Bioprocess Fluid Mixing Systems

Abstract

A bioprocess fluid mixing system (3, 3', 3'', 103, 103') comprising at least two fluid inlets (5a, 5b, 5c, 5d, 5e) configured for providing a first fluid into the fluid mixing system through a first fluid inlet (5a) and for providing a second fluid into the fluid mixing system through a second fluid inlet (5b), and at least one valve arrangement (13a, 13b, 13c, 13a'), wherein the first valve arrangement at least one valve arrangement (13a, 13a') in fluid communication with at least both the first fluid inlet (5a) and the second fluid inlet (5b); and at least two pumps (11a, 11b, 11c, 11d, 11e), wherein a first pump (11a) is in selective fluid communication with at least both the first and second fluid inlets (5a, 5b) via the first valve arrangement (13a, 13a') and a second pump (11a, 11b, 11c, 11d, 11e). The pump (11b) includes at least two pumps (11a, 11b, 11c, 11d, 11e) in fluid communication with at least one of the first and second fluid inlets (5b), and a common fluid outlet (14) in fluid communication with both the outlet (15a) of the first pump (11a) and the outlet (15b) of the second pump (11b), and at least a first fluid from the first fluid inlet (5a) and a second fluid from the second fluid inlet (5b) are mixed together. a bioprocess fluid mixing system (3, 3', 3'', 103, 103') configured such that the pump speeds of at least two pumps (11a, 11b) and the valve positions in at least one valve arrangement (13a, 13a', 13b, 13c) are controllable by a control system (21) to perform up to a required mixing of at least two fluids and up to a required total fluid flow rate at a common fluid outlet (14).

Description

[Technical field]

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

[0002] In bioprocessing systems, such as chromatography systems, fluid mixing is often required to adjust the composition of fluids. To achieve fluid mixing functionality in bioprocessing systems, it is common practice to connect one pump to each fluid inlet for the fluids to be mixed. See for example FIG. 1a, which shows a prior art chromatography system 401 with a fluid mixing system 403. Such systems are usually described as gradient forming systems, since the composition of the fluid blend can be gradually increased or decreased over time to increase or decrease the strength of the components relevant to the separation process. The first inlet 405a is connected to a first pump 411a, and the 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 for mixing the first fluid provided through the first inlet 405a and the second fluid provided through the second inlet 405b downstream of the pumps. FIG. 1b shows a prior art chromatography system 501 including a fluid mixing system 503 in the form of an in-line conditioning system. In-line conditioning systems usually have three or more pumps, making it possible to accomplish various tasks depending on the application, for example, in-line dilution of concentrates fed into a mixing system, or preparation of a desired buffer composition based on mixing water with an acid, base and / or salt. In-line conditioning systems can be an integrated part of other systems, as shown here in the example of a chromatography system 501, and can prepare buffers continuously, in real time and at the point of use. In-line conditioning systems, such as system 503, can also be provided and 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 the pumps are then connected to a common outlet 514 for mixing the fluids provided through the different inlets 505a-505e.

[0003] A problem with these types of fluid mixing systems is that they have a limited operating range at low flow rates. If two or more fluids are to be mixed, the total flow output when the respective pumps are operated together will obviously always be greater than the minimum flow rate that can be achieved when a single pump is operated to pump the fluids from a single fluid inlet. Another problem with these types of fluid mixing systems is that the volumetric mixing ratio that can be achieved is strongly dependent on the operating flow rate and therefore the total total output from said pumps. For example, when having two pumps with the same minimum flow rate, only a mixing ratio containing 50% of each component, corresponding to a 1+1 mixture, can be achieved with twice the flow rate of the individual pumps. However, if a 1+9 mixture is to be achieved, a pump providing fluids tuned to provide 90% of the total fluid flow must be operated at a flow rate at least 9 times the minimum pump flow rate to achieve a 1+9 mixture at a flow rate of 10 times or more the minimum flow rate. As a result, the operating range of the prior art systems is strongly limited with respect to the minimum flow rate and with respect to achieving a wide range of mixing ratios over a wide range of flow rates. Summary of the Invention [Problem to be solved by the invention]

[0004] It is an object of the present invention to provide a bioprocessing fluid mixing system having a greater operating range and a method for mixing fluids in a bioprocessing system over a greater operating range.

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

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

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

[0008] According to one aspect of the present invention, there is provided a bioprocessing fluid mixing system, the 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, a first valve arrangement in fluid communication with at least both the first fluid inlet and the second fluid inlet; at least two pumps, a first pump in selective fluid communication with both at least a first and a second fluid inlet via a first valve arrangement, and a second pump in fluid communication with at least one of the first and second fluid inlets; a common fluid outlet in fluid communication with both the first pump outlet and the second pump outlet; Including, 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 the control system such that mixing of the first fluid from the at least first fluid inlet and the second fluid from the second fluid inlet can be performed up to a required mixing of the at least two fluids and up to a required total fluid flow rate at the common fluid outlet.

[0009] According to another aspect of the invention there is provided a method for mixing fluids in a bioprocess fluid mixing system as described above, said method comprising controlling pump speeds of at least two pumps and valve positions in at least one valve arrangement to effect mixing of at least a first fluid from a first fluid inlet and a second fluid from a second fluid inlet into a required mix of the at least two fluids and into a required total fluid flow rate at a common fluid outlet.

[0010] According to another aspect of the present invention, there is provided a bioprocessing system comprising the bioprocessing fluid mixing system described above.

[0011] According to another aspect of the invention, there is provided a control system connectable to the bioprocessing fluid mixing system described above, said control system configured to control at least two pumps and at least one valve arrangement in accordance with the method as described above.

[0012] According to another aspect of the invention there is provided a computer program product comprising instructions which, when executed on a processor in a control system connected to the fluid mixing system described above, cause the control system to perform the method described above.

[0013] This provides a fluid mixing system and a method for mixing fluids that can provide mixing of fluids both upstream and downstream of the pumps. Upstream mixing is possible thanks to the first valve configuration. This greatly expands the flow rate range at which the fluid mixing system can operate. The minimum possible flow rate is the same as the minimum flow rate for one pump, not the sum of the minimum flow rates for two or more pumps. Furthermore, the combination of upstream and downstream mixing allows a greatly expanded range of mixing ratios between fluids, since the mixing ratio is defined by the average of the difference in pump flow rates and the difference in fluid volumes and / or volumetric flow rates provided to the inlets of the valve configuration that provides the upstream mixing. Furthermore, a more flexible fluid mixing system is achieved with this new invention, which can mix different fluid components in a more effective and accurate way. Both the fluid flow rates, the volumetric mixing ratios, and the required fluid properties of the fluid mixture resulting from the different fluid components can be better controlled with this new invention.

[0014] At low flow rates, all different mixing ratios between the components can be achieved even if only one pump is operating alone, and in contrast to prior art systems such as those shown in Figures 1a and 1b, which can only achieve mixing ratios different from 1+1 blending at flow rates greater than the minimum combined flow rate of the two pumps involved.

[0015] At high flow rates, thanks to the valve configuration and in contrast to prior art systems such as those shown in Figures 1a and 1b, which can only perform a 50% mix at maximum flow rate if the two pumps have the same maximum flow rate, all different mix ratios between the components can be achieved even when both pumps are operating at their maximum capacity.

[0016] In some embodiments of the invention, the pump speeds of the at least two pumps and the valve positions in at least one valve arrangement are configured to be controllable by a control system such that mixing of a first fluid from at least a first fluid inlet and a second fluid from a second fluid inlet into a required mix of the at least two fluids and into a required total fluid flow rate at a common fluid outlet can be performed both upstream of the at least first pump and downstream of the at least two pumps.

[0017] In some embodiments of the invention, the desired mixing of at least two fluids is a desired volumetric mix ratio of the at least two fluids and / or a mixing with one or more desired result fluid properties and / or a mixing with one or more desired changing result fluid properties.

[0018] In some embodiments of the invention, the resultant fluid property that is desired or that is changed is the resultant pH.

[0019] In some embodiments of the invention, a second pump is connected to both the first and second fluid inlets via a second valve arrangement provided in the fluid mixing system.

[0020] In some embodiments of the invention, the fluid mixing system is configured for gradient formation, buffer preparation or in-line conditioning in a bioprocessing system.

[0021] In some embodiments of the invention, the at least one valve arrangement comprises at least two inlets and one outlet, and is optionally a switch valve or a proportional or flow regulating valve.

[0022] In some embodiments of the invention, the bioprocess fluid mixing system further comprises a mixer connected to the common fluid outlet.

[0023] In some embodiments of the invention, the bioprocess fluid mixing system further includes at least one sensor arrangement connectable to the control system, said sensor arrangement configured to measure one or more fluid properties of the mixed at least first and second fluids and / or fluid flow rates at one or more locations in the system, such that the control system can provide feedback control to the at least two pumps and / or at least one valve arrangement based on output from the sensor arrangement.

[0024] In some embodiments of the invention, the method is a method for gradient formation, buffer preparation or in-line conditioning in a bioprocessing system.

[0025] In some embodiments of the invention, the method further comprises sensing at least one property in the fluids at one or more different locations in the fluid mixing system and controlling one or more of the at least two pumps and at least one valve configuration in response to the at least one sensed property to achieve a desired mixing between the at least first and second fluids and / or a desired total fluid flow rate.

[0026] Further embodiments are described in the dependent claims and the detailed description. [Brief description of the drawings]

[0027] [Figure 1a] FIG. 1 shows a schematic diagram of a prior art bioprocessing system. [Figure 1b] FIG. 1 shows a schematic diagram of a prior art bioprocessing system. [Figure 2a] FIG. 1 illustrates a schematic diagram of a bioprocessing system including a fluid mixing system according to one embodiment of the present invention. [Figure 2b] FIG. 1 shows a schematic diagram of a bioprocessing system including a fluid mixing system according to another embodiment of the present invention. [Figure 2c]FIG. 1 shows a schematic diagram of a bioprocessing system including a fluid mixing system according to another embodiment of the present invention. [Figure 3a] FIG. 1 shows a schematic diagram of a bioprocessing system including a fluid mixing system according to another embodiment of the present invention. [Figure 3b] FIG. 1 shows a schematic diagram of a bioprocessing system including a fluid mixing system according to another embodiment of the present invention. [Figure 4] FIG. 2 illustrates the difference in operating range between a prior art fluid mixing system and a fluid mixing system according to the present invention. [Diagram 5] 1 is a flow chart of a method for mixing fluids in a bioprocessing fluid mixing system according to one embodiment of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0028] Figures 2a-2c show three different embodiments of a bioprocessing fluid mixing system 3, 3', 3'' provided in a bioprocessing system 1, 1', 1'' according to the invention, examples of which are chromatography systems. Figures 3a-3b show a bioprocessing system 101, 101', examples of which are chromatography systems including a bioprocessing fluid mixing system 103, 103' in the form of an in-line conditioning system according to two different embodiments of the invention. Similar components are given the same reference numbers and will be described only once with reference to all Figures 2a-2c and 3a-3b. The bioprocessing systems 1, 1', 1'', 101, 101' are here chromatography systems to which a chromatography column 2 can be connected. The chromatography system 1, 1', 1'', 101, 101' usually also includes an air trap 4 and several 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 bioprocessing system may be a separate system from the chromatography system, e.g. a bioreactor, a filtration system, etc., i.e. the bioprocessing fluid mixing system 3, 3', 3'', 103, 103' according to the invention may also be used in other types of bioprocessing systems other than a chromatography system. In other embodiments the bioprocessing fluid mixing system may be provided independently and may not be integrated with other systems and unit operations.

[0029] The bioprocessing fluid mixing system 3, 3', 3'', 103, 103' according to the invention comprises: at least two fluid inlets 5a, 5b, 5c, 5d, 5e configured for providing a first fluid into the fluid mixing system through a first fluid inlet 5a and for providing a second fluid into the fluid mixing system through a second fluid inlet 5b; at least one valve arrangement 13a, 13b, 13c, 13a', where 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; at least two pumps 11a, 11b, 11c, 11d, 11e, where a 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 a second pump 11b is in fluid communication with at least one of the first and second fluid inlets 5b; 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; Includes.

[0030] The pump speeds of at least two pumps 11a, 11b, 11c, 11d, 11e and the valve positions in at least one valve arrangement 13a, 13a', 13b, 13c are configured to be controllable by a control system 21 so that a mixing of at least a first fluid from a first fluid inlet 5a and a second fluid from a second fluid inlet 5b can be performed up to a required mixing of the at least two fluids and up to a required total fluid flow rate at a common fluid outlet 14. The required mixing of the at least two fluids can be a required volumetric mixing ratio of the at least two fluids and / or a mixing with one or more required result fluid properties and / or a mixing with one or more required changing result fluid properties. The result fluid property can be for example pH. By volumetric mixing ratio is meant any ratio of two or more fluids, including a controller requested mixing or mixture having that ratio or having a predefined result property of that ratio.

[0031] In the embodiment shown in Figures 2a-c, only two pumps 11a, 11b are provided in the fluid mixing system, which are called the first pump 11a and the second pump 11b. Similarly, only two fluid inlets 5a, 5b are provided, which are called the first fluid inlet 5a and the second fluid inlet 5b. In the embodiment shown in Figures 3a-b, five pumps 11a, 11b, 11c, 11d, 11e and five fluid inlets 5a-5e are provided in the fluid mixing system. One additional sample pump 11f is also provided in the system. Other numbers of pumps, fluid inlets and valve configurations are possible within the scope of the invention.

[0032] Thanks to at least one valve arrangement 13a, 13a', 13b, 13c, the mixing of at least two fluids into a required mix, such as a mix of at least a first fluid from a first fluid inlet 5a and a second fluid from a second fluid inlet 5b with a required volumetric mix ratio or with required resulting fluid properties, and into a required total fluid flow rate at a common fluid outlet 14, can be performed both upstream of at least the first pump 11a and downstream of the pumps 11a, 11b, instead of only downstream of the pumps as is the case in the prior art systems described with reference to Figs. 1a and 1b. This results in an increased flow rate range in which the fluid mixing system 3, 3', 3'', 103, 103' can operate compared to the prior art systems. The possible minimum flow rate is the same as the minimum flow rate for one pump, instead of the sum of the minimum flow rates for two or more pumps as in the prior art systems. This is discussed further in relation to Fig. 4 below. Furthermore, a more flexible fluid mixing system is achieved, which is able to mix different fluid components in a more effective and precise manner. Both the fluid flow rates and the volumetric mix ratios between the different fluid components can be better controlled with the fluid mixing system 3, 3', 3'', 103, 103' according to the invention. At high flow rates, thanks to the valve arrangement and also when both pumps are working at their maximum capacity, in contrast to the prior art systems as shown in Fig. 1a and 1b, where only a 50% mix can be performed at maximum flow rate if the two pumps have the same maximum flow rate. According to the invention, at least one valve arrangement 13a, 13a', 13b, 13c allows the fluid to be routed between the fluid inlet and the pump, so that all different mix ratios can be achieved and the pump can be operated at all different desired fluid flow rates. This achieves a flexible system where both the volumetric mix ratios and the fluid flow rates can be optimally controlled over the entire range of possible fluid flow rates and mix ratios. Depending on the type of valves used in the valve arrangement, the mix ratios can be controlled with different precisions and ratios. Proportional valves allow adjustment to any desired mix ratio. This is discussed further in relation to Fig. 4 below.

[0033] In some embodiments of the invention, only one pump, for example the first pump 11a, is operated at a low flow rate, for example a flow rate between a first fluid flow rate and a second fluid flow rate, said first fluid flow rate being the minimum possible flow rate for one of the pumps and said second fluid flow rate being twice this minimum possible flow rate. This allows the mixing to be performed only upstream of the first pump 11a in this flow rate range. This allows the system to be operated at lower flow rates than prior art systems. This allows that at some flow rates, i.e. low, for example lower than twice the minimum possible fluid flow rate for one of the pumps, mixing can be performed only upstream by controlling the position of the first valve arrangement 13a. At higher flow rates, both the first and second pumps 11a, 11b (or more pumps if more pumps and more fluid inlets are provided) 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 the mixing of the fluids is performed after the pumps, i.e. downstream of the pumps. An example of a situation where it may be beneficial to use mixing primarily or solely downstream of the pumps and to pump only one fluid type by each pump is when the system is equipped or limited to use valve types that are not fast or accurate enough to blend the desired fluid mixture upstream of the pumps, i.e., at high flow rates. To achieve an accurate, substantially uniform and continuous mixture ratio downstream of the pump over time, the precision and / or responsiveness in the valve action must be acceptable. For example, when switching the switch valve on and off, this action must be fast enough to ensure that sufficiently small packages of different fluids are alternately provided to the pumps and the system to provide a smooth, averaged mixture of substantially steady-state composition even at higher flow rates. One advantage of the system according to the invention is that upstream mixing can be utilized to achieve extreme mixture ratios when operating at low flow rates, while downstream mixing combined with a more gentle mixture ratio in the upstream mixing, or alternatively without upstream mixing, can be used at high flow rates.

[0034] Therefore, especially at higher fluid flow rates, it is advantageous to use both downstream and upstream mixing, i.e. to control both the fluid flow rates of the pumps 11a, 11b, 11c, 11d, 11e and the valve positions in at least one valve arrangement 13a, 13a', 13b, 13c, such that one or more of the pumps pump more than one different fluid, thereby optimizing the flow rates of the system and the different possible mixing ratios.

[0035] In some embodiments of the invention, more than one of the pumps is connected to more than one of the fluid inlets via a valve arrangement. In the embodiment shown in FIG. 2c, both the first pump 11a and the second pump 11b are connected to both the first and second fluid inlets 5a, 5b via the valve arrangements 13a, 13b. The first pump 11a is connected to the first valve arrangement 13a and the second pump 11b is connected to the second valve arrangement 13b. The first valve arrangement 13a is provided upstream of the first pump 11a and the second valve arrangement 13b is provided 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 pumping each of the first and second fluids separately at a maximum flow rate corresponding to a flow rate that is the sum of the maximum flow rate for the first pump 11a and the maximum flow rate for the second pump 11b.

[0036] In the fluid mixing system 3'' as shown in FIG. 2c, fluid mixing can be performed both upstream of the first pump 11a and upstream of the second pump 11b and downstream of the two pumps 11a, 11b in any combination providing a flexible system.

[0037] The fluid mixing system 3, 3', 3'', 103, 103' according to the invention can be configured to perform e.g. gradient formation, buffer preparation or in-line conditioning in a bioprocessing system 1, 1', 1'', 101, 101'. Gradient formation in a chromatography system is illustrated in Fig. 2a-2c and in-line conditioning in a chromatography system is illustrated in Fig. 3a-3b. Since more than two fluids are usually mixed in such an in-line conditioning system, more than two pumps 11a-11e and more than two fluid inlets 5a-5e are usually also provided. In Fig. 3a and 3b five pumps 11a-11e are provided, each connected to one separate fluid inlet 5a-5e and one additional sample pump 11f is connected to the sample inlet 5f. For example acid, base, WFI and salt can be connected to different fluid inlets 5a-5e as shown in Fig. 3a and 3b.

[0038] In the fluid mixing system 103 as shown in FIG. 3a, only one valve arrangement is provided, the first valve arrangement 13a. The first pump 11a is in selective fluid communication with the first inlet 5a and the third inlet 5c via the first valve arrangement 13a. In the fluid mixing system 103′ as shown in FIG. 3b, three valve arrangements 13a, 13b, 13c are provided. The three valve arrangements 13a, 13b, 13c are provided connected to different fluid inlets 5a-5d and pumps 11a-d, such that each of the pumps 11a-11d can be connected to each of the fluid inlets 5a-5d. This allows flexible mixing both upstream and downstream of the pumps to be provided. In this example as shown in FIG. 3b, the first pump 11a is in selective fluid communication with the first inlet 5a and the third inlet 5c via the first valve arrangement 13a. The second pump 11b is in selective fluid communication with the second inlet 5b and the third inlet 5c via the second valve arrangement 13b. The fourth pump 11d is in selective fluid communication with the fourth inlet 5d and the third inlet 5c via the 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 in fluid communication 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 in fluid communication 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 5b via the third and second valve arrangements 13c, 13b.

[0039] In the system shown in Figures 3a and 3b, the concentration of the fluid fed into the system can be diluted with water, WFI, called in-line dilution. Thanks to the present invention that allows upstream mixing, the operating range and mixing possibilities at different flow rates of the system are improved as discussed above.

[0040] As described above, the first, second and third valve arrangements 13a, 13a', 13b, 13c used in the present invention each include at least two inlets and one outlet in some embodiments of the present invention, and can be, for example, a switch valve as shown in FIG. 2a or a proportional valve as shown in FIG. 2b. The switch valve can include, for example, a rotary valve, a rocker valve, a lever valve, a diaphragm valve, a pinch valve, etc. In bioprocessing systems where hygienic design and easy to wash and clean parts are required, diaphragm, pinch or lever valves are commonly used. When a switch valve is used, 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 an appropriate frequency to transfer an appropriate amount of each of the first and second fluids to the pump. When a proportional valve 13a' is used, an appropriate opening degree of the valve is selected to control the flow of each of the first and second fluids over the valve. The valves are controlled to provide different ratios of the first and second fluids and may be suitably controlled by a feedback loop from a sensor arrangement 19 further down in the system 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.

[0041] In some embodiments of the invention, the bioprocess fluid mixing system 3, 3', 3'' further comprises a mixer 17 connected to the common fluid outlet 14, which allows for more effective mixing of the different fluid components. The mixer 17 may be particularly required to average the fluid composition when using a switch valve configuration upstream or when the piping configuration downstream of the mixing point 14 cannot be provided with sufficient length and / or design to achieve sufficient mixing in the piping downstream of the mixing point. The mixer 17 may be a static mixer or a dynamic mixer with some active components such as moving mixing elements, e.g., a rotating or vibrating agitator.

[0042] In some embodiments of the invention, the bioprocessing fluid mixing system 3, 3', 3'', 103, 103' further comprises one or more sensor arrangements 19 connectable to the control system 21, said sensor arrangements 19 being configured for measuring 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, such that the control system 21 can provide feedback control of the first and second pumps 11a, 11b and / or the first valve arrangement 13a, 13a' and possibly the second valve arrangement 13b based on the output from the sensor arrangement 19. The sensor arrangement 19 can comprise different types of sensors such as pressure sensors, flow sensors, conductivity, temperature and pH sensors. This allows the volumetric mixing ratio and / or fluid flow rates to be measured in the bioprocessing fluid mixing system 3, 3', 3'', 103, 103' and this sensor information can be used for feedback control in the system.

[0043] Although flow sensors may be preferred to control the appropriate volumetric mix ratio, other sensors, such as conductivity sensors, may be utilized to equally provide control over the volumetric mix ratio, provided the characteristics of the sensor response versus concentration are known. In other embodiments, sensors may be used to provide feedback and control over properties in the mixture, which are not limited to volumetric mixing, but instead to achieve specific conditions and / or properties of the mixture, which are not necessarily proportional to the volumetric composition. For example, an in-line conditioning system may be used to prepare a buffer with desired properties, such as a specific pH. Here, a pH sensor may be utilized to control the flow rate and volumetric blending of different fluids.

[0044] Figure 4 shows the difference in operating range between a prior art fluid mixing system (dotted line) and a fluid mixing system according to the invention (black, solid line). In the example shown in Figure 4, a system with two pumps with the same operating range (10-100 l / h) is used to explain the invention and its advantages over the prior art system. However, the different pumps in the fluid mixing system according to the invention can also have different operating ranges.

[0045] In prior art systems such as those described in Figures 1a and 1b, the flow rate of the system is limited depending on the pumping power of each pump. For example, if two pumps are used, both with a pumping power of 10-100 l / h, the lowest fluid flow rate that can be used in the system is 20 l / h, at which only a 50% mixing between the first and second fluids is possible. If other mixing ratios are desired, a higher fluid flow needs to be provided. With a fluid flow of 100 l / h, all different mixing ratios are possible. With higher fluid flows, the mixing ratio needs to get closer and closer to 50%.

[0046] According to the new invention described herein, where at least one valve arrangement 13a, 13a', 13b is provided upstream of one of the pumps as described above, the flow rate of the system is considerably increased. Thanks to the possibility of using only one pump and still mixing different fluids through the valve arrangement, the minimum possible fluid flow rate is instead equal to the minimum possible fluid flow rate for one of the pumps, i.e. if for example 10 l / h is the lower limit for both pumps. The possible ratio of the first and second fluids depends on the limitations of the valve arrangement. Some valve arrangements allow wider mixing ratios than other arrangements, which may depend on the selected valve technology and design. With proportional control valves, for example, the operating range in which the valve can be controlled with high precision may be limited. Furthermore, at higher flow rates, both pumps can be operated at their maximum fluid flow rate and by using the valve arrangements in combination, a wider, significantly wider range of mixing ratios than in the prior art, can be achieved. As a result, the operating window of the system in terms of flow rate and / or mixing ratio is considerably higher in the present invention compared to the prior art systems.

[0047] According to the invention there is also provided a bioprocessing system 1, 1', 1'', 101, 101' comprising a bioprocessing fluid mixing system 3, 3', 3'', 103, 103' as described above. The bioprocessing system may for example be a chromatography system 1, 1', 1'', 101, 101'. The bioprocessing system may also for example be a filtration system or a bioreactor system. The bioprocessing system may include a control system 21 connectable to at least two pumps 11a, 11b, 11c, 11d, 11e and at least one valve arrangement 13a, 13a', 13b, 13c in the fluid mixing system 3, 3', 3'', 103, 103', said control system 21 further connected to one or more sensor arrangements 19 in the fluid mixing system 3, 3', 3'', 103, 103', and configured to provide feedback control of the volumetric mixing ratio and / or fluid flow rate between the first and second fluids in the fluid mixing system 3, 3', 3'', 103, 103' depending on the output from the sensor arrangement 19.

[0048] According to the 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 of the method is shown in Figure 5. The method comprises:

[0049] S1: Controlling pump speeds of at least two pumps 11a, 11b, 11c, 11d, 11e and valve positions in at least one valve arrangement 13a, 13a', 13b, 13c so as to be able to perform 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 required mixture of the at least two fluids and into a required total fluid flow rate at a common fluid outlet 14.

[0050] The method comprises controlling pump speeds of at least two pumps 11a, 11b, 11c, 11d, 11e and valve positions in at least one valve arrangement 13a, 13a', 13b, 13c such that 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 required mixture of the at least two fluids, such as a required volumetric mix ratio and / or a mixture with one or more required result fluid properties and / or a mixture with one or more required varying result fluid properties, and into a required total fluid flow rate at a common fluid outlet 14 can be performed both upstream of the first pump 11a and downstream of the first and second pumps 11a, 11b.

[0051] The method can be, for example, a method for gradient formation, buffer preparation, in-line conditioning or in-line dilution in a bioprocessing system, such as, for example, a chromatography system.

[0052] S2: Sense at least one property in the fluids at one or more different locations in the fluid mixing system and control one or more of at least two pumps 11a, 11b, 11c, 11d, 11e and at least one valve assembly 13a, 13a', 13b, 13c according to the at least one sensed property to achieve a required mixing of at least two fluids, such as a required volumetric mixing ratio between at least a first and a second fluid and / or a mixing with one or more required resultant fluid properties and / or a required total fluid flow rate. The sensed property can be, for example, the fluid flow rate of the first and / or second fluid and / or the fluid flow rate of the mixed fluid or fluid composition, i.e., the volumetric mixing ratio of the first and second fluids in the mixed fluid. The sensed property can also be pressure, conductivity, temperature or pH.

[0053] According to the present invention there is also provided a control system 21 connectable to a bioprocess fluid mixing system 3, 3', 3'', 103, 103' as described above, said control system 21 configured to control at least two pumps 11a, 11b, 11c, 11d, 11e and at least one valve arrangement 13a, 13a', 13b, 13c according to the method as described above.

[0054] According to the present invention, there is also provided a computer program product comprising instructions which, when executed on a processor in a control system 21 connected to a fluid mixing system 3, 3', 3'', 103, 103' as described above, cause the control system 21 to carry out the method as described above.

[0055] The present invention provides advantages over the prior art for preparative applications in biomanufacturing where practices and technologies must comply with GMP (Good Manufacturing Practice) requirements. To comply with GMP requirements, the fluid flow path design and its components must be of hygienic design and can be provided in a clean and controlled state or reconditioned after use and before subsequent use. For example, GMP technology may require the use of specific valve technology, 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. Single-use technology provides a flow path, often a plastic consumable, in a clean and ready-to-use state, improving overall processing efficiency and providing drug product safety and integrity. In infectious or hazardous processing steps, such as those involving several virus processing steps, single-use technology can also improve operator safety. The flow path can be provided pre-sterilized and fitted with sterile connectors. One example of an existing GMP-compliant preparative single-use chromatography system is the AKTA ready by GE Healthcare. This system is available in gradient configuration and provides a mixing system capability based on two pumps with separate fluid inlets.

[0056] Preparative GMP systems for bioprocessing can be of different sizes, including large-scale instrumentation in a floor-standing design, such as AKTA ready. However, smaller preparative GMP systems are also needed to produce small quantities of drug substance, e.g. for personalized medicine of individual patients or patient groups. The latter systems are small and can be placed on a bench, with single-use technology being preferred.

[0057] Typical flow rates for preparative GMP systems for bioprocessing can therefore include flow rates of 1 l / h, 10 l / h, 100 l / h and 1000 l / h, although smaller and larger flow rates may also be of value.

[0058] The system of the present invention can be used to provide a mixed output flow suitable for such preparative GMP systems and is therefore intended to function over a wide flow rate range, from below 0.1 l / h to over 1000 l / h depending on the size and scale of the pumps, valves and fluid interconnections used, but for example the AKTA Ready system mentioned above will typically be in the range of 3-500 l / h. [Explanation of symbols]

[0059] 401 Chromatography System 403 Fluid Mixing System 405a First Entrance 405b Second Entrance 411a First Pump 411b Second Pump 414 Exit 501 Chromatography System 503 Fluid Mixing System 505a First Entrance 505b Second Entrance 505c Third Entrance 505d Fourth Entrance 505e 5th Entrance 511a First Pump 511b Second Pump 511c 3rd Pump 511d 4th pump 511e Fifth Pump 514 Exit 1, 1', 1'', 101, 101' Bioprocess Systems 2 Chromatography columns 3, 3', 3'', 103, 103' Bioprocess Fluid Mixing System 4. Air Trap 5a First fluid inlet 5b Second fluid inlet 5c Third fluid inlet 5d Fourth fluid inlet 5e Fifth fluid inlet 5F Sample entrance 11a First pump 11b Second pump 11c Third Pump 11d Fourth Pump 11e Fifth Pump 11f Sample Pump 13a, 13a' First valve configuration 13b Second Valve Configuration 13c Third valve configuration 14 Fluid outlet 15a, 15b, 15c exit 17 Mixer 19 Sensor Configuration 21 Control System 25 Sensors

Claims

1. A bioprocessing fluid mixing system (3, 3', 3'', 103, 103'), comprising: at least two fluid inlets (5a, 5b, 5c, 5d, 5e) configured for providing a first fluid into said fluid mixing system through a first fluid inlet (5a) and for providing a second fluid into said fluid mixing system through a second fluid inlet (5b); at least one valve arrangement (13a, 13b, 13c, 13a'), a first valve arrangement (13a, 13a') being in fluid communication with at least both said first fluid inlet (5a) and said second fluid inlet (5b); at least two pumps (11a, 11b, 11c, 11d, 11e), a first pump (11a) in selective fluid communication with at least both of said first and second fluid inlets (5a, 5b) via said first valve arrangement (13a, 13a') and a second pump (11b) in fluid communication with at least one of said first and second fluid inlets (5b); a common fluid outlet (14) in fluid communication with at least the outlet (15a) of said first pump (11a) and the outlet (15b) of said second pump (11b); a mixer (17) connected to the common fluid outlet (14); Including, 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 controllable by a control system (21) so that a mixing of at least a first fluid from the first fluid inlet (5a) and a second fluid from the second fluid inlet (5b) can be performed up to a required mixing of the at least two fluids and up to a required total fluid flow rate at the common fluid outlet (14), A bioprocessing fluid mixing system (3, 3', 3'', 103, 103').

2. 2. The bioprocess fluid mixing system of claim 1, configured such that pump speeds of the at least two pumps (11a, 11b, 11c, 11d, 11e) and valve positions in the at least one valve arrangement (13a, 13a', 13b, 13c) are controllable by a control system (21) such 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 the required mixing of the at least two fluids and into a required total fluid flow rate at the common fluid outlet (14) can be performed simultaneously or selectively at different times upstream of at least the first pump (11a) and downstream of the at least two pumps (11a, 11b, 11c, 11d, 11e).

3. 3. The bioprocess fluid mixing system of claim 1 or 2, wherein the desired mixing of the at least two fluids is a desired volumetric mix ratio of the at least two fluids and / or a mixing with one or more desired result fluid properties and / or a mixing with one or more desired changing result fluid properties.

4. 4. The bioprocess fluid mixing system of claim 3, wherein the desired or varying result fluid property is result pH.

5. 5. A bioprocess fluid mixing system according to any one of claims 1 to 4, wherein the second pump (11b) is connected to both the first and second fluid inlets (5a, 5b) via a second valve arrangement (13b) provided in the fluid mixing system (3, 3', 3'', 103, 103').

6. 6. The bioprocessing fluid mixing system according to claim 1, wherein the fluid mixing system (3, 3', 3'', 103, 103') is configured for gradient formation, buffer preparation or in-line conditioning in a bioprocessing system (1, 1', 1'', 101, 101').

7. 7. The bioprocessing fluid mixing system of claim 1, wherein the at least one valve arrangement (13a, 13a', 13b, 13c) comprises at least two inlets and one outlet, and is optionally a switch valve or a proportional or flow regulating valve.

8. 8. The bioprocess fluid mixing system according to claim 1, further comprising at least one sensor arrangement (19) connectable to the control system (21), the sensor arrangement (19) configured to measure one or more fluid properties of the mixed at least first and second fluids and / or fluid flow rates at one or more locations in the system, whereby the control system (21) can provide feedback control to the at least two pumps (11a, 11b, 11c, 11d, 11e) and / or the at least one valve arrangement (13a, 13a', 13b, 13c) based on an output from the sensor arrangement (19).

9. 9. A method for mixing fluids in a bioprocess fluid mixing system (3, 3', 3'', 103, 103') according to any one of claims 1 to 8, comprising the step of controlling pump speeds of the at least two pumps (11a, 11b, 11c, 11d, 11e) and valve positions in the at least one valve arrangement (13a, 13a', 13b, 13c) so as to be able to perform mixing of at least a first fluid from the first fluid inlet (5a) and a second fluid from the second fluid inlet (5b) to a required mixture of the at least two fluids and to a required total fluid flow rate at the common fluid outlet (14).

10. 10. The method according to claim 9, comprising controlling pump speeds of the at least two pumps (11a, 11b, 11c, 11d, 11e) and valve positions in the at least one valve arrangement (13a, 13a', 13b, 13c) such 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 required mixing of the at least two fluids and into a required total fluid flow rate at the common fluid outlet (14) can be performed both upstream of the first pump (11a) and downstream of the pumps (11a, 11b).

11. 11. The method of claim 9 or 10, wherein the method is a method for gradient formation, buffer preparation or in-line conditioning in a bioprocessing system.

12. 12. The method according to any one of claims 9 to 11, further comprising the steps of sensing at least one property in fluids at one or more different locations in the fluid mixing system, and controlling one or more of the at least two pumps (11a, 11b, 11c, 11d, 11e) and the at least one valve arrangement (13a, 13a', 13b, 13c) in response to the at least one sensed property to achieve a required mixing between at least the first and second fluids and / or a required total fluid flow rate.

13. A bioprocessing system (1, 1', 1'', 101, 101') comprising a bioprocessing fluid mixing system (3, 3', 3'', 103, 103') according to any one of claims 1 to 8.

14. 14. The bioprocessing system of claim 13, wherein the bioprocessing system is a chromatography system (1, 1', 1'', 101, 101').

15. 15. The bioprocessing system according to claim 13 or 14, further comprising a control system (21) connectable to the at least two pumps (11a, 11b) and the at least one valve arrangement (13a, 13a', 13b, 13c) in the fluid mixing system (3, 3', 3'', 103, 103'), the control system (21) being further connected to one or more sensor arrangements (19) in the fluid mixing system (3, 3', 3'', 103, 103'), the control system (21) being configured for providing a feedback control of the volumetric mixing ratio between at least the first and second fluids and / or of the fluid flow rates in the fluid mixing system (3, 3', 3'', 103, 103') depending on an output from the sensor arrangement (19).

16. A control system (21) connectable to a bioprocess fluid mixing system (3, 3', 3'', 103, 103') according to any one of claims 1 to 8, the control system (21) being 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 a method according to any one of claims 9 to 12.

17. A computer program product comprising instructions which, when executed on a processor in a control system (21) connected to a fluid mixing system (3, 3', 3'', 103, 103') according to any one of claims 1 to 8, cause the control system (21) to perform the method according to any one of claims 9 to 12.

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