Apparatus assembly and method for calibrating single-use sensors - Patents.com

Abstract

An equipment assembly (10) for calibrating a single-use sensor (14) before, during, or after a process step of a biopharmaceutical manufacturing process comprises a single-use process equipment assembly for performing at least a portion of the process step. The single-use process equipment assembly includes a flow line (12) through which a medium flows in a defined direction during the process step. The single-use process equipment assembly further includes an integrated single-use sensor (14) for measuring or detecting a physical or chemical property at a measurement location in the flow line (12). The equipment assembly (10) further includes at least one calibration line (18) and at least one switching means (22) inserted in the flow line (12) upstream of the measurement location. The switching means (22) includes a flow line inlet, a flow line outlet, and a calibration line inlet connected to the calibration line (18). The switching means (22) is adapted to selectively switch between a first (main) flow path in which the flow line inlet (26) and the flow line outlet (28) are open while the calibration line inlet (30) is closed, and a second (calibration) flow path in which the flow line inlet (26) is closed while the calibration line inlet (30) and the flow line outlet (28) are open. The device assembly (10) includes a dedicated reference means provided in the calibration line (18). The dedicated reference means includes a reference sensor (48) or a reference source or reference standard solution (40) related to the physical or chemical property measured or detected by the single-use sensor (14). The calibration line (20) may be provided downstream of the single-use sensor (14).

Description

[Technical field]

[0001] The present invention relates to an apparatus assembly and method for calibrating single-use sensors before, during, or after a biopharmaceutical manufacturing process step. [Background technology]

[0002] In the biopharmaceutical industry, there is a clear trend towards using more single-use equipment, either in clinical trial production or in commercial production following the so-called "current good manufacturing practice (cGMP)" regulations. Often such processes require different control loops, especially for critical process parameters (CPPs), to keep the process and product quality within defined limits. Such control loops require the use of single-use sensors as measuring devices. A wide variety of such sensors are known for different physical or chemical properties, such as pH, dissolved oxygen (DO), conductivity, pressure, flow, temperature, turbidity, viscosity, etc.

[0003] The application of sensors in the cGMP environment of a CCP requires the integrity and reliability of the sensor and its measurement output over the entire process or batch period to ensure a quality level over the entire production time or production lot, respectively. To this end, a standard method for evaluating the measurement capabilities of individual sensor components is pre- and post-use calibration of the sensor to ensure that the sensor can measure within a certain accuracy range during its life. For reusable sensors, for example in stainless steel flowline assemblies, this is relatively straightforward. The sensor is calibrated outside the flowline or in a specific bypass configuration. After calibration, the flowline, including the assembled sensor, is disinfected / sterilized. The process is then run, ensuring that the sensor was operating to specification at the start of the process. After the completion of a process, such as a batch run, the flowline is disinfected / inactivated again using a caustic such as 3 molar sodium hydroxide (NaOH) and then washed with water for injection (WFI). After this step, the sensor can be disassembled and calibrated again using a reference sensor or a certified standard.

[0004] If there is a need or requirement for a single-use environment and a completely closed process, this workflow is no longer applicable. In particular, disassembling the sensor from the single-use tubing line assembly is inconsistent with a closed system or a typical disposable approach.

[0005] WO2020 / 079101A1 shows a bioprocessing fluid sensor with a sensor disposed in the process fluid pathway. A bypass fluid pathway is provided to bypass the sensor. An inlet line for a conditioning or cleaning fluid enters the process fluid pathway upstream of the sensor and an outlet line for the conditioning or cleaning fluid exits the process fluid pathway downstream of the sensor. A flow control controls the fluid to flow either through the process fluid pathway through the sensor, through the bypass fluid pathway omitting the sensor, or through the conditioning or cleaning fluid line that includes the sensor but omits the remainder of the process fluid pathway and the bypass fluid pathway entirely. Summary of the Invention [Problem to be solved by the invention]

[0006] It is an object of the present invention to enable a proper calibration workflow for single-use sensors that are integrated into a single-use process configuration. [Means for solving the problem]

[0007] The above problem is solved by an apparatus assembly according to claims 1 and 4. Advantageous and expedient embodiments of the invention are evident from the dependent claims.

[0008] According to a first aspect, the present invention provides an apparatus assembly for calibrating a single-use sensor before, during or after a manufacturing process step of a biopharmaceutical. The apparatus assembly includes a single-use process equipment apparatus assembly for performing at least a part of the process step. The single-use process equipment assembly includes a flow line through which a medium flows in a defined direction during the process step. The single-use process equipment assembly further includes an integrated single-use sensor for measuring or detecting a physical or chemical property at a measurement location in the flow line. The apparatus assembly according to the present invention further includes at least one calibration line and at least one switching means inserted in the flow line upstream of the measurement location. The switching means includes a flow line inlet, a flow line outlet and a calibration line inlet connected to the calibration line. The switching means is adapted to selectively switch between a first (main) flow path, in which the flow line inlet and the flow line outlet are open while the calibration line inlet is closed, and a second (calibration) flow path, in which the flow line inlet is closed while the calibration line inlet and the flow line outlet are open. The device assembly according to the invention comprises a dedicated reference means provided in the calibration line, the dedicated reference means including a reference sensor or a reference source or a reference standard solution related to the physical or chemical property to be measured or detected by the single-use sensor.

[0009] According to a first aspect, at least one calibration line (inlet line) is selectively connected to a flow line upstream of the single-use sensor to be calibrated. Alternatively or in addition, at least one calibration line (outlet line) may be selectively connected to a flow line downstream of the single-use sensor to be calibrated.

[0010] According to this second aspect, the invention provides an apparatus assembly for calibrating a single-use sensor before, during or after a manufacturing process step of a biopharmaceutical. The apparatus assembly comprises a single-use process equipment assembly for performing at least a part of the process step. The single-use process equipment assembly includes a flow line through which a medium flows in a defined direction during the process step. The single-use process equipment assembly further includes an integrated single-use sensor for measuring or detecting a physical or chemical property at a measurement location in the flow line. The apparatus assembly according to the invention further comprises at least one calibration line and at least one switching means inserted in the flow line downstream of the measurement location. The switching means includes a flow line inlet, a flow line outlet and a calibration line outlet connected to the calibration line. The switching means is adapted to selectively switch between a first (main) flow path, in which the flow line inlet and the flow line outlet are open while the calibration line outlet is closed, and a second (calibration) flow path, in which the flow line inlet and the calibration line outlet are open while the flow line outlet is closed. The device assembly includes a dedicated reference means provided in the calibration line, the dedicated reference means including a reference sensor or a reference source or a reference standard solution related to the physical or chemical property to be measured or detected by the single-use sensor.

[0011] The present invention is generally based on the discovery that an integrated single-use sensor can remain in the flow line of a single-use process equipment assembly used to perform a biopharmaceutical process (step) by adding at least one special calibration line to the process equipment assembly, which includes appropriate means for calibration. This means that calibration of the single-use sensor can be performed before, during or after a biopharmaceutical manufacturing process step without the need to remove the single-use sensor from the single-use process equipment assembly. Thus, the single-use sensor can also be located together with the single-use process equipment assembly.

[0012] The following provides an explanation of the scope of some terms used in connection with the present invention.

[0013] With regard to the term "single-use", it should be noted that a person skilled in the art can precisely distinguish between, on the one hand, dedicated single-use components (disposable elements) that are not intended for cleaning after one use and are intended for disposal, and, on the other hand, reusable components that are intended for repeated use. In both cases, whether a component of an apparatus assembly is disposable or reusable can be clearly determined based on its material and design. Each component is clearly distinguished from the other among experts with regard to its intended use (single-use vs. reusable) and has clear advantages and disadvantages. Laboratory equipment suppliers in particular offer and sell disposable components with clear labels.

[0014] Depending on the measurement technology, the single-use sensor to be calibrated is either installed in the main line (in-line measurement) or in the bypass line (on-line measurement) of the single-use process equipment assembly. Thus, the term "flow line" can refer to the main line or the bypass line. "Integral" means that the sensor is or includes a component that is permanently fixed to the single-use process equipment assembly, particularly the flow line.

[0015] The single-use sensor to be calibrated may be any type of sensor for detecting or measuring one or more physical or chemical properties, such as pH, dissolved oxygen (DO), conductivity, pressure, flow rate, temperature, turbidity, viscosity, etc. The sensor may also be an analyzer. In the context of the present invention, the term "single-use sensor" refers in particular to the part, part, or component of the sensor that is in contact with the medium flowing in the flow line. For example, in the case of a spectrometer, the medium passes through the detection chamber, but other parts of the spectrometer do not contact the medium. In such cases, only the part, part, or component of the sensor that is in contact with the medium needs to be configured for single use.

[0016] The switching means may be any device or arrangement adapted to selectively switch between different flow lines. In the device assembly according to the invention, the switching means is adapted to switch between at least a "normal" first flow line, corresponding to the normal flow of the medium during the biopharmaceutical process step, and a different second flow line, which is used in particular for calibration of the single-use sensor. The switching means may for example be a combination of 3 / 2 way valves or (pinch) valves.

[0017] The dedicated reference means is arranged in the additional calibration line and is provided in particular for the purpose of calibrating single-use sensors. According to the invention, this dedicated reference means can preferably comprise a reference sensor (either single-use or reusable) of the same type as the single-use sensor to be calibrated. The dedicated reference means can also comprise a reference source, e.g. a pressure source or pressure generator for applying a reference pressure. Furthermore, the dedicated reference means can comprise a reference standard solution having at least one precisely known characteristic (pH, dissolved oxygen (DO), conductivity, turbidity, viscosity, etc.).

[0018] The terms "upstream" and "downstream" refer to a location in a flowline relative to the normal direction of flow of a medium during a biopharmaceutical process step. For example, "upstream of a single-use sensor" refers to a location in the flowline where the medium has not yet passed the single-use sensor.

[0019] In a setup where the calibration line connects to the flow line upstream of the single-use sensor, a corresponding switching means may be arranged upstream of the main pump of the process equipment assembly. In this case, the main pump can serve two purposes: on the one hand, according to the conventional intended use, it moves the medium through the flow line to carry out the biopharmaceutical step. On the other hand, the main pump can also be used to supply fluid from the calibration line to the flow line section in which the single-use sensor to be calibrated is located.

[0020] However, if the main pump cannot or should not be used to draw fluid from the calibration line, an additional calibration pump can be placed in the calibration line.

[0021] In a setup where the calibration line is connected to the flow line downstream of the single-use sensor, the liquid used for calibration is either led to a waste container or discharged to the ambient air. In the first case, the calibration line leads to a waste container, in the second case, the calibration line has an open end.

[0022] Any bacterial filter can be placed in the calibration line.

[0023] According to a particular aspect of the invention, the dedicated reference means can be traceable to a standard or calibration according to a national or regional standardization organization such as the National Institute of Standards and Technology (NIST) in the United States or the Deutsche Industrie Norm (DIN) in Germany. Such a reference means can ensure the accuracy of the calibration.

[0024] For some calibration use cases it may be necessary or convenient to have at least two separate calibration lines, one upstream and one downstream of the single-use sensor, the upstream calibration line connected to a calibration line inlet of an upstream switching means inserted in the flow line upstream of the measurement location, and the downstream calibration line connected to a calibration line outlet of a downstream switching means inserted in the flow line downstream of the measurement location.

[0025] Calibrating a single-use sensor that is already or still fixed in a flow line of a process equipment assembly is an important aspect of the present invention. That is, the fluids required for the calibration procedure, including flushing and / or cleaning steps, should be supplied in an efficient manner to the flow line of the process equipment assembly, preferably directly through a calibration line connected to the flow line upstream of the single-use sensor. This can be achieved by the calibration line being connected to at least one reservoir or supply line of a reference standard solution, a disinfectant solution, a sterilizing solution, or a flushing fluid.

[0026] In this context, it is advantageous to provide selection means adapted to connect only one reservoir or supply line to the calibration line at a time.

[0027] To enable an automatic calibration procedure, the switching means for connecting and disconnecting the calibration line are automatically operated by the control unit.

[0028] The invention also provides a method of calibrating a single-use sensor before, during or after a biopharmaceutical manufacturing process step, the method being carried out with an apparatus assembly according to the invention and comprising manipulating a switching means such that a calibration flow path is established in which a calibration line inlet and a flow line outlet are open while a flow line inlet is closed, measuring a physical or chemical property with the single-use sensor, and using the measurement and reference means to calibrate the single-use sensor. [Brief description of the drawings]

[0029] Further features and advantages of the present invention will become apparent from the following description and the accompanying drawings which are referenced. [Figure 1] FIG. 1 shows an apparatus assembly with components that can be used to calibrate a single-use sensor according to the present invention. [Diagram 2] FIG. 2 shows the device assembly setup for the first use case. [Diagram 3] FIG. 3 shows a variation of the setup of FIG. [Figure 4] FIG. 4 shows the device assembly setup for the second use case. [Diagram 5] FIG. 5 shows the device assembly setup for the third use case. [Figure 6] FIG. 6 shows another setup of the device assembly for the third use case. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0030] 1 shows a basic set-up of an apparatus assembly 10. The apparatus assembly 10 comprises a single-use process equipment assembly for performing at least a portion of a biopharmaceutical process step (particularly a unit operation) and includes a main flow line 12 through which media flows in a defined direction during the process step, as indicated by the arrow.

[0031] The single-use process equipment assembly further includes a single-use sensor 14 for measuring or detecting a physical or chemical property relevant to monitoring and / or controlling a process step. The single-use sensor 14 is integrated into the flow line 12 such that at least one portion, part or component of the sensor 14 that contacts the media is permanently attached or inserted into the flow line 12 at a specific measurement location. For convenience, this location will be referred to as the location of the single-use sensor 14.

[0032] The single-use process equipment assembly also includes a main pump 16 for moving the media through the flow line 12 .

[0033] Other components of the process equipment assembly are not shown as they are not relevant here.

[0034] 1 does, however, show additional components of the apparatus assembly 10 for calibrating the single-use sensor 14. These components, all described further below, may be used in special calibration procedures that may occur before, during, or after performing a biopharmaceutical process step. In any event, the calibration procedure is performed while the single-use sensor 14 is installed in the single-use process equipment assembly.

[0035] 1 are not required for the calibration of a single-use sensor 14. Depending on the actual use case and the corresponding calibration technique, different selections of these components can be used, particularly as described further below in conjunction with other figures.

[0036] 1, two calibration lines 18, 20 are selectively connected to the flow line 12 via switching means 22, 24, respectively. The first switching means 22 is incorporated in the flow line 12 upstream of the single-use sensor 14 and includes a flow line inlet 26, a flow line outlet 28, and a calibration line inlet 30. At least the flow line inlet 26 and the calibration line inlet 30 can be either opened or closed. The second switching means 24 is incorporated in the flow line 12 downstream of the single-use sensor 14 and includes a flow line inlet 32, a flow line outlet 34, and a calibration line outlet 36. At least the flow line outlet 34 and the calibration line outlet 36 can be either opened or closed.

[0037] For the first calibration line 18, the first switching means 22 can be operated to switch between a normal flow path in which the calibration line inlet 30 is closed while the flow line inlet 26 and the flow line outlet 28 are open, and a calibration flow path in which the flow line inlet 26 is closed while the calibration line inlet 30 and the flow line outlet 28 are open. For the second calibration line 20, the second switching means 24 can be operated to switch between a normal flow path in which the flow line inlet 32 ​​and the flow line 34 are open while the calibration line outlet 36 is closed, and a calibration flow path in which the flow line inlet 32 ​​and the calibration line outlet 36 are open while the flow line outlet 34 is closed.

[0038] The first calibration line 18 can be used to supply one or more fluids to the flow line 12 upstream of the single-use sensor 14. The fluids may be a cleaning fluid such as water for injection (WFI), a sterilizing or disinfecting fluid, or a reference standard solution.

[0039] A reference standard solution may be a process buffer or caustic for a process step, but has at least one very known property (such as pH, dissolved oxygen (DO), conductivity, turbidity, viscosity, etc.) that is or is closely related to the physical or chemical property measured or detected by the single-use sensor 14. In particular, a reference standard solution may be attributable to a standard or calibration according to a national or regional standardization organization, such as the "National Institute of Standards and Technology" (NIST) in the United States.

[0040] Depending on the use case, other types of fluids may be supplied to the flow line 12 via the first calibration line 18. Figure 1 shows a convenient setup with selection means 38, such as valves, for selectively connecting reservoirs of a reference standard solution 40, a sterile or antiseptic fluid 42, and water for injection (WFI) 44 to the first calibration line 18.

[0041] The calibration pump 46 is used to move the respective fluid to the calibration line inlet 26 of the first switching means 22. However, if the main pump 16 is located downstream of the first switching means 22 (to the right in FIG. 1 ), the calibration pump 46 is not necessarily required as the main pump 16 can be used to supply fluid to the flow line 12 when the flow line inlet 26 of the first switching means 22 is closed and the calibration line inlet 30 and flow line outlet 28 are open.

[0042] If the single-use sensor 14 is a pressure sensor, or if a defined pressure is needed to calibrate the single-use sensor 14 for other reasons, the calibration pump 46 (or the main pump 16 if there is no calibration pump) will need to be calibrated to provide the defined reference pressure. For this reason, a calibrated pressure source (generator) may be used in place of the calibration pump.

[0043] In many use cases, the single-use sensor 14 is calibrated with the aid of an already calibrated reference sensor 48 (single-use or reusable) placed in the first calibration line 18. As described above in connection with the reference standard solution 40, the reference sensor 48 may be a sensor that can be attributed to a standard or calibration according to a national or regional standardization organization, such as the National Institute of Standards and Technology (NIST) in the United States or the Deutsche Industrie Normative (DIN) in Germany.

[0044] Placing a bacterial filter 50 at the calibration line inlet 26 of the first switching means 22 can further ensure that contaminants do not enter the flow line 12 via the first calibration line 18 .

[0045] The second calibration line 20 can be used to draw fluid from the flow line 12 downstream of the single-use sensor 14 .

[0046] A bacterial filter 50 may be positioned at the outlet of the second calibration line 20 in the second switching means 24 to prevent contaminants from exiting the second calibration line 20 when the second calibration line 20 is open ended.

[0047] A calibrated reference sensor 48 (reusable or single-use) is located in the second calibration line 20. As mentioned above, the reference sensor 48 may be a sensor that can be attributed to a standard or calibration according to a national or regional standards body.

[0048] The second calibration line 20 terminates in a waste container 52 or is open ended.

[0049] As described in the use cases below, a reference sensor 48 or a pressure source (or other reference source) or a reference standard solution 40, or a combination of these components, is used as a dedicated reference means for calibration of the single-use sensor 14.

[0050] The switching means 22, 24 may be configured to be manually operated or alternatively configured to be automatically operated, for example by electrical or pneumatic actuation. Automatically operated switching means 22, 24 allow for an automated workflow controlled by a control unit.

[0051] According to a first general workflow, which can be used for example for the calibration of a pH or conductivity single-use sensor 14, most of the components shown in FIG. 1 are used in a setup as shown in FIG. 2 or FIG. 3. The difference between these two setups is the position of the first switching means 22 with respect to the main pump 16. According to the setup according to FIG. 2, the main pump 16 is arranged upstream of the first switching means 22, and therefore cannot be used to supply fluid from the first calibration line 18 to the flow line 12. According to the setup according to FIG. 3, the main pump 16 is arranged downstream of the first switching means 22. In this case, the calibration pump 46 in the first calibration line 18 is optional. The calibration pump 46 can be used in case the main pump 16 stops during the calibration procedure.

[0052] In both setups, the general workflow of the calibration procedure is the same. The calibration procedure is initiated by operating the first switching means 22 such that the flow line inlet 26 is closed and the calibration line inlet 30 and the flow line outlet 28 are opened. Furthermore, the second switching means 24 is actuated such that the flow line inlet 32 ​​and the calibration line outlet 36 are opened while the flow line outlet 34 is closed. Thus, the main flow path is blocked and a calibration flow path is established. The calibration flow path includes the first calibration line 18, the portion of the flow line 12 through the single-use sensor 14, and the second calibration line 20.

[0053] The calibration flow path is supplied with a caustic agent, such as 3 molar sodium hydroxide (NaOH), or a suitable buffer solution. The pH or conductivity value measured by the single-use sensor 14 is compared to a corresponding value measured by the reference sensor 48. Based on the results of the comparison, the single-use sensor 14 is calibrated.

[0054] Fluid passing through the single-use sensor 14 is directed to a second calibration line 20 which terminates in a waste container 52 .

[0055] If the single-use sensor 14 is to be used after calibration (if a calibration procedure was performed before or during a biopharmaceutical process step), the calibration flow path is washed with water for injection 44 before it is closed and the flow main flow path is re-established by appropriately operating the first and second switching means 22, 24.

[0056] 2 and 3, a reference sensor 48 can also be placed on the second calibration line 20. For even greater accuracy, one reference sensor 48 can be placed on the first calibration line 18 and one on the second calibration line 20.

[0057] Additionally, the caustic or buffer solution may be a traceable reference standard container 40 having certified values ​​of properties of interest (such as pH and / or conductivity).

[0058] The same setup can be used to calibrate single-use sensors 14 that measure (or detect) other chemical or physical properties, such as pressure or flow rate.

[0059] The calibration procedure can be combined with the standard inactivation / washing / priming steps of a biopharmaceutical process.

[0060] Next, another workflow based on a setup using some of the components shown in Fig. 1 will be described. This setup does not include a reference sensor, but instead makes use of a reference standard solution 40, preferably a solution that can be attributed to a standard or calibration according to a national or regional standardization body as mentioned above. Such a setup can be used for the calibration of sensors 14 that measure, for example, pH, conductivity, or concentration of an analyte, such as spectroscopic sensors based on the absorption or scattering of radiation.

[0061] The main flow path is blocked and the calibration flow path is established as described above, after which the calibration flow path is thoroughly flushed with water for injection 44.

[0062] After rinsing, a reference standard solution 40 is passed through the calibration flow path and the property of interest is measured by the single-use sensor 14. The measurement is compared to the known value of the reference standard solution 40. Based on the results of the comparison, the single-use sensor 14 is calibrated.

[0063] After calibration, the calibration flow path is flushed or disinfected and, if necessary, the main flow path is re-established by manipulating the first and second switching means 22, 24 appropriately.

[0064] Fluid provided through the first calibration line 18 is moved by either the calibration pump 46 or the main pump 16 (if the main pump 16 is located downstream of the first switching means 22).

[0065] The setup shown in Figure 4 can be used to calibrate the single-use pressure sensor 14. A calibrated pressure source (calibration pump 46 or pressure generator) is set to a defined reference pressure when the main flow path is blocked and the calibration flow path is established. The pressure is measured by the single-use sensor 14 and compared to the defined pressure provided by the calibrated pressure source. Based on the results of the comparison, the single-use sensor 14 is calibrated.

[0066] The fluid used in the calibration procedure flows into the second calibration line 20 and is collected in a waste container 52. Alternatively, the fluid can be discharged into the surrounding air. In this case, it may be advisable to use a bacterial filter in the second calibration line 20 to prevent contaminants from escaping into the air (it is assumed that the bacterial filter does not affect the static pressure).

[0067] 5 and 6 show different setups for calibrating the single-use flow sensor 14. FIG.

[0068] In the setup according to Fig. 5, only one calibration line 20 is used (corresponding to the second calibration line 20 shown in Fig. 1). The flow line 12 is flushed with water for injection 44 displaced by the main pump 16. For calibration, the main pump 16 displaces a suitable fluid, for example a buffer solution, through the single-use sensor 14. Downstream of the single-use sensor 14, the fluid is directed via the switching means 24 to the calibration line 20. In the calibration line 20, the flow rate is measured by a reference sensor 48 and compared with the measurement of the single-use sensor 14. After passing the reference sensor 48, the fluid is directed to a waste container 52 or discharged to the ambient air.

[0069] In the setup according to FIG. 6, only the calibration line 18 connected to the flow line 12 upstream of the single-use sensor 14 is used (corresponding to the first calibration line 18 shown in FIG. 1). After flushing the flow line 12, the switching means 22 closes the main flow path downstream of the main pump 16 and connects the calibration line 18 to the flow line 12. The calibration pump 46 is then used to generate a flow with a buffer or other suitable fluid. A reference sensor 48 in the calibration line 18 measures the flow rate and a comparison of the measurements by the reference sensor 48 and the single-use sensor 14 is used to calibrate the single-use sensor 14. The fluid that has passed the single-use sensor 14 flows further in the flow line 12 and is directed to a waste container (not shown here). After calibration (in the case of pre-use applications), the calibration line 18 is disinfected with a suitable fluid 42 and the switching means 22 re-establishes the main flow path. The flow line 12 is flushed in a standard manner before carrying out the biopharmaceutical step.

[0070] In a setup having a calibration line 20 selectively connected to the flow line 12 downstream of the single-use sensor 14, the dedicated reference means may also include a reference source (such as a calibrated pressure source / generator) or a reference standard solution 40, as described above. Such a reference means may be useful for backflow calibration, i.e., a calibration procedure in which fluid flows through the flow line 12 in a direction opposite to the flow direction of the media during a biopharmaceutical process step.

[0071] Neither setup requires a bypass line to bypass the single-use sensor 14. In particular, the flow of medium through the main flow path 12 can be interrupted by a first switching means 22 upstream of the single-use sensor 14. At the same time, the first switching means 22 establishes a calibration flow path for the calibration procedure, comprising the first calibration line 18, the portion of the flow line 12 passing through the single-use sensor 14 and - optionally - the second calibration line 20. Alternatively, the medium used for calibrating the single-use sensor 14 is supplied by the main flow path 12.

[0072] It should be noted that the general setup shown in Figure 1, and the specific setups shown in the other figures used for the use cases described above, are not to be understood in a limiting sense: specific aspects of the individual setups and workflows may be combined in any suitable manner. [Explanation of symbols]

[0073] 10 Device Assembly 12 Flow Lines 14 Single-use sensors 16 Main pump 18 (1st) Calibration Line 20 (2nd) Calibration Line 22 (1st) Switching means 24 (Second) Switching means 26 flow line inlet of first switching means 28 Flow line outlet of first switching means 30 Calibration line inlet of first switching means 32 flow line inlet of second switching means 34 Flow line outlet of second switching means 36 Calibration line outlet of second switching means 38 Selection methods 40 Reference Standard Solutions 42 Sterilizing or disinfecting fluids 44 Water for injection 46 Calibration Pump 48 Reference Sensor 50 bacterial filter 52 Waste container

Claims

1. An apparatus assembly for calibrating a single-use sensor (14) before, during, or after a biopharmaceutical manufacturing process, It comprises a single-use process equipment assembly for performing at least a portion of the aforementioned process steps, The single-use process equipment assembly includes a flow line (12) in which the medium flows in a defined direction during the process stage. The single-use process equipment assembly further includes an integrated single-use sensor (14) for measuring or detecting physical or chemical properties at a measurement position in the flow line (12). The apparatus assembly includes at least one calibration line (18), The apparatus assembly includes at least one switching means (22) inserted into the flow line (12) upstream of the measurement position, The switching means (22) includes a flow line inlet (26), a flow line outlet (28), and a calibration line inlet (30) connected to the calibration line (18). The switching means (22) is A first flow path, wherein the calibration line inlet (30) is closed, while the flow line inlet (26) and the flow line outlet (28) are open. A second flow path, wherein the calibration line inlet (30) and the flow line outlet (28) are open, while the flow line inlet (26) is closed. It is adapted to selectively switch between the following: The apparatus assembly includes a dedicated reference means provided on the calibration line (18), The dedicated reference means comprises a reference sensor (48) or a reference source or reference standard solution (40) related to the physical or chemical properties measured or detected by the single-use sensor (14), in the apparatus assembly.

2. The switching means (22) is located upstream of the main pump (16) of the process equipment assembly. The apparatus assembly according to claim 1.

3. A calibration pump (46) is located in the calibration line (18). The apparatus assembly according to claim 1.

4. An apparatus assembly for calibrating a single-use sensor (14) before or after a process stage in the manufacturing of a biopharmaceutical, It comprises a single-use process equipment assembly for performing at least a portion of the aforementioned process steps, The single-use process equipment assembly includes a flow line (12) in which the medium flows in a defined direction during the process stage. The single-use process equipment assembly further includes an integrated single-use sensor (14) for measuring or detecting physical or chemical properties at a measurement position in the flow line (12). The apparatus assembly includes at least one calibration line (20), The apparatus assembly includes at least one switching means (24) inserted into the flow line (12) downstream of the measurement position, The switching means (24) includes a flow line inlet (32), a flow line outlet (34), and a calibration line outlet (36) connected to the calibration line (20). The switching means (24) is A first flow path, wherein the calibration line outlet (36) is closed, while the flow line inlet (32) and the flow line outlet (34) are open. A second flow path, wherein the flow line outlet (34) is closed, while the flow line inlet (32) and the calibration line outlet (36) are open. It is adapted to selectively switch between the following: The apparatus assembly includes a dedicated reference means provided on the calibration line (20), The dedicated reference means includes a reference sensor (48) or a reference source or reference standard solution (40) related to a physical or chemical property measured or detected by a single-use sensor (14), in the apparatus assembly.

5. The calibration line (20) has an open end. The apparatus assembly according to claim 4.

6. The calibration line (20) leads to the waste container (52). The apparatus assembly according to claim 4.

7. A bacterial filter (50) is located on the calibration line (18, 20). The apparatus assembly according to claim 1 or 4.

8. The aforementioned dedicated standard means may be attributable to standards or calibrations in accordance with national or regional standardization bodies. The apparatus assembly according to claim 1 or 4.

9. The apparatus assembly includes at least one further calibration line (20), The apparatus assembly includes at least one further switching means (24) inserted into the flow line (12) downstream of the measurement position, The further switching means (24) includes a further flow line inlet (32), a further flow line outlet (34), and a further calibration line outlet (36) connected to the further calibration line (20), The aforementioned further switching means (24) is A further first flow path, wherein the further calibration line outlet (36) is closed, while the further flow line inlet (32) and the further flow line outlet (34) are open, A further second flow path, wherein the further flow line outlet (34) is closed, while the further flow line inlet (32) and the further calibration line outlet (36) are open. It is adapted to selectively switch between the following: The apparatus assembly includes further dedicated reference means provided in the further calibration line (20), The further dedicated reference means includes a further reference sensor (48) or a further reference source or further reference standard solution (40) related to the physical or chemical properties measured or detected by the single-use sensor (14). The apparatus assembly according to claim 1 or 2.

10. The calibration line (18) is connected to at least one reservoir or supply line of the reference standard solution (40), disinfectant solution (42), sterilization solution (42), and flushing fluid (44). The apparatus assembly according to claim 1 or 2.

11. The system includes a selection means (38) adapted to connect only one reservoir or supply line to the calibration line (18) at a time. The apparatus assembly according to claim 10.

12. The switching means (22, 24) are automatically operated by the control unit. The apparatus assembly according to claim 1 or 4.

13. Use of the apparatus assembly according to claim 1 or 4 for calibrating a single-use sensor (14) before, during, or after a biopharmaceutical manufacturing process.

14. A method for calibrating a single-use sensor (14) before, during, or after a biopharmaceutical manufacturing process, the method being carried out using the apparatus assembly described in claim 1 or 2. The switching means (22, 24) is activated to establish a calibration flow path, where the flow line inlet (26) is closed and the calibration line inlet (30) and the flow line outlet (28) are open. The single-use sensor (14) measures physical or chemical properties. Calibrating the single-use sensor (14) using the measured value and the reference means. A method that includes this.

15. The further includes supplying a dedicated reference standard solution (40) to the calibration line (18) of the apparatus assembly, which can be attributed to a standard or calibration in accordance with a national or regional standardization body, relating to the physical or chemical properties measured or detected by the single-use sensor (14), The method according to claim 14.

16. The aforementioned reference standard solution (40) is used to calibrate the sensors (14), which include a pH measuring sensor (14), an electrical conductivity measuring sensor (14), an analyte concentration measuring sensor (14), and a spectroscopic sensor based on radiation absorption or scattering. The method according to claim 15.

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