Calibration Element, Controller For Calibration Element, Calibration System, Transport System And Method For Operating Calibration Element

Abstract

The invention relates to a calibration element (100) comprising at least one measurement chamber (120, 121, 122) and a first liquid sensor (130) arranged at a first measurement point at an inflow opening of the measurement chamber (120, 121, 122) for detecting the presence of a liquid and a second liquid sensor (131, 132) arranged at a second measurement point at an outflow opening of the measurement chamber.

Description

Technical Field

[0001] The present invention relates to a calibration element, a controller for a calibration element, a calibration system, a conveying system, and a method for operating a calibration element. Background Art

[0002] In industrial processes such as bioprocessing, pumps are used to supply media to reactions (e.g., in a bioreactor). In this case, it is crucial to accurately know how much media is conveyed through the pump, for example, in fed-batch processes or perfusion processes. For this purpose, the necessary calibration of the pump in terms of its flow rate is currently usually carried out with the aid of a weighing unit. If the pump is designed with a pump hose or other replaceable elements, this calibration also depends on these elements, especially the material of the elements, the elastic changes over time, and the "squeezing performance", so this calibration must be repeated whenever the element, such as the pump hose, is replaced.

[0003] The solutions used so far in bioprocess technology always require laborious processes with a weighing unit or volumetric measurement of the pumping process. Before the experiment, performing weight-related calibration with a weighing unit requires a lot of time and media. Especially for highly parallel systems, the initial time expenditure required by the user is very high.

[0004] In addition, the currently used weighing unit calibration procedures limit or hinder the use of disposable hose kits. This is because the user directly uses a disposable hose kit, or the connection to the scale / weighing bottle is impractical (time expenditure and material expenditure).

[0005] In addition, due to the risk of contamination of the culture due to the additional necessary hose connectors, the user hopes to avoid this as much as possible in bioprocessing.

[0006] Known flow sensors (especially thermal mass flow sensors) usually cannot be used for the calibration of pumps because precise knowledge of media parameters, such as heat capacity, is required for this purpose. In addition, the flow sensors available on the market are not suitable for the low dosing rates of small bioreactor systems. Summary of the Invention

[0007] Therefore, the object of the present invention is to provide a calibration solution that can be reliably implemented with reduced material expenditure and time expenditure, especially can be used even in the case of low dosing rates and the use of disposable hose kits.

[0008] According to a first aspect of the invention, this object is achieved by a calibration element which comprises at least one measuring chamber and a first liquid sensor for detecting the presence of a liquid at a first measuring point arranged at the inlet of the measuring chamber and a second liquid sensor at a second measuring point arranged at the outlet of the measuring chamber.

[0009] The invention involves the recognition that calibration can also be carried out by precise volume measurement rather than by weighing. Thus, the invention renders the weighing unit redundant and allows calibration to be performed at startup of the system, i.e., during the initial filling of the hose, by using the measuring chamber. By measuring the time required to fill one or more precisely defined volumes, i.e., at least one measuring chamber, the volumetric flow rate can be determined by the equation Q = V / t. Thus, the volumetric flow rate in the construction can be directly determined for each pump and this volumetric flow rate can be used for calibration. This can be used continuously not only initially but at any time to determine the current volumetric flow rate, for example after replacing an accessory or over time, so that deviations in the pumping performance can be determined.

[0010] To determine the volumetric flow rate, the corresponding medium flows through one or more measuring chambers with precisely known volumes, at the inlet and outlet of which sensors are provided that can determine the presence of a liquid. When a liquid enters one of the chambers and when it leaves the same chamber, timestamps can be collected and stored and thus the volumetric flow rate can be determined according to Q = V / t.

[0011] Thus, the invention facilitates operation since calibration can be carried out almost "incidentally" at startup of the production line, which saves time and medium. The structure can also calibrate the integrated flow sensor for the necessary resolution range and the properties of the liquid applied, which particularly allows applications in the range of low dosing rates. Another aspect of the invention is that by possibly storing the detected volumetric flow rate, it is possible to compare current and historical flow parameters and thus enable automatic checks. In addition, the invention allows the detection of air bubbles in the system by comparing the volumetric flow rates.

[0012] An embodiment of the calibration element according to the invention is described below.

[0013] In one embodiment, the input and output regions of at least one measuring chamber are designed such that fluctuations, such as fluctuations in surface tension, can be compensated. For this purpose, it is advantageous if at least one measuring chamber has a rhombic cross-section and is flowed through from one vertex of the rhombus to the opposite vertex. In particular, such embodiments are preferred in which at least one measuring chamber has the shape of a rhombus or a double pyramid.

[0014] In one embodiment of the calibration element, the first and / or second liquid sensor is configured to detect the presence of liquid optically, acoustically, or by resistance or impedance measurement. The contact of the first and / or second liquid sensor can preferably be made by means of a cable or a contact, for example a spring contact.

[0015] In a preferred embodiment, the calibration element further comprises a flow sensor, in particular a mass flow sensor, which is fluidically connected to at least one measuring chamber. By integrating the flow sensor, flow verification can also be carried out during the process, including possible recalibration of the flow sensor. By initially calibrating the flow sensor also for the medium used (e.g. in terms of heat capacity), deviations in the pumping performance can also be continuously detected during the process. Thus, the sensor can also be used in additional process sequences to accurately track the pumping performance. Here, its flow integration represents the entire released volume. This is particularly meaningful if pump hoses are used whose performance changes during the process (e.g. due to the inflow performance or ageing of the hose material). Such deviations can then be detected and thus compensated for by means of a flow sensor calibrated by means of the initial volume flow determination. The flow sensor is preferably arranged between the pump and at least one measuring chamber. Alternatively, the flow sensor can also be arranged downstream of the measuring chamber in the flow direction.

[0016] In another embodiment, the calibration element comprises at least two measuring chambers, each of which has a first and a second liquid sensor, and these measuring chambers can be connected in parallel or in series.

[0017] By connecting a plurality of measuring chambers in series or in parallel, additional precision can be achieved by generating an average value from the results of the plurality of measuring chambers. In addition, gross irregularities in the material transport or volume flow can thus be detected, especially in the measuring chambers that are filled successively. Similarly, the filling times of different measuring chambers can be determined at different pumping rates in order to achieve multi-point calibration of the pump, where each filling of another measuring chamber uses a different pumping rate. For this purpose, a series connection is particularly advantageous.

[0018] Here, preferably, the second liquid sensor of the first measuring chamber is simultaneously the first liquid sensor of the second measuring chamber arranged immediately after the first measuring chamber.

[0019] According to a second aspect, the present invention relates to a controller for a calibration element having at least one measurement chamber. The controller is configured to receive a first signal from a first liquid sensor at a first measurement point disposed at an inlet of the flow of the measurement chamber and a second signal from a second liquid sensor at a second measurement point disposed at an outlet of the flow of the measurement chamber, the signals indicating the presence of liquid at the respective measurement points, and to assign a timestamp to each when the first and second signals are received and determine a volumetric flow rate value of the measurement chamber based on a comparison of the two timestamps and a pre-known volume between the first and second measurement points.

[0020] In one embodiment of a controller for a calibration element having first and second measurement chambers, the controller is configured to generate an average value based on the volumetric flow rate value of the first measurement chamber and the volumetric flow rate value of the second measurement chamber. If there are more than two measurement chambers, the controller may also be configured to generate an average value based on the volumetric flow rate values of all or multiple measurement chambers.

[0021] Alternatively or additionally, the controller is configured to initialize a first pumping rate of a pump connected to the calibration element and determine a first volumetric flow rate value for the first pumping rate to fill the first measurement chamber, and to initialize a second pumping rate of a pump connected to the calibration element and determine a second volumetric flow rate value for the second pumping rate to fill the second measurement chamber. If there are more than two measurement chambers, the controller may also be configured to initialize a respective pumping rate of a pump connected to the calibration element for each measurement chamber and determine a respective volumetric flow rate value for the respective pumping rate. Then, multiple measurement chambers may also be filled at the same pumping rate and an average value for each pumping rate may be generated therewith.

[0022] In another embodiment, in the case of a calibration element having a flow sensor, the controller is configured to receive a flow signal from the flow sensor and calibrate the flow sensor based on at least one pre-determined volumetric flow rate. Here, the controller may also be configured to track the pumping performance of a pump connected to the calibration element after calibrating the flow sensor.

[0023] According to a third aspect, the present invention relates to a calibration system comprising a calibration element according to the first aspect of the present invention and a controller according to the second aspect of the present invention.

[0024] In one embodiment, at least one measurement chamber may be configured as a disposable component and then removed from the system after initial calibration.

[0025] According to a fourth aspect, the present invention relates to a delivery system comprising a calibration system according to the third aspect of the present invention and a pump, in particular a roller pump or a peristaltic pump, fluidly connected to the calibration element via an inflow hose.

[0026] According to a fifth aspect of the present invention, the present invention relates to a method for operating a calibration element having at least one measurement chamber, a first liquid sensor disposed at an inlet of the measurement chamber, and a second liquid sensor disposed at an outlet of the measurement chamber, the method comprising the steps of:

[0027] - Detecting the presence of a liquid at a first measurement point at the inlet of the measurement chamber and outputting a first signal;

[0028] - Receiving the first signal and assigning a first timestamp;

[0029] - Detecting the presence of a liquid at a second measurement point at the outlet of the measurement chamber and outputting a second signal;

[0030] - Receiving the second signal and assigning a second timestamp;

[0031] - Comparing the first and second timestamps;

[0032] - Determining a volumetric flow rate value based on the comparison of the first and second timestamps and a pre-known volume between the first and second measurement points.

[0033] In one embodiment, the method includes the step of generating an average value based on the volumetric flow rate value of the first measurement chamber and the volumetric flow rate value of the second measurement chamber.

[0034] In another embodiment, the method further includes the following steps:

[0035] - Initializing a first pumping rate of a pump connected to the calibration element to fill the first measurement chamber before detecting the presence of a liquid at the first measurement point at the inlet of the first measurement chamber;

[0036] - Determining a first volumetric flow rate value for the first pumping rate;

[0037] - Initializing a second pumping rate of a pump connected to the calibration element to fill the second measurement chamber before detecting the presence of a liquid at the first measurement point at the inlet of the second measurement chamber;

[0038] - Determining a second volumetric flow rate value for the second pumping rate.

[0039] The method may further include the following steps:

[0040] - Receiving a flow signal from a flow sensor fluidly connected to at least one measurement chamber;

[0041] - Calibrating the flow sensor based on at least one pre-determined volumetric flow rate.

[0042] In addition, the method may include tracking the pumping performance of a pump connected to the calibration element.

[0043] Possible design options and advantages regarding the description of the calibration element also relate to the calibration system, the controller, the delivery system, and the method. Accordingly, for the calibration system, the controller, the delivery system, and the method, any embodiment and improvement of the calibration element described above can also be used. Accordingly, for the additional advantages, implementation variants, and implementation details of these additional aspects and their possible improvements, reference is also made to the previously made description of the corresponding features and improvements of the calibration element. Description of the Drawings

[0044] Preferred embodiments of the present invention are illustrated exemplarily with reference to the drawings. In the drawings:

[0045] Figure 1 An embodiment of a delivery system according to a third aspect of the present invention is shown;

[0046] Figure 2 An embodiment of a method for operating a calibration element according to a fifth aspect of the present invention is shown. Detailed Description of the Invention

[0047] Figure 1 An embodiment of a delivery system 1000 according to a third aspect of the present invention is shown. The delivery system 1000 includes, in addition to a reservoir 220 and a bioreactor 300, a calibration system 500 having a calibration element 100 and a controller 400. The calibration element 100 is fluidly connected to a pump 200 via an inflow hose 210. Another inflow hose 310 connects the calibration element 100 to the bioreactor 300. In the delivery system 1000, a liquid is transported from the reservoir 220 into the bioreactor 300. The liquid addition is carried out in a controlled manner by means of the calibration element 100.

[0048] In the illustrated embodiment, the calibration element 100 includes three measurement chambers 120, 121, 122, a first liquid sensor 130 for detecting the presence of liquid at a first measurement point disposed at the inlet of the measurement chamber 120, and a second liquid sensor 131 at a second measurement point disposed at the outlet of the measurement chamber 120. Here, the second liquid sensor 131 of the first measurement chamber 120 is simultaneously the first liquid sensor of the second measurement chamber 121 disposed immediately after the first measurement chamber. Here, the second liquid sensor 132 of the second measurement chamber 121 is simultaneously the first liquid sensor of the third measurement chamber 122 disposed immediately after the second measurement chamber 121. In addition, the third measurement chamber further has a second liquid sensor 133 disposed at the outlet of the third measurement chamber. In the illustrated embodiment, these measurement chambers are connected in series. In the illustrated exemplary state, the first measurement chamber 120 has been completely filled with liquid from the reservoir 220, and the second measurement chamber is being filled. The advantage provided by using multiple measurement chambers is that the volume flow rates determined in the respective measurement chambers can be averaged, which enables higher accuracy or different pumping rates can be used for different measurement chambers, and thus the volume flow rates for different pumping rates can be determined.

[0049] The measurement chambers 120, 121, and 122 each have a rhombic cross-section here and are flowed through from one vertex of the rhombus to the opposite vertex. This structure allows for particularly good compensation of fluctuations, such as fluctuations in surface tension. In the illustrated embodiment, the liquid sensors 130, 131, 132, 133 are configured to optically detect the presence of liquid. Alternatively, detection can also be performed acoustically or by resistance measurement or impedance measurement.

[0050] The illustrated calibration element 100 further has a flow sensor 110 fluidly connected to the measurement chambers, and this flow sensor 110 is a mass flow sensor here.

[0051] The controller 400 for calibrating the element 100 is configured to receive a first signal from a first liquid sensor 130 at a first measurement point located at the inlet of the first measurement chamber 120 and a second signal from a second liquid sensor 131 at a second measurement point located at the outlet of the first measurement chamber, indicating the presence of liquid at the respective measurement points. When receiving the first and second signals, it assigns time stamps respectively and determines the volumetric flow rate value of the first measurement chamber 120 based on the comparison of the two time stamps and a pre-known volume between the first measurement point and the second measurement point. The controller 400 is also configured to receive a first signal from a first liquid sensor 131 at a first measurement point located at the inlet of the second measurement chamber 121 and a second signal from a second liquid sensor 132 at a second measurement point located at the outlet of the second measurement chamber 121, indicating the presence of liquid at the respective measurement points. When receiving the first and second signals, it assigns time stamps respectively and determines the volumetric flow rate value of the second measurement chamber 121 based on the comparison of the two time stamps and a pre-known volume between the first measurement point and the second measurement point. The controller 400 is further configured to receive a first signal from a first liquid sensor 132 at a first measurement point located at the inlet of the third measurement chamber 122 and a second signal from a second liquid sensor 133 at a second measurement point located at the outlet of the third measurement chamber 122, indicating the presence of liquid at the respective measurement points. When receiving the first and second signals, it assigns time stamps respectively and determines the volumetric flow rate value of the third measurement chamber 122 based on the comparison of the two time stamps and a pre-known volume between the first measurement point and the second measurement point.

[0052] In addition, the controller is configured to generate an average value based on the volumetric flow rate value of the first measurement chamber 120, the volumetric flow rate value of the second measurement chamber 121, and the volumetric flow rate value of the third measurement chamber 122. For another usage scenario, the controller is also configured to initialize a first pumping rate of a pump 200 connected to the calibration element and determine a first volumetric flow rate value for the first pumping rate to fill the first measurement chamber 120, and initialize a second pumping rate of the pump 200 connected to the calibration element to fill the second measurement chamber 121 and determine a second volumetric flow rate value for the second pumping rate, and initialize a second pumping rate of the pump 200 connected to the calibration element to fill the third measurement chamber 122 and determine a third volumetric flow rate value for the third pumping rate.

[0053] In addition, the shown controller 400 is configured to receive a flow signal from a flow sensor 110 and calibrate the flow sensor 110 based on at least one of the pre-determined volumetric flow rates. Further, the controller is configured to track the pumping performance of the pump 200 connected to the calibration element after calibrating the flow sensor.

[0054] Figure 2Shows an embodiment of a method for operating a calibration element according to a fifth aspect of the present invention. Here, the calibration element has at least one measurement chamber, a first liquid sensor arranged at the fluid inlet of the measurement chamber, and a second liquid sensor arranged at the fluid outlet of the measurement chamber. In a first step S1, the method includes detecting the presence of liquid at a first measurement point at the fluid inlet of the measurement chamber and outputting a first signal. Then in step S2, the first signal is received and a first timestamp is assigned.

[0055] In step S3, the presence of liquid is detected at a second measurement point at the fluid outlet of the measurement chamber and a second signal is output. In a subsequent step S4, the second signal is received and a second timestamp is assigned.

[0056] In step S5, a comparison of the first and second timestamps is performed.

[0057] Then in step S6, a volumetric flow rate value is determined based on the comparison of the first and second timestamps and a pre-known volume between the first and second measurement points.

[0058] In an embodiment not shown here, in the case where there are two measurement chambers in the calibration element, the method may include the step of generating an average value based on the volumetric flow rate values of the first measurement chamber and the second measurement chamber. In another embodiment not shown, the method further includes the following steps:

[0059] - Before detecting the presence of liquid at a first measurement point at the fluid inlet of the first measurement chamber, initialize a first pumping rate of a pump connected to the calibration element to fill the first measurement chamber;

[0060] - Determine a first volumetric flow rate value for the first pumping rate;

[0061] - Before detecting the presence of liquid at a first measurement point at the fluid inlet of the second measurement chamber, initialize a second pumping rate of a pump connected to the calibration element to fill the second measurement chamber;

[0062] - Determine a second volumetric flow rate value for the second pumping rate.

[0063] If a flow sensor is included in the calibration element, the method may further include the steps of receiving a flow signal from the flow sensor fluidly connected to at least one measurement chamber and calibrating the flow sensor based on at least one pre-determined volumetric flow rate.

[0064] Explanation of reference numerals:

[0065] 100 Calibration element

[0066] 110 Flow sensor

[0067] 120 Measurement chamber

[0068] 121 Measurement chamber

[0069] 122 Measurement chamber

[0070] 130 Liquid sensor

[0071] 131 Liquid sensor

[0072] 132 Liquid sensor

[0073] 133 Liquid sensor

[0074] 200 Pump

[0075] 210 Inflow hose

[0076] 220 Reservoir

[0077] 300 Bioreactor

[0078] 310 Inflow hose

[0079] 400 Controller

[0080] 500 Calibration system

[0081] 1000 Delivery system

Claims

1. A calibration element (100) comprising at least one measurement chamber (120, 121, 122) and a first liquid sensor (130) for detecting the presence of liquid at a first measurement point arranged at the inlet of the flow of the measurement chamber (120, 121, 122) and a second liquid sensor (131, 132) at a second measurement point arranged at the outlet of the flow of the measurement chamber.

2. The calibration element (100) according to claim 1, wherein, The at least one measurement chamber has a rhombic cross-section and is flowed through from one vertex of the rhombus to the opposite vertex, wherein, in particular, the at least one measurement chamber has the shape of a rhombus or a double pyramid.

3. The calibration element (100) according to any one of the preceding claims, wherein, The first and / or second liquid sensor is configured to detect the presence of liquid optically, acoustically, or by resistance measurement or impedance measurement.

4. The calibration element (100) according to any one of the preceding claims, further comprising a flow sensor (110), in particular a mass flow sensor, fluidly connected to the at least one measurement chamber.

5. The calibration element (100) according to any one of the preceding claims, having at least two measurement chambers (120, 121, 122), each of the at least two measurement chambers having a first and a second liquid sensor, wherein, The at least two measurement chambers are fluidically connected in series, and wherein, in particular, the second liquid sensor of the first measurement chamber is simultaneously the first liquid sensor of the second measurement chamber arranged immediately after the first measurement chamber.

6. The calibration element (100) according to any one of claims 1 to 4, having at least two measurement chambers (120, 121, 122), each of the at least two measurement chambers having a first and a second liquid sensor, wherein, The at least two measurement chambers are fluidically connected in parallel.

7. A controller (400) for a calibration element (100) having at least one measurement chamber, wherein, The controller is configured to receive a first signal from a first liquid sensor (130) at a first measurement point at the inlet of the measurement chamber (120) and a second signal from a second liquid sensor (131) at a second measurement point at the outlet of the measurement chamber, the signals indicating the presence of liquid at the respective measurement points, and to assign a timestamp to each when receiving the first and second signals and determine a volumetric flow rate value of the measurement chamber based on a comparison of the two timestamps and a pre-known volume between the first measurement point and the second measurement point.

8. The controller (400) for a calibration element having a first and a second measurement chamber according to claim 7, wherein, The controller is configured to generate an average value based on the volumetric flow rate value of the first measurement chamber (120) and the volumetric flow rate value of the second measurement chamber (121), and / or wherein the controller is configured to initialize a first pumping rate of a pump (200) connected to the calibration element to fill the first measurement chamber and determine a first volumetric flow rate value for the first pumping rate, and initialize a second pumping rate of the pump connected to the calibration element to fill the second measurement chamber and determine a second volumetric flow rate value for the second pumping rate.

9. The controller (400) according to any one of claims 7 or 8, configured in a calibration element having a flow sensor to receive a flow signal from the flow sensor and to calibrate the flow sensor according to at least one predetermined volume flow rate, wherein, The controller is in particular also configured to track the pumping performance of the pump connected to the calibration element after calibrating the flow sensor.

10. A calibration system (500) comprising a calibration element (100) according to any one of claims 1 to 5 and a controller (400) according to any one of claims 7 to 9.

11. A delivery system (1000) comprising the calibration system according to claim 10 and a pump (200), in particular a roller pump or a peristaltic pump, fluidly connected to the calibration element via an inlet hose (210).

12. A method for operating a calibration element (100), the calibration element having at least one measurement chamber (120) and a first liquid sensor (130) arranged at the inlet of the measurement chamber (120) and a second liquid sensor (131) arranged at the outlet of the measurement chamber, the method comprising the steps of: - Detect the presence of liquid at a first measurement point at the inlet of the measurement chamber (120) and output a first signal; - Receive the first signal and assign a first timestamp; - Detect the presence of liquid at a second measurement point at the outlet of the measurement chamber (120) and output a second signal; - Receive the second signal and assign a second timestamp; - Compare the first and second timestamps; - Determine a volumetric flow rate value based on a comparison of the first and second timestamps and a pre-known volume between the first and second measurement points.

13. The method according to claim 12, further comprising the step of generating an average value based on the volumetric flow rate value of the first measurement chamber and the volumetric flow rate value of the second measurement chamber.

14. The method according to claim 12 or 13, further comprising the following steps: - Initialize a first pumping rate of a pump connected to the calibration element to fill the first measurement chamber before detecting the presence of liquid at a first measurement point at the inlet of the first measurement chamber; - Determine a first volumetric flow rate value for the first pumping rate; - Initialize a second pumping rate of a pump connected to the calibration element to fill the second measurement chamber before detecting the presence of liquid at a first measurement point at the inlet of the second measurement chamber; - Determine a second volumetric flow rate value for the second pumping rate.

15. The method according to any one of claims 12 to 14, comprising the following steps: - Receive a flow signal from a flow sensor fluidically connected to the at least one measurement chamber; - Calibrate the flow sensor according to at least one pre-determined volumetric flow rate. and - Optionally track the pumping performance of a pump connected to the calibration element.

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