Disposable and hygienic process connection including an integrated wet storage for use with process sensors

Abstract

A process fluid connector (204) for a single-use process fluid sensing system is provided. The process fluid connector (204) includes a pair of process fluid connections (300, 302), each configured to couple to a cooperating process fluid fitting. A process fluid conduit section (301) is operably coupled to each process fluid connection (300, 302). A sensor mounting port (308) is coupled to the process fluid conduit section (301) and configured to receive and mount a process fluid sensor (360). An openable fluid chamber (312) is coupled to the process fluid conduit (301) section and configured to provide wet storage for a sensing component of the process fluid sensor (360). A process fluid sensing system using the process fluid connector is also provided.

Description

Technical Field

[0001] Background Art Over the past 20 years, Disposable bioprocessing systems have advanced significantly, replacing stainless-steel systems in biopharmaceutical manufacturing. In contrast to conventional systems built with stainless-steel equipment, Disposable systems rely on highly engineered polymers and are pre-sterilized by gamma irradiation. For end-users, there are several major advantages, such as reduced initial investment, elimination of complex processes like pre-washing, sterilization, and validation, and improved process cycle times. As a result, Disposable bioprocessing systems are being adopted at an accelerating pace, from initial research and development labs to large-scale commercial pharmaceutical manufacturing.

[0002] In many processes of biopharmaceutical manufacturing, pH is an important process parameter. In upstream bioreactor applications, the pH of the media culture is continuously monitored and controlled within a narrow physiological range, and deviation from this ideal pH range can potentially affect viable cell concentration, protein productivity, and quality. Conventional pH sensors used in biopharmaceutical manufacturing are based on electrochemical measurement methods using a highly pH-sensitive glass electrode and a reference electrode. Due to their high reliability, accuracy, and stability, they are a proven technology in the biotechnology and pharmaceutical industries.

[0003] However, since conventional pH sensors are designed to be compatible with conventional stainless-steel bioreactor systems, Disposable they have several significant limitations when used in [the] systems. First, conventional sensors must be sterilized by the end-user using autoclave, steam-in-place, or clean-in-place procedures. Generally, they are not compatible with gamma irradiation sterilization processes. Gamma irradiation is sensed Componentbecause it can damage them and cause undesirable performance degradation. To ensure satisfactory accuracy, conventional pH sensors typically require the end user to perform a two-point calibration before use, which is cumbersome and complicates the process. Furthermore, the storage period of conventional pH sensors is usually one year because the pH-sensing glass ages over time and sensor performance degrades. Unfortunately, a longer sensor storage life is an essential requirement because the sensor may be attached to a plastic bioreactor bag or Downstream placed in a tube set for applications where a much longer storage life is expected.

SUMMARY OF THE INVENTION

PROBLEMS TO BE SOLVED BY THE INVENTION

[0004] Disposable A process fluid connector for a process fluid sensing system is provided. The process fluid connector includes a pair of process fluid connections, each of which is configured to couple to a cooperating process fluid fitting. A process fluid conduit is operably coupled to each process fluid connection. A sensor attachment port is coupled to the process fluid conduit and configured to receive and attach a process fluid sensor. A storable fluid chamber is coupled to the process fluid conduit and configured to provide wet storage for the sensing components of the process fluid sensor. A process fluid sensing system using the process fluid connector is also provided.

BRIEF DESCRIPTION OF THE DRAWINGS

[0005]

Figure 1A

Figure 1B

Figure 2A

Figure 2B

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

Figure 11

DETAILED DESCRIPTION OF THE INVENTION

[0006] “ Upstream ” To address the limitations of the bioreactor bag, in particular, Disposable A pH sensor has been developed for bioreactor applications. The concept of this sensor is based on the 550pH Disposable sensor commercially available from the Rosemount® group of Emerson® Automation Solutions. This Disposable pH sensor is compatible with gamma irradiation sterilization, DisposableIt can be attached to a bioreactor bag to form one assembly. By incorporating its own storage buffer, the sensor does not require two-point calibration by the end user and can be standardized at one point using this storage buffer. More importantly, since the storage buffer is in contact with the pH electrode and the reference electrode, the sensor can remain in a moist and fresh state while being stored. This wet storage has achieved an extended storage period of two years, along with excellent sensor performance including high precision, high sensitivity, and high stability. Rigorous real-time tests using unaged prototypes, one-year-aged prototypes, and two-year-aged prototypes have demonstrated that the performance of the sensor remains at a high level without degradation even after two years of storage.

[0007] Figure 1A is a schematic diagram of a pH sensor showing the storage position. In one example, the pH sensor shown in Figure 1A is a 550 pH Disposable sensor. The sensor 100 generally shown in cross-section has a distal end 102 configured to engage a process such as a bioreactor bag and a proximal end 104 having an electrical connector 106 configured to couple to instrumentation. Some pH sensors Inside are amperometric and generate a current indicative of pH. Other types of sensors, such as potentiometric sensors, may generate a potential indicative of a process variable. The process sensors used herein are intended to include any sensor having electrical characteristics that vary with a process variable.

[0008] As shown in FIG. 1A, the sensor 100 is provided in a storage position configuration where the process plunger 108 is spaced from the locking member 110. When in the storage configuration, the pH sensing glass electrode 112 is maintained within a storage chamber 114 filled with a buffer solution. As seen in FIG. 1A, a reference electrode 116 is provided within an electrolyte solution 118, which is configured to be electrically coupled to the process via a reference contact 120. The sensor 100 is maintained in the storage position for both storage and calibration immediately prior to operation. This is because the buffer solution within the storage chamber 114 has a known pH, and the pH can be measured with the electrode 112 and the sensor can be calibrated or otherwise characterized by comparing the measured value to the known pH of the buffer solution.

[0009] FIG. 1B is a schematic view of the pH sensor 100 showing the operating position. Comparing FIG. 1B with FIG. 1A, it can be seen that the process plunger 108 has been slid so as to be close to the locking member 110. Due to this sliding movement, an end portion 122 extends from a side wall 124, and the pH glass electrode 112 is exposed to the process 126. As can be seen, the reference contact 120 is also exposed to the process 126. Thus, the sliding movement from the storage position to the operating position exposes the wet storage chamber 114 to the process 126. In the configuration shown in FIG. 1B, the sensor 100 may be used to sense the pH of a process fluid such as a bioreaction solution, a cell culture solution, a mash, etc.

[0010] As shown in FIGS. 1A and 1B, the sliding movement is facilitated by O-rings 128, 130, and 132. These O-rings maintain the electrolyte solution and the buffer solution in a sealed arrangement in the storage configuration, ensuring that the electrolyte solution remains sealed from the process during the operating position. The illustrated sensor provides wet storage for the pH glass and the reference contact via a separate storage chamber and a sliding sensor assembly that is axially moved within a process connector and moved into the process at startup. The sliding sensor assembly provides reliable measurements at low process pressures. The process connector sleeve remains fixed relative to the process media and the sensor moves when inserted into the process.

[0011] After the cell culture process is completed within the bioreactor bag, the medium is transferred to the Downstream part. Here, the medium is pushed through a filtration stage in a small line size tube assembly at a high pressure of about 60 psi. Downstream The tube assemblies or "tube sets" are provided as pre-assembled, equipped, and sterilized assemblies. It is most important to maintain the sterility of all inner surfaces of these pharmaceutical assemblies. Further, the storage period of these tube sets is Upstream / in-bag Disposable the same as that of the assembly, which is two years. Downstream The process conditions of Upstream are very different from those of Downstream the assembly, but Upstream the assembly is also expected to maintain full functionality after two years of storage, similar to the assembly of

[0012] Downstream In particular, in the case of a pH sensor, this storage period can be achieved by storing the wet pH glass and the reference connection part. The high process pressures seen in the

[0013] process can cause problems for conventional pH sensors. Some approaches to dealing with such high pressures include pressurizing the internal reference electrolyte. However, some wet storage mechanisms of pH sensors are not compatible with internal reference pressurization. For example, under internal reference pressurization, O-ring seals such as seals 128, 130, 132 that allow sliding movement (shown in Figure 1B) have been demonstrated to be leak paths through which the internal reference electrolyte can leak. DisposableIt is an enlarged view of a pH sensor. As shown, the electrolyte of the sensor passes through the O-ring seal 142 and is extruded into the measurement chamber / environment. As a result, the pH sensor may exhibit unstable behavior with unpredictable signal spikes or drifts, especially when the sensor is exposed to an external process pressure lower than the internal reference pressure.

[0014] Figure 3 is a graph showing sensor pH measurements over time at various sensors and various pressures. The values shown in Figure 3 indicate that at process pressures below 30 psi, irregular values may occur.

[0015] The embodiments described herein generally arise from an understanding of the limitations of commercially available Upstream that has been pH sensors and the mechanisms of such limitations. More specifically, Downstream in order to accommodate pH sensing of Downstream it is important that the reference electrolyte be pressurized so that a small flow rate of the electrolyte into the process solution is ensured, even at high pressures of up to 60 PSI at times. However, simply pressurizing the reference electrolyte with a known pH sensing structure that uses an O-ring and accommodates the sliding function between the storage configuration and the operating configuration may not meet the storage period requirements demanded in the disposable hygienic industry.

[0016] To solve this problem, the sliding reference chamber is replaced with a fixed configuration without an O-ring connection to the process of the Downstream pH sensor.

[0017] Figure 4 shows the fixed portion of a position pH sensor 200 without an O-ring between the process chamber and the reference chamber according to one embodiment. As shown in Figure 4, a portion of the pH sensor 200 includes a pH sensor element 202 that threads into a process connector 204. DownstreamAs a pH sensor system, the process connector 204 can be coupled to the hose or tube set of the bioreactor system. The sensor 200 includes a glass pH electrode 212 and a reference junction 220. As indicated by reference numeral 250, a solid polymer reference chamber housing 252 is employed to contain a reference electrolyte 254. In one example, the polymer housing 252 is formed of plastic. In the illustrated example, the pH sensor element 202 is a fixed-position pH sensor in that it does not accommodate slidable movement for switching between a storage configuration and an operating configuration like the sensor 100 of FIGS. 1A and 1B. Instead, the sensor 202 is screwed into the process connector 204 with a screw interface 256, and the positions of the reference junction 220 and the pH glass electrode 212 within the opening 258 of the process connector 204 are fixed. After eliminating the O-ring connection, the measured values are dramatically improved.

[0018] FIG. 5 is a graph showing various sensor measurements over time at various process pressures. The test results shown in FIG. 5 are based on a pH sensor having an internal reference pressure of 60 psi, and the O-ring seal has been replaced with a solid epoxy seal. FIG. 5 shows very stable and consistent pH values observed over a process pressure range of 10 - 90 psi. Comparing FIG. 3 and FIG. 5, it can be seen that eliminating the O-ring seal significantly improves the pH sensor in its interaction with the pressurized process. However, changing the seal leads to the need for a new wet storage mechanism.

[0019] When the process pressure is high, the storage chambers of some known Disposable pH sensors employing a sliding O-ring seal do not function. To provide stable measurements, it is necessary to eliminate the O-ring that separates the reference chamber from the process. Since it is the slidability of the internal plunger assembly of this sensor that provides the wet storage capacity, a new method for enabling wet storage is needed.

[0020] Figures 6 to 8 are schematic views of a process connection part having a wet sensor storage chamber according to an embodiment of the present invention.

[0021] Figure 6 is a schematic perspective view of a process connector for a Disposable pH sensing system. The example shown is a special process connection part having a sliding tube that can mount a sensor, surround the process end of the sensor, and provide a sealed wet storage chamber. The process connector 204 generally includes a pair of process fluid connection parts 300 and 302. In the example shown in Figure 6, the process connection part 300 is an inlet and the process connection part 302 is an outlet. As shown, each of the process fluid connection parts 300, 302 generally includes, in one embodiment, a corresponding Hygiene O-ring 306 that may also be included to facilitate sealing to the flange Hygiene flange, the flange 304. The process fluid conduit part 301 is interposed between the process fluid connection parts 300 and 302 and fluidly couples the process fluid connection parts 300 and 302 together. The embodiment shown in Figure 6 includes a pair of flange connection parts, but the connection parts do not have to be of the same type. The connection parts can take various forms including, but not limited to, threaded connection parts, flange connection parts (as shown), Bamboo shoot connection parts, sterile connection parts, Open pipe parts, attached tubes, and secondary adapters.

[0022] The sensor attachment port 308 is fluidly interposed between the process fluid connectors 300 and 302. The sensor attachment port 308 is configured to receive and attach a fixed position pH sensor as shown in FIG. 4. In one embodiment, the sensor attachment port 308 includes an internal thread 310 that threads onto the external threads of the fixed position pH sensor. The process connector 204 has both a storage configuration and an operating configuration. As shown in FIG. 6, the process connector 204 is in a storage configuration where the wet storage cylinder 312 is in a closed position. In this configuration, the pH sensor element of the fixed position pH sensor coupled to the sensor attachment port 308 is isolated from the flow of the process fluid. Further, a buffer solution having a known pH is supplied into the wet storage cylinder 312 (shown in more detail in a later figure) to maintain the pH sensor in wet storage and to provide a one-point calibration prior to operation.

[0023] As shown in FIG. 6, the process connector 204 includes one or more operable members 314, 316. In the illustrated example, the operable members 314, 316 are a pair of wings that extend oppositely and extend substantially perpendicular to the longitudinal axis of the wet storage cylinder 312. Further, the process connector 204 also includes one or more wet storage chamber position locks 320, 322. These locks 320, 322 prevent inadvertent downward pressure on the operable members 314, 316 from causing downward movement or actuation of the operable members 314, 316, thereby preventing the pH sensing element from being exposed to the process fluid.

[0024] FIG. 7 is a front view of the process connector 204 engaged with the fixed position pH sensor 360 within the sensor port 308, with the process sensor 204 in a closed position. In this configuration, the wet storage cylinder 312 isolates the pH sensing element 212 and the reference contact 220 (shown schematically as a circle) from the process fluid flowing through region 330.

[0025] As shown in FIGS. 6 and 7, this storage chamber provides wet storage for the pH glass and reference contact of the pH sensor. The assembled systemFixed position pH sensor , facing the sensor Fixed position piston , and a movable cylindrical member. The movable member slides completely out of the process flow, minimizing dead - flow volume. Together with various O - rings for sealing the movable member to the fixed member, this solution provides self - contained wet pH sensor storage with minimal flow obstruction. The entire assembly can be connected to an OEM tube set and gamma - sterilized.

[0026] Figure 8 is a perspective view of the process fluid connector 204 moved to the operating position. As shown in Figure 8, each of the wet storage chamber position locks 320, 322 has been moved from its respective position in the directions indicated by the arrows 340, 342 respectively. With the wet storage chamber position locks 320, 322 removed, the wings 314, 318 can translate fully from a position close to the shoulder 344 to the bottom 346. At this time, the wet storage cylinder 312 also descends axially, and the pH glass electrode 212 and the reference contact 220 are exposed to the process fluid in the conduit 348.

[0027] Figure 9 is according to an embodiment of the present invention Disposable and hygienicIt is an exploded view of a process fluid connector for a pH sensing system. The process connector 403 includes a body 400 having an inlet 304 and an outlet 302. The body 400 also includes, in the illustrated example, a sensor port 308 having an internal threaded portion for receiving a fixed position pH sensor. The body 400 also includes a lower external threaded portion 402 configured to threadedly engage a collar 404. The collar 404 includes a pair of circular side wall portions 406, 408 extending downward therefrom. Each of the circular side wall portions 406, 408 includes an engagement feature 410 configured to engage an end cap 412 when the system is assembled. The process connector 403 is illustrated as having a pair of wet storage chamber position locks 320, 322. Each of the position locks 320, 322 includes a handle portion 414 to facilitate gripping by a user. Further, each of the position locks 320, 322 preferably includes a clip 416 extending inward therefrom. As shown in FIG. 9, each clip 416 preferably has a width 418 that is approximately half the width of the entire position lock. Thus, when the opposing position locks 320, 322 engage a shaft 420, the momentum inhibited by the position locks 320, 322 is the two widths 418.

[0028] The process connector 403 includes a wet storage cylinder 312 coupled to a pair of wings 314, 316. Further, an O-ring 422 is configured to be disposed within an O-ring groove 424 and serves to isolate the pH sensing element from the process when the process connector is in a storage configuration.

[0029] The process connector 403 also includes a lower housing 426 having an end 428 and a pair of circular side wall portions 430, 432 extending upward therefrom. Further, a shaft 420 is attached to the center of the end 428. The shaft 420 Fixed position piston includes an end that is attached to 434. In one example, Fixed position piston 434 Fixed position piston includes a threaded opening that engages a threaded portion on the outside of the shaft 420 to attach 434 to the shaft 420. Fixed position piston434 includes one or more O-ring seals 436, 438 that seal against the inner surface 440 of the wet storage cylinder 312.

[0030] FIG. 10 is a perspective view of a pH sensing system according to an embodiment of the present invention. Disposable , Hygienic , FIG. 10 shows a fixed position sensor 500 coupled to the sensor port 308. As shown, the wings 314, 316 are spaced from the end cap 412, and thus the process connector 204 is in the storage position. The fixed position pH sensor 502 includes a cylindrical sidewall 504 that extends upward from the sensor port 308. The sensor 500 also includes an inclined sidewall 506 that houses the use point pressure applicator 508. The use point pressure applicator 508 is Downstream used to pressurize the reference electrode immediately prior to operation of the pH sensing system to support the application of. In one embodiment, the pressurization may simply be the release of a spring-based mechanism to generate a preselected pressure within the reference electrolyte, such as 60 PSI. In other examples, the use point pressure applicator may be adjustable, such as a screw-type applicator that can generate a user-selectable level of pressure within the reference electrolyte. In any case, the use of the use point applicator allows the system to be stored in a non-pressurized state and then pressurized immediately prior to operation.

[0031] FIG. 11 is a perspective view of a pH sensing system according to an embodiment of the present invention. Disposable and hygienic downstreamIt is a cross-sectional view of a pH measurement system. FIG. 10 shows the system in a storage configuration, while FIG. 11 shows the system in an operating configuration. Accordingly, wings 314 and 316 are translated or otherwise displaced to end cap 412, thereby sliding wet storage cylinder 312 to a retracted position that allows pH sensing element 212 and reference contact 220 to be in fluid communication with process fluid passage 258. Further, FIG. 11 shows reference electrode 520 disposed proximate to reference contact 220. Reference pressurizing mechanism 508 is illustrated as having a plunger 522 disposed therein that is movable in the direction indicated by reference numeral 524. Movement of plunger 522 in the direction of arrow 524 generates pressure within the reference electrolyte. The plunger can be released by turning knob 526 (shown in FIG. 10). Further, the pressure can be selected by rotating knob 526 until the desired pressure within the reference electrolyte is obtained.

[0032] Wet pH glass storage is Disposable important for applications. Because an extended (two-year) storage period is Upstream a requirement not only for bag manufacturers, but also for Downstream tubing set manufacturers. The embodiments disclosed herein are thought to provide a Disposable pH solution that meets the requirements of today's Downstream market. Referring to FIGS. 10 and 11, the operation of the wet storage chamber can be performed in several ways. In one example, the cylindrical member is axially pulled away from the fixed sensor by hand. (See FIG. 11). In another example, the user pushes or pulls the cylinder from the same side as the side where the fixed sensor is attached. Preferably, the operation of the wet storage chamber is Disposable performed without breaking the aseptic Downstream of the process fluid connector. Barrier

[0033] The invention has been described with reference to the preferred embodiments, and those skilled in the art will recognize that changes can be made in form and detail without departing from the spirit and scope of the invention.

Claims

1. A process fluid connector for a disposable process fluid sensing system, a pair of process fluid connections, each of said process fluid connections being configured to couple to a cooperating process fluid fitting; a process fluid conduit operably coupled to each of said process fluid connections; a sensor attachment port coupled to said process fluid conduit and configured to receive and attach a process fluid sensor; and a storable fluid chamber coupled to said process fluid conduit and configured to provide wet storage for a sensing component of said process fluid sensor, said storable fluid chamber being operably coupled to at least one user-activatable element, said at least one user-activatable element including a pair of wings extending from opposing sides of said storable fluid chamber, said pair of wings being configured to transition said storable fluid chamber from a storage configuration to an operating configuration, a process fluid connector.

2. The process fluid connector of claim 1, wherein said storable fluid chamber is storable without breaking a sterile barrier of a downstream process fluid connector.

3. The process fluid connector of claim 1, further comprising at least one locking member operably coupled to said at least one user-activatable element, said at least one locking member being configured to inhibit displacement of said user-activatable element.

4. The process fluid connector of claim 3, wherein said at least one locking member includes a pair of locks, each of said locks being differently positioned from the other, and a release of said pair of locks is required before displacement of said user-activatable element to an operating configuration is enabled.

5. The process fluid connector of claim 1, wherein said storable fluid chamber contains a buffer solution having a known pH.

6. The process fluid connector of claim 1, wherein each of said pair of process fluid connections includes a sanitary flange.

7. The process fluid connector of claim 6, wherein each of said sanitary flanges includes an O-ring groove configured to receive an O-ring.

8. An end cap, a shaft having a distal end attached to the end cap and a proximal end spaced from the distal end, and a fixed-position piston attached to the proximal end of the shaft, the fixed-position piston having a diameter sized to cooperate with the inner surface of the wet storage cylinder of the storable fluid chamber; The process fluid connector according to claim 1, further comprising.

9. The process fluid connector according to claim 8, further comprising at least one O-ring disposed on the outer diameter of the fixed-position piston.

10. The process fluid connector according to claim 8, further comprising an O-ring disposed on the outer diameter of the wet storage cylinder.

11. The process fluid connector according to claim 1, wherein a movable member of the storable fluid chamber is configured to completely shift outside the flow of the process flow of the process fluid conduit portion.

12. The process fluid connector according to claim 1, wherein at least one of the pair of process fluid connection portions is selected from the group consisting of a threaded connection portion, a flange connection portion, a bamboo joint connection portion, a sterile connection portion, an open pipe portion, an attached tube, and a secondary adapter.

13. A process fluid sensing system comprising a process fluid connector, The process fluid connector is, a pair of process fluid connection portions, each of the process fluid connection portions being configured to couple to a cooperating process fluid joint; a process fluid conduit portion operably coupled to each of the process fluid connection portions; a sensor attachment port coupled to the process fluid conduit portion and configured to receive and attach a process fluid sensor; a storable fluid chamber coupled to the process fluid conduit portion and configured to provide wet storage for the sensing components of the process fluid sensor, the storable fluid chamber being operably coupled to at least one element operable by a user, the at least one element operable by the user including a pair of wings extending from opposite sides of the storable fluid chamber, the pair of wings being configured to transition the storable fluid chamber from a storage configuration to an operating configuration; and A process fluid sensing system including a fixed-position amperometric process fluid sensor attached to a sensor attachment port of the process fluid connector, the fixed-position amperometric process fluid sensor having a plurality of sensing elements disposed in a buffer solution within the storable fluid chamber.

14. The process fluid sensing system according to claim 13, wherein the fixed-position amperometric process fluid sensor is configured to be pressurized at the time of use.

15. The process fluid sensing system according to claim 14, wherein the fixed-position amperometric process fluid sensor includes a pressurizing mechanism configured to be manually operated to pressurize a reference electrolyte solution of the fixed-position amperometric process fluid sensor.

16. The process fluid sensing system according to claim 15, wherein the pressurizing mechanism includes a piston biased by a spring.

17. The process fluid sensing system according to claim 16, wherein the pressurizing mechanism includes a manually operable knob configured to engage the pressurizing mechanism.

18. The process fluid sensing system according to claim 17, wherein the knob is configured to generate a user-selectable amount or pressure in the reference electrolyte solution.

Images