Patent Application
20240248104
Biomanufacturing is a technology that utilizes biological systems to produce commercially important biomaterials and biomolecules for use in medicines, food and beverage processing, and industrial applications. Biomanufacturing products may be generated from cultures of microbes, animal cells, or plant cells grown in specialized equipment. The cultured seeds used during production may be naturally occurring or derived using genetic engineering techniques. When using one or more bioreactors, one may develop automated processes that assist biotech companies to optimize manufacturing processes and to facilitate bringing products to market faster. Typical biomanufacturing processes can be very time consuming and require a large amount of manual handling by a trained individual in a contaminant-free environment. For example, seed preparation and sample preparation and analysis may also require individualized attention in addition to bioreactions. Such techniques can be particularly burdensome for an experiment that may benefit from high throughput biomanufacturing.
In biomanufacturing systems, probes may typically be used to monitor conditions for each specific bioreactor so that systems for monitoring experiments and/or individuals in charge of facilitating experiments may observe specific measurable parameters for each bioreactor. For example, a probe may be used to monitor the pH of a specific culture, oxygen levels for a specific culture, or other measurable parameters. These feedback parameters allow automated systems and human controllers to adjust each bioreactor individually so as to maintain control over each culture during manufacturing.
As one may expect, the probes used in each bioreactor may deteriorate over time due to repeated use—especially with respect to monitoring pH levels as initial characteristics of the probes may shift after repeated and prolonged use. Without tracking each probe individually, laboratories would simply treat all probes as either “still good” or in need of replacement. As a result, this all or nothing decision was simply based on the number of uses or the passage of time regardless of whether each probe needed maintenance or not. This is inefficient and does not accurately reflect reality.
Embodiments of the subject matter disclosed herein in accordance with the present disclosure will be described with reference to the drawings, in which:
Note that the same numbers are used throughout the disclosure and figures to reference like components and features.
The subject matter of embodiments disclosed herein is described here with specificity to meet statutory requirements, but this description is not necessarily intended to limit the scope of the claims. The claimed subject matter may be embodied in other ways, may include different elements or steps, and may be used in conjunction with other existing or future technologies. This description should not be interpreted as implying any particular order or arrangement among or between various steps or elements except when the order of individual steps or arrangement of elements is explicitly described.
Embodiments will be described more fully hereinafter with reference to the accompanying drawings, which form a part hereof, and which show, by way of illustration, exemplary embodiments by which the systems and methods described herein may be practiced. These systems and methods may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy the statutory requirements and convey the scope of the subject matter to those skilled in the art.
Biomanufacturing processes can be used for many applications. For instance, biomanufacturing can be utilized for production of biomass (e.g., viable cellular material), production of extracellular metabolites (e.g., chemical compounds), production of intracellular components (e.g., enzymes and other proteins), or transformation of a substrate (e.g., the substrate itself may be a product). Biomanufacturing processes are useful for biological experiments, drug manufacturing, food industry, biofuels, and many other applications. In some instances, it may be desirable to provide automated biomanufacturing systems and methods that allow for low risk of contamination, high levels of accuracy and repeatability, high throughput, controlled variations, quicker turnaround, and/or require less manpower.
As briefly discussed above, the bioreactor array 140 may comprise multiple bioreactors 145 that each include one or more respective individual sensor probes 150 for monitoring conditions of the environment inside each bioreactor 145 as well as individual agitators 147 for provides agitation for each bioreactor 145. Each vessel (e.g., each bioreactor) may be associated with multiple probes each configured to determine a specific characteristic of the solution in the vessel such as pH level, temperature via a thermocouple (or the like), and dissolved oxygen (DO) levels. In some embodiments, these characteristics may be determined by a single probe configured to determine pH levels, temperature and DO levels simultaneously, or any combination of two or more characteristics. In still further embodiments, combinations of different characteristics may be determined by one probe with multiple characteristic sensing capabilities. Further, each probe may be communicatively coupled to the sensor subsystem 122 and each agitator 147 may be communicatively coupled to the agitation subsystem 124. Collectively, these subsystems may be under the control and direction of the control system 110 whereupon a user may utilize the user interface system 112 to control and direct the activities and procedures of the overall biomanufacturing system 100. Further, data about the control, state, and productions of the biomanufacturing system 100 may be communicated and stored in a cloud-based data store 114.
One or more processes within the biomanufacturing system 100 may be fully automated. That is, any process may be automated and executed without requiring human intervention. Further, such processes may be automated with the aid of one or more processors embodied in one or more computer systems. In some embodiments, transfer of materials from a seeding subsystem 120 to the bioreactor array 140 may be fully automated. In some embodiments, transfer of materials from the bioreactor array 140 to the material-handling subsystem 124 may be fully automated. In some embodiments, one or more robotic components may aid in the automated processes. In some cases, one or more robotic components may comprise one or more robotic arms or other robotic components such as gantry.
As discussed previously, the biomanufacturing system 100 may comprise one or more bioreactors 145 within a bioreactor array 140. Each bioreactor may correspond to an experiment. Each bioreactor 145 may correspond to an individual biomanufacturing process, which may be associated with a unique, individual experiment. Each bioreactor 145 may be independently operating and/or controllable relative to another bioreactor in the bioreactor array 140. Any number or arrangement of bioreactors 145 may be provided, as provided in greater detail elsewhere herein. Further yet, one or more modular components may be provided in the biomanufacturing system 100. For instance, components, such as bioreactors 145 and/or other equipment (e.g., sensor probes 150, agitators 147, and the like) may be swapped in or out as needed.
Each individual bioreactor 145 may be seeded with input strains from the seeding subsystem 120. For strain input, a strain or set of strains may be provided to the bioreactor 145. Any description herein of providing an input strain may be applied to providing a set of input strains or multiple input strains. An input strain may be provided via one or more tubes, frozen stocks, plates, beads, wells, channels, or any other technique. The input strain may be provided manually or may be loaded in an automated fashion. In some embodiments, the bioreactor 145 may be capable of accommodating multiple types of strain inputs. For example, the bioreactor 145 may be able to accept one or more tubes, and/or one or more plates with an input strain or set of input strains. Similarly, each individual bioreactor 145 may be populated with media from the seeding subsystem 120. Any description herein of providing media may also be applied to providing a set of input strains or multiple input strains or vice versa.
Each individual bioreactor 145 may include one or more sensor probes 150 for detecting conditions of any media therein. These conditions may include pH levels, temperature, oxygen levels, cell density, biomass, glucose levels, lactate levels, and the like. The biomanufacturing system may include additional sensors (not shown) used to monitor and detect additional conditions (e.g., volume, weight, height, and the like). Such additional sensors for additional conditions are not the subject of the present application and are not discussed further herein. However, as is discussed further below, the sensor probes 150 as shown, typically require calibration after one or more uses and, as with any sensor probe 150, may be prone to degradation and failure. As such, after each use, these sensor probes 150 may undergo testing and calibration procedures to ensure optimal operating conditions. Such testing and calibration procedures are discussed next with respect to
The elongated cylindrical body 202 is designed to be submersed in media (or at least in contact with media) within a bioreactor 145 and secured to a lid of a bioreactor 145 with a threaded head end 208. That is, the threads of the threaded head end 208 are configured to rotatably engage with an orifice in a lid or top side of any bioreactor 145 thereby making the sensor probes 150 interchangeable between any bioreactor 145. Further, the sensor probe 150 includes a rubber seal 206 designed to provide a fluid-tight interface between the sensor probe 150 and the orifice of the top side of the bioreactor 145. Further, the sensor probe 150 includes a communication module 210 designed to interface a communication lead (not shown) from the sensor subsystem of
The probe 150 may be configured to detect characteristics of the contents of its respectively engaged bioreactor. For example, in one embodiment, the probe 150 may be configured to determine pH levels of the contents. In another example, the probe may be configured to determine relative temperatures of the contents. In still further examples, the probe 150 may be configured to determine DO levels of the contents. In some embodiments, the probe may be configured to perform more than one of these example detections.
As will become evident further, sometimes the ability of a probe to perform these detections may be subject to degradation over repeated use. This is especially true for pH detection as probes after each use may be in need of repair and/or recalibration for continued use. Sensor probes 150 may be recalibrated and put back into use, but over time, the ability of sensor probes to accurately determine some solution characteristics, such as pH, may be permanently degraded indicating that such a sensor probe should be retired from use due to lack of accuracy.
Many autoclaves include an inner chamber 304 that is used to receive equipment and to sterilize the equipment placed therein by subjecting the equipment to pressurized saturated steam at 250° F. for around 30-60 minutes at a pressure of 15 psi depending on the size of the load and the contents. The autoclave may operate according to settings entered through a control panel 302 by a user. Sterilization autoclaves are widely used in microbiology and mycology, medicine, and prosthetics fabrication. They vary in size and function depending on the media to be sterilized and are sometimes called retort in industry. The autoclave 300, as used herein, may be part of the overall system 400 (described further below) for tracking probes used in the biomanufacturing system 100, but further details about the autoclave are not discussed in further detail.
The overall probe tracking system 400 may be ultimately controlled though use of a control system 110 as depicted in
The overall probe tracking system 400 further includes several bioreactor vessels in a bioreactor array that includes, as shown, at least bioreactors 145a-145n with respective “in-use” probes 150au-150nu. A skilled artisan understands that the probes 150au-150nu may represent a respective set of probes for multiple deterministic characteristics (e.g., pH, temperature, DO, or any other probe parameters and characteristics as previously described) for each respective bioreactor that are currently in use. These in-use probes may be queried at any time and often during experiment runs while in use (e.g., dynamic performance characteristics such as error codes, offsets, calibration curves, and actual dedicated sensor data like pH level for probes that are pH probes). Such use data not only informs operators about the progress of experiments but may also be indicative of failed probes that may need to be removed and repaired/recalibrated regardless of the underlying purpose and/or nature of the probes.
The overall probe tracking system 400 further includes a probe calibration system 444 that may be used to test or calibrate respective probes after use. The probe calibration system 444 may test and/or calibrate probes 150ac through 150nc that have recently been removed from use in one or more experiments. As is discussed in greater detail below with respect to
As alluded to above, the probe may be used in an experiment in a bioreactor of a biomanufacturing system at step 510. During this use, additional data may be determined and communicated to the meta data in the cloud data store about specific performance characteristics of the sensor probe during use such that in-use data updates and alters some meta data stored about the sensor probe. These in-use data points may include:
Once the experiment concludes, the sensor probe may be removed from the bioreactor at step 512. The contents of the bioreactor may be transferred to other containers not shown for intended uses not covered in the descriptions herein. However, the removed probes are then set to be cleaned, tested, and calibrated (if necessary) for repeated use. Prior to repeating (e.g., iterative) use, each probe is subject to one or more procedures at step 514. These procedures may include cleaning, testing, calibrating and the like. The cloud data may be updated accordingly after each procedure in response to determine these static performance characteristics (e.g., probe characteristics while not in use in any current experiment). For example, after a cleaning procedure, a use counter may be incremented in the cloud data. As another example, after a calibration testing, specific data about the calibration testing may be uploaded to the cloud data store (e.g., responsiveness (slope) to pH detection, responsiveness to dissolved oxygen detection, responsiveness to temperature detection, and the like).
Thus, a query step 518 is next after any specific procedural test that may result in one of three possible paths. As was noted earlier, flags 507 (not all of which are denoted by the designation numeral 507 on
Alternatively, after the procedural test at step 518, the probe may be determined to have failed the test at step 550 thereby resulting in simply retiring the probe from further use at step 555. Further yet, after the procedural test at step 518, the probe may be determined to have passed the test in a qualified manner at step 540. The qualified manner may be that the probe still maintains usefulness but may need recalibration to ensure proper sensitivity and responsiveness to detecting specific characteristics such as pH or dissolved oxygen. Thus, at step 545, remedial procedures may be taken to recalibrate or repair the probe for further testing until the probe can pass each procedural test. After testing again at step 518, the recalibrated or repaired probe is likely to pass the procedural tests and move the path that includes step 530. If all procedural tests cannot be passed (even after recalibration and/or repair), the probe will be removed from service though the path that includes step 560.
During the time in which the probe is removed from use and may be undergoing any number of procedures, specific meta data for inclusion and updating in the cloud data store may be realized. This trackable meta data includes:
As was discussed above, the procedural testing at step 518 may include any number of procedural tests for the subject probe. As one example, a pH testing and calibration procedure may include several sub-steps (not shown in
As has been discussed, any number of steps indicate the storage and/or updating of cloud data about the fleet of probes in use as denoted by various flags 507 in the method of
With such a calibration data determination, prediction and tracking system in place, a fleet manager may gain the advantage of saving time and reducing manual labor and chances for errors for any given predicted use and failures. In turn, this facilitates additional uniformity and consistent calibration processes compared to manual calibrations on single probes.
The present disclosures as described above can be implemented in the form of control logic using computer software in a modular or integrated manner. Based on the disclosure and teachings provided herein, a person of ordinary skill in the art will know and appreciate other ways and/or methods to implement the present disclosure using hardware and a combination of hardware and software.
Any of the software components, processes or functions described in this application may be implemented as software code to be executed by a processor using any suitable computer language such as, for example, Assembly language Java, JavaScript, C, C++, or Perl using, for example, conventional or object-oriented techniques. The software code may be stored as a series of instructions, or commands on a computer readable medium, such as a random-access memory (RAM), a read only memory (ROM), a magnetic medium such as a hard-drive or a floppy disk, or an optical medium such as a CD-ROM. Any such computer readable medium may reside on or within a single computational apparatus and may be present on or within different computational apparatuses within a system or network.
All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and/or were set forth in its entirety herein.
The use of the terms “a” and “an” and “the” and similar referents in the specification and in the following claims are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms “having,” “including,” “containing” and similar referents in the specification and in the following claims are to be construed as open-ended terms (e.g., meaning “including, but not limited to,”) unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value inclusively falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate embodiments, and does not pose a limitation to the scope of the disclosure unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to each embodiment of the present disclosure.
Different arrangements of the components depicted in the drawings or described above, as well as components and steps not shown or described are possible. Similarly, some features and sub-combinations are useful and may be employed without reference to other features and sub-combinations. Embodiments have been described for illustrative and not restrictive purposes, and alternative embodiments will become apparent to readers of this patent. Accordingly, the present subject matter is not limited to the embodiments described above or depicted in the drawings, and various embodiments and modifications can be made without departing from the scope of the claims below.
This application claims the benefit of U.S. Provisional Application No. 63/440,844 entitled “METHODS AND SYSTEMS FOR TRACKING PERFORMANCE CHARACTERISTICS OF PROBES FOR A FERMENTATION SYSTEM” filed Jan. 24, 2023, which is incorporated by reference in its entirety herein for all purposes.
| Number | Date | Country | |
|---|---|---|---|
| 63440844 | Jan 2023 | US |
