Temperature control system for a fermentation vessel

Abstract

The invention relates to a temperature control system (10) for a fermentation vessel (11), wherein one or more heat exchange elements (12) are arranged in or on the fermentation vessel (11), and wherein the heat exchange elements (12) are flowed through by a heat transfer fluid. The temperature control system (10) comprises: a temperature sensor arrangement configured to detect, for each of the one or more heat exchange elements (12), a temperature difference between the heat transfer fluid flowing into and flowing out of the heat exchange element (12) and / or a return temperature of the heat transfer fluid flowing out of the heat exchange element (12); at least one pump (13) configured to individually adjust the flow rates of the heat transfer fluid through each of the one or more heat exchange elements (12); and a controller (14) configured to control the at least one pump (13) based on the detected temperature differences and / or return temperatures.

Description

[0001]Grundfos Holding A / S 1 TEMPERATURE CONTROL SYSTEM FOR A FERMENTATION VESSEL TECHNICAL FIELD OF THE INVENTION The invention relates to a temperature control system and a temperature control method for a fermentation vessel. The invention further relates to a fermentation system. BACKGROUND OF THE INVENTION Fermentation refers to the microbial or enzymatic conversion of organic substances into acids, gases or alcohol. For instance, fermentation is used in the production of a wide range of products, including pharmaceuticals, chemicals, and food ingredients. A fermentation process is typically carried out in a so-called fermentation vessel (or fermenter). During this process, heat is generated from the biological activity and mechanical agitation inside the vessel. The mechanical agitation can be caused by an agitator used to keep the process fluid homogeneously mixed throughout the fermentation vessel. Conventional fermentation vessels are cooled to remove the heat generated during the fermentation process. For instance, the temperature control is done by circulation of coolant in heat exchangers. Typically, the heat generation varies during a fermentation run. For instance, in the beginning of the fermentation run there is less biological activity meaning less heat must be removed than later in the fermentation run, where the biological activity is higher. As a consequence, the flow through the heat exchangers Grundfos Holding A / S 2 typically varies during a fermentation run. However, such variations of the coolant flow velocities can affect the heat transfer and the temperature distribution over the heat exchangers. Thus, it is an objective to provide an improved temperature control system and method for a fermentation vessel which avoid the above-mentioned disadvantages. SUMMARY OF THE INVENTION The object of the present invention is achieved by the solution provided in the enclosed independent claims. Advantageous implementations of the present invention are further defined in the dependent claims. According to a first aspect, the invention relates to a temperature control system for a fermentation vessel, wherein one or more heat exchange elements are arranged in or on the fermentation vessel, and wherein the heat exchange elements are flowed through by a heat transfer fluid. The temperature control system comprises: a temperature sensor arrangement configured to detect, for each of the one or more heat exchange elements, a temperature difference between the heat transfer fluid flowing into and flowing out of the heat exchange element and / or a return temperature of the heat transfer fluid flowing out of the heat exchange element; at least one pump configured to individually adjust the flow rates of the heat transfer fluid through each of the one or more heat exchange elements; and a controller configured to control the at least one pump based on the detected temperature differences and / or return temperatures. This achieves the advantage that the flow rate of the heat Grundfos Holding A / S 3 transfer fluid through each heat exchange element of the fermentation vessel can be individual controlled. In this way, a differential temperature between the inlet and outlet of each heat exchange elements can be controlled, securing a uniform temperature of the heat exchange elements and between each heat exchange element throughout a fermentation run regardless of the thermal load (i.e., in phases of both low and high heat generation inside the vessel and potentially unevenly loaded heat exchange elements). Furthermore, unwanted effects such as cold spots or warm areas on the surface of the heat exchange elements that could be caused by strong temperature variations in the heat transfer fluid and that could inhibit or alter the bioactivity during the fermentation process can be avoided. The heat transfer fluid can be a cooling liquid (coolant) and / or a heating liquid. For instance, if the temperature control system is a cooling system, the heat exchange elements are flowed through by the coolant. The heat transfer fluid may be water. The controller can be formed by a central controller or by multiple individual control units which may be distributed over the system. For instance, each pump of the system can comprise a respective control unit of the controller. The at least one pump may be a fluid transfer pump, such as a circulation pump. The heat exchange element(s) can be connected to a central cooling and / or heating supply via pipes. The temperature control system may comprise a plurality of heat Grundfos Holding A / S 4 exchange elements and / or a plurality of pumps. For instance, the temperature control system comprises one pump for each heat exchange element, wherein each of the pumps are configured to individually control and / or adjust the flow rate of the heat transfer fluid through one of the heat exchange elements. For instance, each of the one or more heat exchange elements can receive the heat transfer fluid at the same temperature from a central supply. The return temperature of the heat transfer fluid from each heat exchange element may vary, e.g., based on the arrangement of the heat exchange element and / or the flow rate of the heat transfer fluid. For instance, the return temperature varies based on the vertical placement of the heat exchange element. In an embodiment, the controller is configured to control the at least one pump to keep the detected temperature differences below or at a respective reference value or below or following a respective temperature profile during a fermentation process. The reference value or profile can be identical for all heat exchange elements. It is also possible that different reference values / profiles are used for the different heat exchange elements. In an embodiment, the controller is configured to adjust the reference value or the temperature profile such that at least one of the pumps runs at an upper speed limit. This achieves the advantage that the heat exchange elements can run at high flow rates which is expected to reduce a fouling rate in the heat exchange elements. Grundfos Holding A / S 5 For example, the upper speed limit of a pump can be defined as 80% (or any other fraction) of its maximum speed. In an embodiment, each heat exchange element comprises a cooling and / or heating jacket or a cooling and / or heating coil. In an embodiment, the temperature control system further comprises at least one tempering element configured to adjust a temperature of the heat transfer fluid upstream of the heat exchange elements in order to control a temperature inside the fermentation vessel. For instance, if the temperature inside the fermentation vessel rises above a threshold value, the controller decrease the inflow temperature and / or increasing the flow rate through the heat exchange elements to increase their cooling effect. In an embodiment, the at least one tempering element is arranged to receive the heat transfer fluid from a central supply at a certain temperature; wherein the at least the tempering elements comprises a mixing element which is configured to adjust the temperature of the heat transfer fluid upstream of the heat exchange elements by mixing a portion of the heat transfer fluid which flows back from at least one of the heat exchange elements to the heat transfer fluid which is received from the central supply. The mixing element may be a control valve, e.g. a three-way control valve. In an embodiment, the temperature control system comprises one tempering element for each heat exchange element, wherein each Grundfos Holding A / S 6 of the tempering elements is configured to individually control the temperature of the heat transfer fluid which flows into one of the heat exchange elements. For instance, each heat exchange element can have its own cooling and / or heating cycle. This allows to control the mean temperature of each heat exchange element independently. In an embodiment, the temperature sensor arrangement comprises: at least one first temperature sensor configured to measure a temperature of the heat transfer fluid flowing into at least one of the heat exchange elements, and / or at least one second temperature sensor configured to measure a temperature of the heat transfer fluid flowing out of at least one of the heat exchange elements. For instance, the temperature sensor arrangement comprises one first temperature sensor in case all heat exchange elements receive the heat transfer fluid at the same temperature, or a plurality of first temperature sensors in case all heat exchange elements receive the heat transfer fluid at individual temperatures. Each of the plurality of first temperature sensors can then measure the temperature flowing into one of the heat exchange elements. Furthermore, the temperature sensor arrangement may comprise a plurality of second temperature sensors to measure the temperature of the heat transfer fluid flowing out of each heat exchange element and / or a further second temperature sensor configured to measure a temperature of the heat transfer fluid flowing out of the heat exchange elements in a common return channel (i.e., after the fluid from all heat exchange elements has merged again). Grundfos Holding A / S 7 The temperature difference between the heat exchange fluid flowing into and flowing out of the heat exchange elements can be calculated from the temperatures measured with the first and second temperature sensors. In an embodiment, the temperature sensor arrangement comprises at least one internal temperature sensor which is arranged in the fermentation vessel and configured to measure a temperature inside the fermentation vessel. For example, the controller is configured to control the at least one tempering element based on temperatures measured with the at least one internal temperature sensor. For instance, the internal temperature sensor(s) measure(s) at least one temperature of the process fluid in the fermentation vessel. The controller can control the at least one pump and / or tempering element(s) to keep the process fluid at a certain temperature or temperature profile. The process fluid can be a broth. In an embodiment, the temperature sensor arrangement is further configured to detect a respective mean temperature of each heat exchange element; wherein the controller is configured to control the at least one pump such that the mean temperature of all heat exchange elements do not deviate from each other by more than a predefined value. For instance, this can be realized by controlling the pump flows to have the same return temperatures (within a certain tolerance) on all heat exchange elements. In an embodiment, the temperature control system further Grundfos Holding A / S 8 comprises at least one flow estimation unit configured to measure: a total flow rate of the heat transfer fluid through all heat exchange elements, and / or individual flow rates of the heat transfer fluid through each of the heat exchange elements. The controller can be configured to calculate a cooling and / or heating power of the heat exchange elements based on the individual flow rates and based on the detected temperature differences, or based on the total flow rate and a temperature difference of the heat transfer fluid between a shared inlet and a shared outlet of all heat exchange elements. The at least one flow estimation unit can comprise at least one flowmeter of the system. In addition or alternatively, the at least one flow estimation unit can be implemented in the pump(s), e.g., in the form of a hardware and / or software module which estimates the flow rate based on pump parameters, such as speed and / or electrical power. In an embodiment, the controller is configured to monitor said cooling and / or heating power during a fermentation process and to detect if the cooling and / or heating power deviates from a predefined threshold value or profile. For instance, a deviation from the predefined threshold value or profile can be indicative of a failure state of the fermentation and / or the cooling system. The predefined threshold value or profile can be determined based on previous fermentation runs with preferred outcome. In an embodiment, the controller is configured to indicate if the cooling and / or heating power deviates from the predefined threshold value or profile. Grundfos Holding A / S 9 In an embodiment, the controller is configured to detect a fouling on (or in) at least one of the heat exchange elements based on the temperature of the heat transfer fluid flowing into the at least one heat exchange element, the temperature of the heat transfer fluid flowing out of the at least one of the heat exchange element, the temperature inside the fermentation vessel, and the flow rate of the heat exchange fluid through the at least one heat exchange element. For instance, based on the same parameters, a heat transfer coefficient of the at least one heat exchange element can be calculated. According to a second aspect, the invention relates to a fermentation system which comprises: a fermentation vessel; one or more heat exchange elements which are arranged in or on the fermentation vessel, wherein the one or more heat exchange elements are flowed through by a heat transfer fluid; and the temperature control system according to the first aspect of the invention. According to a third aspect, the invention relates to temperature control method for a fermentation vessel, wherein one or more heat exchange elements are arranged in or on the fermentation vessel. The temperature control method comprises: pumping a heat transfer fluid through the one or more heat exchange elements; detecting, for each of the one or more heat exchange elements, a temperature difference between the heat transfer fluid flowing into and flowing out of the heat exchange element and / or a return temperature of the heat transfer fluid flowing out of the heat exchange element; and individually adjusting the flow rates of the heat transfer fluid through each of the one or more heat exchange elements based on the detected temperature differences and / or return temperatures. Grundfos Holding A / S 10 In an embodiment, the flow rates of the heat transfer fluid are adjusted in order to keep the detected temperature differences and / or return temperatures below or at a respective reference value or below or following a respective temperature profile during a fermentation process. For example, the reference value or the temperature profile can be adjusted such that at least one pump which controls and / or adjusts the flow rates of the heat transfer fluid through the one or more heat exchange elements runs at an upper speed limit. In an embodiment, the method further comprises: measuring a total flow rate of the heat transfer fluid through all heat exchange elements and / or individual flow rates of the heat transfer fluid through each of the heat exchange elements; calculating a cooling and / or heating power of the heat exchange elements based on the individual flow rates and the detected temperature differences, or based on the total flow rate and a temperature difference of the heat transfer fluid between a shared inlet and a shared outlet of all heat exchange elements. The method can further comprise monitoring said cooling and / or heating power during a fermentation process. For example, the method further comprises: detecting if the cooling and / or heating power deviates from a predefined threshold value or profile. The method can comprise the further step of: indicating if the cooling and / or heating power deviates from the predefined threshold value or profile. In an embodiment, the method further comprises: adjusting a temperature of the heat transfer fluid upstream of the heat Grundfos Holding A / S 11 exchange elements to control a temperature inside the fermentation vessel. For example, the temperature of the heat transfer fluid is adjusted upstream of the heat exchange elements by mixing a portion of the heat transfer fluid which flows back from at least one of the heat exchange elements to the heat transfer fluid which is received from the central supply. In an example, the temperature of the heat transfer fluid which flows in each of the heat exchange elements is individually controlled. In an embodiment, the method further comprises: measuring the temperature of the heat transfer fluid flowing into at least one of the heat exchange elements, and / or measuring the temperature of the heat transfer fluid flowing out of at least one of the heat exchange elements. In an embodiment, the method further comprises: measuring at least one temperature inside the fermentation vessel, wherein the temperature of the heat transfer fluid upstream of the heat exchange elements is adjusted based on the at least one temperature inside the fermentation vessel. In an embodiment, the method further comprises: detecting a respective mean temperature of each heat exchange element; wherein the flow rates of the heat transfer fluid are adjusted such that the mean temperature of all heat exchange elements do not deviate from each other by more than a predefined value. According to a further embodiment, the method comprises: detecting a fouling on at least one of the heat exchange elements Grundfos Holding A / S 12 based on the temperature of the heat transfer fluid flowing into the at least one heat exchange elements, the temperature of the heat transfer fluid flowing out of the at least one heat exchange elements, the temperature inside the fermentation vessel, the flow rate of the heat exchange fluid through the at least one heat exchange element. For example, the temperature control method according to the third aspect of the invention can be carried out by the temperature control system according to the first aspect of the invention. BRIEF DESCRIPTION OF THE DRAWINGS Embodiments of the invention will be explained in the following together with the figures. Fig. 1 shows a schematic diagram of a temperature control system for a fermentation vessel according to an embodiment; Fig. 2 shows a schematic diagram of a temperature control system for a fermentation vessel according to an embodiment; Fig. 3 shows exemplary process parameters during a fermentation run according to an embodiment; and Figs. 4A-B show flow diagrams of a temperature control method for a fermentation vessel according to an embodiment. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Grundfos Holding A / S 13 Fig. 1 shows a schematic diagram of a temperature control system 10 for a fermentation vessel 11 according to an embodiment. Thereby, one or more heat exchange elements 12 are arranged in or on the fermentation vessel 11, wherein the heat exchange elements 12 are flowed through by a heat transfer fluid. For example, the fermentation vessel 11, the one or more heat exchange elements 12 and the temperature control system 10 can form a fermentation system. The temperature control system 10 comprises: a temperature sensor arrangement configured to detect, for each of the one or more heat exchange elements 12, a temperature difference between the heat transfer fluid flowing into and flowing out of the heat exchange element 12 and / or a return temperature of the heat transfer fluid flowing out of the heat exchange element 12; and at least one pump 13 configured to adjust (in particular, individually adjust) the flow rates of the heat transfer fluid through each of the one or more heat exchange elements 12. The temperature control system 10 further comprises a controller 14 configured to control the at least one pump 13 based on the detected temperature differences and / or return temperatures. The temperature control system 10 can be a cooling system and the heat transfer fluid can be a cooling liquid (e.g., a coolant). However, in principle, the temperature control system could also be used for heating the vessel 11 with the temperature control fluid being a heating liquid. In general, the fermentation vessel 11 is cooled during a fermentation run, wherein the cooling requirements may vary over time. For instance, in the beginning of the fermentation run Grundfos Holding A / S 14 there is less biological activity meaning less heat should be removed by the heat exchange elements 12 than later in the fermentation run, where the biological activity is higher. For many bioprocesses, a part of the heat removed by the heat exchange elements 12 can originate from the shaft work added by an agitator 18 used to keep the process fluid (e.g., a broth) in the vessel 11 homogeneously mixed throughout the fermentation vessel 11. When shaft work is present to facilitate the bioprocess, it usually constitutes a significant part of the heat produced. The power removed from the fermentation vessel 11 by the system 10 can be calculated using the flow rate of the heat exchange fluid through the heat exchange elements 12 and the supply and return temperatures of the heat exchange fluid as inputs to the calculation. In this context the power, i.e. Joules per second, or the energy in absolute terms, i.e. Joules, are simply referred to as cooling effect or heat removal effect. The cooling effect delivered to a fermentation vessel can be used as a proxy for the biological activity inside the vessel 11. The cooling effect can thus be an input for biocalorimetric estimations of the process going on inside the fermentation vessel. Thereby, biocalorimetry is the description of the heat balance of the total system, and hence the contribution derived from the heat exchange fluid (coolant) may be corrected for other inputs / outputs to reveal information about the biological activity in absolute terms. The heat balance for a fermentation process may be described as: Q = [Agitator work] + [Heat of reaction] – [Heat loss by evaporation] + [Heat of liquids in] – [Heat of liquids out] – Grundfos Holding A / S 15 [Heat loss to surroundings] + [Heat of solution / mixing of chemicals] + [Energy added by air flow] For instance, for anaerobic fermentation the [energy by added air flow] is zero and in certain reactors where aeration is performed the [Energy added by agitator] can in some circumstance be zero as well. The [Heat of reaction] and the [Agitator work] are usually the largest contributors of the heat balance, thus an approximate heat balance equation can be formulated as: Q = [Heat of reaction] + [Agitator work] To ensure an optimal fermentation run, at least a part of this heat can be removed from the vessel 11 by the temperature control system 10. The heat exchange elements 12 of the system 10 can be cooling and / or heating jackets or cooling and / or heating coils (or any other suitable heat exchangers). For instance, the cooling and / or heating jackets can be arranged on and around the fermentation vessel 11, and the cooling and / or heating coils can be arranged in the fermentation vessel 11. In case of a plurality of heat exchange elements 12, the elements 12 can be arranged at different locations in or on the vessel 11, e.g. at different levels of the vessel 11). The heat exchange element(s) 12 can be connected to a central cooling and / or heating supply 17 via pipes. The central supply 17 can provide the heat transfer fluid (e.g., water) at a certain temperature. The heat exchange elements 12 can be a component of the Grundfos Holding A / S 16 fermentation vessel 11, e.g., an integral part of the fermentation vessel 11. The at least one pump 13 can be a circulation pump and / or a fluid transfer pump. The temperature control system 10 may comprise a plurality of heat exchange elements 12 and a plurality of pumps 13, as shown in Fig. 1. For instance, the temperature control system 10 comprises one pump 13 for each heat exchange element 12. Thereby, each pump 13 can be configured to individually control and / or adjust the flow rate of the heat transfer fluid through one of the heat exchange elements 12. The controller 14 can be formed by a central controller or by multiple individual control units which can be distributed over the system 10. For instance, the controller 14 can be distributed or partly distributed into local pump 13 or valve 21 hardware. The controller 14 of the temperature control system 10 can be communicatively connected to a fermentation control system 15, which, e.g., controls an agitator of the system or other parameters of the fermentation process that are only indirectly related to the heating / cooling of the fermentation vessel and / or a SCADA (supervisory control and data acquisition) system 16. For instance, the fermentation control system 15 is implemented partly in a pump or valve hardware, or an edge device in close proximity to the valves 21 and pumps 13. However, the controller 14, the fermentation control system 15 and / or the SCADA system 16 could also be implemented as a single central controller of the fermentation system. Grundfos Holding A / S 17 For instance, the temperature control system 10 further comprises at least one tempering element 21 configured to adjust a temperature of the heat transfer fluid upstream of the heat exchange elements 12. In this way, a temperature of a process fluid inside the fermentation vessel can be controlled and / or adjusted. The tempering element 21 may comprise a control valve which can further regulate the flow of heat transfer fluid to heat exchange elements 12. This valve 21 can be a three-way valve. For instance, the valve 21 is controlled by the controller 14 or by a PI or PID controller located in the central SCADA system. In the example shown in Fig. 1, all heat exchange elements 12 receive the heat transfer fluid (e.g., coolant) from the same supply line and, thus, at the same temperature. This temperature can be adjusted by the tempering element 21 which is arranged upstream of a branching of the coolant supply line to the individual heat exchange elements 12. The system 10 may further comprise an optional non-return valve 19 protecting against a “short circuit” of the heat transfer fluid supply and return lines. For instance, the non-return valve 19 prevents the coolant from flowing in the wrong direction. The non-return valve 19 might not be required if the tempering element 21 is a three-way valve. For instance, the at least one tempering element 21 is arranged to receive the heat transfer fluid from the central supply 17 at a certain temperature and further comprises a mixing element which is configured to adjust the temperature of the heat transfer fluid upstream of the heat exchange elements 12 by mixing a portion of the heat transfer fluid which flows back Grundfos Holding A / S 18 from at least one of the heat exchange elements to the heat transfer fluid which is received from the central supply. This mixing element can be formed by the before mentioned control valve. In this way, for example, a fraction of a hot return coolant can be mixed into the coolant received from the supply 17. Such a mixing may happen through fluid flowing into a by-pass line in Fig. 1. That is, the control valve 21 can adjust how much coolant recirculates in the heat exchange elements 12, and therefore also how much coolant comes from the coolant supply 17. In the interpretation of the drawing, it is implicit that the pumps, the valve, and the temperature sensor arrangement, are connected to the controller 14 (“Pump / Valve Control”) through an actuator sensor connection (e.g., a communication connection for forwarding sensor readings and control commands). With this hydraulic and sensor layout it is possible to monitor a cooling from each heat exchange element 12 indicating an imbalance of biological activity inside the fermentation vessel 11. The temperature sensor arrangement can comprise a number of temperature sensors. For instance, the temperature sensor arrangement comprises at least one first temperature sensor TFconfigured to measure the temperature of the heat transfer fluid flowing into the heat exchange elements. For instance, the first temperature sensor TFis arranged downstream of the tempering element(s) 21 and upstream of the heat exchange elements 12. The temperature sensor arrangement can further comprise at least one second temperature sensor TR1, TR2, TR3configured to measure the temperature of the heat transfer fluid flowing out of each heat exchange element 12. For instance, the system 10 comprises a respective second temperature sensor TR1, TR2, TR3for each heat Grundfos Holding A / S 19 exchange element 12. Furthermore, the temperature sensor arrangement could comprise at least one internal temperature sensor TBwhich is arranged in the fermentation vessel. This at least internal temperature sensor TBcan measure a temperature inside the vessel 11, e.g. the temperature of a process fluid (e.g., broth) inside the vessel during a fermentation run. Optionally, the temperature sensor arrangement can comprise further temperature sensors TS, TRwhich e.g. measure the temperature of the heat transfer fluid received from the central supply 17 or flowing back to the central supply 17. The temperature sensors TFand TR1, TR2, TR3can measure the temperature differences and / or the return temperature which are used by the controller 14 to individually control the pump(s) 13, e.g. to control the pump speeds and thus the flow rate through the individual heat exchange elements 12. Hereinafter, the references used for the temperature sensors (TF,TF1-3,TR,TR1-3,TS,and TB) in Figs. 1 and 2 are also used to indicate the temperatures measured by these temperature sensors. The controller 14 can further control the tempering element(s) 21 based on temperature measurements. For instance, the controller 14 can use the temperature of the process fluid (e.g., a broth) in the fermentation vessel as input for a control loop that controls the tempering element(s) 21. This regulation ensures that the broth temperature is kept at the required set- point with a certain limit of tolerance. Further optionally, the system 10 can comprise at least one flow Grundfos Holding A / S 20 estimation unit. The at least one flow estimation unit can comprise at least one flowmeter 20. In addition or alternatively, the at least one flow estimation unit can be implemented in the pump(s) 13, e.g., in the form of a hardware and / or software module which estimates the flow rate based on pump parameters, such as speed and / or electrical power. In the example shown in Fig. 1, the flow estimation unit is implemented by a single flowmeter 20 which is arranged upstream of a branching of a supply line to the individual heat exchange elements 12. In this configuration, the flow estimation unit can measure a total flow rate of the heat transfer fluid through all heat exchange elements 12. In an example, the temperature control system 10 shown in Fig. 1, uses the controller 14 to adjust the tempering element 21 position such that the forward temperature, TF, is maintained at a temperature setpoint (which is, e.g., provided to the controller 14 by the system 10). The controller 14 can also control the pumps 13 such that the differential temperature TF- TR,iacross each heat exchange element 12 is controlled according to a predefined setpoint (e.g., a reference value or profile) giving a low temperature gradient along the flow direction of the heat exchange elements. At peak cooling conditions, e.g., at the end of a fermentation run, the controller 14 may adjust the pump speeds to increase, if possible, the heat transfer of the heat exchange elements 12, while preferably the coolant by-pass connection is closed by the tempering element 21 (e.g., a three-way valve). In this way the pumps 13 help pulling coolant towards the fermentation vessel 11 from the central coolant source 17. A peak cooling condition may Grundfos Holding A / S 21 for example be identified based on the setpoint for TFand / or the actual temperature of the process fluid, TB. With the system 10, as e.g. shown in Fig. 1, the flow of the heat transfer fluid through the individual heat exchange elements 12 can be adjusted according to the differential temperature (i.e., the temperature difference) between the inlet and outlet of each heat exchange element 12. For instance, the pumps 13 can be controlled to minimize the temperature gradient along the individual heat exchange elements 12 (e.g., cooling coils / jackets) in phases of both low and high heat generation in the fermentation vessel 11. In this way, a distribution of heat load between the heat exchange elements can be controlled. Furthermore, cold spots and / or warm areas on the heat exchange elements 12, which could inhibit or alter the bioactivity, can be avoided. At the same time, it is expected that running the heat exchange elements 12 at high flow rates reduces their fouling rate due to a higher shear stress on the walls of the heat exchange elements 12, i.e. it is more difficult for fouling to attach to their walls. For instance, the controller 14 can be configured to control the at least one pump 13 to keep the detected temperature differences below or at a respective reference value or below or following a respective temperature profile during a fermentation process. In general, the higher the flow rates, the lower the temperature gradient over an individual heat exchange element 12. In case the temperature difference approaches the threshold value for a certain heat exchange element 12, the controller 14 can increase the flow rate through the heat exchange element 12 by increasing the speed of the pump 13 which controls the flow through this element 12. Grundfos Holding A / S 22 The controller 14 could also be configured to adjust the respective reference values or temperature profiles such that at least one of the pumps 13 runs at an upper speed limit. In this way, a maximum flow rate through the heat exchange elements 12 can be achieved. For example, the upper speed limit of a pump can be defined as 80% (or any other fraction) of its maximum speed. The reference value or profile can be identical for all heat exchange elements 12. It is also possible that different reference values / profiles are used for the different heat exchange elements 12. In case the system 10 comprises tempering elements 21, e.g. one or more fluid mixing points in the cooling system upstream the fermentation vessel 11, these can be used to control the temperature of the heat transfer fluid flowing into the heat exchange elements 12 independently from the temperature of the coolant provided by the coolant supply. This provides the advantage that the supply temperature for the heat exchange elements 12 may be controlled to better match the actual heat generation inside the fermentation vessel 11. In this way, the temperature of the process fluid, which can be measured by sensor TB, can be kept at a set-point. For instance, the system 10 can control the temperature of the process fluid inside the fermentation vessel 11 using at least two control inputs. The first control input can be adjusting directly or indirectly the supply of coolant from the coolant supply (e.g., the coolant temperature). The second control input can be adjusting directly or indirectly the amount of coolant circulated in the cooling jacket / coil of the fermentation vessel Grundfos Holding A / S 23 (e.g., via the valve 21 and pumps 13). A further possible function of the system 10, is to detect if a cooling is sufficient based on a temperature error given by a difference between the mixing point temperature (e.g., measured with sensor TF) and a temperature set point. If the cooling is insufficient, the variable flow (controlled by the pumps 13) and / or a valve 21 position can be adjusted to give a sufficient flow of coolant from the coolant supply 17. In addition or alternatively, the system 10 can supply the heat transfer fluid to each of the heat exchange elements 12 at a different temperature. For example, this can be done in situations where there is most activity in the bottom of the fermentation vessel 11 and least at the top, or in fed batch operations where the fermentation vessel 11 is not completely filled in the beginning leaving such that one or more heat exchange elements 12 are unsubmerged. Thereby, the controller 14 can control the individual heat exchange elements 12 to have similar mean temperatures. For instance, the temperature sensor arrangement can be configured to detect a respective mean temperature of each heat exchange element 12, and the controller 14 can be configured to control the at least one pump 13 and / or the at least one tempering element 21 such that the mean temperature of all heat exchange elements 12 do not deviate from each other by more than a predefined value. For instance, a similar mean temperature could also be obtained by simply controlling the pump flows to have the same return temperature on all heat exchange elements 12. With this setup the heat flow can be adjusted to the actual heat generated along Grundfos Holding A / S 24 the vessel 11. Thereby the temperature of the substance inside the vessel 11 can be more uniformly distributed over the vessel height. Fig. 2 shows an exemplary embodiment of the temperature control system 10, which builds on the temperature control system 10 shown in Fig. 1. Same elements are labelled with the same reference signs. Hereinafter, only the differences between Fig. 1 and Fig. 2 are explained. In the exemplary embodiment shown in Fig. 2, each heat exchange element 12 is individually connected to the central cooling and / or heating supply 17 via an inlet and outlet pipe. In other words: each heat exchange element 12 has its own cooling and / or heating cycle. Thereby, the system 10 can comprise one tempering element 21 for each heat exchange element 12 (i.e., in each individual “cooling and / or heating cycle”). In this way, the system 10 or more specifically the tempering elements 21 can control the temperature of the heat transfer fluid that flows into the individual heat exchange elements 12. In this way, it is possible not only to monitor the cooling / heating from each heat exchange element 12 indicating an imbalance of biological activity inside the fermentation vessel, but also, to control the mean temperature of each heat exchange element 12 independently, e.g., in a way that matches the loads on the individual heat exchange elements 12. In this example, the flow estimation unit can be implemented as individual flowmeters 20 configured to measure the individual flow rates of the heat transfer fluid through each of the heat exchange elements 12. Grundfos Holding A / S 25 The temperature sensor arrangement can comprise one first temperature sensor TF1, TF2,TF3and one second temperature sensor TR1, TR2, TR3upstream respectively downstream of each heat exchange element. In the following, further possible aspects and implementations of the temperature control system 10, as e.g. shown in Fig. 1 or 2, will be discussed: Optimal temperature distribution: There exist many combinations for the supply temperature TFand the volumetric flow q of the heat exchange elements 12 that lead to the same heat flow at the same mixture temperature in the vessel TB. Therefore, it can be difficult to optimize the combinations to obtain other benefits. The biological processes in the vessel 11 are most efficient when the temperature is well distributed. The best distribution of the temperature is obtained at high volumetric flow values, leading to low temperature difference between inlet and outlet of the heatexchange elements 12, that is, small values of Δ^ = |^^ − ^^|.The forward temperature(s) TF(or TF,i)can be adjusted such that the temperature TBof the mixture in the vessel 11 is kept at a desired reference value. Then the flow at the local heat exchange elements 12 can be increased by decreasing the reference for the temperature differences ΔT. This adjustment should be slow enough to ensure that the temperature in the vessel is kept at its reference value. The adjustment of the references for the temperature differences may adhere from the solution to an optimization problem, e.g. Grundfos Holding A / S 26minimizing Δ^ = |^^ − ^^| under constraints of maximum pump speedsand fulfilling requirements for the mixture temperature TB. Using cooling effect for process monitoring / irregularity detection: The temperature control system 10 can use its various sensor readings to monitor a cooling effect of the heat exchange element during a fermentation process and, optionally, to detect process irregularities. This approach utilizes the fact that the heat of a reaction in the fermentation vessel 11 is a proxy for cellular activity and biocalorimetric data and can aid as a Process Analytical Technology (PAT) ensuring consistency of production. Fig. 3 shows exemplary process parameters during a fermentation run in the fermentation vessel 11. Thereby, the left diagram shows a change of a concentration of a fermentation product in the vessel 11 over time for a current batch (bold line 33). The product concentration can be the desired output of the fermentation run. The dashed line 31 in the same diagram represents a golden batch (i.e., ideal process conditions) and the bold lines 32 show acceptable tolerances (i.e., deviations from the golden batch). As can be seen in Fig. 3, the product concentration of the current batch 33 deviates outside acceptable bounds after ca. 100 hours into the fermentation run (as indicated by the arrow). The right diagram in Fig. 3 shows the respective cooling power provided by the heat exchange elements for the current batch 33, as well as the golden batch 31 and the acceptable tolerance 32. At time of the drop in concentration (ca. 100 hours), the cooling Grundfos Holding A / S 27 power provided to the current batch 33 greatly exceeds the acceptable tolerances 32. This shows that the cooling effect can be indicative of a deviation in the fermentation process. The controller 14 of the temperature control system 10 (e.g., of any one of the systems shown in Fig. 1 or 2) can be configured to calculate the cooling and / or heating effect (also referred to as: cooling and / or heating power) of the heat exchange elements 12 to provide indications of such deviations. For instance, in a system 10 as shown in Fig. 1, the controller 14 can calculate the cooling effect (cooling power) based on a total flow rate q and a temperature difference (TR– TS) of the heat transfer fluid between a shared inlet and a shared outlet of all heat exchange elements 12, according to ^̇ = ^^^(^^ − ^^) (eq.1)In a system 10 as shown in Fig. 2, the controller 14 can calculate the cooling effect (cooling power) of the heat exchange elements 12 based on the individual flow rates qiand based on the detected temperature differences (TR,i– TS.i), according to: ^̇ = ∑^ ^^^^(^^,^ − ^^,^) (eq.2)The heat generated from shaft work of a mechanical agitator 18 can contribute significantly to the temperature in the vessel 11. Subtracting this heat from the cooling effect, may give a better indication of the heat of reaction generated inside the fermentation vessel 11, and thus a better indicator if the outcome of the bioprocess is deviating, i.e. ^^̇ = ^̇ − ^, (eq.3) Grundfos Holding A / S 28 where P is the agitator work converted to heat in the process fluid. It can be related to the agitator motor power uptake through an efficiency factor. There can be additional terms that are left out from the full heat balance in eq. 3 to obtain a simplified heat balance. These terms can be included if known. Although, as long as their contribution in quantitative terms are the same during fermentation runs, additional terms may provide no additional information of the heat of reaction in the fermentation vessel. That is, when comparing two fermentation batches they cancel out, and using ^̇or ^^̇typically gives the same result regarding connecting the heat balance to the cooling effect. The controller 14 can be configured to monitor said cooling and / or heating effect (power) during a fermentation process. The controller 14 can further be configured to detect if the cooling and / or heating power deviates from a predefined threshold value or profile. The predefined threshold value or profile can be determined based on previous fermentation runs with preferred outcome. The controller 14 can further be configured to indicate if the cooling and / or heating power deviates from the predefined threshold value or profile. For instance, the controller 14 issues a warning signal, e.g., an optical or acoustical signal and / or sends out a warning message via a communication network if the cooling and / or heating power deviates from the predefined threshold value or profile. The warning signal can indicate that the fermentation run is not progressing as expected. E.g., the warning signal can provide Grundfos Holding A / S 29 early warnings on possible deviations in the biological activity and alert operators that some action must be taken to keep the process on track. A possible process flow which can be carried out by the controller 14 for such a deviation calculation has the following steps: - Monitoring the cooling effect from the fermentation vessel 11. - Indicating if the current fermentation run deviates from a fermentation run giving a preferred outcome and thereby having a preferred cooling effect profile, e.g. a time series of the cooling effect. - The indication being established by using the preferred cooling effect profile and the cooling effect associated with the current fermentation run. Optionally, the indication is based on anomaly detection of the current cooling effect compared to the preferred cooling effect. When deriving the indication the controller 13 can carry out a time series analysis. The agitator power can be an input to the cooling effect profile calculation and can be subtracted from the calculated cooling effect before the calculation of the deviation to a preferred profile. The controller 14 can further receive information indicating a type of process that is run in the fermentation vessel 11, e.g. process 1 or 2 or 3 or 4 etc. The preferred profile can be statistically generated from previous heat profiles from other successful fermentation runs of the same process type. The controller 14 can use a data- driven approach to find the preferred profile and decide if an Grundfos Holding A / S 30 anomaly of the heat development in a running batch is detected. Hence it tracks consistency of production. In addition to indicating if the bioprocess is deviating from a preferred process, monitoring the cooling effect from fermenters can have the following advantages and potential derived use cases: - Real-time monitoring of heat development allows for proactive control decisions as the operator contextualizes the delivered cooling effect data for the exact cause of deviation. These changes in heat of reaction inside the fermenter can be either unwanted e.g., originating from contamination or process faults, or the changes can be intentionally e.g., when switching feeding regime or inducing protein expression. - Monitoring the cooling effect can provide information about maximum cooling gradients for a specific fermenter and its coolant supply system, a knowledge that can be used when processes are scaled up from laboratory to production. - Knowing the timely cooling effect uptake and the total cooling effect uptake can be required by different fermentation processes of the factory, can enable production planning, can utilize the capacity of the cooling system most optimally and can facilitate scheduling maintenance of the coolant supply system. Furthermore, the heat flow measurements which can be used for evaluating the biological process, can also be used for evaluating the conditions of the cooling system itself. That is, comparing the temperature inside the vessel 11 with the supply temperature TS, return temperature TR, and the heat flow, a heat flow coefficient for the heat exchange elements 12 can be estimated. A change in this coefficient can indicate a problem Grundfos Holding A / S 31 in the cooling system. Heat exchange fouling detection: For instance, for fouling detection, a number of measurements carried out by the system 10 can be used for evaluating the heat transfer coefficient of the heat exchange elements 12. The available measurements can comprise: the inlet temperature ^^, the outlet temperature ^^, and the flow ^ through the heat exchange elements. These measurements, together with the temperature of the mixture in the vessel ^^holds the necessary information to estimate the heat transfer coefficient. That is, using the temperature inside the fermentation vessel 11, the supply temperature, the return temperature, and the volumetric flow of the cooling jacket, in a suitable model of the heat exchange elements can lead to an estimate of the heat transfer coefficient. A change in this coefficient can indicate problems in the cooling system 10, typically fouling. Specifically, if the system is operating under steady state conditions (not heating up or cooling down) and the mixture in the vessel is well mixed, then a suitable model is: ^ ^^,^ = (^^ − ^^)^^^^^^^ + ^^ (eq.4)Here, ^^is the volumetric heat capacity of the coolant liquid, which is known and qiis the flow rate of the heat transfer fluid through the individual heat exchange elements 12 (which could be measured or estimated). This expression can be solved for the heat transfer coefficient ^^for one of the heat exchange elements 12, according to: Grundfos Holding A / S 32 ^= ^ ^ l^^^^^^ ^ ^ og ^^ ^^ (eq.5) ^^^,^A decrease in the value of ^^indicates fouling on the heat exchanger. Typically, such fouling occurs on the cold water side of the heat exchange elements (in case of a cooling system). For instance, in cost sensitive processes the relation between the supply temperature, the return temperature, and the heat flow can indicate the temperature inside the vessel 11. Hence, the temperature sensor TBinside the vessel 11 could be omitted. In the cases where the sensor TBis not present, indication of the actual temperature could be established. In particular, the expression for the heat exchanger can also be used for calculating the temperature of the process fluid (or substance) ^^in case the heat transfer coefficient is known. The estimated substance temperature is in this case equal to (eq.6) Or in a slightly different format: (eq.7) The value TBcan be different for the individual heat exchange elements 12 and might depend on the heat distribution within the fermentation vessel. The values TBfor the heat exchange elements could be averaged to receive an average temperature inside the vessel. Grundfos Holding A / S 33 In a system 10 as shown in Fig. 2, the individual temperature readings TF,icould be used in the equations 4 to 7. Possible implementation of the control loop(s): The solution for fermentation vessel cooling could have the temperature control loop for the process fluid temperature TBintegrated. In that case, the process fluid temperature datapoint can be available to the controller 14. The system 10 may be extended to also detect a fouling degree on the cooling water side of the heat exchange elements 12. The fouling degree can be used for controlling dosage of anti-scaling chemicals or other additives in the coolant supply. In an example, the system 10 can have a 1-point SCADA communication (for set-points and data). All other components of the temperature control system 10 could be tied to this “central” system controller. Fig. 4A shows a flow diagram of a temperature control method 40 for the fermentation vessel 11 according to an embodiment. The method 40 can be carried out by the temperature control system 10, as e.g. shown in Figs. 1 or 2. The temperature control method 40 comprises: pumping 41 the heat transfer fluid through the one or more heat exchange elements 12; detecting 42, for each of the one or more heat exchange elements 12, a temperature difference between the heat transfer fluid flowing into and flowing out of the heat exchange element 12 and / or a return temperature of the heat transfer fluid flowing out of the heat exchange element 12; and adjusting 43 (in particular, individually adjusting) the flow rates of the heat transfer fluid through each of the one or more heat exchange Grundfos Holding A / S 34 elements 12 based on the detected temperature differences and / or return temperatures. For instance, as explained above, the flow rates of the heat transfer fluid can be adjusted in order to keep the detected temperature differences and / or return temperatures below or at a respective reference value or below or following a respective temperature profile during a fermentation process. In addition to adjusting the flow rate in step 43, also the temperature of the heat transfer fluid can be adapted upstream of the heat exchange elements. Fig. 4B shows additional optional steps of the method 40 which allow a monitoring of the system 10 during a fermentation run. As shown in Fig. 4B, the method 40 may comprise the further steps of: measuring 44 a total flow rate of the heat transfer fluid through all heat exchange elements and / or individual flow rates of the heat transfer fluid through each of the heat exchange elements; calculating 45 a cooling and / or heating power of the heat exchange elements based on the individual flow rates and the detected temperature differences, or based on the total flow rate and a temperature difference of the heat transfer fluid between a shared inlet and a shared outlet of all heat exchange elements; and monitoring 46 said cooling and / or heating power during a fermentation process. The method 40 may further comprise: detecting if the cooling and / or heating power deviates from a predefined threshold value or profile. In case such deviations are detected, they can be indicated to a user.

Claims

Grundfos Holding A / S 35 Claims 1. A temperature control system (10) for a fermentation vessel (11), wherein one or more heat exchange elements (12) are arranged in or on the fermentation vessel (11), and wherein the heat exchange elements (12) are flowed through by a heat transfer fluid; the temperature control system (10) comprising: a temperature sensor arrangement configured to detect, for each of the one or more heat exchange elements (12), a temperature difference between the heat transfer fluid flowing into and flowing out of the heat exchange element (12) and / or a return temperature of the heat transfer fluid flowing out of the heat exchange element (12); at least one pump (13) configured to individually adjust the flow rates of the heat transfer fluid through each of the one or more heat exchange elements (12); and a controller (14) configured to control the at least one pump (13) based on the detected temperature differences and / or return temperatures.

2. The temperature control system (10) of claim 1, wherein the controller (14) is configured to control the at least one pump (13) to keep the detected temperature differences below or at a respective reference value or below or following a respective temperature profile during a fermentation process.

3. The temperature control system (10) of claim 2, wherein the controller (14) is configured to adjust the reference value or the temperature profile such that at least one of the pumps (13) runs at an upper speed limit.

4. The temperature control system (10) of any one of the preceding claims, further comprising:Grundfos Holding A / S 36 at least one tempering element (21) configured to adjust a temperature of the heat transfer fluid upstream of the heat exchange elements (12) in order to control a temperature inside the fermentation vessel (11).

5. The temperature control system (10) of claim 4, wherein the at least one tempering element (21) is arranged to receive the heat transfer fluid from a central supply (17) at a certain temperature; and wherein the at least one tempering element (21) comprises a mixing element which is configured to adjust the temperature of the heat transfer fluid upstream of the heat exchange elements (12) by mixing a portion of the heat transfer fluid which flows back from at least one of the heat exchange elements (12) to the heat transfer fluid which is received from the central supply (17).

6. The temperature control system (10) of claim 4 or 5, wherein the temperature control system comprises one tempering element (21) for each heat exchange element (12), wherein each of the tempering elements (21) is configured to individually control the temperature of the heat transfer fluid which flows into one of the heat exchange elements (12).

7. The temperature control system (10) of any one of the preceding claims, wherein the temperature sensor arrangement comprises: - at least one first temperature sensor (TF, TF1-3) configured to measure a temperature of the heat transfer fluid flowing into at least one of the heat exchange elements (12), and / or - at least one second temperature sensor (TR, TR1-3) configured to measure a temperature of the heatGrundfos Holding A / S 37 transfer fluid flowing out of at least one of the heat exchange elements (12).

8. The temperature control system (10) of any one of claims 4 to 6, wherein the temperature sensor arrangement comprises at least one internal temperature sensor (TB) which is arranged in the fermentation vessel (11) and which is configured to measure a temperature inside the fermentation vessel (11); wherein the controller (14) is further configured to control the at least one tempering element (21) based on temperatures measured with the at least one internal temperature sensor (TB).

9. The temperature control system (10) of any one of the preceding claims, wherein the temperature sensor arrangement is further configured to detect a respective mean temperature of each heat exchange element (12); wherein the controller (14) is configured to control the at least one pump (13) such that the mean temperature of all heat exchange elements (12) do not deviate from each other by more than a predefined value.

10. The temperature control system (10) of any one of the preceding claims, further comprising: at least one flow estimation unit configured to measure: - a total flow rate of the heat transfer fluid through all heat exchange elements (12), and / or - individual flow rates of the heat transfer fluid through each of the heat exchange elements (12); wherein the controller (14) is configured to calculate a cooling and / or heating power of the heat exchange elements (12) based on the individual flow rates and based on the detectedGrundfos Holding A / S 38 temperature differences, or based on the total flow rate and a temperature difference of the heat transfer fluid between a shared inlet and a shared outlet of all heat exchange elements (12).

11. The temperature control system (10) of claim 10, wherein the controller (14) is configured to monitoring said cooling and / or heating power during a fermentation process and to detect if the cooling and / or heating power deviates from a predefined threshold value or profile.

12. The temperature control system (10) of claim 11, wherein the controller (14) is configured to indicate if the cooling and / or heating power deviates from the predefined threshold value or profile.

13. The temperature control system (10) of claims 7 and 8 and of and any one of claims 10 to 12, wherein the controller (14) is configured to detect a fouling on at least one of the heat exchange elements (12) based on the temperature of the heat transfer fluid flowing into the at least one heat exchange element (12), the temperature of the heat transfer fluid flowing out of the at least one heat exchange element (12), the temperature inside the fermentation vessel (11), and the flow rate of the heat exchange fluid through the at least one heat exchange element (12).

14. A fermentation system, comprising: a fermentation vessel (11); one or more heat exchange elements (12) which are arranged in or on the fermentation vessel (11), wherein the one or more heat exchange elements (12) are flowed through by a heat transfer fluid; andGrundfos Holding A / S 39 the temperature control system (10) of any one of the preceding claims.

15. A temperature control method (40) for a fermentation vessel (11), wherein one or more heat exchange elements (12) are arranged in or on the fermentation vessel (11), the method comprising: pumping (41) a heat transfer fluid through the one or more heat exchange elements (12); detecting (42), for each of the one or more heat exchange elements (12), a temperature difference between the heat transfer fluid flowing into and flowing out of the heat exchange element (12) and / or a return temperature of the heat transfer fluid flowing out of the heat exchange element (12); and individually adjusting (43) the flow rates of the heat transfer fluid through each of the one or more heat exchange elements (12) based on the detected temperature differences and / or return temperatures.

16. The method (40) of claim 15, wherein the flow rates of the heat transfer fluid are adjusted in order to keep the detected temperature differences and / or return temperatures below or at a respective reference value or below or following a respective temperature profile during a fermentation process.

17. The method (40) of claim 15 or 16, wherein the method further comprises: measuring (44) a total flow rate of the heat transfer fluid through all exchange elements and / or individual flow rates of the heat transfer fluid through each of the heat exchange elements (12); calculating (45) a cooling and / or heating power of the heatGrundfos Holding A / S 40 exchange elements (12) based on the individual flow rates and the detected temperature differences, or based on the total flow rate and a temperature difference of the heat transfer fluid between a shared inlet and a shared outlet of all heat exchange elements (12); and monitoring (46) said cooling and / or heating power during a fermentation process.

18. The method (40) of claim 17, further comprising: detecting if the cooling and / or heating power deviates from a predefined threshold value or profile.

Images