. 5, the vacuum source 116 is fluidly connected to the gas-liquid separator 110 and can operate to draw a sample from the reservoir 130 through the flow path into the separation chamber with a negative pressure applied to the gas-liquid separator 110 as described in other embodiments herein. The negative pressure can be effective to degas the sample (i.e., separate gas from the liquid) through the semipermeable membrane 350 in the gas-liquid separator 110. The system 500 of FIG. 5 can operate to push the sample back into the reservoir 130 via the pressurized gas source 550 and the T-tube 544, rather than relying only on sufficient positive pressure on the permeate side of the membrane 350 to push the sample along the flow path.

[0051] FIG. 6 shows a schematic diagram of an exemplary aseptic sampling system 600 that includes multiple reservoirs for a single gas-liquid separator. An advantage of this embodiment is that it is not necessary to sterilize the gas-liquid separator 110 by autoclaving and the system is configured to draw samples from multiple different reservoirs / bioreactors. In some embodiments, two or more reservoirs can be fluidly connected to a multi-port selection valve 610. The multi-port selection valve 610 can include a cleaning agent port 638 configured to introduce a cleaning agent into the flow path between the multi-port selection valve 610 and the gas-liquid separator 110. The gas-liquid separator 110 can be configured to draw the cleaning agent through the flow path by the vacuum source 116.

[0052] FIG. 7 shows a schematic diagram of an exemplary aseptic sampling system 700 that includes a cleaning agent reservoir 702 configured to sterilize a portion of the intermediate flow path 127. In some embodiments, pump 102 can draw cleaning agent from the cleaning agent reservoir through intermediate flow path 127. The cleaning agent can be drawn into that portion of the flow path to disinfect (i.e., sterilize or aseptically clean) the flow path between valve 708b and multi-port selection valve 106. Valve 708a is closed to prevent the cleaning agent from flowing into the gas-liquid separator 110. Pump 102 can aspirate the cleaning agent from intermediate flow path 127 through multi-port selection valve 106 to a second flow path 128. Valve 708a may be open during aspiration by pump 102. In some cases, cleaning agent can remain between valve 708a and T-tube 744. The pressurized gas source 114 of the gas-liquid separator can be used to push the remaining cleaning agent from T-tube 744 to cleaning agent reservoir 702.

[0053] Figures 8A - 8C illustrate an exemplary aseptic sampling system 800 including a multi - port selection valve 106 positioned between a reservoir 130 and a gas - liquid separator 110, according to some embodiments. A pressurized gas source 114 may be fluidly connected to a multi - port selection valve 106 positioned between a reservoir 130 and a gas - liquid separator 110. A first flow path 820 may fluidly connect the reservoir 130 to the multi - port selection valve 106, and an intermediate flow path 804 may fluidly connect the multi - port selection valve 106 to the gas - liquid separator 110. When a sample port 132 is fluidly connected to a vacuum source 116 via the multi - port selection valve 106, the vacuum source 116 may draw a sample from the reservoir 130 into the intermediate flow path 804. In some embodiments, the multi - port selection valve 106 may include a plurality of sample ports 132 each fluidly connectable to the reservoir. The multi - port selection valve 106 may selectively connect the pressurized gas source 114 to the intermediate flow path 804 to push any sample located within the intermediate flow path 804 into a second flow path 806 positioned between the gas - liquid separator 110 and a downstream analyzer (not shown). Thus, the aseptic sampling system 800 may operate as a push - pull system, with the vacuum source 116 drawing the sample into the intermediate flow path 804 at a negative pressure and the pressurized air source pushing the sample towards the downstream analyzer at a positive pressure. The aseptic sampling system 800 may switch between drawing a sample (using the vacuum source 116) and pushing a sample (using the pressurized gas source 114) via the operation of the multi - port selection valve 106.

[0054] In some embodiments, before a sample is withdrawn from reservoir 130, multi-port selection valve 106 can be connected to a pressurized gas source 114 (see, e.g., FIG. 8B). Pressurized gas source 114 can push a gas, such as air, through intermediate flow path 804, gas-liquid separator 110, and second flow path 806 to purge residual air, cleaning agent, sample, or other materials located within the flow path from the flow path. Multi-port selection valve 106 can act to fluidly connect intermediate flow path 804 to air port 142 to release the pressure within the flow path. If multi-port selection valve 106 shifts directly from pressurized gas source 114 to reservoir 130, the positive pressure in the flow path can push the sample into reservoir 130.

[0055] In some embodiments, to withdraw a sample from reservoir 130, multi-port selection valve 106 can connect reservoir 130 to intermediate flow path 804 (see, e.g., FIG. 8A). Vacuum source 116 can create a low-pressure condition within the permeate portion of gas-liquid separator 110. The low-pressure condition in the permeate portion can permeate through membrane 350 and create a low-pressure condition in the retained liquid portion of gas-liquid separation module 111. The low-pressure condition permeating through membrane 350 can provide a suction force to intermediate flow path 804 and first flow path 802. Thus, the sample can be drawn from reservoir 130 to first flow path 802 and then through multi-port selection valve 106 to intermediate flow path 804. In some embodiments, the piping between multi-port selection valve 106 and gas-liquid separator 110 is selected such that the internal volume of the retained liquid portion of gas-liquid separator 110 added to the internal volume of intermediate flow path 804 is the maximum sample volume that can be delivered to the downstream analyzer for each cycle.

[0056] In some embodiments, the multi-port selection valve 106 can be operative to fluidly connect to a pressurized gas source 114 to push samples drawn from the intermediate flow path 804 and the holding liquid portion of the gas-liquid separator 110 (see, e.g., FIG. 8B). The pressurized gas source 114 can push samples located within the intermediate flow path 804 and the gas-liquid separator 110 to a downstream analyzer (via the second flow path 806). In some embodiments, the pressurized gas source 114 can provide an adjusted gas pressure to control the sample delivery rate, e.g., higher or lower pressures may be required to deliver the sample to the downstream analyzer depending on the viscosity and / or sample volume. In some cases, if the gas pressure is too high, the sample segment may be disrupted by the pressure, i.e., broken, overly agitated, aerated, or damaged. Thus, in some embodiments, the pressurized gas source 114 can include a pump configured to control the flow rate of the sample. In some embodiments, the flow rate can be controlled such that the vacuum source 116 can degas the sample as the sample passes through the separation chamber. For example, if only a portion of the drawn sample can fit within the separation chamber, the gas-liquid separator can continue to degas the sample as the pressurized gas source 114 pushes the sample through.

[0057] In some embodiments, the intermediate flow path 804 can include a gas-liquid separator (not shown) integrated into the flow path. The integrated gas-liquid separator can create negative pressure conditions in the intermediate flow path 804 and draw dissolved gas through a gas-permeable and liquid-impermeable membrane.

[0058] In some embodiments, to clean the flow path, the multi-port selection valve 106 can be actuated to fluidly connect the cleaning agent port 138 to the cleaning agent reservoir (see, e.g., FIG. 8C). The vacuum source 116 can create a low pressure condition to draw the cleaning agent into the intermediate flow path 804 and / or the gas-liquid separator 110. The multi-port selection valve 106 can then be actuated to fluidly connect the pressurized gas source 114 to the intermediate flow path 804 and can push the cleaning agent through the gas-liquid separator 110 and the second flow path 806. The pressurized gas source 114 can push substantially all of the cleaning agent out of the flow path, and in this way, the aseptic sampling system 800 can be sterilized and be ready for the next sample collection cycle.

[0059] Figures 9A - 9C illustrate an exemplary aseptic sampling system 900 including a multi - port selection valve 106 positioned between a reservoir 130 and a gas - liquid separator 110, and an injection valve 910. The aseptic sampling system 900 can selectively connect and disconnect the gas - liquid separator 110 from the multi - port selection valve 106 by operation of the injection valve 910. Such a configuration can be beneficial because the gas - liquid separator 110 can contribute to sample carry - over between sampling cycles and can be difficult to sterilize with a cleaning agent. The aseptic sampling system 900 allows for selective bypass of the gas - liquid separator 110 when drawing a sample from the reservoir 130 to a downstream analyzer. The aseptic sampling system 900 can include a first flow path 902 fluidly connecting the reservoir 130 to the multi - port selection valve 106. The aseptic sampling system can include an intermediate flow path 904 fluidly connecting the multi - port selection valve 106 to the injection valve 910. In some embodiments, a fluid sensor 908 can be positioned on the intermediate flow path 904. The fluid sensor 908 can sense when a sample reaches the fluid sensor 908 on the intermediate flow path 904 and generate a signal for controlling the injection valve 910 in response. For example, when a sample reaches the fluid sensor 908, the fluid sensor 908 can send a signal to the injection valve 910 to operate to disconnect from the gas - liquid separator 110, thus preventing the sample from entering the gas - liquid separator 110. The aseptic sampling system 900 can include a second flow path 906 fluidly connecting the injection valve 910 to a downstream analyzer.

[0060] In some embodiments, to draw a sample from the first flow path 902 to the intermediate flow path 904, the injection valve 910 fluidly connects the gas - liquid separator 110 to the multi - port selection valve 106 (see, for example, FIG. 9A). The gas - liquid separator 110 can generate a suction force to draw a sample from the reservoir 130 to the intermediate flow path 904. The sample can fill the internal volume of the intermediate flow path 904 until it reaches the fluid sensor 908.

[0061] In some embodiments, fluid sensor 908 may generate a signal in response to fluid (e.g., a sample) passing through fluid sensor 908. The signal may be communicated to a processor, CPU, or user interface (not shown) and may control the operation of multi-port selection valve 106 and / or injection valve 910. For example, in some cases, if a sample is detected by fluid sensor 908, the signal may cause injection valve 910 to be fluidly disconnected from gas-liquid separator 110 and multi-port selection valve 106 to be fluidly connected to pressurized gas source 114 (see, e.g., FIG. 9B). Thus, the sample may bypass gas-liquid separator 110 by proceeding directly from intermediate flow path 904 to second flow path 906. In some embodiments, fluid sensor 908 may measure one or more characteristics of the sample, including, but not limited to, entrained air volume percentage, viscosity, transparency, ultrasonic acoustic impedance, and / or other gas-in-fluid detection characteristics known in the art. In some embodiments, if the one or more characteristics indicate gas in the fluid that exceeds a threshold amount, fluid sensor 908 (or the CPU) may selectively send the sample to gas-liquid separator 110 to degas the sample. If the one or more characteristics indicate gas in the fluid that is less than the threshold amount, aseptic sampling system 900 may bypass gas-liquid separator 110 by operating multi-port selection valve 106 and / or injection valve 910 as shown in FIG. 9B. In some embodiments, additional cleaning agent may be introduced into gas-liquid separator 110 through one or more ports of injection valve 910.

[0062] In some embodiments, aseptic sampling system 900 may be sterilized by a cleaning agent introduced through cleaning agent port 138 (see, e.g., FIG. 9C). The injection valve may fluidly connect gas-liquid separator 110 to multi-port selection valve 106, and the negative pressure generated by vacuum source 116 may create a suction to draw the cleaning agent into intermediate flow path 904. In some embodiments, the cleaning agent may selectively bypass gas-liquid separator 110. Bypassing gas-liquid separator 110 may depend on whether the sample bypassed gas-liquid separator 110, and the cleaning agent follows the same flow path as the sample.

[0063] Figure 10 shows an exemplary flowchart of a method 1000 for automated aseptic sampling. Method 1000 includes providing a sampling system 1002. The sampling system can include any of the embodiments described and / or illustrated above. The sampling system can include a gas-liquid separator having a separation chamber. The gas-liquid separator includes a membrane that separates the separation chamber into a retained liquid portion and a permeate liquid portion. The gas-liquid separator includes a pressure regulation system fluidly connected to the permeate liquid portion of the separation chamber.

[0064] Method 1000 includes selectively operating a pressure regulation system 1004. The pressure regulation system can operate in a first mode to establish a first gas pressure condition for withdrawing a sample of the liquid material from the reservoir through a first flow path to the retained liquid portion of the separation chamber in the permeate liquid portion of the separation chamber. The pressure regulation system can operate in a second mode to establish a second condition for pushing the sample in some embodiments from the permeate liquid portion of the separation chamber through the first flow path towards the reservoir in the permeate liquid portion of the separation chamber.

[0065] In some embodiments, the membrane is gas permeable and liquid impermeable. The first mode can be effective to remove gas from the sample through the membrane. Method 1000 can further include pumping the sample through the first flow path using a positive displacement pump fluidly connected to the first flow path. The positive displacement pump can be fluidly connected to the first flow path through a multi-port selection valve that is selectively adjustable between a plurality of positions. The first position fluidly connects the first flow path to a second flow path, and the second position fluidly disconnects the first flow path from the second flow path. The second position fluidly connects the second flow path to a third flow path. The method can further include pumping the sample through the third flow path when the selection valve is in the second position. The third flow path can be fluidly connected to an analysis system.

[0066] FIG. 11 shows an exemplary flowchart of an automated aseptic sampling method. Method 1100 includes providing a sampling system 1102. The sampling system includes a gas-liquid separator having a separation chamber. The separation chamber is separated by a membrane into a retained liquid portion and a permeate liquid portion. The gas-liquid separator includes a pressure adjustment system configured to control the gas pressure in the permeate liquid portion. Method 1100 includes providing a first flow path 1104. The first flow path connects the separation chamber to a reservoir containing a liquid-like material. Method 1100 includes operating the pressure adjustment system to apply a negative gas pressure to the permeate liquid portion 1106. The negative pressure in the permeate liquid portion is effective to draw a sample of the liquid-like material from the reservoir to the retained liquid portion of the separation chamber. The negative pressure in the permeate liquid portion is effective to remove gas from the sample through the membrane.

[0067] In some embodiments, method 1100 further includes operating the pressure adjustment system to apply a positive pressure to the permeate liquid portion. The positive pressure in the permeate liquid portion is effective to push the sample from the retained liquid portion of the gas-liquid separation chamber towards the reservoir. The pressure adjustment system can include a vacuum source fluidly connected to the permeate liquid portion, a pressurized air source fluidly connected to the permeate liquid portion, and a control valve. The control valve can selectively connect and / or selectively disconnect the pressurized air source and the vacuum source to the permeate liquid portion of the separation chamber. Method 1100 can further include providing a second flow path fluidly connecting the retained liquid portion of the separation chamber to a positive displacement pump, and pumping the sample from the retained liquid portion of the separation chamber through the second flow path towards the positive displacement pump. The first flow path can be fluidly connected to the second flow path through a multi-port selection valve. Each of the plurality of ports can be selectively connectable to the positive displacement pump.

[0068] Although the present disclosure has been described with reference to exemplary embodiments, it will be understood by those skilled in the art that various changes can be made without departing from the scope of the embodiments, and equivalents can be substituted for elements of the embodiments. Further, many modifications can be made to adapt a particular situation or material to the teachings of the embodiments without departing from the essential scope thereof. Accordingly, the present disclosure is not limited to the disclosed embodiments, but is intended to cover all embodiments falling within the scope of the appended claims. Various examples have been described. These and other examples are within the scope of the following claims.

Claims

1. 1. A method for sampling a liquid material using a sampling system, comprising: The sampling system may further include a gas-liquid separator, the gas-liquid separator comprising: A separation chamber; a membrane separating the separation chamber into a retentate portion and a permeate portion, the membrane being gas permeable and liquid impermeable; a pressure regulation system fluidly connected to the permeate portion of the separation chamber, the pressure regulation system adapted to control a gas pressure in the permeate portion. To provide and The pressure regulation system, a first mode of establishing first gas pressure conditions in the permeate portion of the separation chamber effective to draw a sample of the liquid material from a reservoir through a first flow channel to the retentate portion of the separation chamber; and a second mode of establishing a second gas pressure condition in the permeate portion of the separation chamber effective to push the sample from the retentate portion of the separation chamber through the first flow channel. And to operate selectively A method for providing the above.

2. The method of claim 1 , wherein the first gas pressure condition is effective to remove gas from the sample through the membrane.

3. pumping the sample through the first flow channel with a positive displacement pump in fluid communication with the first flow channel. The method of claim 1 further comprising:

4. 4. The method of claim 3, wherein the positive displacement pump is fluidly connected to the first flow channel through a multi-port selection valve selectively adjustable between a plurality of positions, a first position fluidly connecting the first flow channel to a second flow channel, a second position fluidly disconnecting the first flow channel from the second flow channel, and the second position fluidly connecting the second flow channel to a third flow channel.

5. pumping the sample through the third flow channel when the multi-port selection valve is in the second position. The method of claim 4 further comprising:

6. The method of claim 5 , wherein the third flow channel is fluidly connected to an analytical system.

7. 2. The method of claim 1, further comprising operating the pressure regulation system in a third mode to establish a third pressure condition in the permeate portion of the degassing chamber effective to produce substantially no fluid flow in the first flow channel.

8. 1. A method for sampling a liquid material, comprising: A sampling system having a gas-liquid separator, the gas-liquid separator comprising: a separation chamber having a retentate portion, a permeate portion, and a membrane separating the retentate portion and the permeate portion, the membrane being gas permeable and impermeable to the liquid-like material; and a pressure regulation system configured to control the pressure in the permeate portion. To provide and providing a first flow channel fluidly connecting the separation chamber to a reservoir containing the liquid material; operating the pressure regulation system in a first mode to apply a negative gas pressure to the permeate section, the negative gas pressure in the permeate section being effective to draw a sample of the liquid material from the reservoir to the retentate section of the separation chamber, the negative gas pressure in the permeate section being effective to remove gas from the sample through the membrane; operating the pressure regulation system in a second mode to apply a positive gas pressure to the permeate portion, the positive gas pressure in the permeate portion being effective to push the sample out of the retentate portion of the separation chamber; A method for providing the above.

9. 9. The method of claim 8, wherein the pressure regulation system includes a vacuum source fluidly connected to the permeate portion, a pressurized air source fluidly connected to the permeate portion, and a control valve.

10. 10. The method of claim 9, comprising operating the control valve to selectively connect or disconnect at least one of the pressurized air source and the vacuum source to the permeate portion of the separation chamber.

11. providing a second flow channel fluidly connecting the retentate portion of the separation chamber to a positive displacement pump; pumping the sample from the retentate portion of the separation chamber through the second flow channel towards the positive displacement pump; The method of claim 8 further comprising:

12. 12. The method of claim 11 , wherein the retentate portion of the separation chamber is fluidly connected to the positive displacement pump along the second flow channel through a selection valve, the selection valve including a plurality of ports, each of the plurality of ports being selectively fluidly connectable to the positive displacement pump.

13. The method of claim 12 , wherein the plurality of ports includes an analyzer port fluidly connected to an analyzer flow channel.

14. pumping the sample through the analyzer flow channel into an analytical system; The method of claim 13 further comprising:

15. operating the pressure regulation system in a third mode to provide a neutral gas pressure in the permeate portion, the neutral gas pressure in the permeate portion being effective to cause substantially no fluid flow in the first flow channel. The method of claim 8 further comprising:

16. a reservoir containing a liquid material; 1. A gas-liquid separator comprising: a separation chamber having a retentate portion, a permeate portion, and a membrane separating the retentate portion and the permeate portion, the membrane being gas permeable and impermeable to the liquid material; a pressure regulation system configured to control the gas pressure in the permeate portion; A gas-liquid separator comprising: a first flow channel fluidly connecting the reservoir to the retentate portion of the gas-liquid separator; A positive displacement pump; A multi-port selection valve; a second flow channel fluidly connecting the positive displacement pump to the multi-port selection valve, the multi-port selection valve being selectively adjustable between a plurality of positions, a first position fluidly connecting the first flow channel to the second flow channel; Equipped with the pressure regulation system is configured to selectively provide a negative gas pressure in the permeate portion, the negative gas pressure in the permeate portion being effective to pull the sample of the liquid material from the reservoir to the retentate portion of the separation chamber; and the pressure regulation system is configured to selectively provide a positive gas pressure in the permeate portion, the positive gas pressure in the permeate portion being effective to push the sample of the liquid material from the retentate portion of the separation chamber to the reservoir. Sampling system.

17. 17. The sampling system of claim 16, wherein the negative pressure in the permeate portion is effective to remove gas from the sample through the membrane.

18. a probe for obtaining the sample from the reservoir; a second valve for selectively opening and closing the first flow channel between the multi-port selection valve and the probe; The sampling system of claim 16 further comprising:

19. 17. The sampling system of claim 16, wherein a second position of the multi-port selection valve fluidly disconnects the first flow channel from the second flow channel and fluidly connects the second flow channel to a third flow channel.

20. The sampling system of claim 16, wherein a third flow channel fluidly connects the multi-port selection valve to one or more of an analytical system, a fluid source, and a waste receptacle.

21. 17. The sampling system of claim 16, further comprising an intermediate flow passage fluidly connectable to the retentate portion and the multi-port selection valve, the intermediate flow passage including a flow passage valve for selectively opening and closing the intermediate flow passage.

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