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EP-4308678-B1 - ROCKING BIOREACTOR WITH INTEGRATED MONITORING PROBE SYSTEM

EP4308678B1EP 4308678 B1EP4308678 B1EP 4308678B1EP-4308678-B1

Inventors

  • HASSELL, Bryan A.
  • MARCHESSAULT, David, P.

Dates

Publication Date
20260506
Application Date
20220316

Claims (20)

  1. A system (11) for monitoring a process conducted within a bag (100,12) for a bioreactor, the system comprising: a patch (13) configured to be secured to a wall (106) of the bag and defining a sample gap (19) in the interior of the bag, wherein the patch (13) comprises at least one hood that projects into the bag; and a probe module (15), configured to be inserted into or to mate with the patch (13), for monitoring contents (22) of the bag, the probe module (15) comprising a source element (21) and a detector element (25) for receiving light transmitted from the source element (21) and through the sample gap (19) after interaction with the contents (22).
  2. The system as claimed in claim 1, wherein the bag (100,12) is a flexible bag of a rocking bioreactor (10).
  3. The system as claimed in claim 1, wherein the patch (13) comprises a source hood (31) and a detector hood (33), which project inward from an outer wall (106) of the bag, a wall of the source hood and a wall of the detector hood defining the sample gap (19) therebetween.
  4. The system as claimed in claim 3, wherein the source hood (31) and the detector hood (33) are each accessible from outside the bag.
  5. The system as claimed in claim 4, wherein the probe module (15) inserts into the patch (13) such that the source hood (31) receives a source assembly (23) housing the source element (21) and the detector hood receives (33) a detector assembly (27) housing the detector element (25).
  6. The system as claimed in claim 5, wherein the source assembly (23) and the detector assembly (27) are both secured to or integral with a common assembly base (45) of the probe module (15).
  7. The system as claimed in claim 6, wherein sizes and shapes of the source assembly (23) and the detector assembly (27) and spacing between the source assembly and the detector assembly correspond to sizes and shapes of the source hood (31) and the detector hood (33) and the spacing therebetween.
  8. The system as claimed in claim 1, wherein the patch (13) is configured to be secured to the wall (106) of the bag via welding, thermo-forming, or adhesive.
  9. The system as claimed in claim 1, wherein the bag (100,12) and the patch (13) are disposable or single-use components, and the probe module (15) is reusable with different patches and bags.
  10. The system as claimed in claim 1, wherein the patch comprises one or more window plates (41,43) for transmitting the light between the sample gap (19) and at least one of the source hood (31) and the detector hood (33).
  11. A method for monitoring a process conducted within a bag (100,12) for a bioreactor using the system of claim 1, the method comprising: securing the patch (13) to a wall (106) of the bag (100,12); directing light from the source element (21) of the probe module (15) through the sample gap (19); and detecting the light at the detector element (25) of the probe module (15) after interaction between the light and the contents (22) of the bag.
  12. The method as claimed in claim 11, wherein the bag (100,12) is a flexible bag of a rocking bioreactor (10).
  13. The method as claimed in claim 11, further comprising a source hood (31) of the patch (13) and a detector hood (33) of the patch projecting inward from an outer wall (106) of the bag (100,12), a wall of the source hood (31) and a wall of the detector hood (33) defining the sample gap (19) therebetween.
  14. The method as claimed in claim 13, wherein the source hood (31) and the detector hood (33) are each accessible from outside the bag.
  15. The method as claimed in claim 14, further comprising inserting the probe module (15) into the patch (13) such that the source hood (31) receives a source assembly (23) housing the source element (21) and the detector hood (33) receives a detector assembly (27) housing the detector element (25).
  16. The method as claimed in claim 15, wherein the source assembly (23) and the detector assembly (27) are both secured to or integral with a common assembly base (45) of the probe module.
  17. The method as claimed in claim 16, further comprising configuring sizes and shapes of the source assembly (23) and the detector assembly (27) and spacing between the source assembly and the detector assembly to correspond to sizes and shapes of the source hood (31) and the detector hood (33) and spacing therebetween.
  18. The method as claimed in claim 11, further comprising securing the patch (13) to the wall (106) of the bag via welding, thermo-forming, or adhesive.
  19. The method as claimed in claim 11, wherein the bag (100,12) and the patch (13) are disposable or single-use components, and the probe module is reusable with different patches and bags.
  20. The method as claimed in claim 11, wherein the patch comprises one or more window plates (41,43) for transmitting the light between the sample gap (19) and at least one of the source hood (31) and the detector hood (33).

Description

RELATED APPLICATIONS This application claims the benefit under 35 USC 119(e) of U.S. Provisional Application No. 63/162,304, filed on March 17, 2021. BACKGROUND OF THE INVENTION Many processes in the chemical, biochemical, pharmaceutical, food, beverage and in other industries require some type of monitoring. Sensors have been developed and are available to measure pH, dissolved oxygen (DO), temperature or pressure in-situ and in real-time. Common techniques for detecting chemical constituents include high performance liquid chromatography (HPLC), gas chromatography-mass spectroscopy (GCMS), or enzyme- and reagent-based electrochemical methods. While considered accurate, many existing approaches are conducted off-line, tend to be destructive with respect to the sample, often require expensive consumables and/or take a long time to complete. In many cases, the equipment needed to perform these analyses is expensive, involves complex calibrations, and trained operators. Procedures may be time- and labor-intensive, often mitigated by decreasing the sampling frequency of a given process, thus reducing the data points. Often, samples are run in batches, after the process has been completed, yielding little or no feedback for adjusting conditions on an ongoing basis. Drawbacks such as these can persist even with automated sampling operations. Various optical spectroscopy approaches are available to assess components, also referred to as analytes, in a sample. Among these, probably the most common is absorption spectroscopy. Incident light excites electrons of the analyte from a low energy ground state into a high energy, excited state, and the energy can be absorbed by both non-bonding n-electrons and π-electrons within a molecular orbital. Absorption spectroscopy can be performed in the ultraviolet, visible, and/or infrared region, with analytes of varying material phases and composition being interrogated by specific wavelengths or wavelength bands of light. The resulting transmitted light is then used to resolve the absorbed spectra, to determine the analyte's or sample's composition, temperature, pH and/or other intrinsic properties for applications ranging from medical diagnostics, pharmaceutical development, food and beverage quality control, to list a few. To this end, Hassell, et al. in U.S. Pat. Pub. No.: US 2021/0088433 describe an in-situ probe that can be inserted and/or maintained in a bioreactor and incorporates elements for interrogating as well as elements needed to analyze the contents of a bioreactor, e.g., in the NIR region of the electromagnetic spectrum. The analysis can be conducted in real time, in a nondestructive manner. EP 3 045 521 A1 discloses a system for monitoring a process within a bioreactor bag wherein a portion of the bag with its content is traversed by the light path of a turbidity sensor positioned outside the bag. Another option is Raman spectroscopy, which works by the detection of inelastic scattering of typically monochromatic light from a laser. SUMMARY OF THE INVENTION Robust, hands-free, non-destructive techniques for identifying and/or quantifying constituents in a given process in real time are highly desirable. Typically, the process is conducted in a vessel, e.g., a bioreactor. The contents of the bioreactor can change as the process unfolds and data collected at various stages can be used to monitor, adjust and/or control process parameters. Whereas many existing approaches rely on removing and/or circulating cells in loops external to the process vessel, typically through a pumping system, an in-situ probe can reduce, minimize and often eliminate the exposure of the bag contents to external conditions. In addition, cells are prevented from being drawn into a pumping system, where they could become damaged. The low sheer rocking motion often used with flexible reactors, as well as the absence of stirrers, impellers and the like, are other factors that contribute to protecting cells from damage, while also minimizing contamination. Nevertheless, a need continues to exist for methods and equipment designed to monitor processes conducted in modern bioreactors, and, in particular, flexible bioreactors, also referred to herein as "bag bioreactors" and/or "rocking bioreactors". Advantageously, rocking reactors come in a wide range of sizes, to accommodate many applications and needs. Typically, pre-sterilized and often designed for single use, such reactors reduce the need for time-consuming vessel clean-up steps and simplify the process. Embodiments described herein reduce manual intervention, increasing reproducibility from one run to the next, streamlining the process, and reducing the potential for errors. Generally, bags for reactors, such as rocking reactors, are single use, flexible bags made of polymeric materials. They can be configured in a variety of sizes and are often pre-sterilized. Easy to handle, often inexpensive, these bags offer time and labor advanta