Biological process fluid mixing system

Abstract

A bioprocess fluid mixing system (3; 3'; 3''; 103; 103'), the fluid mixing system (3; 3'; 3''; 103; 103') comprising: - at least two fluid inlets (5a, 5b, 5c, 5d, 5e), which are configured to provide a first fluid into the fluid mixing system through a first fluid inlet (5a) and to provide a second fluid into the fluid mixing system through a second fluid inlet (5b); - at least one valve arrangement (13a, 13b, 13c, 13a'), wherein the first valve arrangement (13a; 13a') is in fluid communication with at least the first fluid inlet (5a) and the second fluid inlet (5b); - at least two pumps (11a, 11b, 11c, 11d, 11e), wherein the first pump (11a) is in fluid communication with the second pump (11a) via the first valve arrangement (13a; 13a'). At least first and second fluid inlets (5a, 5b) are in selective fluid communication, and a second pump (11b) is in fluid communication with at least one of the first and second fluid inlets (5b); and a common fluid outlet (14) is in fluid communication with both the outlet (15a) of the first pump (11a) and the outlet (15b) of the second pump (11b), wherein the pump speeds of the at least two pumps (11a, 11b) and the valve positions in the at least one valve arrangement (13a; 13a'; 13b, 13c) are configured to be controllable by a control system (21) so that a requested mixing of at least a first fluid from the first fluid inlet (5a) and a second fluid from the second fluid inlet (5b) into a requested mixing of the at least two fluids and a requested combined fluid flow rate at the common fluid outlet (14) can be performed.

Description

Technical Field

[0001] The present invention relates to a bioprocess fluid mixing system, a method for mixing fluids in a bioprocess fluid mixing system, a bioprocess system, a control system connectable to a bioprocess fluid mixing system, and a computer program product. Background Art

[0002] In bioprocess systems such as chromatography systems, fluid mixing is often required to adjust the composition of the fluid. To implement fluid mixing functionality in a bioprocess system, it is common practice to connect a pump to each fluid inlet in order to mix the fluids. For example, see Figure 1 a, which shows a prior art chromatography system 401 with a fluid mixing system 403. Such systems are often described as gradient forming systems because the composition of the fluid blend can gradually increase or decrease over time, thereby increasing or decreasing the concentration of a component relevant to the separation process. A first inlet 405a is connected to a first pump 411a, and a second inlet 405b is connected to a second pump 411b. The outlets of the first and second pumps are then connected to a common outlet 414 to mix the first fluid provided through the first inlet 405a and the second fluid provided through the second inlet 405b downstream of these pumps. Figure 1b A prior art chromatography system 501 is shown, which includes a fluid mixing system 503 in the form of an online dispensing system. Online dispensing systems typically have three or more pumps and allow for various tasks, depending on the application, to be performed, such as online dilution of a concentrate delivered to the mixing system or preparation of a desired buffer composition by mixing water with an acid, base, and / or salt. An online dispensing system can be an integrated part of another system, as shown here in the example of chromatography system 501, in which a buffer can be continuously prepared in real time at the time of use. Online dispensing systems such as system 503 can also be provided, which can be operated independently, for example, to prepare a desired volume of buffer that can be stored in a container. A first inlet 505a is connected to a first pump 511a, a second inlet 505b is connected to a second pump 511b, a third inlet 505c is connected to a third pump 511c, a fourth inlet 505d is connected to a fourth pump 511d, and a fifth inlet 505e is connected to a fifth pump 511e. The outlets of these pumps are then connected to a common outlet 514 for mixing the fluids provided through the different inlets 505a-505e.

[0003] One problem with these types of fluid mixing systems is that their operating range at low flow rates is limited. If two or more fluids are to be mixed, the combined flow rate output by the pumps when operating together will obviously always be greater than the minimum flow rate achievable when operating a single pump and drawing fluid from a single fluid inlet. Another problem with these types of fluid mixing systems is that the volumetric mixing ratio that can be achieved depends heavily on the operating flow rate, and thus on the combined total output from the pumps. For example, when two pumps have the same minimum flow rate, only a mixing ratio twice the flow rate of each pump can be achieved, 50% of each component, equivalent to a 1+1 mixture. However, to achieve a 1+9 mixture, the pump providing the fluid adjusted to provide 90% of the total fluid flow would need to operate at a flow rate at least nine times the minimum pump flow rate to achieve a 1+9 mixture at a flow rate equal to or greater than ten times the minimum flow rate. Consequently, the operating range of prior art systems is significantly limited in terms of both the minimum flow rate and the ability to achieve a wide range of mixing ratios over a wide range of flow rates. Summary of the Invention

[0004] An object of the present invention is to provide a bioprocess fluid mixing system having a large operating range and a method for mixing fluids in a bioprocess system within a large operating range.

[0005] It is a further object of the present invention to provide a bioprocess fluid mixing system that can provide more flexible mixing capabilities over a wider range of flow rates.

[0006] It is a further object of the present invention to provide an improved method for mixing fluids and an improved bioprocess fluid mixing system that provides flexible and precise mixing capabilities.

[0007] This is achieved in a bioprocess fluid mixing system, a method for mixing fluids in a bioprocess fluid mixing system, a bioprocess system, a control system connectable to a bioprocess fluid mixing system, and a computer program product according to the independent claims.

[0008] According to one aspect of the present invention, a bioprocess fluid mixing system is provided, the fluid mixing system comprising:

[0009] at least two fluid inlets configured to provide a first fluid into the fluid mixing system through a first fluid inlet and to provide a second fluid into the fluid mixing system through a second fluid inlet;

[0010] - at least one valve arrangement, wherein a first valve arrangement is in fluid communication with at least both the first fluid inlet and the second fluid inlet;

[0011] at least two pumps, wherein a first pump is in selective fluid communication with both of at least the first and second fluid inlets via a first valve arrangement, and a second pump is in fluid communication with at least one of the first and second fluid inlets; and

[0012] a common fluid outlet in fluid communication with at least both the outlet of the first pump and the outlet of the second pump,

[0013] wherein the pump speeds of the at least two pumps and the valve positions in the at least one valve arrangement are configured to be controllable by a control system such that mixing of at least a first fluid from a first fluid inlet and a second fluid from a second fluid inlet into a requested mixing of the at least two fluids and a requested combined fluid flow rate at a common fluid outlet can be performed.

[0014] According to another aspect of the present invention, a method for mixing fluids in a bioprocess fluid mixing system according to the above is provided, wherein the method comprises controlling the pump speeds of the at least two pumps and the valve positions of the at least one valve arrangement so that mixing of at least a first fluid from a first fluid inlet and a second fluid from a second fluid inlet can be performed into a requested mixture of the at least two fluids and a requested combined fluid flow rate at a common fluid outlet.

[0015] According to another aspect of the present invention, there is provided a bioprocess system comprising the bioprocess fluid mixing system according to the above.

[0016] According to another aspect of the present invention, a control system is provided, which is connectable to the bioprocess fluid mixing system according to above, wherein the control system is configured to control the at least two pumps and the at least one valve arrangement according to the method as described above.

[0017] According to another aspect of the present invention, there is provided a computer program product comprising instructions which, when executed in a processor in a control system connected to a bioprocess fluid mixing system according to above, cause the control system to perform a method according to above.

[0018] Thus, a fluid mixing system and a method for mixing fluids are provided, wherein fluid mixing can be provided both upstream and downstream of a pump. Thanks to the first valve arrangement, upstream mixing becomes possible. As a result, the flow rate range in which the fluid mixing system can operate is greatly expanded. The lowest possible flow rate is the same as the lowest flow rate of one pump, rather than the sum of the lowest flow rates of two or more pumps. In addition, the combination of upstream and downstream mixing allows a significantly expanded range of mixing ratios between fluids, as the mixing ratio is defined by the average of the difference in pump flow rates and the fluid volumes and / or volumetric flows provided to the inlet of the valve arrangement(s) providing the upstream mixing. In addition, a more flexible fluid mixing system is achieved, in which different fluid components can be mixed in a more efficient and precise manner using the novel invention. Using the novel invention, both the fluid flow rate, the volumetric mixing ratio, and the desired fluid properties of the fluid mixture produced by the different fluid components can be better controlled.

[0019] For low flow rates, as with Figure 1 Compared to prior art systems such as the systems shown in Figures 1a and 1b, all different mixing ratios between the components can be achieved even with only one pump operating alone, while in prior art systems, mixing ratios different from 1+1 blending can only be achieved at flow rates greater than the combined minimum flow capacity of the two pumps involved.

[0020] For high flow rates, as with Figure 1 Compared to prior art systems such as the systems shown in 1a and 1b, thanks to the valve arrangement, all different mixing ratios between the components can also be achieved when both pumps are operated at their maximum capacity, whereas in prior art systems, if the two pumps had the same maximum flow capacity, only 50% mixing could be performed at the maximum flow rate.

[0021] In some embodiments of the present invention, the pump speeds of the at least two pumps and the valve positions in the at least one valve arrangement are configured to be controllable by a control system such that mixing of at least a first fluid from a first fluid inlet and a second fluid from a second fluid inlet into a requested mixture of the at least two fluids and a requested combined fluid flow rate at a common fluid outlet can be performed both upstream of at least the first pump and downstream of the at least two pumps.

[0022] In some embodiments of the present invention, the requested mixing of the at least two fluids is a requested volumetric mixing ratio of the at least two fluids and / or a mixing having one or more requested resulting fluid properties and / or a mixing having one or more requested varied resulting fluid properties.

[0023] In some embodiments of the present invention, the requested synthetic fluid property or the changed synthetic fluid property is a synthetic pH value.

[0024] In some embodiments of the invention, the second pump is connected to both the first and second fluid inlets via a second valve arrangement provided in the fluid mixing system.

[0025] In some embodiments of the present invention, the fluid mixing system is configured for gradient formation, buffer preparation, or in-line dosing in a bioprocess system.

[0026] In some embodiments of the present invention, the at least one valve arrangement comprises at least two inlets and one outlet, and is optionally a switching valve or a proportional valve or a regulating flow valve.

[0027] In some embodiments of the present invention, the bioprocess fluid mixing system further comprises a mixer connected to the common fluid outlet.

[0028] In some embodiments of the present invention, the bioprocess fluid mixing system further comprises at least one sensor arrangement connectable to a control system, the sensor arrangement being configured to measure one or more fluid properties of the mixed at least first and second fluids and / or fluid flow rates in one or more locations in the system, whereby the control system can provide feedback control to the at least two pumps and / or the at least one valve arrangement based on output from the sensor arrangement.

[0029] In some embodiments of the present invention, the method is a method for gradient formation, buffer preparation, or online solution preparation in a bioprocess system.

[0030] In some embodiments of the present invention, the method further comprises the steps of sensing at least one property of the fluid at one or more different locations in the fluid mixing system; and controlling one or more of the at least two pumps and the at least one valve arrangement in dependence on the sensed at least one property to achieve a requested mixing and / or a requested combined fluid flow rate between at least the first and second fluids.

[0031] Further embodiments are described in the dependent claims and in the detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 a schematically shows a prior art bioprocess system.

[0033] Figure 1b A prior art bioprocess system is schematically shown.

[0034] Figure 2a A bioprocess system including a fluid mixing system according to one embodiment of the present invention is schematically illustrated.

[0035] Figure 2bA bioprocess system including a fluid mixing system according to another embodiment of the present invention is schematically shown.

[0036] Figure 2c A bioprocess system including a fluid mixing system according to another embodiment of the present invention is schematically shown.

[0037] Figure 3a A bioprocess system including a fluid mixing system according to another embodiment of the present invention is schematically shown.

[0038] Figure 3b A bioprocess system including a fluid mixing system according to another embodiment of the present invention is schematically shown.

[0039] Figure 4 is a graph showing the difference in operating range between a prior art fluid mixing system and a fluid mixing system according to the present invention.

[0040] Figure 5 is a flow chart of a method for mixing fluids in a bioprocess fluid mixing system according to one embodiment of the present invention. DETAILED DESCRIPTION

[0041] Figure 2a -c shows three different embodiments of a bioprocess fluid mixing system 3; 3'; 3'' arranged in a bioprocess system 1; 1'; 1'' according to the present invention, wherein the example of the bioprocess system 1; 1'; 1'' is a chromatography system. Figure 3a -b shows a bioprocess system 101; 101' comprising a bioprocess fluid mixing system 103; 103' in the form of an online dosing system according to two different embodiments of the present invention, wherein the bioprocess system 101; 101' is an example of a chromatography system. Similar components are given the same reference numerals, and similar components are only referred to in all Figure 2a -c and Figure 3a-b is described once. Here, the bioprocess system 1; 1'; 1''; 101; 101' is a chromatography system, to which a chromatography column 2 can be connected. The chromatography system 1; 1'; 1''; 101; 101' typically also includes an airtight valve 4 and a plurality of different sensors 25, such as one or more of a pressure sensor, a pH sensor, a flow sensor, a temperature sensor, a conductivity sensor, and a UV sensor. The bioprocess system can be another system other than the chromatography system, such as, for example, a bioreactor, a filtration system, etc., that is, the bioprocess fluid mixing system 3; 3'; 3''; 103; 103' according to the present invention can also be used for another type of bioprocess system other than the chromatography system. In other embodiments, the bioprocess fluid mixing system can be set up independently instead of being integrated with another system and unit operation.

[0042] The bioprocess fluid mixing system according to the present invention 3; 3'; 3''; 103; 103' comprises:

[0043] at least two fluid inlets 5a, 5b, 5c, 5d, 5e configured for providing a first fluid into the fluid mixing system via a first fluid inlet 5a and for providing a second fluid into the fluid mixing system via a second fluid inlet 5b;

[0044] - at least one valve arrangement 13a, 13b, 13c, 13a', wherein the first valve arrangement 13a; 13a' is in fluid communication with at least both the first fluid inlet 5a and the second fluid inlet 5b;

[0045] at least two pumps 11a, 11b, 11c, 11d, 11e, wherein the first pump 11a is in selective fluid communication with at least both the first and second fluid inlets 5a, 5b via a first valve arrangement 13a; 13a', whereby the first valve arrangement 13a; 13a' is provided upstream of the first pump 11a and the second pump 11b is in fluid communication with at least one of the first and second fluid inlets 5b; and

[0046] A common fluid outlet 14 in fluid communication with at least the outlet 15a of the first pump 11a and the outlet 15b of the second pump 11b.

[0047] The pump speeds of the at least two pumps 11a, 11b, 11c, 11d, 11e and the valve positions in the at least one valve arrangement 13a; 13a'; 13b, 13c are configured to be controllable by a control system 21 so that mixing of at least a first fluid from the first fluid inlet 5a and a second fluid from the second fluid inlet 5b into a requested mix of the at least two fluids and a requested combined fluid flow rate at the common fluid outlet 14 can be performed. The requested mix of the at least two fluids can be a requested volumetric mix ratio of the at least two fluids and / or a mix having one or more requested composite fluid properties and / or a mix having one or more requested variations of composite fluid properties. The composite fluid property can be, for example, a pH value. A volumetric mix ratio refers to any ratio of two or more fluids and includes controller-requested mixes or mixtures having that ratio or predefined composite properties having that ratio.

[0048] In such Figures 2a-2c In the embodiment shown, only two pumps 11a and 11b are provided in the fluid mixing system, and these pumps are referred to as the first pump 11a and the second pump 11b. Similarly, only two fluid inlets 5a and 5b are provided, and these inlets are referred to as the first fluid inlet 5a and the second fluid inlet 5b. Figure 3a-3b In the embodiment shown, five pumps 11a, 11b, 11c, 11d, 11e and five fluid inlets 5a-5e are provided in the fluid mixing system. An additional sample pump 11f is also provided in the system. Other numbers of pumps, fluid inlets and valve arrangements are also possible within the scope of the present invention.

[0049] Thanks to the at least one valve arrangement 13a; 13a'; 13b; 13c, both upstream of at least the first pump 11a and downstream of the pumps 11a, 11b are possible, rather than only downstream of these pumps (which is like reference Figure 1 a and 1b ) performs mixing of at least a first fluid from a first fluid inlet 5a and a second fluid from a second fluid inlet 5b into a requested mixture of the at least two fluids (such as a requested volumetric mixing ratio or a mixture having requested resultant fluid properties) and a requested combined fluid flow rate at a common fluid outlet 14. Thereby, the flow rate range within which the fluid mixing system 3; 3'; 3''; 103; 103' can operate is extended compared to prior art systems. The lowest possible flow rate is the same as the lowest flow rate of one pump, rather than being the sum of the lowest flow rates of two or more pumps as in prior art systems. This will be relevant with respect to the following Figure 4Further discussion. In addition, a more flexible fluid mixing system is achieved, in which different fluid components can be mixed in a more efficient and precise manner. With the fluid mixing system 3; 3'; 3''; 103; 103' according to the invention, both the fluid flow rate and the volume mixing ratio between the different fluid components can be better controlled. For higher flow rates, when both pumps are working at their maximum capacity, all different mixing ratios between the components can also be achieved thanks to the valve arrangement, which is different from, for example, Figure 1 This is in contrast to prior art systems such as the systems shown in 1a and 1b, where, if both pumps have the same maximum flow capacity, only 50% mixing can be performed at the maximum flow rate. According to the invention, the at least one valve arrangement 13a; 13a'; 13b; 13c makes it possible to redirect the fluid between the fluid inlet and the pump so that all different mixing ratios can be achieved and the pump can be operated at all different desired fluid flow rates. Thereby, a flexible system is achieved, in which both the volumetric mixing ratio and the fluid flow rate can be optimally controlled over the entire range of possible fluid flow rates and mixing ratios. Depending on the type of valve used in the valve arrangement, the mixing ratio can be controlled with different precision and proportions. The proportional valve can be adjusted for any desired mixing ratio. This will have implications for the following Figure 4 Further discussion.

[0050] In some embodiments of the present invention, for low flow rates, such as those between the first and second fluid flow rates (where the first fluid flow rate is the minimum possible flow rate of one of the pumps and the second fluid flow rate is twice the minimum possible flow rate), only one pump (e.g., first pump 11a) is in operation. Thus, within this flow rate range, mixing occurs only upstream of first pump 11a. This allows the system to operate at lower flow rates than prior art systems. Thus, for some flow rates, mixing can be performed only upstream by controlling the position of first valve arrangement 13a. This applies to low flow rates, such as those below twice the minimum possible fluid flow rate of one of the pumps. For higher flow rates, both first and second pumps 11a, 11b are used simultaneously (or, if more pumps and fluid inlets are provided, more pumps are used). For some mixing ratios, it may be appropriate to use only downstream mixing, i.e., each pump pumps only one fluid type, and mixing of the fluids occurs after (i.e., downstream of) these pumps. An example of a situation where using mixing primarily or solely downstream of the pumps and pumping only one fluid type per pump may be beneficial is when the system is equipped with or limited to the use of valve types that are not fast enough or precise enough to blend the desired fluid mixture upstream of the pumps, i.e., at high flow rates. In order to achieve an accurate, substantially uniform, and continuous mixing ratio over time downstream of the pumps, the accuracy and / or responsiveness of the valve action needs to be acceptable. For example, when opening and closing the on-off valve, the action needs to be fast enough to ensure that different fluids packaged in sufficiently small volumes are alternately provided to the pump and system, thereby allowing a smooth and even mixture of substantially steady-state composition to be provided even at higher flow rates. One of the advantages of the system according to the present invention is that upstream mixing can be used to achieve extreme mixing ratios when operating at low flow rates, while downstream mixing can be used at high flow rates in combination with a more moderate mixing ratio in upstream mixing, or alternatively without upstream mixing.

[0051] Therefore, especially for higher fluid flow rates, it is advantageous to use both downstream and upstream mixing simultaneously, i.e., to control both the fluid flow rate of the pumps 11a, 11b, 11c, 11d, 11e and the valve position in the at least one valve arrangement 13a; 13a'; 13b; 13c so that one or more pumps will pump more than one different fluid. This allows the system flow capacity and the different possible mixing ratios to be optimized.

[0052] In some embodiments of the invention, more than one pump is connected to more than one fluid inlet via a valve arrangement. Figure 2cIn the illustrated embodiment, both the first pump 11a and the second pump 11b are connected to both the first and second fluid inlets 5a and 5b via valve arrangements 13a and 13b. The first pump 11a is connected to the first valve arrangement 13a, while the second pump 11b is connected to the second valve arrangement 13b. The first valve arrangement 13a is positioned upstream of the first pump 11a, while the second valve arrangement 13b is positioned upstream of the second pump 11b. This further increases the flexibility of the system. For example, both the first pump 11a and the second pump 11b can be used to pump only the first fluid or only the second fluid, thereby enabling the respective first and second fluids to be pumped separately at a maximum flow rate corresponding to the sum of the maximum flow rate of the first pump 11a and the maximum flow rate of the second pump 11b.

[0053] In such Figure 2c In the fluid mixing system 3 ″ shown, fluid mixing can be performed both upstream of the first pump 11 a and upstream of the second pump 11 b , as well as downstream of both pumps 11 a , 11 b in any combination, which provides a flexible system.

[0054] The fluid mixing system 3; 3'; 3''; 103; 103' according to the present invention can be configured to perform, for example, gradient formation, buffer preparation or online dosing in a bioprocess system 1; 1'; 1''; 101; 101'. Gradient formation in a chromatography system such as Figure 2a -c, and the online liquid preparation in the chromatographic system is as follows Figure 3a In such an online liquid dispensing system, more than two fluids are often mixed, and therefore, more than two pumps 11a-11e and more than two fluid inlets 5a-5e are often provided. Figure 3a and Figure 3b In the embodiment, five pumps 11a-11e are provided, each pump being connected to a separate fluid inlet 5a-5e, and an additional sample pump 11f being connected to the sample inlet 5f. Figure 3a and 3b As shown, acid, base, WFI and salt can be connected to different fluid inlets 5a-5e.

[0055] In such Figure 3a In the fluid mixing system 103 shown, only one valve arrangement is provided, namely the first valve arrangement 13a. The first pump 11a maintains selective fluid communication with the first inlet 5a and the third inlet 5c via the first valve arrangement 13a. Figure 3bIn the fluid mixing system 103' shown, three valve arrangements 13a, 13b, 13c are provided. These three valve arrangements 13a, 13b, 13c are arranged to be connected to different fluid inlets 5a-5d and pumps 11a-d, so that each pump 11a-11d can be connected to each fluid inlet 5a-5d. Thus, flexible mixing can be provided both upstream and downstream of these pumps. Figure 3b In the illustrated example, the first pump 11a is in selective fluid communication with the first and third inlets 5a, 5a, via a first valve arrangement 13a. The second pump 11b is in selective fluid communication with the second and third inlets 5b, 5c, via a second valve arrangement 13b. The fourth pump 11d is in selective fluid communication with the fourth and third inlets 5d, 5d, via a third valve arrangement 13c. The first pump 11a is further in fluid communication with the second fluid inlet 5b via the first and second valve arrangements 13a, 13b, and with the fourth fluid inlet 5d via the first and third valve arrangements 13a, 13c. The second pump 11b is further in fluid communication with the first fluid inlet 5a via the second and first valve arrangements 13b, 13a, and with the fourth fluid inlet 5d via the second and third valve arrangements 13b, 13c. The third pump 11c is in fluid communication with the first fluid inlet 5a via the first valve arrangement 13a, in fluid communication with the second fluid inlet 5b via the second valve arrangement 13b, in direct fluid communication with the third fluid inlet 5c, and in fluid communication with the fourth fluid inlet 5d via the third valve arrangement 13c. The fourth pump 11d is further in fluid communication with the first fluid inlet 5a via the third and first valve arrangements 13c, 13a, and in fluid communication with the second fluid inlet 5d via the third and second valve arrangements 13c, 13b.

[0056] In such Figure 3a and Figure 3b In the system shown, the concentration of the fluid injected into the system can be diluted with water, WFI, which is called in-line dilution. Thanks to the upstream mixing possible in the present invention, the operating range and mixing possibilities of the system at different flow rates are improved as discussed above.

[0057] In some embodiments of the present invention, the first, second and third valve arrangements 13a; 13a'; 13b; 13c used in the present invention as described above each comprise at least two inlets and one outlet, and may be, for example, Figure 2a The switch valve shown or Figure 2bThe proportional valve shown. The switch valve may, for example, include a rotary valve, a swing valve, a lever valve, a diaphragm valve, a pinch valve, etc. For biological treatment systems that require a sanitary design and components that are easy to flush and clean, diaphragm valves, pinch valves, or lever valves are typically used. When using a switch valve, the ratio of the first and second fluids in the mixed fluid is set by controlling the switch valve to switch between the first and second inlets 5a, 5b at a suitable frequency and transferring the appropriate amount of the corresponding first and second fluids to the pump. When using a proportional valve 13a', the appropriate opening of the valve is selected to control the flow rate of each of the first and second fluids on the valve. The valve is controlled to provide different proportions of the first and second fluids, and the valve can be appropriately controlled by a feedback loop from a sensor arrangement 19, which is further arranged below the system to measure one or more fluid properties of the mixed first and second fluids and / or the fluid flow rate in one or more locations in the system.

[0058] In some embodiments of the present invention, the bioprocess fluid mixing system 3; 3 '; 3 ' further includes a mixer 17 connected to the common fluid outlet 14. This allows for further efficient mixing of the different fluid components. Mixer 17 may be particularly desirable to equalize the fluid composition when an on-off valve arrangement is used upstream, or when the piping downstream of the mixing point is not sufficiently long and / or designed to achieve adequate mixing in the piping downstream of the mixing point 14. Mixer 17 may be a static mixer or a dynamic mixer with some active component, such as a moving mixing element, e.g., a rotating or vibrating agitator.

[0059] In some embodiments of the present invention, the bioprocess fluid mixing system 3; 3'; 3''; 103; 103' further includes one or more sensor arrangements 19 connectable to a control system 21. The sensor arrangements 19 are configured to measure one or more fluid properties of the mixed first and second fluids and / or fluid flow rates at one or more locations in the system. Control system 21 can thereby provide feedback control of first and second pumps 11a, 11b and / or first valve arrangement 13a; 13a', and possibly second valve arrangement 13b, based on output from sensor arrangements 19. Sensor arrangements 19 can include various types of sensors, such as pressure sensors, flow sensors, conductivity sensors, temperature sensors, and pH sensors. Thus, volumetric mixing ratios and / or fluid flow rates can be measured in the bioprocess fluid mixing system 3; 3'; 3''; 103; 103', and such sensor information can be used for feedback control within the system.

[0060] While flow sensors may be more suitable for controlling the appropriate volumetric mixing ratio, other sensors (such as conductivity sensors) can also be used to provide similar control of volumetric mixing ratio, provided the characteristics of the sensor response relative to concentration are known. In other embodiments, sensors can be used to provide feedback and control properties in the mixture, not limited to volumetric mixing, but to achieve a certain state and / or property of the mixture that is not necessarily proportional to the volumetric composition. For example, an in-line liquid dispensing system can be used to prepare a buffer with desired properties (such as, for example, a specific pH value). Here, a pH sensor can be used to control the flow rate and volumetric blending of different fluids.

[0061] Figure 4 is a graph showing the difference in operating range between a prior art fluid mixing system (dashed line) and a fluid mixing system according to the present invention (black solid line). Figure 4 In the example shown, a system comprising two pumps with the same operating range (10-100 l / h) is used to illustrate the invention and its advantages over prior art systems. However, the different pumps in the fluid mixing system according to the invention may also have different operating ranges.

[0062] For something like Figure 1 a and Figure 1b Prior art systems, such as the one described in [ ], limit the system flow capacity based on the pumping capacity of each pump. For example, if two pumps are used, each with a pumping capacity of 10-100 l / h, the lowest possible fluid flow rate in the system is 20 l / h, and only a 50% mixing ratio between the first and second fluids is possible. If a different mixing ratio is desired, a higher fluid flow rate must be provided. At a fluid flow rate of 100 l / h, all different mixing ratios are possible. For higher fluid flow rates, the mixing ratio needs to be increasingly closer to 50%.

[0063] According to the novel invention described herein, in which at least one valve arrangement 13a, 13a', or 13b is positioned upstream of one of the pumps, as described above, the system flow capacity is significantly increased. Because it is possible to use only one pump and still mix different fluids via the valve arrangement, the lowest possible fluid flow rate is now equal to the lowest possible fluid flow rate of one of the pumps—for example, 10 l / h, if that is the lower limit of the pump. The possible ratio of the first and second fluids depends on the limitations of the valve arrangement. For some valve arrangements, the mixing ratio may be wider than for others, which may depend on the selected valve technology and design. For example, with proportional control valves, the operating range within which the valve can be controlled with good precision may be limited. Furthermore, for higher flow rates, both pumps can operate at their maximum fluid flow rates, and the combined use of the valve arrangements allows for a much wider range of mixing ratios than is possible with prior art systems. Consequently, the system of the present invention offers a significantly higher operating window for flow capacity and / or mixing ratios than prior art systems.

[0064] According to the present invention, a bioprocess system 1, 1', 1'', 101, 101' is also provided, comprising the bioprocess fluid mixing system 3, 3', 3'', 103, 103' as described above. The bioprocess system can be, for example, a chromatography system 1, 1', 1'', 101, 101'. The bioprocess system can also be, for example, a filtration system or a bioreactor system. The bioprocess system may include a control system 21, which may be connected to the at least two pumps 11a, 11b, 11c, 11d, 11e and the at least one valve arrangement 13a; 13a'; 13b; 13c in the fluid mixing system 3; 3'; 3''; 103; 103', wherein the control system 21 is further connected to one or more sensor arrangements 19 in the fluid mixing system 3; 3'; 3''; 103; 103', wherein the control system 21 is configured to provide feedback control of the volumetric mixing ratio between the first and second fluids and / or the fluid flow rate in the fluid mixing system 3; 3'; 3''; 103; 103' in dependence on an output from the sensor arrangement 19.

[0065] According to the present invention, there is further provided a method for mixing fluids in a bioprocess fluid mixing system 3; 3'; 3''; 103; 103' as described above. A flow chart showing some steps in the method is shown in FIG. Figure 5 The method includes:

[0066] S1: Controlling the pump speeds of the at least two pumps 11a, 11b, 11c, 11d, 11e and the valve positions in the at least one valve arrangement 13a; 13a'; 13b; 13c so that mixing of at least a first fluid from the first fluid inlet 5a and a second fluid from the second fluid inlet 5b into a requested mixing of the at least two fluids and a requested combined fluid flow rate at the common fluid outlet 14 can be performed.

[0067] The method comprises controlling the pump speeds of the at least two pumps 11a, 11b, 11c, 11d, 11e and the valve positions in the at least one valve arrangement 13a; 13a'; 13b; 13c so that mixing of at least a first fluid from the first fluid inlet 5a and a second fluid from the second fluid inlet 5b into a requested mixture of the at least two fluids (such as a requested volumetric mixing ratio and / or a mixture with one or more requested resulting fluid properties and / or a mixture with one or more requested varied resulting fluid properties) and a requested combined fluid flow rate at the common fluid outlet 14 can be performed both upstream of the first pump 11a and downstream of the first and second pumps 11a, 11b.

[0068] The method may be, for example, a method for gradient formation, buffer preparation, online dosing or online dilution in a bioprocess system, such as, for example, a chromatography system.

[0069] S2: Sense at least one property of a fluid at one or more different locations in the fluid mixing system and control one or more of the at least two pumps 11a, 11b, 11c, 11d, 11e and the at least one valve assembly 13a; 13a'; 13b; 13c in dependence on the at least one sensed property to achieve a requested mixing of the at least two fluids, such as a requested volumetric mixing ratio between at least the first and second fluids and / or a mixing having one or more requested resultant fluid properties and / or a requested combined fluid flow rate. The sensed property may be, for example, the fluid flow rate of the first and / or second fluids and / or the fluid flow rate or fluid composition of the mixed fluid, i.e., the volumetric mixing ratio of the first and second fluids in the mixed fluid. The sensed property may also be pressure, conductivity, temperature, or pH.

[0070] According to the present invention, a control system 21 is also provided, which can be connected to the bioprocess fluid mixing system 3; 3'; 3''; 103; 103' as described above, wherein the control system 21 is configured to control the at least two pumps 11a, 11b, 11c, 11d, 11e and the at least one valve arrangement 13a; 13a'; 13b; 13c according to the method as described above.

[0071] According to the present invention, there is also provided a computer program product comprising instructions which, when executed in a processor in a control system 21 connected to a fluid mixing system 3; 3'; 3''; 103; 103', causes the control system 21 to perform the method as described above.

[0072] The present invention offers advantages over existing technologies for preparative applications in biomanufacturing, where practices and technologies require compliance with GMP (Good Manufacturing Practice) requirements. To comply with GMP requirements, the fluid flow path design and its components must be hygienic, allowing them to be provided in a clean and controlled state or to be reconditioned after use and prior to subsequent use. For example, GMP technology may require the use of specific valve technologies, such as diaphragm valves or pinch valves. In one embodiment of the present invention, the flow path and / or its components can be provided as single-use technology. With single-use technology, the flow path is typically provided as a plastic consumable in a clean, ready-to-use state, thereby improving overall processing efficiency and enhancing the safety and integrity of the drug product. Single-use technology can also increase operator safety during infectious or hazardous processing steps, such as those for certain viral processing steps. The flow path can be provided pre-sterilized and equipped with sterile connectors. An example of an existing GMP-compliant preparative single-use chromatography system is GE Healthcare's ÄKTA ready. This system can be used in a gradient configuration to provide mixing system capabilities based on two pumps with separate fluid inlets.

[0073] Preparative GMP systems for bioprocessing can come in various sizes, including large, floor-standing instruments such as the ÄKTA ready. However, small-scale preparative GMP systems are also needed to produce small batches of drug substances, such as for personalized medicines for individual patients or patient populations. These latter systems may be small and benchtop, and single-use technology may be preferred.

[0074] Thus, typical flow rates for a preparative GMP system for bioprocessing may include flow rates of 1 1 / h, 10 1 / h, 100 1 / h, and 1000 1 / h, however, smaller and larger flow rates may also be of interest.

[0075] The system of the present invention can be used to obtain a mixed output flow rate suitable for such a manufacturing GMP system and, therefore, is intended to operate over a wide flow range of 0.1 l / h or less to 1000 l / h or more, depending on the size and scale of the pumps, valves and fluidic interconnections used, but will typically be in the range of 3-500 l / h, for example for the ÄKTA Ready system mentioned above.

Claims

1. A bioprocess fluid mixing system, comprising: - at least two fluid inlets configured to provide a first fluid into the fluid mixing system through a first fluid inlet and to provide a second fluid into the fluid mixing system through a second fluid inlet; - at least one valve arrangement, wherein a first valve arrangement is in fluid communication with at least both the first fluid inlet and the second fluid inlet; at least two pumps, wherein a first pump is in selective fluid communication with at least both of said first and second fluid inlets via said first valve arrangement, and a second pump is in fluid communication with at least one of said first and second fluid inlets; and a common fluid outlet in fluid communication with at least the outlet of the first pump and the outlet of the second pump, wherein the pump speeds of the at least two pumps and the valve positions of the at least one valve arrangement are configured to be controllable by a control system such that a requested mixing of at least a first fluid from the first fluid inlet and a second fluid from the second fluid inlet into the at least two fluids and a requested combined fluid flow rate at the common fluid outlet can be performed upstream of at least the first pump and downstream of the at least two pumps at the same time or, alternatively, at different times.

2. The bioprocess fluid mixing system of claim 1, wherein: The requested mixing of the at least two fluids is a requested volumetric mixing ratio of the at least two fluids and / or a mixing with one or more requested resulting fluid properties and / or a mixing with one or more requested varied resulting fluid properties.

3. The bioprocess fluid mixing system of claim 2, wherein: The requested synthetic fluid property or the synthetic fluid property that is varied is synthetic pH.

4. The bioprocess fluid mixing system of claim 1, wherein: The second pump is connected to both the first and second fluid inlets via a second valve arrangement provided in the fluid mixing system.

5. The bioprocess fluid mixing system of claim 1, wherein: The fluid mixing system is configured for gradient formation, buffer preparation, or online dosing in a bioprocess system.

6. The bioprocess fluid mixing system of claim 1, wherein: The at least one valve arrangement comprises at least two inlets and one outlet and is optionally an on-off valve or a proportional valve or a regulating flow valve.

7. The bioprocess fluid mixing system of claim 1, further comprising a mixer connected to the common fluid outlet.

8. The bioprocess fluid mixing system of claim 1 , further comprising at least one sensor arrangement connectable to the control system, the sensor arrangement configured to measure one or more fluid properties of the mixed at least first and second fluids and / or fluid flow rates in one or more locations in the system, whereby the control system can provide feedback control to the at least two pumps and / or the at least one valve arrangement based on output from the sensor arrangement.

9. A method for mixing fluids in a bioprocess fluid mixing system according to any one of claims 1 to 8, wherein: The method includes controlling the pump speeds of the at least two pumps and the valve positions in the at least one valve arrangement so that mixing of at least a first fluid from the first fluid inlet and a second fluid from the second fluid inlet into a requested mixing of the at least two fluids and a requested combined fluid flow rate at the common fluid outlet can be performed.

10. The method of claim 9, wherein: The method comprises controlling the pump speeds of the at least two pumps and the valve positions of the at least one valve arrangement such that mixing of at least a first fluid from the first fluid inlet and a second fluid from the second fluid inlet into a requested mixing of the at least two fluids and a requested combined fluid flow rate at the common fluid outlet can be performed both upstream of the first pump and downstream of the pump.

11. The method according to any one of claims 9 to 10, wherein: The method is used for gradient formation, buffer preparation or online solution preparation in a bioprocess system.

12. The method according to any one of claims 9 to 10, further comprising the steps of: sensing at least one property of the fluid at one or more different locations in the fluid mixing system; and controlling one or more of the at least two pumps and the at least one valve arrangement in dependence upon the sensed at least one property to achieve a requested mixing and / or a requested combined fluid flow rate between at least the first and second fluids.

13. A bioprocess system comprising the bioprocess fluid mixing system according to any one of claims 1 to 8.

14. The bioprocess system of claim 13, wherein: The bioprocess system is a chromatography system.

15. The bioprocess system of claim 13 or 14, further comprising a control system connectable to the at least two pumps and the at least one valve arrangement in the fluid mixing system, wherein The control system is further connected to one or more sensor arrangements in the fluid mixing system, wherein the control system is configured to provide feedback control of the volumetric mixing ratio between at least the first and second fluids and / or the fluid flow rate in the fluid mixing system in dependence on output from the sensor arrangements.

16. A control system connectable to the bioprocess fluid mixing system according to any one of claims 1 to 8, wherein: The control system is configured to control the at least two pumps and the at least one valve arrangement according to the method of any of claims 9-12.

17. A computer program product comprising instructions which, when executed in a processor in a control system connected to a fluid mixing system according to any one of claims 1 to 8, cause the control system to perform the method according to any one of claims 9 to 12.

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