Apparatus, System, and Method for Detecting Thermal Bubbles

Abstract

A bubble discrimination system including a thermal imaging camera and a controller connected to the thermal imaging camera. The thermal imaging camera images the surface of the liquid in the container that is exposed to the upper space of the container. The upper space is either warmer or colder than the liquid. The camera and the controller detect changes in the temperature of the exposed surface of the liquid to identify bubbles on the exposed surface of the liquid.

Description

Technical Field

[0001] Embodiments of the present invention generally relate to bioprocessing apparatuses, systems, and methods, and more particularly to thermally observing and analyzing fluid within a bioreactor to detect bubbles.

Background Art

[0002] Bioreactors are often employed to perform biochemical and / or biological processes and / or to manipulate liquids and other products of such processes. Such bioreactors often include a flexible or foldable single-use disposable bag supported by an outer rigid structure such as a stainless steel shell or frame. The bag is made of a thin flexible sheet of plastic film, positioned within the rigid shell, and filled with the desired fluid for processing.

[0003] When growing biological materials such as mammalian cells, bacteria, or yeast within a bioreactor, an unwanted layer of bubbles often forms at the top of the fluid within the bioreactor, for example within the upper space of the bioreactor bag. This bubble layer is the result of several factors, including the addition of pressurized air to maintain aerobic microorganisms, nutrients and growth factors present in the liquid growth medium, and waste products produced by the microorganisms. Over time, the bubble layer can become unacceptably thick and, if untreated, can contaminate the exhaust ports and filters of the bioreactor, impede CO2 emissions, and adversely affect the structural integrity of the bag. Bubbles can also form a barrier to liquids injected from above the fluid within the bioreactor and can be problematic even when the fluid volume level is low.

[0004] To reduce the foam layer to a reasonable thickness, chemical solutions such as defoaming compounds are typically employed. For such compounds, multiple applications may be required during a single manufacturing run to ensure effectiveness. Conversely, too much defoaming compound can be harmful to the biological material within the reactor. Mechanical solutions such as thermal probes and foam breakers also exist, however they are more effective at reducing a significant amount of existing foam rather than inhibiting foam formation.

[0005] Considering the above, accurate detection and monitoring of foam within a bioreactor bag is important for determining when intervention is necessary. Solutions for foam detection exist, but they do not evaluate the entire exposed fluid surface within the bag, rather they detect the foam level in a narrow region within the bioreactor bag, or in some cases only at a single point. Furthermore, many such systems have been found to be generally effective only for detecting extreme foam events where the biological material or the structure of the bag itself may already be compromised. Known solutions are also relatively expensive and do not function to ensure that the required amount of defoaming compound is applied according to the actual foam level within the bag, nor do they have the ability to quantify the amount of foam present.

[0006] Considering the above, there is a need for an apparatus and system for observing the fluid within a bioreactor bag that provides improved detection, monitoring, and mitigation of foam within the bag. SUMMARY OF THE INVENTION

[0007] Specific embodiments corresponding to the scope of the claimed subject matter are summarized below. These embodiments are not intended to limit the scope of the claimed subject matter, rather these embodiments are only intended to provide a brief overview of possible embodiments. Indeed, the present disclosure may encompass various forms that may be the same as or different from the embodiments described below.

[0008] In one embodiment, the foam discrimination system includes a thermal imaging camera and a controller connected to the thermal imaging camera. The thermal imaging camera images the surface of the liquid in the container exposed to the upper space of the container, and the upper space is either warmer or colder than the liquid. The camera and the controller detect changes in the temperature of the exposed surface of the liquid to identify the foam on the exposed surface of the liquid.

[0009] In another embodiment of the present invention, a method for identifying foam on the surface of a liquid in a container includes obtaining a temperature measurement of the liquid in the container, determining whether the upper space of the container is warmer or colder than the liquid, obtaining one or more temperature measurements of the surface of the liquid exposed to the upper space of the container by a thermal imaging camera, detecting changes in the temperature of the exposed surface of the liquid, and identifying the foam on the exposed surface based on the detected temperature changes.

[0010] In yet another embodiment, the bioreactor system includes a frame, a thermal imaging camera, and a controller connected to the thermal imaging camera. The frame houses and supports the container. The thermal imaging camera is fixed to the frame and images the surface of the liquid exposed to the upper space of the container. The upper space is either warmer or colder than the liquid. The camera and the controller detect changes in the temperature of the exposed surface of the liquid to identify the foam on the exposed surface.

[0011] The present invention will be better understood by reading the following description of non-limiting embodiments with reference to the accompanying drawings.

Brief Description of the Drawings

[0012]

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DETAILED DESCRIPTION OF THE INVENTION

[0013] Hereinafter, exemplary embodiments of the present invention will be referred to in detail, and examples thereof are shown in the accompanying drawings. As much as possible, the same reference numerals used throughout the drawings refer to the same or similar parts.

[0014] As used herein, the terms "flexible" or "foldable" refer to a structure or material that is flexible or can be bent without breaking, and may also refer to a material that can be compressed or expanded. An example of a flexible structure is a bag formed from a polyethylene film. The terms "rigid" and "semi-rigid" are used interchangeably herein to describe a "non-foldable" structure, i.e., a structure that is not folded, bent, or otherwise deformed such that its elongated dimensions are significantly reduced by normal forces. Depending on the context, "semi-rigid" can also refer to a structure that is more flexible than a "rigid" element, such as a bendable tube or conduit, but that still cannot be longitudinally folded under normal conditions and forces.

[0015] As used herein, "container" may, in some cases, mean a flexible bag, a flexible container, a semi-rigid container, or a rigid container. The term "container" as used herein is intended to encompass flexible or semi-rigid single-use flexible bags, bioreactor containers having walls or portions of walls, and other containers or conduits commonly used in biological or biochemical processes, including, for example, cell culture / purification systems, fermentation systems, mixing systems, media / buffer preparation systems, and filtration / purification systems.

[0016] As used herein, the term "bag" means a flexible or semi-rigid container or vessel, for example, used as a bioreactor or mixer for the internal contents. Embodiments of the invention are described for use with bioprocessing bags, including but not limited to bioreactor bags and mixer bags, but the embodiments may also be configured for use with other bags or vessels. Similarly, the embodiments may be used to image, evaluate, and mitigate / treat other properties or conditions in addition to the accumulation of foam in a bioreactor.

[0017] Furthermore, while embodiments are described in connection with single-use stirred tank bioreactors and bioreactor systems, they are not limited thereto and may be used with various vessels and associated equipment used in biological or biochemical processes. Additionally, embodiments may be suitable for use in identifying bubbles in other non-biological / biochemical situations. Certain embodiments may be useful for detecting other non-foam related conditions or events on a surface that can be identified by the temperature differences or temperature changes described herein.

[0018] Referring to FIG. 1, a bioreactor system 10 suitable for use in an embodiment of the present invention is shown. The bioreactor system 10 includes a substantially rigid bioreactor housing 12 mounted on top of a frame 14. The rigid housing 12 may be formed, for example, from stainless steel, polymer, composite material, glass, or other metal and may be cylindrical in shape, although other shapes may be utilized without departing from the broader aspects of the present invention. As will be appreciated, the housing is configured to contain and support a vessel, such as a bioreactor bag 15. In certain embodiments, the housing 12 may be a substantially rectangular mixer housing.

[0019] As shown, a single-use flexible bioreactor bag 15 is disposed within the housing 12. As described above, the housing 12 can be of any size (or shape) as long as it can support a vessel such as a single-use flexible bioprocess bag 15. For example, according to one embodiment, the housing 12 can receive and support a flexible or foldable bioprocess bag from 10 to 2000 L.

[0020] The bioreactor system 10 further includes a support structure 18 to which various equipment used in biochemical and / or biological processes is attached. The support structure 18 may also be used to lift the bag 15 and keep it in a predetermined position within the housing 12. The support structure 18 is shown as having a plurality of legs 19, although other configurations may be employed.

[0021] The housing 12 includes, among other things, an opening or aperture 20 through which the temperature probe 24 can be inserted into a thermowell or port within the container 15 and then coupled, for example via a cable, to the instrument tower 22. As will be appreciated, the temperature probe 24 provides the temperature of the fluid within the container 15.

[0022] Next, referring to FIG. 2, a foam discrimination system 100 according to an embodiment of the present invention is shown. As illustrated, the foam discrimination system 100 includes a thermal imaging camera 120 and a controller 130 operably connected to the thermal imaging camera 120. In an embodiment, the thermal imaging camera 120 is fixed to the support structure 18 of the frame 14 (FIG. 1). As will be described in more detail below, the thermal imaging camera 120 images the surface 142 of the liquid 144 within a container (e.g., a bag) 15. In particular, the camera 120 images the surface 142 exposed in the upper space 146 of the container 15. The upper space 146 is the volume within the container 140 that is not occupied by the liquid 144 or the foam 148. The upper space 146 includes a gas 147, such as air, held within the container 15 in contact with the exposed surface 142 of the liquid 144.

[0023] In the illustrated embodiment, the container 15 includes an inlet 141 and an outlet 149 that allow the passage of a fluid, such as the gas 147, into and out of the upper space 146. The gas 147 within the upper space 146 is either warmer or cooler than the liquid 144 within the container 15. The temperature of the ambient air surrounding the container has a significant impact on the temperature of the gas 147 within the upper space 146. In an embodiment, even when the temperature of the gas 147 flowing into the upper space 146 through the inlet 141 is not controlled, there is a sufficient temperature difference (e.g., 2 - 4 °C) between the temperature of the liquid 144 and the temperature of the gas 147. Given the temperature difference between the temperature of the gas 147 and the temperature of the liquid 144, the camera 120 and the controller 130 can detect changes in the temperature of the exposed surface 142 and identify the presence and amount of foam 148 on the surface 142.

[0024] In an embodiment, the thermal imaging camera 120 utilizes mid-wave to long-wave infrared imaging to collect temperature and radiation measurement data by directly reading heat without the need for illumination. The mid-wave and long-wave infrared imaging discussed herein should not be confused with short-wave or near-wave infrared imaging, which requires illumination to generate an image. In some embodiments, the thermal imaging camera 120 detects infrared light having a wavelength of from about 7 μm to about 14 μm.

[0025] Importantly, the thermal imaging camera 120 views a wide field of view V, in contrast to a point source, which is important due to the unpredictable nature of bubble accumulation. In an embodiment, the field of view V is substantially the entire exposed surface 142. In certain embodiments, the thermal camera 120 may utilize a wide-angle lens and may include an autofocus function.

[0026] In one embodiment, the camera 120 and the controller 130 detect a change in the temperature of the exposed surface 142 of the liquid 144 indicating the formation or presence of bubbles 148 on the exposed surface 142. More specifically, the temperature of the exposed surface 142 of the liquid 144 will deviate from, i.e., rise or fall from, the temperature of the liquid 144 within the container 15 that is not exposed to the upper space, depending on whether the upper space is warmer or colder than the liquid 144.

[0027] In certain embodiments, the thermal imaging camera 120 is by radiometric measurement. The thermal imaging camera 120 having an integrated radiometer may provide temperature data for each pixel of an image that enables the system 100 to aggregate and quantify bubbles by percentages such as area, height, persistence, etc. (e.g., create a histogram, etc.). The thermal imaging camera 120 obtains a heat map without the need for an algorithm and enables the system 100 to model the heat map as height and / or over time.

[0028] Bubble identification system 100 may also include a temperature control system that maintains the upper space 146 at a temperature warmer or colder than the temperature of the liquid 144. The temperature control system may include a gas temperature controller 160 and at least one temperature monitor 162. In certain embodiments, the temperature control system may utilize one or more temperature monitors 162 that may include a monitor 162 for the gas flowing into the container 15 through the inlet 141, a monitor 162 for the temperature of the upper space 146, and / or a monitor for the gas flowing out of the container outlet 149. As will be appreciated, various temperature monitors, such as temperature probe sensors, etc., may be utilized without departing from the scope of the present invention. In an embodiment, the temperature sensor 164 is employed to monitor the region of interest, i.e., the outer surface of the container 15, without contacting the environment inside the container. The gas temperature controller 160 and / or the temperature monitor 162 communicate with the controller 130 to provide the desired temperature.

[0029] The temperature monitor 162 detects the temperature of the gas flowing into the upper space 146 through the inlet 141, the temperature of the gas flowing out of the upper space 146 through the outlet 149, and / or the temperature of the gas 147 within the upper space 146. In response to the measured temperature, the temperature control system may adjust the upper space temperature to maintain the upper space temperature at a certain set temperature or at a degree (e.g., 5 °C) higher or lower than the temperature of the liquid 144 within the container 15. In an embodiment, the gas temperature controller 160 may be provided with a controlled temperature value of the liquid 144 within the container 15, may be provided with an ambient air value of the air outside the container 15, may be operably connected to a temperature probe 24 within a thermowell or port within the container 15 and / or the instrument tower 22, or may be operably connected to a temperature monitor 162 that detects the temperature of the gas flowing into the upper space 146 through the inlet 141.

[0030] In other embodiments, the temperature of the liquid 144 within the container 15 may be approximated by measuring the temperature of the container wall through the exposed surface. More specifically, the temperature of the container wall through the exposed surface (when not blocked by bubbles) may be a suitable calibration proxy for the controlled container temperature. That is, for example, if the controlled container temperature is 37°C, the thermal camera may be able to record this same temperature value by thermally imaging the container wall at or through the exposed surface. In this way, the system can be continuously calibrated without the need to provide real-time temperature measurements of the liquid 144.

[0031] As will be appreciated, the gas temperature controller 160 may heat or cool the gas from the mass flow controller 180 before exhausting the gas into the upper space 146 via the inlet 141. In embodiments, the gas temperature controller 160 need not actively heat or cool the gas and may simply include a coil of tubing that approaches the ambient air temperature. Such embodiments may be effective when the difference between the temperature of the liquid 144 and the ambient air temperature outside the container 15 is sufficient for bubble detection. For example, an ambient air temperature of about 22°C may be sufficient.

[0032] In certain embodiments, temperature control systems and / or gas introduction may not be necessary and may be completely omitted. Here, the gas 147 within the upper space 146 is sufficiently cooler than the liquid 144 due to the top of the container (e.g., a bag) 15 that includes the upper space 146 protruding above and outside of the rigid (e.g., stainless steel) container housing 12.

[0033] Alternative means for controlling the temperature of the gas 147 within the upper space 146 (such as heaters, lamps, ambient air, etc.) do not depart from the invention disclosed herein.

[0034] Next, referring to FIGS. 2 through 4, in the embodiment, the foam discrimination system 100 determines the presence and / or size of foam for substantially the entire surface 142 of the liquid 144 exposed in the upper space 146. Typically, the upper space 146 will have a temperature lower than the temperature of the liquid in the container 15. The upper space 146 is exposed to the ambient room air at about 22° C., which is substantially lower than the liquid temperature that is often set to about 37° C. The foam 148 on the exposed surface 146 will approach the temperature of the upper space 146 over time. The liquid on the exposed surface is less affected by the temperature of the upper space 146 and remains relatively close to the controlled container temperature. Thus, the presence and / or size of the foam can be identified based on thermal imaging, radiometric data, and / or temperature changes detected by the rate at which the exposed surface 142 changes temperature.

[0035] As shown in FIG. 3, as the temperature of the gas 147 in the upper space 146 decreases over time (represented by the bottom line in the chart), the foam temperature (central line) approaches the upper space temperature, as indicated by reference numeral “A”. As described above, the liquid 144 (top line) is less affected by the temperature of the upper space 146, as indicated by reference numeral “B”. The rate of change of the surface temperature when the gas 147 in the upper space 146 changes, as indicated by reference numeral “C”, is also an indicator of the formation and size of the foam on the surface 142. As will be appreciated, a relatively high rate of temperature change indicates a relatively high amount / size of foam formation. Conversely, a low rate of change indicates a relatively low amount / size of foam. A very low rate of change may indicate normal cooling of the exposed surface 142 without foam formation.

[0036] As a non-limiting example, FIG. 4 shows a container 15 set to a controlled container temperature of 37° C., where the headspace gas 147 has a temperature lower than that of the liquid 144. In certain embodiments, it has been found that a temperature difference (plus or minus) between the headspace gas 147 and the liquid 144 of at least 0.5° C. is sufficient for bubble discrimination, although smaller temperature differences may also be sufficient. The exposed surface 142 has been measured at 36° C., and the presence of small / lesser-sized bubbles is indicated by a measurement surface temperature of 35° C., i.e., 0.5 to 1.5 degrees lower than the temperature of the exposed surface 142. A large amount / size of bubbles is indicated by a temperature of the exposed surface 142 of 33° C., i.e., 2 to 3 degrees lower than the temperature of the liquid 144. In this example, it was found that the container wall temperature measured through the bubble-free portion of the exposed surface 142 is the same 37° C. as the controlled container temperature.

[0037] As will be appreciated, the magnitude of the particular temperature and / or temperature difference (higher or lower), which is an indicator of bubbles, can vary based on several factors including, but not limited to, the temperatures of the headspace gas 147 and the liquid 144, and the temperature and velocity of the head sweep gas flow.

[0038] As will be appreciated, embodiments of the present invention are useful for determining when chemical or mechanical defoaming should be performed, the amount of defoaming required considering the size / rate of bubble formation, and the effectiveness of the defoaming process.

[0039] Next, referring to FIGS. 2 and 6, in an embodiment, the bubble discrimination system 100 includes a container 15 having a viewport 50 that enables a thermal imaging camera 120 to image the exposed surface 142 of the liquid 144. In some embodiments, the viewport 50 may be heated to reduce condensation or may be equipped with an air curtain, as will be described in more detail below.

[0040] In an embodiment, the container 15 has a multilayer film structure including an innermost layer of a liquid-contact material 200 (e.g., polyethylene) in contact with the liquid inside the container. The viewport 50 may be formed on the liquid-contact material 200 or may be joined to the liquid-contact material. In a particular embodiment, the viewport 50 is made of low-density polyethylene (LDPE) and is made of a material that is known to have excellent transmittance in a target spectral range of, for example, 7 to 14 μm. As will be appreciated, the thickness of the viewport 50 can vary depending on the material properties. Other materials having the required transmittance may be utilized without departing from the scope of the present invention. In certain embodiments, polypropylene and polystyrene may be utilized.

[0041] In a particular embodiment, the viewport 50 can be the same single-layer or multilayer material as the material of the container 15 itself. In other words, the container 15 may not have a dedicated viewport having a configuration that deviates from the configuration of the container 15. For example, an LDPE sheet with a thickness of 15 to 20 mils can provide a transmittance and structure suitable for such embodiments. In still other embodiments, the port 50 may be an inner liquid-contact material 200 layer and may be formed simply by removing the layer at the top of the liquid-contact material 200.

[0042] In a particular embodiment, the viewport 50 is circular and has a diameter that is substantially wider / larger than the lens of the thermal camera 120. Without departing from the present invention, other sizes and shapes of the viewport 50 can be adopted.

[0043] As described above, the camera 120 can be mounted on the support structure 18 such that it is positioned above the container 15 and directed vertically downward so that substantially the entire exposed surface 142 can be imaged. In this regard, the viewport 50 may be positioned on the upper or top surface of the container 15. As will be appreciated, the viewport 50 can be in various locations as long as substantially the entire exposed surface 142 can be imaged.

[0044] In one embodiment, as shown in FIGS. 7 and 8, the foam discrimination system 100 includes an air curtain 52. The air curtain 52 reduces container condensation to facilitate thermal imaging of the exposed surface 142. In an embodiment, the air curtain 52 is positioned within a container (e.g., a bag) 15 and is directed towards a viewport 50 or other optically transparent viewing area of the container 15. The air curtain 52 may be removably or fixedly attached to the wall of the container 15 and may utilize a gas (e.g., air, O2, or N2) from an existing head sweep gas flow from the mass flow controller 180. As will be appreciated, in embodiments where the air curtain 52 utilizes an existing gas flow, no additional hardware is required and the air curtain 52 is simply added to the container 15. Further, the existing head sweep gas flow provides a supply of gas having a very low dew point of less than -40° C., which is ideal for preventing condensation. Additionally, by using the air curtain 52, it may not be necessary to use a heater.

[0045] Specifically referring to FIG. 7, an exemplary air curtain 52 includes a nozzle or outlet portion 53 through which a gas / air flow is directed and a threaded base portion 55. The threaded base portion 55 may be directly attached to the mass flow controller 180 (FIG. 8) or may otherwise be in fluid communication with the mass flow controller 180.

[0046] In use, the air curtain 52 directs a flow of gas / air F towards the viewport 50 to clear the condensation region. In certain embodiments, the air curtain 52 may be selectively positionable such that the operator can direct the flow of gas F to maximize condensation removal. Further, the velocity of the gas / air F flow may vary depending on the moisture content of the air in the upper space, the air temperature in the upper space, or other variables. Additionally, the air curtain 52 may be paired with a sensor or meter that measures moisture content or the like.

[0047] As will be appreciated, the air curtain 52 may be used for purposes other than thermal imaging, for example, for various external optical measurements or to remove condensation from a portion of the container / bag.

[0048] In certain other embodiments, an air knife may be employed, although in such a configuration additional pressurized air and flow control may be required.

[0049] Next, referring to FIGS. 9 through 11, an alternative arrangement of the thermal camera may be employed. In one embodiment, the thermal camera 120 may be positioned to image the side of the upper space of the container 15. Such an arrangement may be suitable for a container (e.g., a bag) made entirely of a material that is substantially transparent in the thermal spectral range or a container having a side viewport.

[0050] In another embodiment, the system may include a plurality of thermal cameras 120 spaced around the container 15 and directed toward the upper space. In certain embodiments, one or more thermal cameras may be incorporated within the rigid bioreactor housing 12. In yet other embodiments, the thermal camera may be integral with the container / bag itself. In embodiments where multiple cameras or cameras incorporated within the container / bag are used, a lower resolution thermal imaging camera may be employed to reduce costs.

[0051] In use, the system 100 identifies the presence and / or size of the bubbles 148 on the surface 142 of the liquid 144 exposed in the upper space 146 in several ways. In one embodiment, the system 100 detects the rate of change of temperature on the exposed surface 142. In another embodiment, the thermal camera 120 and the controller 130 compare the temperature of the exposed surface 142 with the temperature of the liquid 144 to evaluate whether the exposed surface 142 is warmer or colder than the liquid 144 by a predetermined amount that is an indicator of bubbles, thereby identifying the area of the bubbles 148.

[0052] In yet another embodiment, the thermal camera 120 and the controller 130 evaluate whether the exposed surface 142 is within a predetermined temperature range of the upper space temperature, which is an indicator of bubbles, by comparing the temperature of the exposed surface 142 with the temperature of the upper space 146, thereby identifying the area of the exposed surface 142 as the bubble 148.

[0053] A method for identifying bubbles 148 on the surface of the liquid 144 in the container 15 is provided. The method includes obtaining a temperature measurement of the liquid 144 in the container 15, determining whether the upper space 146 of the container 15 is warmer or colder than the liquid 144, obtaining one or more temperature measurements of the surface 142 of the liquid 144 exposed to the upper space 146 of the container 15 by the thermal imaging camera 120, detecting a change in the temperature of the exposed surface 142 of the liquid 144, and identifying the bubble 148 on the exposed surface 142 based on the detected change in temperature.

[0054] In one embodiment, the step of identifying the bubble 148 on the exposed surface 142 includes evaluating whether the exposed surface 142 is warmer or colder than the liquid 144 by a predetermined amount, which is an indicator of bubbles, by comparing the temperature of the exposed surface 142 of the liquid 144 with the temperature of the liquid 144. In another embodiment, the step of identifying the bubble 148 on the exposed surface 142 includes evaluating whether the exposed surface 142 is within a predetermined temperature range of the upper space temperature, which is an indicator of bubbles, by comparing the temperature of the exposed surface 142 with the temperature of the upper space 146.

[0055] In yet another embodiment, the step of identifying the bubble 148 on the exposed surface 142 includes obtaining a plurality of temperature measurements of the exposed surface 142 of the liquid 144, determining a rate of change of temperature on the exposed surface 142 from the plurality of temperature measurements of the exposed surface 142, and identifying the presence and / or size of the bubble 148 on the surface of the liquid 144 by comparing the rate of change of temperature with a predetermined value that is an indicator of bubbles.

[0056] In one embodiment, the step of identifying the bubbles 148 incorporates maintaining the temperature of the upper space 146 either warmer or colder than the liquid 144. In one embodiment, the method of identifying the bubbles 148 also includes alleviating the detected bubbles 148 on the exposed surface 142 of the liquid 144, for example, by adding an anti-foaming agent into the container 15.

[0057] In an embodiment, the method of identifying the bubbles 148 also includes removing condensation from the viewing port 50 of the container 15 by a condensation prevention system (such as the air curtain 52, etc.) to facilitate the identification of the bubbles 148 by the thermal imaging camera 120.

[0058] In some embodiments, the bubble identification system 100 provides defoaming injection feedback by analyzing the bubble size during and after using mechanical or gaseous solutions in addition to chemical anti-foaming agents. The thermal imaging camera 120 provides data that quantifies the input of the anti-foaming agent and / or the response of the bubbles 148 to the anti-foaming agent.

[0059] As used herein, an element or step recited in the singular and preceded by the word "a" or "an" should be understood as not excluding a plurality of said elements or steps unless such exclusion is explicitly stated. Further, reference to "one embodiment" of the present invention is not intended to be construed as excluding the existence of additional embodiments that also incorporate the recited features. Further, unless explicitly stated to the contrary, embodiments "comprising," "including," or "having" an element or elements with a particular characteristic may include additional such elements that do not have that characteristic.

[0060] This specification uses examples to disclose some embodiments of the invention, including the best mode, and to enable those skilled in the art to practice embodiments of the invention, including the making and using of any device or system and the performing of any incorporated method. The patentable scope of the invention is defined by the claims and may include other examples that occur to those skilled in the art. Such other examples are intended to be within the scope of the claims if they have structural elements that do not differ from the literal language of the claims or if they include equivalent structural elements that do not differ substantially from the literal language of the claims.

Explanation of Signs

[0061] 10 Bioreactor system 12 Rigid bioreactor housing, rigid housing, lifting housing, container housing 14 Frame 15 Single-use flexible bioreactor bag, single-use flexible bioprocess bag, container 18 Support structure 19 Plurality of legs 20 Opening or aperture 22 Instrument tower 24 Temperature probe 50 Viewport 52 Air curtain 53 Outlet portion 55 Threaded base portion 100 Bubble identification system 120 Thermal imaging camera, thermal camera 130 Controller 140 Container 141 Inlet 142 Exposed surface 144 Liquid 146 Upper space, exposed surface 147 Upper space gas 148 Bubble 149 Container outlet 160 Gas temperature controller 162 Temperature monitor 164 Temperature sensor 180 Mass flow controller 200 Wetted materials F Gas / air, gas V Visual field

Claims

1. A thermal imaging camera configured to image the surface and bubbles of a liquid in the container, which is exposed in the upper space of the container, wherein the upper space is either warmer or colder than the liquid and the bubbles. A controller operably connected to the thermal imaging camera Comprising The camera and the controller are configured to detect a change in the temperature of the exposed surface and identify bubbles on the exposed surface. Bubble identification system.

2. A temperature control system configured to maintain the upper space at a temperature warmer or colder than the liquid The bubble identification system according to claim 1, further comprising

3. The temperature control system is A gas temperature controller and at least one temperature monitor for detecting the temperature of at least one of the gas flowing into the upper space, the gas flowing out of the upper space, and the gas around the container The bubble identification system according to claim 2, comprising

4. A temperature monitor configured to measure the temperature of the upper space The bubble identification system according to claim 1, further comprising

5. The thermal imaging camera provides data for quantifying the addition of an anti-foaming agent and / or the reaction of the bubbles to the anti-foaming agent. The bubble identification system according to claim 1.

6. The thermal imaging camera detects infrared light having a wavelength of about 7 μm to about 14 μm. The bubble identification system according to claim 1.

7. The thermal imaging camera is by radiometric measurement. The bubble identification system according to claim 1.

8. The bubble identification system according to claim 1, further comprising a container having a viewing port configured to enable the thermal imaging camera to image the exposed surface of the liquid.

9. The viewing port is heated to reduce condensation. The bubble identification system according to claim 8.

10. An air curtain configured to reduce container condensation and facilitate thermal imaging of the exposed surface. The bubble identification system according to claim 1, further comprising

11. The bubble identification system according to claim 1, further comprising a housing configured to house and support the container, the housing having a support structure to which the thermal imaging camera is mounted.

12. ​ ​ The bubble discrimination system according to claim 11, wherein the camera is mounted on the support structure so as to be positioned above the container and is directed vertically downward so that substantially the entire exposed surface can be imaged.

13. The bubble discrimination system according to claim 1, wherein the container is a foldable bioreactor bag.

14. The bubble discrimination system according to claim 1, wherein the system is configured to identify the presence and / or size of bubbles on the surface of the liquid exposed to the upper space by detecting the rate of change of temperature on the exposed surface.

15. The bubble discrimination system according to claim 1, wherein the camera and the controller compare the temperature of the exposed surface with the temperature of the liquid to evaluate whether the exposed surface is warmer or colder than the liquid by a predetermined amount that is an indicator of bubbles, thereby identifying the area of the exposed surface.

16. The bubble discrimination system according to claim 1, wherein the camera and the controller compare the temperature of the exposed surface with the temperature of the upper space to evaluate whether the exposed surface is within a predetermined temperature range of the upper space temperature that is an indicator of bubbles, thereby identifying the area of the exposed surface as a bubble.

17. The bubble discrimination system according to claim 1, wherein the upper space is colder than the liquid in the container.

18. A method for identifying bubbles on the surface of a liquid in a container, comprising: obtaining a temperature measurement value of the liquid in the container; determining whether the upper space of the container is warmer or colder than the liquid; obtaining at least one temperature measurement value of at least one of the surface of the liquid and the bubbles exposed to the upper space of the container by a thermal imaging camera; detecting a change in the temperature of the exposed surface; and identifying bubbles on the exposed surface based on the detected change in temperature. A method comprising the steps of:

19. The step of identifying bubbles on the exposed surface comprises: evaluating whether the exposed surface is warmer or colder than the liquid by a predetermined amount that is an indicator of bubbles by comparing the temperature of the exposed surface with the temperature of the liquid. The method according to claim 18, comprising the step of:

20. The step of identifying bubbles on the exposed surface comprises: A step of comparing the temperature of the exposed surface with the temperature of the upper space to evaluate whether the exposed surface is within a predetermined temperature range of the upper space temperature, which is an index of bubbles The method according to claim 18, comprising:

21. The step of identifying bubbles on the exposed surface Comprises the steps of obtaining a plurality of temperature measurement values of the exposed surface; Determining a rate of change of temperature on the exposed surface from the plurality of temperature measurement values of the exposed surface; Identifying the presence and / or size of bubbles on the surface of the liquid by comparing the rate of change of temperature with a predetermined value that is an index of bubbles The method according to claim 18, comprising:

22. The method according to claim 18, further comprising the step of providing data for quantifying the addition of the antifoaming agent and / or the reaction of the bubbles to the antifoaming agent

23. The step of maintaining the temperature of the upper space either warmer or colder than the liquid The method according to claim 18, further comprising:

24. The method according to claim 18, wherein the upper space is colder than the liquid

25. The step of alleviating the detected bubbles on the exposed surface of the liquid The method according to claim 18, further comprising:

26. The method according to claim 18, wherein the thermal imaging camera detects infrared light having a wavelength of about 7 μm to about 14 μm

27. The method according to claim 18, wherein the thermal imaging camera is by radiation measurement

28. The step of determining whether the upper space of the container is warmer or colder than the liquid Comprises the steps of obtaining the temperature of the upper space by an upper space temperature sensor and comparing the upper space temperature with the temperature measurement value of the liquid The method according to claim 18, comprising:

29. The step of determining whether the upper space of the container is warmer or colder than the liquid Comprises the steps of obtaining the temperature of a part of the container wall in the upper space by the thermal imaging camera and then comparing the container wall temperature with the temperature measurement value of the liquid The method according to claim 18, comprising:

30. The step of removing condensation from the container by a condensation prevention system to facilitate the identification of bubbles by the thermal imaging camera The method according to claim 18, further comprising:

31. A housing configured to house and support a container A thermal imaging camera fixed to the housing, the thermal imaging camera being configured to image the surface of the liquid and the bubbles exposed in the upper space of the container, the upper space being either warmer or colder than the liquid, a thermal imaging camera; A controller operably connected to the thermal imaging camera; Comprising; The camera and the controller are configured to detect a change in temperature of the exposed surface and identify bubbles on the exposed surface. A bioreactor system.

32. A temperature control system configured to maintain the upper space at a temperature warmer or colder than the liquid. The bioreactor system according to claim 31, further comprising.

33. The temperature control system is such that A gas temperature controller and at least one temperature monitor for detecting the temperature of at least one of the gas flowing into the upper space, the gas flowing out of the upper space, and the gas around the container. The bioreactor system according to claim 32, comprising.

34. A temperature monitor configured to measure the temperature of the upper space. The bioreactor system according to claim 31, further comprising.

35. The thermal imaging camera provides data for quantifying the addition of an anti-foaming agent and / or the reaction of the bubbles to the anti-foaming agent. The bubble identification system according to claim 31.

36. The thermal imaging camera of the bioreactor system according to claim 31, which detects infrared light having a wavelength of about 7 μm to about 14 μm.

37. The thermal imaging camera of the bioreactor system according to claim 31 is by radiation measurement.

38. A container having a viewport configured to enable the thermal imaging camera to image the exposed surface. The bioreactor system according to claim 31, further comprising.

39. The viewport of the bioreactor system according to claim 38 is heated to reduce condensation.

40. An air curtain configured to reduce container condensation and facilitate thermal imaging of the exposed surface. The bioreactor system according to claim 31, further comprising.

41. Further comprising a container, The air curtain is positioned within the container. The bioreactor system according to claim 40.

42. The bioreactor system according to claim 31, wherein the camera is mounted on a support structure such that the camera is positioned above the container and directed vertically downward so that substantially the entire exposed surface can be imaged.

43. The bioreactor system according to claim 38, wherein the container is a foldable bioreactor bag.

44. The bioreactor system according to claim 31, wherein the system is configured to identify the presence and / or size of bubbles on the surface of the liquid exposed in the upper space by detecting a rate of change in temperature on the exposed surface.

45. The bioreactor system according to claim 31, wherein the camera and the controller evaluate whether the exposed surface is warmer or colder than the liquid by a predetermined amount that is an indicator of bubbles by comparing the temperature of the exposed surface with the temperature of the liquid, thereby identifying the area of the exposed surface.

46. The bioreactor system according to claim 31, wherein the camera and the controller evaluate whether the exposed surface is within a predetermined temperature range of the upper space temperature, which is an indicator of bubbles, by comparing the temperature of the exposed surface with the temperature of the upper space, thereby identifying the area of the exposed surface as bubbles.

47. The bioreactor system according to claim 31, wherein the upper space is colder than the liquid in the container.

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