Sensor measurement compensation in bioprocessing systems

Abstract

A pH system is disclosed that is capable of compensating for changes in pressure and conductivity. The system includes a pH sensor, a pressure sensor, and an optional conductivity sensor, each of which transmits its output to a controller. The controller multiplies a compensation factor by the difference between the measured pressure and a threshold pressure. This result is then added to the measured pH value. Furthermore, the compensation factor is dependent on the conductivity of the solution. In some examples, the compensation factor is calculated by raising the conductivity to a power and multiplying the result by a constant. The pH system may be incorporated into various bioprocessing systems, such as a multi-column chromatography system and a virus inactivation system.

Description

[Technical field]

[0001] Embodiments of the present disclosure relate to systems and methods for compensating measurements received from a sensor based on other environmental conditions. [Background technology]

[0002] In many applications, such as bioprocessing applications, it is important to carefully and accurately monitor and control parameters associated with the environment, such as pH, pressure, temperature, conductivity, etc. These parameters can determine the effectiveness of a particular process and can be critical to the desired outcome.

[0003] For example, in virus inactivation applications, the pH must be tightly controlled to ensure virus inactivation without compromising product quality, and this is also true for a variety of other processes.

[0004] Furthermore, in some bioprocessing applications, various operating parameters at various points in the system are displayed for the user, and the accuracy of these displayed parameters is paramount to provide confidence to the user. Summary of the Invention [Problem to be solved by the invention]

[0005] It would therefore be beneficial to have a system that produces accurate pH sensor readings that are adjusted based on pressure and conductivity. Further, it would be advantageous for these adjusted or compensated values ​​to be utilized in bioprocessing applications. [Means for solving the problem]

[0006] A pH system is disclosed that is capable of compensating for changes in pressure and conductivity. The system includes a pH sensor, a pressure sensor, and an optional conductivity sensor, the output of each being transmitted to a controller. The controller multiplies a compensation coefficient by the difference in pressure between the measured pressure and a threshold pressure. This result is then added to the measured pH value. Furthermore, the compensation coefficient is dependent on the conductivity of the solution. In some examples, the compensation coefficient is calculated by raising the conductivity to a power and multiplying the result by a constant. The pH system may be incorporated into various bioprocessing systems, such as multi-column chromatography systems and viral inactivation systems.

[0007] For a better understanding of the present disclosure, reference is made to the accompanying drawings, which are incorporated herein by reference. [Brief description of the drawings]

[0008] [Figure 1] 1 is a representative graph showing the effect of pressure on pH sensor measurements for various selected solution conductivities. [Diagram 2] 1 is an exemplary graph illustrating the effect of conductivity on pressure compensation coefficient. [Diagram 3] FIG. 1 illustrates a multi-column chromatography system in different configurations. [Figure 4] FIG. 1 illustrates a multi-column chromatography system in different configurations. [Diagram 5] FIG. 1 illustrates a multi-column chromatography system in different configurations. [Figure 6] FIG. 1 shows a viral inactivation system. [Figure 7] FIG. 1 illustrates a system having multiple sensors and a controller. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] Embodiments of the present disclosure describe systems and methods that compensate for inaccuracies in sensor measurements due to environmental conditions.

[0010] In many applications, such as bioprocessing applications, it is important to carefully and accurately monitor and control parameters associated with the environment, such as pH, pressure, temperature, conductivity, etc.

[0011] It is known that temperature can affect the accuracy of a pH sensor, in fact many pH sensors are designed with an integrated temperature sensor to allow compensation for temperature changes.

[0012] However, unexpectedly, it has been found that pH sensors are also sensitive to other parameters.

[0013] FIG. 1 shows a graph illustrating pH readings for a sensor in a fluid having a known pH while pressure and conductivity are changed. Line 100 shows pH measurements as a function of pressure for a solution of known pH with a conductivity of 0.579 mS / cm. As shown, the pH increases linearly with increasing pressure with a first slope. Line 101 shows pH measurements as a function of pressure for a solution of known pH with a conductivity of 5.51 mS / cm. As shown, the pH increases linearly with increasing pressure with a second slope that is less than the first slope. Line 102 shows pH measurements as a function of pressure for a solution of known pH with a conductivity of 7.84 mS / cm. As shown, the pH increases linearly with increasing pressure with a third slope that is less than the second slope. Finally, line 103 shows pH measurements as a function of pressure for a solution of known pH with a conductivity of 10.2 mS / cm. As shown, the pH increases linearly with increasing pressure with a fourth slope that is smaller than the others.

[0014] Note that for each line, the slope is approximately linear. In other words, the pH appears to vary linearly with pressure for all pressures greater than the threshold pressure. The slope of each line is related to the conductivity of the solution. In other words, P measured >P threshold Whenever pH actual =pH measured +compensation_coefficient(σ)×(P measured -P threshold ) where: P measured is the environmental pressure, P threshold is the threshold pressure, which may be 10 psi; Compensation_coefficient(σ) is the slope of the line as a function of pressure, which in turn is a function of conductivity (σ).

[0015] Below this pressure no compensation is necessary.

[0016] Using Figure 1, the slope at each of the four conductivity values ​​can be determined. Figure 2 shows the relationship between these slope values ​​and conductivity, which is represented as line 200.

[0017] As shown, there is a power law relationship between the conductivity and the slope of the pressure line. In one embodiment, this relationship is: compensation_coefficient(σ)=0.0298σ -0.901 It can be approximated as follows.

[0018] In other words, the higher the conductivity of the solution, the less the pH measurement is affected by pressure. Thus, in certain embodiments, the compensation factor may be calculated by raising the conductivity value to a power and multiplying the result by a constant. In some embodiments, the power may be a negative number.

[0019] Combining these results: pH actual (P measured ,σ)=pH measured +0.0298σ -0.901 ×(P measured -P threshold ) This results in:

[0020] It should be noted that the above relationship is one particular embodiment. Rather, the general form of this equation is: pH actual (P measured ,σ)=pH measured +compensation_coefficient(σ)×(P measured -P threshold ) It is expressed as follows.

[0021] This compensation is important because the pressure range within bioprocessing equipment typically ranges from 0 to 4 bar (58 psi) and the conductivity of solutions, which may be buffers or biomaterial solutions, may be between 500 μS / cm and tens of mS / cm. This wide variation in operating conditions can lead to pH readings that may be inaccurate.

[0022] Having determined that the actual pH of a solution is in fact a function of pressure and conductivity, this knowledge can be used to improve the operation of various bioprocesses.

[0023] 3 to 5 show a multi-column chromatography system having three columns: a first column 300, a second column 301 and a third column 302. A controller 390 is used with the system and is in communication with the valves, pressure sensors, pH sensors and conductivity sensors.

[0024] Product fluid conduit 310 is used to deliver product material to one or more of the columns. For example, product fluid conduit 310 may deliver one or more of the following: buffers, products, and other materials. Various mixing valves are used to introduce these components into product fluid conduit 310.

[0025] One or more solvents are delivered to one or more of the columns using a solvent fluid conduit 311. Various mixing valves are used to introduce one or more of a number of different solvents into the solvent fluid conduit 311.

[0026] An inlet mixing valve is associated with each column. The first inlet mixing valve 320 is positioned in a position to enable or disable the flow of product and / or solvent to the first column 300. The second inlet mixing valve 321 is positioned in a position to enable or disable the flow of product and / or solvent to the second column 301. The third inlet mixing valve 322 is positioned in a position to enable or disable the flow of product and / or solvent to the third column 302.

[0027] An input inline mixing valve is associated with each column. The first input inline mixing valve 330 is positioned in a position to enable or disable the flow of material from the output of the second column 301 to the first column 300. The second input inline mixing valve 331 is positioned in a position to enable or disable the flow of material from the output of the third column 302 to the second column 301. The third input inline mixing valve 332 is positioned in a position to enable or disable the flow of material from the output of the first column 300 to the third column 302.

[0028] In addition, an output series mixing valve is associated with each column. The first output series mixing valve 340 is positioned in a position to enable or disable the flow of material from the output of the first column 300 to the third column 302. The second output series mixing valve 341 is positioned in a position to enable or disable the flow of material from the output of the second column 301 to the first column 300. The third output series mixing valve 342 is positioned in a position to enable or disable the flow of material from the output of the third column 302 to the second column 302.

[0029] Each output series mixing valve also communicates with a respective outlet valve 350, 351, 352 which, when open, discharges waste material from one or more columns to a storage tank or other system.

[0030] It should be noted that the columns and mixing valves may be configured differently. For example, the output from the third column 302 may be fed to the first column 300; the output from the first column 300 may be fed to the input of the second column 301, and the output of the second column 301 may be fed to the input of the third column 302. Thus, Figures 3-5 show one particular embodiment; however, the disclosure is not limited to this embodiment.

[0031] Sensors may be located at various points within this multi-column chromatography system. For example, pH and conductivity sensors may be located at locations 360, 361, and 362. Pressure sensors may be located at locations 370, 371, and 372. In addition, pressure sensors may be located at locations 380 and 381.

[0032] In FIG. 3, the third column 302 and the second column 301 are being loaded. To do this, the product flows through the product fluid line 310 and through the third input mixer valve 322, which is open. Note that the second input mixer valve 321 is closed at this point. The product flows through the third input series mixer valve 332 and into the third column 302. The product then flows out the output of the third column 302 and is routed by the output series mixer valve 342 into the second input series mixer valve 331 and into the input of the second column 301. The product then flows through the second column 301 and exits through the second output series mixer valve 341 and the second outlet valve 351. The remaining valves are closed. Thus, in this configuration, it may be beneficial to measure the pH in the third column 302 and the second column 301. As mentioned above, pH sensors may be placed at locations 360, 361 and 362. In addition, conductivity sensors may also be placed at these locations.

[0033] While the third column 302 and the second column 301 are loaded, the first column 300 is unloaded. This is done by allowing the solvent to pass through the solvent fluid conduit 311 and into the first input mixer valve 320. The solvent passes through the first column 300 and exits through the first output series mixer valve 340.

[0034] Additionally, during the loading process, the pressure in the third column 302 may be approximated using a pressure sensor located at location 380. The conductivity of the material entering the third column 302 may be measured using a conductivity sensor located at location 362. The pressure in the second column 301 may be approximated at the output of the third column 302 using a pressure sensor located at location 372. The conductivity of the material entering the second column 302 may be measured using a conductivity sensor located at location 361. Using the conductivity and pressure measurements from these sensors, the readings from the pH sensors located at locations 361 and 362 may be compensated.

[0035] In other embodiments, pressure sensors may be located at locations 360, 361 and 362.

[0036] FIG. 4 shows the loading of the second column 301 and the first column 300. To do this, the product flows through the product fluid line 310 and through the second input mixer valve 321, which is open. Note that the first input mixer valve 320 is closed at this point. The product flows through the second input series mixer valve 331 and into the second column 301. The product then flows out the output of the second column 301 and is routed by the output series mixer valve 341 into the first input series mixer valve 330 and into the input of the first column 300. The product then flows through the first column 300 and exits through the first output series mixer valve 340 and the first outlet valve 351. The remaining valves are closed. Thus, in this configuration, it may be beneficial to measure the pH in the second column 301 and the first column 300.

[0037] While the second column 301 and the first column 300 are loaded, the third column 302 is unloaded. This is done by allowing the solvent to pass through the solvent fluid conduit 311 and into the third input mix valve 322. The solvent passes through the third column 302 and exits through the third output series mix valve 342.

[0038] As mentioned above, pH sensors may be placed at locations 360, 361 and 362. In addition, conductivity sensors may also be placed at these locations. Furthermore, the pressure of the second column 301 may be approximated using a pressure sensor placed at location 380. The pressure in the first column 301 may be approximated at the output of the second column 301 using a pressure sensor placed at location 371. Using these measurements, the pH readings for the second column 301 and the first column 300 may be compensated.

[0039] FIG. 5 illustrates the loading of the first column 300 and the third column 302. To do this, the product flows through the product fluid line 310 and through the first input mixer valve 320, which is open. Note that the third input mixer valve 322 is closed at this point. The product flows through the first input series mixer valve 330 and into the first column 300. The product then flows out the output of the first column 300 and is routed by the first output series mixer valve 340 into the third input series mixer valve 332 and into the input of the third column 302. The product then flows through the third column 302 and exits through the third output series mixer valve 342 and the third outlet valve 352. The remaining valves are closed. Thus, in this configuration, it may be beneficial to measure pH in the first column 300 and the third column 302.

[0040] The first column 300 and the third column 302 are loaded while the second column 301 is unloaded. This is done by allowing the solvent to pass through the solvent fluid conduit 311 and into the second input mix valve 321. The solvent passes through the second column 301 and exits through the second output series mix valve 341.

[0041] As mentioned above, pH sensors may be placed at locations 360, 361 and 362. In addition, conductivity sensors may also be placed at these locations. Furthermore, the pressure in the first column 300 may be approximated using a pressure sensor placed at location 380. The pressure in the third column 301 may be approximated at the output of the first column 300 using a pressure sensor placed at location 370. Using these measurements, the pH readings for the first column 300 and the third column 302 may be compensated.

[0042] In addition, various sensors may be used during the unloading and regeneration process. A pressure sensor located at location 381 may be used to indicate the pressure entering the column during the unloading process. In FIG. 3, the first column 300 is unloaded. A conductivity sensor and a pH sensor located at location 360 may be used to compensate the pressure readings, if desired. In FIG. 4, the third column 302 is unloaded. A conductivity sensor and a pH sensor located at location 362 may be used to compensate the pressure readings, if desired. In FIG. 5, the second column 301 is unloaded. A conductivity sensor and a pH sensor located at location 361 may be used to compensate the pressure readings, if desired.

[0043] Figure 6 shows another embodiment in which a compensated pH sensor may be utilized. In this figure, a system for virus inactivation is shown. The system for virus inactivation includes a controller 690. The controller 690 is in communication with valves, pumps, pressure sensors, pH sensors, and conductivity sensors.

[0044] In operation, protein 600 may be delivered using protein pump 601. Protein 600 passes through first mixing valve 612. In addition, acid 610 is delivered to first mixing valve 612 using acid pump 611. Protein 600 and acid 610 then enter first static mixer 630 downstream of first mixing valve 612 where they are thoroughly mixed to form a mixture. The mixture then enters incubation chamber 640 where it can remain for a predetermined time. Upon exiting incubation chamber 640, the mixture passes through second mixing valve 622. In addition, base 620 is delivered to second mixing valve 622 using base pump 621. The mixture and base 620 then enter second static mixer 650 downstream of second mixing valve 622 where they are thoroughly mixed. The output of the static mixer 650 may then be used as an input to an anion exchange (AEX), a cation exchange (CEX) or other device or system.

[0045] It may be beneficial to measure the pH of the mixture leaving the first static mixer 630, for example at location 660. Therefore, a first pH sensor may be installed at this location. However, to compensate for changes in pressure and conductivity, a first conductivity sensor and / or a first pressure sensor may also be placed at location 660. This allows a first compensated pH value of the acid and protein mixture to be calculated by the controller 690.

[0046] However, in certain embodiments, the conductivity of the mixture may not change significantly. In this embodiment, the conductivity sensor may be placed elsewhere, for example, before the first static mixer 630, before the first mixing valve 612, or even at the source of protein 600. In other words, the conductivity sensor may be placed upstream of the incubation chamber 640.

[0047] In other embodiments, the conductivity of the mixture may be known and may be manually entered into the controller 690. In this case, a conductivity sensor may not be necessary.

[0048] Similarly, it may be beneficial to measure the pH of the mixture exiting the second static mixer 650, for example at location 670. Therefore, a second pH sensor may be installed at this location. However, to compensate for changes in pressure and conductivity, a second pressure sensor may be placed at location 670. In some embodiments, a second conductivity sensor is also used. This allows a second compensated pH value of the base, acid and protein mixture to be calculated by the controller 690. In other embodiments, the previously provided conductivity is suitable for use in determining the second compensated pH value, and therefore a second conductivity sensor is not used.

[0049] FIG. 7 illustrates an example embodiment that may be applied to any of the bioprocessing systems described above. Typically, a pH sensor, such as pH sensor 700, includes an integrated temperature sensor to compensate for known temperature dependence. Each of the bioprocessing systems described herein may also have a conductivity sensor 710. In certain embodiments where the conductivity of the solution is known, a conductivity sensor may not be used. Rather, the conductivity of the solution may be provided to the controller 750 in other ways. The conductivity may be entered manually or estimated from the buffering agent utilized. In addition, each of the bioprocessing systems described herein may also have at least one pressure sensor 720. Measurements from each of these sensors may be transmitted via a communication system 730, which may be an analog signal or a bus.

[0050] The three values; conductivity, pressure and pH are then fed to the controller 750. The controller 750 first uses the conductivity to determine the slope of the pH / pressure graph, also referred to as the compensation factor. As mentioned above, the relationship between the compensation factor and the conductivity may be a power law, where the conductivity is raised to a power and then multiplied by a constant to produce the slope. The power may be negative.

[0051] Once the compensation factor is determined, this value is then used to compensate the pressure of the solution. As mentioned above, above the threshold pressure, the relationship between pressure and pH is linear, with the slope being determined based on the conductivity of the solution. Thus, if the measured pressure is greater than the threshold pressure, the compensation factor is multiplied by the difference between the measured pressure and the threshold pressure. This result is then added to the measured pH value to produce a compensated value, which is much more accurate than the measured pH value. This compensated pH value may then be used by the controller 750 in a number of ways. In one embodiment, the value may be displayed to a user. As another example, the value may be used by the controller 750 to control the operation of the system. As mentioned above, if the measured pressure is less than the threshold pressure, no compensation is necessary.

[0052] As mentioned above, in some embodiments, the pressure sensor and the conductivity sensor may be co-located with the pH sensor such that all relevant measurements are taken from the same physical location. In other embodiments, the conductivity of the solution may be a constant, known value, so that a conductivity sensor is not required; rather, the conductivity is simply input into the controller. In other embodiments, the pressure sensor may not be co-located with the pH sensor, or may be located in a location that has the same pressure as where the pH sensor is located.

[0053] The embodiment described above in this application may have many advantages. For example, for the multi-column chromatography system of Figures 3 to 5, the pressure at the input to the first column being loaded is much greater than the pressure of the second column being loaded. With a conventional pH sensor, users of this system may be confused or dissatisfied that the pH readings of these two columns differ by up to 0.4. By compensating the pH sensor with conductivity and pressure, the readings from the two columns are much closer to each other. In one test, the compensated pH readings are within 0.03, which is less than the tolerance of the pH sensor. For virus inactivation, the actual pH value is critical because it must remain between the upper and lower limits. If the actual pH is too low, the product quality may deteriorate and the production yield may decrease. If the actual pH is too high, the inactivation may fail and the virus may remain in the solution, creating a safety risk since the inactivation was thought to be successful.

[0054] The present disclosure is not limited in scope by the specific embodiments described herein. Indeed, various other embodiments of the present disclosure and modifications thereof, in addition to the embodiments described herein, will be apparent to those skilled in the art from the above description and the accompanying drawings. Thus, such other embodiments and modifications are intended to be within the scope of the present disclosure. Furthermore, although the present disclosure has been described herein in the context of specific embodiments in specific environments for specific purposes, those skilled in the art will recognize that its usefulness is not limited thereto, and the present disclosure may be beneficially implemented in any number of environments for any number of purposes. Therefore, the appended claims should be construed in light of the full scope and spirit of the present disclosure as described herein.

Claims

1. 1. A system for measuring pH, comprising: A pH sensor for measuring the pH of a solution; A pressure sensor for measuring pressure; Controller and a controller in communication with the pH sensor and the pressure sensor, the controller calculating a compensation amount by multiplying a difference between a pressure measured by the pressure sensor and a threshold pressure by a compensation coefficient, and adding the compensation result to a pH measured by the pH sensor to obtain a compensated pH.

2. The system of claim 1 , wherein the compensation factor is responsive to the conductivity of the solution.

3. The system of claim 2 further comprising a conductivity sensor for measuring the conductivity of the solution.

4. The system of claim 2 , wherein the conductivity of the solution is provided to the controller.

5. 3. The system of claim 2, wherein the compensation factor is the conductivity of the solution raised to a power and multiplied by a constant.

6. The system of claim 5 , wherein the power is a negative number.

7. The system of claim 3 , wherein the conductivity sensor, the pressure sensor and the pH sensor are co-located.

8. 4. The system of claim 3, wherein the conductivity sensor and the pH sensor are co-located and the pressure sensor is located at a location having the same pressure as the location where the pH sensor is located.

9. 1. A multi-column chromatography system comprising: At least three columns; a plurality of valves for directing flow to and from the at least three columns; A pressure sensor; A conductivity sensor; A pressure sensor; Controller and wherein a controller receives inputs from a pressure sensor, a conductivity sensor, and a pH sensor and determines a compensated pH value.

10. 10. The multi-column chromatography system of claim 9, wherein the controller calculates a compensation amount by multiplying a difference between the pressure measured by the pressure sensor and a threshold pressure by a compensation coefficient that is responsive to the conductivity measured by the conductivity sensor, and adds the compensation result to the pH measured by the pH sensor to obtain a compensated pH.

11. 1. A system for virus inactivation comprising: A source of protein; A source of acid; a source of base; a first mixing valve in communication with the protein source and the acid source; a first static mixer downstream of the first mixing valve, an output of the first static mixer comprising the mixture; and an incubation chamber in communication with the output of the first static mixer; a first pH sensor disposed between the output of the first static mixer and the incubation chamber; a first pressure sensor for measuring a pressure of the mixture; a controller that receives information regarding the conductivity of the mixture, receives inputs from the first pressure sensor and the first pH sensor, and determines a first compensated pH value; A system comprising:

12. The system of claim 11 , wherein the first conductivity sensor is disposed between the output of the first static mixer and the incubation chamber.

13. The system of claim 11 , wherein a conductivity sensor is disposed upstream of the incubation chamber to provide information regarding the conductivity of the mixture.

14. The system of claim 11 , wherein the information regarding the conductivity of the mixture is manually provided to the controller.

15. a second mixing valve in communication with the output of the incubation chamber and with a source of base; a second static mixer downstream of the second mixing valve; a second pH sensor disposed at the output of the second static mixer; a second pressure sensor disposed at the output of the second static mixer; 12. The system of claim 11, further comprising: a controller receiving information regarding the conductivity of the mixture and inputs from the second pressure sensor and the second pH sensor and determining a second compensated pH value.

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