Sensor device for bioprocessing systems and method for its operation

Abstract

Disclosed is a sensor device 1;1';1'' configured to be connected into a fluid channel of a bioprocessing system for measuring at least one property of a fluid being transported through the fluid channel. The sensor device 1;1';1'' comprises a fluid chamber 13 surrounding at least a portion of the sensor probe 3 of the sensor device 1;1';1'', the fluid chamber 13 being movable to at least two different positions along the sensor probe 3, including a process position in which a sensor element 5 in the sensor probe extends outside the fluid chamber 13 and a service position in which the sensor element 5 is surrounded by the fluid chamber 13. The sensor device 1;1';1'' further comprises a fluid channel connection block 21;21' comprising an internal fluid channel 23 configured to connect to a fluid channel of a system in which the sensor device 1;1';1'' is used. Fluid passage connection blocks 21;21' are configured to receive sensor probes 3 of sensor devices 1;1';1'' and include a fluid chamber closure section 27 that closes the fluid chamber 13 around the sensor element 5 together with the surrounding wall 14 of the fluid chamber 13 when the fluid chamber is in a service position. A method 100 for operating at least one sensor probe 3 in sensor devices 1;1';1' provided in a bioprocessing instrument is also described. Method 100 includes the steps of i) setting each sensor probe 3 to a calibration position 101, wherein the sensor element 5 of the sensor probe 3 is in fluid contact with a fluid passage of the bioprocessing instrument; ii) introducing a first calibration medium into the sensor probe 3 102; iii) calibrating the sensor probe 3; iv) removing the first calibration medium from the sensor probe 3 103; and v) setting the sensor probe 3 to an operating position 105.

Description

TECHNICAL FIELD

[0001] The present invention relates to a sensor device configured to be connected in a fluid path of a system for measuring at least one property of a fluid conveyed through the fluid path of a bioprocessing system, and to a method for calibrating and / or cleaning a sensor element in such a sensor device. BACKGROUND ART

[0002] Measuring properties such as chemical or physical process variables in a fluid within a process system is performed by the use of different types of sensors. Some sensors, such as pH sensors, require regular cleaning and calibration. One possibility is to remove the sensor from the process system and perform the required service before the sensor is returned to its predetermined position within the process system. Retractable sensor assemblies are also provided, in which the sensor probe can be retracted into a service chamber within the sensor assembly during servicing. One such retractable sensor assembly is disclosed in U.S. Pat. No. 9,228,863. A problem with such retractable sensor assemblies is that the sensor probe of the sensor assembly requires space outside the process system to be retractable. Furthermore, the sensor probe needs to be provided with a plug at the end of the sensor probe, which plug is arranged to close the inlet to the process fluid vessel when the sensor is retracted. Such a plug requires space within the process fluid vessel during sensor measurement, and may disturb the flow of fluid if the process fluid vessel whose properties are to be measured is a fluid flow path. PRIOR ART DOCUMENTS PATENT DOCUMENTS

[0003] PATENT DOCUMENT 1 U.S. Pat. No. 9,228,863 SUMMARY OF THE INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION

[0004] The object of the present invention is to provide an improved sensor device for bioprocessing applications.

[0005] A further objective is to provide a sensor device suitable for connection in sterile fluid flow channels.

[0006] These and various other objectives are addressed by the present invention, as defined by the appended claims. [Means for solving the problem]

[0007] In one or more embodiments, the disclosure relates to disposable devices. The sensor may be included in the body as a sensor unit that can be disposed of, for example, after the completion of a bioprocess.

[0008] Disposable technologies (SUTs) are a recent development addressing the need to reduce production costs, improve production throughput and quality, and enhance safety in bioprocessing / biomonetization. Using disposable processing technologies and components / equipment, wet parts that come into contact with process fluids and drug products during processing, such as fluid storage containers, piping, and separation components / equipment, are provided as clean, ready-to-use consumables that are installed and used only for specific processes, products, or for a limited time, and then disposed of.

[0009] SUT consumables are typically manufactured, assembled, and packaged in a cleanroom environment to avoid contamination by microorganisms, particulate matter, etc. SUT wet components can also be supplied in a clean and pre-sterilized state, thus enabling aseptic and / or sterilization, thereby reducing the aforementioned risks related to product, operator, or patient safety. Typically, SUT wet components are subjected to sterile gamma irradiation before use in the biomanufacturing process, in which case they are deployed as “pre-sterilized” at the time of use. This may include providing a formal and verified sterilization claim for the consumable after sterilization, or alternatively, providing a sterilized consumable that is supplied without a formal sterilization claim. Under controlled and strict manufacturing conditions, SUT consumables can also be deployed non-sterilized and / or in a process that controls the state and conditions of the consumable. This allows the level of microbial contamination, commonly referred to as “bioburden,” or the level of contamination or presence of contaminants or particles, to be controlled and maintained within a predetermined level. [Brief explanation of the drawing]

[0010] [Figure 1a] This is a cross-sectional view of a sensor device according to one embodiment of the present invention at a process location. [Figure 1b] This is the same as Figure 1a, but in perspective. [Figure 2a] These are cross-sectional views of the same sensor device shown in Figures 1a and 1b at the service location. [Figure 2b] This is the same as Figure 2a, but in perspective. [Figure 3a] This is a perspective view of a sensor device according to another embodiment of the present invention at a service location. [Figure 3b] This is a cross-sectional view of the sensor device shown in Figure 3a at the service location. [Figure 4] This is a cross-sectional view of a sensor device according to another embodiment of the present invention at a service location. [Figure 5] This is a flowchart of the method according to one embodiment of the present invention. [Figure 6] The present invention illustrates various embodiments of a bioreactor for use in one or more bioprocessing operations, comprising a flexible bag bioreactor container equipped with a pH sensor device fluid-connected to the fluid channel within it. [Figure 7] The present invention illustrates various embodiments of a bioreactor for use in one or more bioprocessing operations, comprising a flexible bag bioreactor container equipped with a pH sensor device fluid-connected to the fluid channel within it. [Figure 8] This specification provides alternative embodiments of sensor devices that can be used with various bioreactors and the like described herein. [Modes for carrying out the invention]

[0011] Figures 1 and 2 show a sensor device 1 according to one embodiment of the present invention in two different positions. The process position is shown in Figures 1a and 1b, and the service position is shown in Figures 2a and 2b. Figures 3a and 3b show a sensor device 1' according to another embodiment of the present invention in the service position. Many of the details are the same for both of these embodiments and are therefore given the same or similar reference numbers, and both embodiments are described together with reference to all the following drawings. The difference between these two embodiments is that the fluid path connection block 21;21' of sensor device 1;1' has different components. The fluid path connection block 21' of sensor device 1' in Figures 3a and 3b has more parts, such as a valve and additional flow paths, thereby allowing the fluid flow to be guided through the fluid path connection block 21' in different ways. For example, by controlling a valve (not shown) in the fluid path connection block 21', the fluid flow can be guided through the sensor element 5 of sensor device 1' or guided to bypass the sensor element 5.

[0012] The sensor device 1;1' according to both of these embodiments of the present invention is configured to be connected into a fluid path of a system for measuring at least one characteristic of a fluid being transported through the fluid path. The system may be a bioprocessing system or a subsystem thereof, or may include them. The fluid path connection block 21;21' according to both embodiments of the present invention shown in Figures 1 to 3 can be easily and directly connected to a fluid path of a process system such as a bioprocess system (e.g., a chromatography system, a bioreactor system, a virus inactivation system, a fluid mixing system, a filtration system (e.g., including a tangential flow filter (TFF), etc.), a flow cell, a filling and finishing system, etc.). This allows at least one characteristic of the fluid to be measured by a sensor element 5 provided in the sensor device 1;1'.

[0013] Sensor device 1;1' comprises an elongated sensor probe 3 having a sensor element 5 at its end 3a. Sensor device 1;1' further comprises a probe housing 11 connected to the sensor probe 3 such that the sensor probe 3 protrudes through the probe housing 11. The probe housing 11 comprises a fluid chamber 13 surrounding at least a portion of the sensor probe 3, the fluid chamber 13 being positioned relative to the sensor probe 3 such that the fluid chamber 13 can be moved along the sensor probe 3 to at least two different positions, including a process position in which the sensor element 5 within the sensor probe 3 extends outside the fluid chamber 13 and a service position in which the sensor element 5 is surrounded by the fluid chamber 13. The probe housing 11 further comprises a first port 15 connected to the fluid chamber 13 and configured to be connected to an external fluid supply device 16a and / or an external suction device 16b. This allows a service fluid, such as a calibration fluid, cleaning fluid, or storage fluid, to be supplied into the fluid chamber 13 via the first port 15. Next, the service fluid can be drawn from the fluid chamber 13 by an external suction device 16b connected to the first port 15. The probe housing 11 further includes a second port 17 connected to the fluid chamber 13 and configured to allow air to enter and exit the fluid chamber 13. In some cases, more ports may be provided so that, for example, fluid can be supplied through one port and drawn through another. In some cases, different types of service fluid can be added through different ports. Another possibility is to connect a valve to the first port 15 to allow multiple uses of the first port 15.

[0014] The sensor apparatus 1;1' further includes the fluid line connection block 21;21' as described above. The fluid line connection block 21;21' includes an internal fluid line 23 having an inlet 23a and an outlet 23b (only the inlet 23a is visible in Figure 3a) configured to connect to the fluid line of the system. The fluid line connection block 21;21' further includes a receiving unit 25 for receiving the probe housing 11 and the sensor probe 3, such that the sensor element 5 is disposed within the internal fluid line 23 of the fluid line connection block 21;21'. The fluid line connection block 21;21' further includes a fluid chamber closing portion 27 that closes the fluid chamber 13 around the sensor element 5 together with the peripheral wall 14 of the fluid chamber 13 when the fluid chamber 13 is placed in the service position. Thereby, when the fluid chamber 13 is placed in the service position, a service fluid such as a calibration fluid, a cleaning fluid or a storage fluid can be supplied into the fluid chamber 13 without leaking into the fluid line of the system to which the sensor apparatus 1;1' is connected.

[0015] In both embodiments shown in Figures 1 to 3, the fluid chamber closing portion 27 includes a protruding plug provided on the internal fluid line 23 of the fluid line connection block 21;21', and when the fluid chamber 13 is placed in the service position, the peripheral wall 14 of the fluid chamber 13 fits around the protruding plug to achieve sealing.

[0016] In some embodiments of the present invention, the sensor element 5 is configured to measure pH, that is, the sensor element 5 is a pH sensor. A pH sensor needs to be calibrated periodically between different batches to function properly. It also needs to be cleaned periodically between different batches / processes. In addition, when measurement is not required, it is often necessary to store the pH sensor away from the process fluid. According to the present invention, both calibration, cleaning and storage can be provided within the sensor apparatus 1;1' without the need to remove the sensor probe 3 for treatment outside the system. This facilitates the handling of the system.

[0017] Suitably, the surrounding wall 14 comprises a sealing device 24 configured to seal around the fluid chamber closure 27 in the service position and around the sensor probe 3 in the process position. The sealing device 24 can be, for example, an O-ring or a gasket. In another embodiment, a sealing device may alternatively be provided at the end of the surrounding wall 14, and may be configured to seal against a flat surface in the internal fluid passage 23 of the fluid passage connection block 21;21'. In such an embodiment, the fluid chamber closure 27 does not comprise a protruding plug as shown in Figures 1a, 2a and 3b, but rather comprises a portion of the flat inner wall surface of the internal fluid passage 23 of the fluid passage connection block 21;21'. Thereby, the sealing device is pressed between the end of the surrounding wall 14 and the inner wall surface in such an embodiment, whereby the fluid chamber 13 is closed around the sensor element 5 when the fluid chamber 13 is provided in the service position.

[0018] The first port 15, in some embodiments (as shown in Figures 1 to 3), is connected to the first end 13a of the fluid chamber 13, and the first end 13a is provided at the end of the fluid chamber 13 located closest to the sensor element 5. The first port 15 comprises an extension tube 15a connecting the first end 13a of the fluid chamber 13 to the port connector 15b of the first port 15. Thereby, the port connector 15b of the first port 15 is arranged at a distance from the first end 13a of the fluid chamber 13 and can still be directly connected to the first end 13a of the fluid chamber 13, which may be suitable for efficiently supplying service fluid to and removing service fluid from the fluid chamber. Furthermore, the port connector 15b can be arranged outside the receiving unit 25 of the fluid passage connection block 21;21', which improves access to the port connector 15b for the user.

[0019] The second port 17 can be connected to the second end 13b of the fluid chamber 13, which is the end opposite to the first end 13a of the fluid chamber 13. This allows air to be efficiently discharged through the second port 17 when service fluid is added through the first port 15, and air to enter the fluid chamber through the second port 17 when service fluid is drawn in through the first port 15. One or more check valves may optionally be provided at the second port 17 to allow for air filtration and, in some cases, fluid removal. For best efficiency when removing service fluid from the fluid chamber 13, the sensor device 1;1' can be tilted slightly from the vertical plane toward the side of the sensor device 1;1' where the extension tube 15a enters the first end 13a of the fluid chamber 13, for example, 5 to 70°. This allows all service fluid to be efficiently drawn in through the first port 15.

[0020] In some embodiments (as shown in Figures 1 to 3), the peripheral wall 14 of the fluid chamber 13 may include an end portion 14a having a smaller inner circumference than the rest of the peripheral wall in order to close the fluid chamber 13 with its first end 13a toward the sensor probe 3 at the process position of the fluid chamber 13. The end portion 14a of the peripheral wall 14 may comprise the sealing device 24, which seals the fluid chamber 13 toward the outer surface of the sensor probe 3 at the process position. Alternatively, instead of the end portion 14a having a smaller inner circumference, the sealing device 24 may be larger. Furthermore, the sealing device 24 seals toward the fluid chamber closure 27 at the service position, as described above. The end portion 14a of the peripheral wall 14 is the end of the peripheral wall 14 closest to the first end 13a of the fluid chamber 13. Thus, in some embodiments, the circumferential shape of the fluid chamber closure 27 corresponds to the circumferential shape of the sensor probe 3. The circumferential shape is often circular, so that the diameter of the fluid chamber closure 27 and the diameter of the sensor probe 3 are appropriately the same. In this way, the circumferential wall 14 closes the fluid chamber 13 to the outer surface of the sensor probe 3 at the process position and to the fluid chamber closure 27 at the service position. However, in another embodiment as described above, the fluid chamber closure 27 does not have to be a protruding plug, but may instead be a flat surface of the inner wall of the internal fluid passage.

[0021] In some embodiments of the present invention, the internal fluid passage 23 of the fluid passage connection block 21;21' allows fluid to pass between the inlet 23a and outlet 23b of the internal fluid passage 23 at both the process and service positions of the fluid chamber 13. Thus, in such embodiments of the present invention, the outer circumference of the surrounding wall 14 of the fluid chamber 13 is smaller than the inner circumference of the internal fluid passage 23 at least at some positions, so that fluid can pass alongside the fluid chamber 13 within the internal fluid passage 23 of the fluid passage connection block 21;21'. This can be seen in the embodiment shown in Figure 3b. However, this can also be provided in the embodiments shown in Figures 1 and 2.

[0022] In another embodiment of the present invention, when the fluid chamber 13 is installed in a process position, the fluid chamber 13 seals the internal fluid passage 23 of the fluid passage connection block 21;21' to prevent fluid from passing between the inlet 23a and outlet 23b of the internal fluid passage 23. As a result, the surrounding wall 14 of the fluid chamber 13 is sealed toward the inner surface of the internal fluid passage 23, possibly via a sealing device.

[0023] In some embodiments of the present invention, the probe housing 11, and optionally the fluid passage connection blocks 21;21', are also 3D printed. Resin-based 3D printing techniques such as SLA or CLIP may be particularly advantageous for the manufacture of the probe housing. Powder-based 3D printing techniques such as SLS are another alternative. An alternative method for manufacturing the probe housing 11 can be diffusion bonding, thereby providing the probe housing in such an example as two halves that can be machined by milling. The two halves are then joined to each other by diffusion bonding. The design and materials used in the sensor device according to the present invention are preferably suitable for sterilization. Furthermore, the sensor device should function properly against pressures of at least 6 bar or up to 10 bar.

[0024] The sensor probe 3 may be detachably mounted on the probe housing 11. In both embodiments shown in Figures 1 to 3, the sensor probe 3 and the probe housing 11 are detachably connected by screws, but other alternative configurations for connection are also possible. This allows the sensor probe 3 to be removed for replacement or external maintenance.

[0025] Figure 4 is a cross-sectional view of sensor device 1'' according to another embodiment of the present invention in the service position. The only significant difference in this embodiment is the presence of a screw mechanism 43 provided for moving the fluid chamber 13 between the service position and the process position. The screw mechanism 43 is connected to the surrounding wall 14 of the fluid chamber 13 so that a user of sensor device 1'' can rotate the cap 45 of the screw mechanism 43 in one direction to move the fluid chamber 13 to the service position and in the other direction to move the fluid chamber 13 to the process position. The fluid path connection block 21 in Figure 4 can be the same as that shown in Figures 1 and 2, except in this example the design differs slightly in that it has two extension flanges. However, the functions and features important to the present invention are the same as those shown for the fluid path connection block 21 in Figures 1 and 2.

[0026] Figure 5 shows a flowchart of a method according to one embodiment of the present invention. This method is for performing a service process on a sensor element 5 in a sensor device 1;1' according to the present invention while the sensor device is connected to a fluid path in a system. This method includes the following steps:

[0027] a) Step 101: Move the fluid chamber 13 to the service position. When the sensor element needs servicing, for example, calibration or cleaning, the fluid chamber 13 is moved to the service position as described above. This closes the fluid chamber 13 around the sensor element 5 with the help of the fluid chamber closure 27.

[0028] b) Step 102, supplying service fluid from an external fluid supply device 16a into the fluid chamber 13 via the first port 15 and performing the service process. If the service is calibration, the service fluid is calibration fluid and the service process is calibration process. It can also be a cleaning fluid or a storage fluid.

[0029] c) Step 103: Remove the service fluid from the fluid chamber 13 by an external suction device 16b via the first port 15. Thanks to the extension tube 15a provided at the first end 13a of the fluid chamber, and the inclined position of the sensor device 1;1' according to the embodiments shown in Figures 1 to 3, all the service fluid is efficiently removed from the fluid chamber 13.

[0030] d) Step 104, in which steps b(102) and c(103) are repeated during the service process, if applicable. In some cases, the calibration process may require the provision of a different calibration fluid, and in some cases, a cleaning fluid may also be required before the calibration process is ready.

[0031] e) Step 105 to return the fluid chamber 13 to the process position, thereby allowing the measurement of at least one characteristic of the fluid being transported through the fluid path provided with the sensor device 1;1' to continue.

[0032] In various embodiments, one or more components may be formed from a variety of materials. Such materials may be compatible with bioprocessing operations and can be easily sterilized without compromising their integrity. For example, components may be formed using one or more of polymer materials and / or reinforced polymer materials, polypropylene (PP), polyamide (PA), and / or polyoxymethylene (POM).

[0033] Figures 6 and 7 show various embodiments of a bioreactor for use in one or more bioprocessing operations, comprising a flexible bag bioreactor container equipped with a pH sensor device fluid-connected to the fluid channel therein.

[0034] In Figure 6, the sensor device 1 is housed inside the flexible bag 202. The sensor device 1 may be the same as described above, or it may be fixed inside the flexible bag 202, or it may be removablely insertable inside it. A boat-shaped encapsulation portion 207 is provided that defines a fluid flow channel inside. A pH sensor can be introduced into the sensor device 1 and the fluid flow channel through the top of the flexible bag 202. Such a pH sensor may initially be provided in a dry state.

[0035] An optional mechanical support structure 210 is also shown, which allows the use of large (e.g., up to 2000 liters in volume) preferably sealed and sterile bioprocessing bags 202.

[0036] Piping (not shown) may be provided to fluidly connect the flow path within the sensor device 1 to the fluid flow path within it. Such piping may be used, for example, to removably supply calibration fluid into the fluid flow path from a syringe. The piping may have various diameters (e.g., relatively small inner diameters such as 1.0 to 1.6 mm, optionally on both sides), and the sensor device 1 is configured to connect to one or more such tubes. Optionally, one or more sterile filters may also be provided in the first port, second port, and / or piping connected to at least one sensor device 1.

[0037] Figure 7 shows another sensor device 201 housed within the flexible bag 202'. Sensor device 1 may also be similar to the one described above. The wall portion 203 of the flexible bag 202' provides a projection that is removably sealed to sensor device 1 (for example, by an O-ring provided at the distal end of sensor device 201). In this embodiment, the sensor element 5 is shown as a glass sphere tip sensor. However, various alternative sensors may be used, and it is conceivable that the sensor element may be housed, for example, in the wall portion 203 itself.

[0038] The protrusions are angled with respect to the direction normal to the wall of the flexible bag 202'. The angle is preferably at least 15 degrees, more preferably about 55 degrees. This helps to ensure proper filling of the fluid channel 205 and wetting of the sensor element 5 (e.g., substantially without contact with air bubbles). The wall portion 203 and the opposing welded ports of the sensor device 201 (e.g., incorporating TC flanges) may be configured so that when the flexible bag 202' is filled, the sensor device 201 aligns with the bag wall at about 55 degrees. As in other embodiments, the sensor device 201 may be supplied as a disposable (SU) component and / or as part of a disposable system. These may be injection molded from a variety of materials (e.g., plastics).

[0039] In various embodiments, the movement of the sensor device between a calibration position and an operating position may be automated, for example, the sensor device may be driven between such positions by an electrically or pneumatically actuated actuator under computer control. If such a mechanized system is provided, one or more sensors may also be used to detect the position of the sleeve. The sensor output may then be connected to a control system for performing one or more bioprocesses using, for example, Unicorn® software available from Cytiva®.

[0040] Figure 8 shows an alternative embodiment of the sensor device 301 that can be used with various bioreactors described herein. The sensor device 301 is similar to that of the previous embodiment, but instead of having a linearly operable / retractable pH probe, a calibration fluid channel is opened and closed by a rotational motion.

[0041] More specifically, the sensor device 301 includes a swivel sleeve 306 provided in a sleeve housing 309. The swivel sleeve 306 is connected to a handle 310 used to rotate the swivel sleeve 306 within the sleeve housing 309. Thus, the substantially linear flow channel 305 provided in the swivel sleeve 306 can be aligned with the central axis / fluid conduit in the tube 308 to adjust the sensor device 301 between the illustrated closed and open positions.

[0042] A handle 310 is shown that can be used to manually operate the swivel sleeve 306 between open and closed states, but those skilled in the art will recognize that such operation can also be performed by various mechanical / electrical devices, for example, under the control of a bioprocess system controller. It is also possible to provide a design that allows bypass flow while the sensor is in a calibration (shielding) position. Furthermore, it is possible to provide the swivel sleeve either inside or outside the stationary part, for example outside such a stationary part, in which case the fluid channel is provided inside the stationary part.

[0043] Using the various embodiments described herein, a method can be employed to operate at least one probe (e.g., a pH probe as used in a preferred embodiment) within a sensor device provided in a bioprocessing instrument. Such a method may include setting each pH probe to a calibration position (where the sensor element of the pH probe is kept aseptically sealed within the fluid flow path of the bioprocessing instrument so as not to be exposed to the external environment / air, etc.). This may be done by sliding the pH probe longitudinally to fluidly connect the pH probe port to a pH probe cavity / chamber, or by rotating the components of the sensor device to open or close one or more fluid channels, etc. Various sliding embodiments can be provided that have the advantage of being essentially self-cleaning. In various embodiments, a self-sealing pH probe port (e.g., having a slitted partition component inside) may be provided.

[0044] Upon entering the calibration position, a first calibration medium may be introduced into the pH probe (for example, after introducing distilled water into the pH probe cavity / chamber and removing the distilled water from the pH probe cavity / chamber, a calibration solution / fluid may be introduced via a syringe through the pH probe port). The calibration operation may then be performed (for example, by an externally connected bioprocessing system controller running Unicorn® software).

[0045] Once sufficient calibration data has been obtained, the first calibration medium may be washed away / removed from the pH probe (for example, by flushing the pH probe cavity / chamber with a syringe via the pH probe port, possibly using distilled water, to remove the first calibration medium). Further similar calibration steps / operations may be used. For example, second, third, etc. calibration media (e.g., different from the first calibration medium) may be introduced into the pH probe port, or further calibration operations may be performed. The use of multiple different calibration steps is beneficial in obtaining more accurate and reproducible pH measurement results during subsequent operation of the bioprocessing instrument.

[0046] The fluid flow path is preferably provided in an initial sterile / sterile state (e.g., in a flow kit). Calibration data may also be recorded / subsequently analyzed to ensure an audit trail for any products subsequently produced. In such a flow kit, it may be preferable that any piping therein includes at least one flow tube oriented substantially vertically during operation (e.g., with the sensor tip pointing downwards at an angle of no more than 15 degrees) to provide optimal pH sensor performance. Such pH sensors (e.g., Mettler Toledo® pH(InSUS®) probes or Hamilton® OneFerm® pH sensors delivered in a dry state) may be delivered in a wet or dry state, as desired. However, delivery in a dry state may be preferred to reduce the risk of leakage and subsequent destruction of the complete flow kit. Such sensors may also be delivered as separate modules.

[0047] Various embodiments may also incorporate various connectors (e.g., TCs) designed to provide a single, efficient sleeve module with pH sensing capabilities that can be paired with many different sizes / shapes of process fluid components. These may be further designed to optimize ergonomic use and placement and can provide the operator with visual or tactile feedback (e.g., to indicate open / closed status). One or more sterile connectors may also be incorporated into embodiments of the present invention. In the case of a flexible bag-based sensor, its bottom plug portion may also be provided to have a combined probe tip protection function.

[0048] As described above, one or more embodiments relate to disposability. The sensor may be contained within the body as a sensor unit that can be disposed of, for example, after the bioprocess is completed. Various parts / components may be 3D printed, for example. This allows for innovative designs of sleeves, for example, which in turn allows for the application of solutions used (for calibration, cleaning, storage, etc.) in very small hold-up volumes. Furthermore, the novel sleeves allow for efficient fluid distribution (including rinsing / washing) around the tip and wet surface of the sensor probe. 3D printed metal sleeves may be used, or sleeves printed from polymer materials may be used.

[0049] Disposable technologies (SUTs) are a recent development addressing the need to reduce production costs, improve production throughput and quality, and enhance safety in bioprocessing / biomonetization. Using disposable processing technologies and components / equipment, wet parts that come into contact with process fluids and drug products during processing, such as fluid storage containers, piping, and separation components / equipment, are provided as clean, ready-to-use consumables that are installed and used only for specific processes, products, or for a limited time, and then disposed of.

[0050] SUT consumables are typically manufactured, assembled, and packaged in a cleanroom environment to avoid contamination by microorganisms, particulate matter, etc. SUT wet components can also be supplied in a clean and pre-sterilized state, thus enabling aseptic and / or sterilization, thereby reducing the aforementioned risks related to product, operator, or patient safety. Typically, SUT wet components are subjected to sterile gamma irradiation before use in the biomanufacturing process, in which case they are deployed as “pre-sterilized” at the time of use. This may include providing a formal and verified sterilization claim for the consumable after sterilization, or alternatively, providing a sterilized consumable that is supplied without a formal sterilization claim. Under controlled and strict manufacturing conditions, SUT consumables can also be deployed non-sterilized and / or in a process that controls the state and conditions of the consumable. This allows the level of microbial contamination, commonly referred to as “bioburden,” or the level of contamination or presence of contaminants or particles, to be controlled and maintained within a predetermined level.

[0051] Non-limiting advantages of various embodiments of the present invention include providing a novel dynamic pH flow cell that is replaceable in current bioprocess systems (i.e., retrofittable) and / or can provide in situ recalibration; providing a retractable slider for cleaning and calibration; providing a slider operable by a screw handle; using a pH sensor in a fixed position; the possibility of cleaning and calibration without disassembly; sealing to prevent the process area / volume from being contaminated by non-sterile parts; improved sensor accuracy compared to conventional SU pH, reduced drift issues, and the ability to store (potential reuse of the flow kit), recalibrate during processing, and verify accuracy after processing as needed. Various aspects and embodiments of the present invention are also defined by the following numbered clauses.

[0052] 1. A sensor device (1;1';1') configured to be connected within a fluid path of a system for measuring at least one characteristic of a fluid being transported through the fluid path, wherein the sensor device is A long, slender sensor probe (3) has a sensor element (5) at its end (3a), A probe housing (11) connected to a sensor probe (3) such that the sensor probe (3) protrudes through the probe housing (11), wherein the probe housing (11) is A fluid chamber (13) surrounding at least a portion of the sensor probe (3), wherein the fluid chamber (13) is positioned relative to the sensor probe (3) such that the fluid chamber (13) can be moved along the sensor probe (3) to at least two different positions, including a process position in which the sensor element (5) within the sensor probe (3) extends outside the fluid chamber (13) and a service position in which the sensor element (5) is surrounded by the fluid chamber (13), A first port (15) is connected to a fluid chamber (13) and configured to be connected to an external fluid supply device (16a) and / or an external suction device (16b), A second port (17) is connected to the fluid chamber (13) and is configured to allow air to enter and exit the fluid chamber (13), and A probe housing (11) is provided, A fluid path connection block (21;21') comprising an internal fluid path (23) having an inlet (23a) and an outlet (23b) configured to connect to a fluid path in a system in which the sensor device is used, wherein the fluid path connection block (21;21') further comprises a receiving unit (25) for receiving a probe housing (11) and a sensor probe (3) such that a sensor element (5) is positioned within the internal fluid path (23) of the fluid path connection block (21;21'), and the fluid path connection block (21) further comprises a fluid chamber closing unit (27) that closes the fluid chamber (13) around the sensor element (5) together with the surrounding wall (14) of the fluid chamber (13) when the fluid chamber (13) is in a service position, and A sensor device (1;1';1') equipped with the following.

[0053] 2. The sensor device (1;1';1') according to Clause 1, wherein the fluid chamber closing portion (27) is provided with a protruding plug in the internal fluid passage (23) of the fluid passage connection block (21;21'), and when the fluid chamber (13) is in the service position, the surrounding wall (14) of the fluid chamber (13) fits around the protruding plug to seal it.

[0054] 3. The sensor device (1;1';1') according to Clause 1 or 2, wherein the first port (15) is connected to a first end (13a) of a fluid chamber (13), the first end (13a) being located at the end of the fluid chamber (13) closest to the sensor element (5), and thereby the first port (15) comprises an extension tube (15a) connecting the first end (13a) of the fluid chamber (13) to a port connector (15b) of the first port (15).

[0055] 4. The sensor device according to any one of clauses 1 to 3, wherein the sensor element is configured to measure pH.

[0056] 5. The internal fluid passage (23) of the fluid passage connection block (21') allows fluid to pass between the inlet (23a) and outlet (23b) of the internal fluid passage (23) in both the process position and the service position of the fluid chamber (13), as described in any one of the clauses 1 to 4 (1;1';1').

[0057] 6. The fluid chamber (13) seals the internal fluid passage (23) of the fluid passage connection block (21) so as to prevent fluid from passing between the inlet (23a) and outlet (23b) of the internal fluid passage (23) when the fluid chamber (13) is installed in the process position, as described in any one of the clauses 1 to 4 (1;1';1').

[0058] 7. The sensor device (1;1';1') according to any one of clauses 1 to 6, wherein at the service position of the fluid chamber (13), the sensor element (5) can be both calibrated, cleaned, and stored in the service fluid supplied to the fluid chamber (13) via the first port (15).

[0059] 8. The sensor device (1;1';1') according to any one of clauses 1 to 7, wherein the surrounding wall (14) comprises a sealing device (24) configured to seal the fluid chamber closure (27) at the service position and around the sensor probe (3) at the process position.

[0060] 9. The probe housing (11) is at least partially 3D printed, as described in any one of the clauses 1 to 8 (1;1';1').

[0061] 10. The sensor device (1;1';1') according to any one of the clauses 1 to 9, wherein the second port (17) is connected to a second end (13b) of the fluid chamber (13), the second end (13b) being the end opposite to the first end (13a) of the fluid chamber (13).

[0062] 11. The sensor device (1;1';1') according to any one of the clauses 1 to 10, wherein the sensor probe (3) is detachably provided within the probe housing (11).

[0063] 12. A sensor device according to any one of Clauses 1 to 11 (1;1';1'), wherein at least a portion thereof comprises polymer material and / or reinforced polymer material, polypropylene (PP), polyamide (PA) and / or polyoxymethylene (POM), and / or is sterilized.

[0064] 13. The system is a bioprocessing system, a sensor device as described in any one of clauses 1 to 12 (1;1';1').

[0065] 14. A probe housing (11) configured for use in a sensor device (1;1';1'') as described in any one of clauses 1 to 13, wherein the probe housing is configured to connect to the sensor probe (3) of the sensor device such that the sensor probe (3) protrudes through the probe housing (11), and the probe housing (11) is A fluid chamber (13) surrounding at least a portion of the sensor probe (3), wherein the fluid chamber (13) is positioned relative to the sensor probe (3) such that the fluid chamber (13) can be moved along the sensor probe (3) to at least two different positions, including a process position in which the sensor element (5) within the sensor probe (3) extends outside the fluid chamber (13) and a service position in which the sensor element (5) is surrounded by the fluid chamber (13), A first port (15) is connected to a fluid chamber (13) and configured to be connected to an external fluid supply device (16a) and / or an external suction device (16b), A second port (17) is connected to the fluid chamber (13) and is configured to allow air to enter and exit the fluid chamber (13), and Equipped with, The probe housing (11) is configured to receive the sensor device (1;1';1'') within the receiving unit (25) of the fluid path connection block (21;21') such that the sensor element (5) of the sensor probe (3) is positioned within the internal fluid path (23) of the fluid path connection block (21;21'), and the surrounding wall (14) of the fluid chamber (13) is configured to close the fluid chamber (13) around the sensor element together with the fluid chamber closing portion (27) of the fluid path connection block (21) when the fluid chamber (13) is in the service position. Probe housing (11).

[0066] 15. A method for performing a service process of a sensor element (5) in a sensor device (1;1') described in any one of clauses 1 to 13, while the sensor device is connected to a fluid path of a system, the method being: a) Step (101) of moving the fluid chamber (13) to the service position, b) Step (102) of supplying service fluid from an external fluid supply device (16a) into the fluid chamber (13) via a first port (15) and performing a service process, c) Step (103) to remove the service fluid from the fluid chamber (13) by an external suction device (16b) via a first port (15), d) In some cases, the step (104) repeats steps b) and c) during the service process, e) Step (105) to return the fluid chamber (13) to the process position and Methods that include...

[0067] 16. The method according to Clause 15, wherein the service process is one or more of the calibration, cleaning, or storage processes, and the service fluid is one or more of the calibration fluid, cleaning fluid, or storage fluid. [Explanation of Symbols]

[0068] 1, 1', 1'' Sensor device 3. Sensor probe 3a end 5 Sensor elements 11 Probe Housing 13 Fluid Chamber 13a First end 13b Second end 14. Surrounding walls 14a End part 15. Port 1 15a Extension tube 15b Port Connector 16a External fluid supply device 16b External suction device 17. Second port 21, 21' Fluid path connection block 23 Internal fluid path 23a Entrance 23b Exit 24 Encapsulation devices 25 Receiving Units 27 Fluid chamber closing section 43 Screw mechanism 45 caps 201 Sensor device 202, 202' Flexible Bag 203 Wall section 205 Fluid flow path 207 Encapsulation portion 210 Mechanical support structure 301 Sensor device 306 Swivel Sleeve 308 Tube 309 Sleeve Housing 310 Handle

Claims

1. A method (100) for operating at least one sensor probe (3) in a sensor device (1;1';1') provided in a bioprocessing instrument, i) A step (101) of setting each sensor probe (3) to a calibration position, wherein the sensor element (5) of the sensor probe (3) is in fluid contact with the fluid flow path of the bioprocessing device, ii) Step (102) of introducing the first calibration medium into the sensor probe (3), iii) A step of calibrating the sensor probe (3), iv) Step (103) of removing the first calibration medium from the sensor probe (3), v) Step (105) to set the sensor probe (3) to the operating position and Methods that include...

2. After step iv), a) A step of introducing a second calibration medium into the sensor probe (3), wherein the second calibration medium is different from the first calibration medium, b) A step of calibrating the sensor probe (3), c) The step of removing the second calibration medium from the sensor probe (3) The method according to claim 1 (100), including the method according to claim 1.

3. The method according to claim 1 (100), comprising the step of repeating steps a) to c) for one or more further calibration media.

4. vi) Operating the bioprocessing apparatus to introduce a process medium into the fluid channel of the bioprocessing apparatus, and measuring the process parameters of the process medium using at least one sensor probe (3). The method according to any one of claims 1 to 3, further comprising (100).

5. The method according to claim 4 (100), wherein the bioprocessing equipment is operable to perform one or more mixing, filtration and / or chromatographic bioprocessing operations.

6. The method according to any one of claims 1 to 5 (100), wherein the sensor probe (3) is a pH sensor probe and / or the sensor element (5) is a pH sensor element.

7. The method according to any one of claims 1 to 6 (100), wherein the fluid channel is sterile / sterilized.

8. The method according to any one of claims 1 to 7 (100), wherein the at least one sensor probe (3) is provided as or as part of a disposable (SU) component.

9. A bioreactor (200) for use in one or more bioprocessing operations, the bioreactor comprising a bioreactor container (202, 202') and at least one sensor device (1; 1'; 1', 201, 301) fluidly connected to a fluid channel (205) therein.

10. The bioreactor (200) according to claim 9, wherein the bioreactor container (202, 202') comprises a flexible bag.

11. The bioreactor (200) according to claim 9 or 10, wherein the at least one sensor device (1; 1'; 1', 201, 301) is configured to be connected to input / output pipes of at least two different diameters.

12. A bioreactor (200) according to any one of claims 9 to 11, wherein one or more sterile filters are provided in a first port (15), a second port (17), and / or piping connected to the at least one sensor device (1; 1'; 1', 201, 301).

13. The bioreactor (200) according to any one of claims 9 to 12, wherein the sensor element (5) of at least one sensor device (1; 1'; 1', 201, 301) is provided on the wall portion (203) of the bioreactor container (202, 202').

14. The bioreactor (200) according to any one of claims 9 to 13, wherein the sensor element (5) of at least one sensor device (1; 1'; 1', 201, 301) comprises a dry-delivery pH sensor element (5).

15. The bioreactor (200) according to any one of claims 9 to 14, wherein, when in use, the longitudinal axis of the at least one sensor device (1; 1'; 1', 201, 301) is inclined from the horizontal at an angle of at least 15 degrees, 15 to 40, 50, 60, 70, 80 degrees, or preferably 55 degrees.

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