Control system and method for a perpetual automated bioprocessing system

Abstract

Provided is a unified or closed system of an integrated bioprocessing system where all needed equipment is connected while eliminating a cleanroom. The unified system would reduce CapEx and OpEx and reduce the consumption of energy. The unified system further reduces reliance on a highly skilled labor force associated with bioprocess-based production, such as biologicals and cell-cultivated meat.

Description

CONTROL SYSTEM AND METHOD FOR A PERPETUAL AUTOMATED BIOPROCESSING SYSTEMTechnical Field

[0001] Aspects of the invention generally relate to bioprocessing systems. In particular, embodiments of the invention relate to an automated bioprocessing system for cell-cultivated meat production.Background

[0002] Bioprocessing typically involves an upstream process that involves cell proliferation and a downstream process that involves isolating and purifying the target molecule in the spent medium using chemical separation methods. Until the mid-2010s, bioprocess was primarily used to provide materials secreted by cells, e.g. yeast cells, Escherichia coli cells, and animal cells such as CHO cells, or products that include vaccines, growth factors, and monoclonal antibodies. Since then, bioprocessing provided a wide application to those who wish to deal with cells.

[0003] Currently, individual bioprocess equipment is highly programmable. For example, a bioreactor can be programmed to vary the operating temperature, an agitator speed, a gas input and pressure, a medium feeding regime, etc. Individual equipment can be monitored and controlled by devices such as Programmable Logic Controller (PLC) and Remote Terminal Units (RTU). Several pieces of equipment can be programmed to work in synchronization by a Supervisory Control and Data Acquisition (SCADA) system that collects data from equipment, analyzes and determines the course of action, and sends signals back to the bioprocessing equipment to adjust the actuators, sensors, valves, pumps, etc., of the equipment.

[0004] Yet, most biological productions are only partially automated and not fully automated end-to-end. Manually handling is still considerably involved in the overall bioprocessing. A fully automated and integrated system that can self-run perpetually and consecutively and with minimal human monitoring or intervention is not commonly seen.

[0005] A key reason is the gap between the upstream equipment (e.g., fermenters and bioreactors) and downstream equipment (e.g., centrifuge and chromatography columns). The upstream and downstream equipment'smechanism, design and operation differ greatly, making it difficult to be integrated into one cohesive closed system. For example, upon completion of the upstream process, cells and spent medium are to be separated using a centrifuge. The spent medium is then passed through chromatography columns to extract the target molecules. The equipment's input / output and flow rate differ, and connecting all into a closed system can be difficult. As a result, certain manual handling is inevitable under the current setup.

[0006] Most of the biologicals are for injection use. The requirement for the production environment is very stringent, such as to be compliant with standards such as ISO 8 and upwards. Contamination risks are high, and compliance is of utmost importance. As such, most bioprocessing is conducted inside a cleanroom environment. Within the cleanroom, it is easy to perform some steps manually.

[0007] The above two factors strengthen each other, supporting the need for cleanroom and reducing the need to automate the process in entirety.

[0008] Currently, most automation or programming in bioprocess production is localized to individual equipment or only a small set of equipment. The main drive for automation is to reduce human error and to implement robust batch records performed by a historian device for compliance purposes.

[0009] Furthermore, the considerations are different with the rise of the new bioprocess application in cell-cultivated meat.

[0010] In cell-cultivated meat production, the bioprocess end product is the cell mass. Subsequent steps of incorporating cell mass into food products typically require a food factory environment only, which is of much lower specification than a cleanroom.

[0011] Cleanroom costs a lot to build and run, which does not suit the cell- cultivated meat application; the product’s, i.e. meat, selling price is much lower than that of biologicals. The capital expenditures (CapEx) and operating expenses (OpEx) of the cleanroom cannot be justified.

[0012] In addition, the cell-cultivated meat process requires a minimal downstream process, i.e. washing and draining the cells, which can be completed either in a food factory environment or in vessels similar in design toa bioreactor while still maintaining the quality and sanitary requirements for meat products.

[0013] Moreover, prior approaches attempt to provide perfusion bioreactors to advocate a localized perpetual loop within the equipment. Perfusion is a continuous culturing method in which cells are either retained in the bioreactor or fed back into it. Thus, the harvested medium contains no cells, resulting in higher cell concentrations and product yields in the reactor while reducing the working volume. This is not a system-wide looping.Summary

[0014] Embodiments of the invention provide a unified or closed system of an integrated bioprocessing system where all needed equipment is connected while eliminating a cleanroom. According to embodiments of the invention, the unified system may provide a collection of parameters to easily configure the unified system so that bioprocessing system may perpetually conduct the necessary tasks with the desirable effects and outcomes. Furthermore, embodiments of the invention may further reduce CapEx and OpEx and reduce the consumption of energy for any given bioprocessing tasks and goals. In another embodiment, the unified system further reduces reliance on a highly skilled labor force associated with bioprocess-based production, such as biologicals and cell-cultivated meat.

[0015] Moreover, embodiments of the invention create a standardization of data and / or parameters of all pieces of equipment so that aspects of the invention enable the synchronization of doubling time in all apparatuses to allow perpetual loop to minimize the need for Clean-ln-Place (CIP) and Sterilization- In-Place (SIP) to reduce OpEx and use of water and energy.Brief Description of Drawings

[0016] The disclosure may be better understood by reference to the detailed description when considered in connection with the accompanying drawings. The components in the figures are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the disclosure.

[0017] FIG. 1 illustrates a block diagram of an overall system of a perpetual bioprocessing system according to one embodiment.

[0018] FIG. 2 illustrates a block diagram of hardware configurations of the perpetual bioprocessing system according to some embodiments.

[0019] FIGS. 3A and 3C illustrate diagrams of single-series and multi-series variation arrangements according to some embodiments.

[0020] FIG. 4 illustrates a diagram illustrating a perpetual loop according to one embodiment.

[0021] FIG. 5 illustrates a diagram of a portable computing device communicating with a remote computing device or the overall system according to one embodiment.

[0022] FIG. 6 illustrates a diagram of a remote computing device connected to the overall system or the portable computing device according to one embodiment.

[0023] FIG. 7 illustrates a flow diagram illustrating a computerized process according to one embodiment.Detailed Description

[0024] Embodiments may now be described more fully with reference to the accompanying drawings, which form a part hereof, and which show, by way of illustration, specific exemplary embodiments which may be practiced. These illustrations and exemplary embodiments may be presented with the understanding that the present disclosure is an exemplification of the principles of one or more embodiments and may not be intended to limit any one of the embodiments illustrated. Embodiments may 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 may be thorough and complete and may fully convey the scope of embodiments to those skilled in the art. Among other things, the present invention may be embodied as methods, systems, computer-readable media, apparatuses, or devices. Accordingly, the present invention may take the form of an entire hardware embodiment, an entirely software embodiment, or an embodimentcombining software and hardware aspects. The following detailed description may, therefore, not to be taken in a limiting sense.

[0025] In general, a bioreactor may include an apparatus in which a biological reaction takes place for making target molecules. In one example, there are different types of bioreactors, such as a stirred tank bioreactor, a bubble column bioreactor, a packed bed bioreactor, a wheel bioreactor, etc. The biological reaction may be culturing animal cells, plant cells, bacteria or yeast.

[0026] A bioreactor may be capable to perform one or more of the following functions, such as seed train, inoculation, and culture expansion. For example, regardless of the type of bioreactor used, one of the reactors may start with a seed train. In other words, the reactors are staged and requires a well- coordinated process for a given goal for the reaction.

[0027] For example, it may start with a very small volume of the culture, usually in milliliter (ml), contained in a vial or tube stored at a very low temperature at a first stage. In another embodiment, in a second stage, the seed train may begin with thawing the culture and bringing it to the required temperature. As such, the parameters of the temperature and the timing of the thawing may be important and relevant. In another embodiment, the culture may first grow inside a small apparatus, such as a T-flask, a spinner flask or a shake flask of a few hundred millilitre. After several doublings, when the culture density reaches a desirable amount or an optimal amount, the culture and medium in the small apparatus may be moved to a larger apparatus.

[0028] In a possible third stage, a medium may then be added, resulting in the culture density decreasing. With this stage, the culture has more space to double until it reaches optimal density again, when the culture and medium may be moved to an even bigger apparatus. This way, the culture may grow in progressively larger apparatuses until the largest production apparatus.

[0029] The culture and medium may be separated to produce biologicals such as vaccines, growth factors, and monoclonal antibodies. The target molecules may be isolated and purified from the medium. In general approach, to make cell-cultivated meat, the cells may be separated from the medium, washed, and processed into food products.

[0030] For cell-cultivated meat production, risks and measures against contamination are critical. In a closed system of some of the existing practices, the whole culturing process must take place in an environment free from contaminants such as bacteria, mould, viruses, yeast, and mycoplasma. Contaminants that grow faster than the culture can override the culturing. Endotoxins can kill the culture. Even if the culture survives, the contaminants impact the quality and safe use of the final products. Common causes of contamination include (i) contaminated media components, (ii) insufficient disinfection or sterilization of apparatus and equipment, and (iii) improper handling, for example, when moving culture from one apparatus to another apparatus.

[0031] A crucial consideration for bioprocessing design is to ensure the culture does not come into direct contact with unfiltered indoor air. At a small scale, moving the culture from one flask to another using a pipette means that the culture is exposed to air outside of the apparatus. As such, this kind of open handling of culture must occur inside a biosafety cabinet that has an air filter to remove most contaminants present in the air. The moving of culture among apparatus that cannot fit inside a biosafety cabinet, such as from one bioreactor to another, must occur via pipes and pumps. The latter arrangement among apparatuses that prevents exposing the culture to the environment external to the apparatus is called a closed system.

[0032] Cleanroom CapEx and OpEx

[0033] Depending on the process, a completely closed system is not always possible. In those circumstances, the room where the process occurs must be fitted with specialized air filters, such as HEPA and LILPA filters. Instead of a small volume of air, less than one cubic meter, that needs to be filtered inside a biosafety cabinet, the whole volume of air inside the bioprocess room must be filtered. In addition, the room's wall, floor, and ceiling finishes must be made of materials and details that do not harbor any contaminants and must be easily cleaned and regularly disinfected.

[0034] In one example, a cleanroom is an engineered space that maintains a very low concentration of airborne particulates. It is well-isolated, well- controlled from contamination, and actively cleansed. To keep the requiredcleanroom air quality, an ISO-8 / class 100k cleanroom, for example, requires 20 filtered air changes per hour. A cleaner ISO-7 / class 10k cleanroom requires 60 filtered air changes per hour. Compare these with an office, at most 5, and shopping centers, around 10 air changes per hour. Due to the air change requirements, a cleanroom requires elaborate and enhanced HVAC systems, chilled air, and power supply. A cleanroom also requires specialized finish materials that are generally expensive to procure and build. Maintaining a cleanroom requires dedicated labor to clean and disinfect all surfaces and monitor the number of particulates in the air daily. Depending on the statutory and quality assurance of the biological products, a cleanroom must be regularly inspected and certified by a third party. The capital expenditures (CapEx) and operating expenditures (OpEx) are very high for cleanrooms.

[0035] Standardizing Bioprocessing Production

[0036] In addition to the high CapEx and OpEx, bioprocess production requires specifically educated and trained personnel to conduct crucial tasks, such as seed train preparation, inoculation, culture expansion, and in-line quality control. As a result, bioprocesses are capital and skilled labor-intensive undertakings. Setting up bioprocess production in places without access to the essential skilled labor force can be challenging, even with money. Bioprocess-related industries exist mainly in developed countries with the relevant skilled labor force. The COVID pandemic has accentuated this plight, with many developing countries having much delayed or no vaccine access.

[0037] With the advancement in research of biotechnology, more and more applications have been developed. One significant application is cell-cultivated meat, using bioprocess to culture animal cells at a large scale for food as an alternative to animal husbandry. With well-designed and optimized processes, cell-cultivated meat offers an overall more sustainable method of producing animal proteins that uses less arable land, uses less time to make, generates less waste, reduces public health risks due to zoonotic diseases, and increases the resilience of supply in the face of climate change.

[0038] Cell-cultivated Meat Industry

[0039] The cell-cultivated meat industry started in the mid-2010s. Capital investment supporting research has led to fast technological development inthe past decade. As of the early 2020s, some startups have demonstrated viable products. The cell-cultivated meat industry has multiple key challenges.

[0040] The first challenge is the high production cost due to the high cost of cell culture medium. This challenge, however, is gradually overcome as companies have formulated media that replace high-cost components, such as fetal bovine serum, with lower-cost materials, such as recombinant growth factors, plant hydrolysates, etc.

[0041] The second challenge is the need for regulatory provisions for the new tech food in most countries. This challenge is partially addressed. Singapore Food Agency approved the first cell-cultivated meat product to be sold to the general public in December 2020. The first approval by the US FDA was in June 2023. With the increasing amount of safety data and safe use records, governments of other countries are expected to catch up with the legislation gradually.

[0042] The third challenge is scale-up. Global meat consumption increased by 58% over the 20 years to 2018 to reach 360 million tons per year. Population growth accounted for half of this increase, and per person consumption growth accounted for the remainder, with developing countries accounting for around 85% of the rise in global meat consumption. The production scale of cell- cultivated meat as of 2023 is still too small for cell-cultivated meat to be considered a meaningful solution. The scale-up of cell-cultivated meat production faces the same challenges as similar bioprocesses mentioned above.

[0043] Aspects of the invention aim to eliminate all intermediate manual handling tasks by attempting to automate all tasks by conducting all tasks in a closed system to eliminate the need for a cleanroom. Referring now to FIG. 1 , a diagram of an overall system 100 showing a perpetual bioprocessing system according to one embodiment. In one embodiment, the system 100 may attempt to run or execute the bioprocess perpetually unless contamination or other operational needs trigger the interrupt or pause. In another embodiment, system 100 may attempt to reduce the frequency of Cl P & SIP drastically, reduce reliance on highly skilled labor, reduce CapEx and OpEx of bioprocessdependent manufacturing, including biologicals and cell-cultivated meat,reduce water and energy use to improve the environmental sustainability of bioprocess-dependent manufacturing, increase standardization of bioprocessdependent manufacturing, including biologicals and cell-cultivated meat.

[0044] Referring to FIG. 1 , a diagram of the overall system 100 may show a perpetual bioprocessing system according to one embodiment. In one embodiment, the system 100 may include one or more bioreactors. For example, each of the one or more bioreactors, the system 100 may comprise (i) Software configurations 120 installed in a computer or other device or machine to provide coded instructions for the automatic performance of a series of tasks of the Hardware and (ii) Hardware configurations 122 that includes mechanical devices and apparatuses, such as sensors 102, detectors 104, actuators 106, control valves 108, pumps 110, mixers 112, apparatuses 114, modules 116, and sub-systems 118 or the like. In yet another embodiment, the hardware components 122 may further include apparatuses 114, modules 116 and sub-systems 118 that are part of a group or line of connected and collectively controlled bioreactors. In one embodiment, data network, pipework, or the like are linked, connected to the software configuration 120 and the hardware configuration 122 to work in a coordinated and integrated manner according to the signals of the Software configuration 120. In another embodiment, the software configurations 120 may further be connected to devices shown in FIGS. 5 and 6.

[0045] In another embodiment, referring to FIG. 2, a system 200 may include a set of hardware configurations. In one embodiment, the set of hardware’s boundary of aspects of the invention may start from a Culture Seed Train Input 202 and a Culture Medium Input 204 into a Starting Apparatus (“SA”) 206. After the Starting Apparatus 206, the culture is transferred to culture in subsequent Intermediary Apparatuses (“I A”) 208 of progressively larger size as the culture proliferates and expands in volume. In one embodiment, aspects of the invention provide at least one Intermediary Apparatus 208.

[0046] In one aspect, the bioprocess system's boundary may end with a harvest of a resultant cell culture in the Final Apparatuses (“FA”) 210 and a Harvest Processing System 212 and Spent Medium Waste Removal and Refreshment System 214. In one aspect, the Spent Medium Waste Removal andRefreshment System 214 may further be connected to a drainage system 216, which may be then connected to a wastewater treatment system 218. In one embodiment, aspects of the invention provide at least one Final Apparatus 210. In another embodiment, the Spent Medium Waste Removal and Refreshment System 214 may be further connected to or provide input to a Refreshed Spent Medium Holding and Flow Control System 224 before the output is provided to the culture medium input 204.

[0047] In all cases, aspects of the invention envision at least one Starting Apparatus 206, at least one Intermediary Apparatus 208 and at least one Final Apparatus 210. In another embodiment, the respective number of Intermediary Apparatuses 208 and Final Apparatuses 210 may be more than one and may be configured with any amount depending on the needs.

[0048] In all cases, there will be at least one set of Cleaning-ln-Place (CIP) and Sterilization-ln-Place (SIP) Systems 220 that may be connected in a closed system manner to each and all of the culture apparatuses, such as the starting apparatus 206, intermediary apparatuses 208, and final apparatuses 210. In one embodiment, the connection between the apparatuses may be shut off or paused to allow CIP and SIP to take place for individual apparatus, one or multiple at a time. In another embodiment, all apparatuses may have a discharge module or drainage point to allow the removal of the CIP and SIP agents to a CIP & SIP drain 222.

[0049] In another embodiment, the culture medium input 104 may connect or provide input to IA 208 and FA 210. Further, as shown in FIG. 2, the SA 206 may be connected to or provide input to harvest processing system 212. In yet a further embodiment, the IA 208 may be connected to or provide input to the harvest processing system 212.

[0050] In another embodiment, a city power grid or in-situ alternative energy sources, such as solar energy, may power the CIP and SIP Systems 220 or CIP & SIP drain 222. Aspects of the invention attempt to provide a perpetual automated bioprocessing system to minimize the frequency drastically for CIP and SIP between culture batches as in the case of non-perpetual arrangement in the prior art. In another embodiment, an operator may run the perpetual orcontinuous process indefinitely until the need to pause arises, such as contamination or product change.

[0051] Referring now to FIGS. 3A to 30, block diagrams illustrate various arrangements of components, as shown in FIG. 1 , according to one embodiment. For example, FIGS. 3A to 30 illustrate single-series and multiseries variation arrangements, for example, according to FIG. 3A, in a singleseries arrangement, aspects of the invention may provide a system 330 along with corresponding computerized methods to manage and control a starting apparatus (SA) 302 that may feed into one larger Intermediary Apparatus 304. Depending on the bioprocess programmed or configured, the Intermediary Apparatus 304 may be connected in series to one or more step-up-sized intermediate apparatuses 306 until one Final Apparatus 308. Further, as applicable to FIGS. 3A to 3C, FIGS. 3A to 3C illustrate the white background arrows to indicate the connections are feeds while the black background arrows to indicate the connections are for harvest. Accordingly, the system 330 may employ the software programming to control and monitor the timing, volume or size of the bio-material, starting and ending density thereof, and the changes as it progresses along the bio-reaction.

[0052] Referring to another embodiment where a multi-series arrangement may be provided, as shown in FIG. 3B, the system 332 may incorporate one Starting Apparatus 302, which may feed via an array of one or more Intermediary Apparatuses 310 or 312, ending in multiple Final Apparatuses 314. The apparatuses in different series may be of dissimilar volumes, designs and scale-up ratios depending on the design of the overall system 100. Again, computer software and programming may be used to configure the system 332 in one cohesive and closed system according to aspects of the invention.

[0053] In another embodiment, FIG. 3C illustrates a diagram of yet another arrangement of the overall system according to one embodiment. In this arrangement, after the starting apparatus 302, a small set, such as two, of intermediary apparatus 316-1 and 316-2 before feeding to a set of one more intermediary apparatuses 318. These configurations are controlled by the software or programming processes of aspects of the invention. These feeds may be provisioned to the corresponding final apparatuses 320.

[0054] Referring now to FIG. 4, a further diagram illustrates a process flow according to one embodiment. In one aspect, embodiments of the invention attempt to automate the movement and progression of culture through the apparatuses, the duration of culture in all apparatuses has to be standardized. In another aspect, FIG. 4 is a diagram illustrating a process flow diagram showing time or batch in the x-axis and the flow of cell culture from seed train to harvest from starting to final apparatus in the Y-axis according to one embodiment. In one embodiment, when the culture is moved to the next apparatus as represented by the thin arrows, such as an arrow 460, the seed train for the next batch may be ready to be fed into the current apparatus. In another example, the white background block arrows, such as an arrow 462. In another embodiment, the culture in one batch can remain in the Apparatus to become part of the next batch, as represented by the thick dark arrows, such as an arrow 464. Aspects of the invention may provide a perpetual loop and are calculated by the Software configuration and method in FIG. 1 that contains the pre-set relationship between various parameters. Moreover, in one embodiment, FIG. 4 uses rectangular blocks to represent the cell culture inside the respective containers as they move along the flow in apparatuses.

[0055] For example, according to FIG. 4, the left margin provides notations of each level as presented in FIG. 4. For example, at a first level, it is noted as “Culture Seed Train Input”. At a second level, “SA” is noted for starting apparatus. At a third level, “IA” is noted for intermediary apparatus. At a fourth level, “FA” is noted for final apparatus. At a fifth level, “Harvest Processing System”. These notations apply to elements in the horizontal direction and each level is separated by broken lines. It is to be understood that these separations are used as illustration purposes and not as a limitation to the scope of the invention.

[0056] In one aspect, a first culture input 402 may be provided to a Batch 1 404 to the starting apparatus, such as the starting apparatus 206. In one example, a culture seed train input 402 may be the point of feeding the starting culture into the Starting Apparatus. In another embodiment, the Culture Seed Train Input may be of different designs. For example, it may be a localized small space with indoor air quality control systems to keep the particulates in the air,like inside a biosafety cabinet or a cleanroom. In another embodiment, it may be a purpose-made module that serves as a sterile connector to feed the starting culture, which can produced off-site, in a sealed sterile container into the Starting Apparatus in a closed system manner without exposing the starting culture to air outside the sterile starting culture container and the Starting Apparatus.

[0057] In another embodiment, the Culture Medium Input, such as Batch 1 406, may be the point of feeding the culture medium per the specifications necessary to support the culture. For example, the Batch 1 404 may be transitioned to Batch 1 406 where the culture medium input may be turned into input culture materials, either by a purpose-made module or multi-module sub-system. In another example, various culture formula components in powder or liquid form, into a combined liquid culture medium suitable for the bioprocess. In another embodiment, it may encompass weighing, mixing, dissolving components in water, solvent or buffer, filtering, sterilizing, warming or cooling, or other steps necessary to prepare the culture medium to a specification required for the culture. Moreover, in addition to the purpose-made module, the Culture Medium Input may also be a localized small space with indoor air quality control systems to keep the particulates in the air at a level as per the specification of the culture process. In another example, the Culture Medium Input may incorporate a controlled flow rate and amount of medium from the Refreshed Spent Medium Holding and Control System (224).

[0058] In one aspect, the Final Apparatus (e.g., final apparatus 210) may be the last step of the bioprocess. For example, Batch 1 406 may be transitioned to Batch 1 408 for the processing by the Final apparatus for harvest 410. In another embodiment, the final apparatus may be an apparatus of different design from the Starting and Intermediary Apparatuses. For example, the final apparatus may be where the culture proliferates to the final largest volume before harvesting. In another example, the final apparatus may be where the culture undergoes differentiation and maturation. In yet another example, the final apparatus may be where the culture interacts with other materials, for example, scaffold materials for cells to attach to for tissue culturing. As such,it is to be understood that the final apparatus may be deemed “final” with respect to the bioprocessing but not in terms of the final product in certain aspects.

[0059] The Harvest Processing System (212) is where the resulting cell culture from the Final Apparatus is processed into solid and liquid phases. The Harvest Processing System (212) may be either appended after or run simultaneously with the Final Apparatus. It may be a group of purpose-made modules that processes the culture in the Final Apparatus into the end product of the bioprocess. For example, the bioprocess may involve separating the solid and liquid phases of the final culture, cleaning, isolation or purification of the end product. The end product may be the solid or liquid phase of the culture. For example, the end product may be in the spent medium in biological production. The Harvest Processing System may involve a centrifuge to separate the cell, bacteria or yeast from the spent medium and then a set of chromatography columns to isolate and purify the molecules of interest. In the production of cell- cultivated meat, the end product may be the solid phase. The Harvest Processing System may involve a centrifuge to separate the cells or cultured tissues from the spent medium and a sub-system to rinse the cells or cultured tissues with water or food-grade solution. There are three types of waste: spent biomass (e.g. in the case of biological production), spent medium (e.g. in the case of cell-cultivated meat production), and discarded cleaning agents (e.g. water, saline). In another embodiment, the scope of the Harvest Processing System may connect to a Spent Medium Waste Removal and Refreshment System (214) or any purpose-made modules to recycle, upcycle, or re-condition any liquid waste for circular use within the system 100 of the aspects of the invention, as well as any purpose-made modules to pre-treat any waste before disposal. Besides purpose-made modules, the Harvest Processing System and the Spent Medium Waste Removal and Refreshment System may also be a localized small space with indoor air quality control systems to keep the particulates in the air at a level as per the specification of the end product. For cell-cultivated meat production, for example, cleanroom condition is not required beyond the Final Apparatus; the indoor air condition for the Harvest Processing System and the Spent Medium Waste Removal and Refreshment System may be the same as that of a food factory.

[0060] Furthermore, referring to FIG. 4Further, embodiments of the invention are not limited by the illustrations in FIG. 4. For example, a second culture input 412 may be provided as an input to Batch 2 414, which may be deemed an input for the intermediary apparatus in the next bioprocess as Batch 2 416. In a similar lock-step process, the Batch 2 418 may be an input to the final apparatus for the harvest 420. Moreover, a Batch 3 culture input 422, a Batch 4 culture input 432, a Batch N culture input 442 and Batch N+1 culture input 452 may follow previous description above that will provide subsequent input to subsequent processes.

[0061] For example, the Batch 3 culture input 422 may be provided as an input to Batch 3 424, which may be deemed an input for the intermediary apparatus in the next bioprocess as Batch 3426. In a similar lock-step process, the Batch 3 428 may be an input to the final apparatus for the harvest 430.

[0062] In another embodiment, the Batch 4 culture input 432 may be provided as an input to Batch 4434, which may be deemed an input for the intermediary apparatus in the next bioprocess as Batch 4436. In a similar lock-step process, the Batch 3 438 may be an input to the final apparatus for the harvest 440.

[0063] In another embodiment, the Batch N culture input 442 may be provided as an input to Batch N 444, which may be deemed an input for the intermediary apparatus in the next bioprocess as Batch N 446. In a similar lock-step process, the Batch 4 438 may be an input to the final apparatus for a harvest.

[0064] In another embodiment, the Batch N+1 culture input 452 may be provided as an input to Batch N+1 454, which may be deemed an input for the intermediary apparatus in the next bioprocess as a Batch N+1. In a similar lockstep process, the Batch 4 446 may be an input to the final apparatus for a harvest.

[0065] As such, aspects of the invention may configure a perpetual loop or a lock-step stage arrangement for a given bioprocessing production. In another embodiment, aspects of the invention provide software and hardware-software interfaces to execute the bioprocessing production. Referring back to FIG. 1 , the Software may operate on the Supervisory Control and Data Acquisition (SCADA) level of a plant operation. For example, it may be installed in a computer, machine or device, such as a Programmable Logic Controller (PLC).Sensors, detectors, and other devices on the hardware measure parameters of the bioprocess, such as speed, temperature, pH, cell density, flow rate, pressure, etc., may further be standardized. In one example, these raw data are sent to the PLC for processing by the Software. Based on the analysis of the Software, a set of actions is deduced, executed or performed. The recommended action may be implemented automatically without human intervention via PLC that sends signals to the hardware, such as actuators, pumps, valves, etc. The recommended action may also be presented via a Human Machine Interface (HMI) device for human operators to make decisions, on-site or off-site, as required. Sensors, detectors, and other devices on the hardware conduct real-time measurements of parameters and perpetually feed raw data to the Software via PLC for non-stop loops of processing, analyzing and action recommendations. In another embodiment, the Software may be web-based or client-based. In the case of web-based Software, real-time data collection and analysis can be viewed off-site. This may allow companies with multiple production sites to monitor and compare data of all sites at any time. In the case of device-based Software, the local device can be connected to the internet to allow real-time access to the data and analysis off-site.

[0066] In one example, aspects of the invention provide one or more input parameters for the software and the overall system 100:

[0067] In some aspects, Table 2 below further illustrates the relationship between parameters:

[0068] Table 3 provides further information of the process

[0069] It is understood that other parameters or relationships among the parameters may be available without departing from the scope or motivation of the invention.

[0070] In one aspect, the computerized system or software system 120 may include default or user-configurable placeholders for parameters and user- configurable or pre-set relationships among the parameters.

[0071] In one aspect, there may be four stages of usage of the Software system 120: 1. Process Setup; 2. Equipment Setup; 3. Controlled Production, 4. Production Data Collection and Analysis.

[0072] As an overview, the system 120 may enable the operator or the user to enter information to automate the process. In another embodiment, these stages may be configured as components with manageable computing units for organization and processing. For example, at the first stage, when the operatorknows a growth pattern of the cell culture in a R&D lab, the operator may use the software and the system 120 to calculate the size of the bioreactors the operator may need to build to project the time for each batch (thus annual output) etc.

[0073] In another embodiment, at the 2. Equipment Setup stage, the operator may then proceed to build the bioreactors of sizes (e.g., 10L, 500L, 3000L) that may cover the range of output the operator may want to achieve for that particular factory production line.

[0074] At Step 3 (controlled production), when the operator may be at the factory with the bioreactors set up, the operator may change those flexible parameters via the system 120 to adjust the input cell mass, the standardized duration of the cell culture in each tank, the projected output, or the like.

[0075] At Step 4 (production data collection and analysis), the system 120 may collect the actual date, (e.g., the actual time to double will vary from batch to batch and there will be pattern or trend based on the change of medium formula, pH, temperature etc., so that the operator may know the drivers for different cell culture behavior.

[0076] In one further embodiment, the Software system 120 may contain a set of calculations that define default or pre-existing relationships among the parameters. These parameters may be dictated or determined by the bioprocessing, the bio-materials needed or other conditions to provide other info about the process for management review at different stages.

[0077] In one embodiment, FIG. 7 may illustrate a flow diagram showing the process of the software system 120 according to one embodiment. For example, the user or human operator may interact with the software system 120 in operating the software system 120.

[0078] In one embodiment, the software system 120 may include a user interface or a graphical user interface (GUI) to receive input or instructions from the user at 702. In one aspect, as discussed before FIGS. 5 and 6 may be computerized devices that are connected to the system 120 so that the system 120 may work with the devices illustrated in FIGS. 5 and 6.

[0079] In one embodiment, the user may enter values for "Input", "Input & Adjust", and "Variables to Solve" in Table 4.

[0080] At 704, once the input is received, the software system 120 may output a process plan or an execution plan utilizing the software system 120. For example, Table 5 may include an exemplary set of information on a process plan, where values as a result of the calculation of parameters may be provided.

[0081] After the output of the process plan, the software system 120 may receive a confirmation instruction from the user to place the values to corresponding calculations or algorithms for the calculations.

[0082] In another aspect, at 706, in response to the user instruction or confirmation, the software system 120 may evaluate or check whether ALL operating criteria are fulfilled and return status "OK" (if yes) or "Review Required" (if no).

[0083] For example, Table 6 provide the checks for the parameters and the basis of the evaluations:

[0084] In one aspect, if the status returned from the software system 120 is “OK,” the software system 120 may begin the execution of the processing plan at 708. However, if the status returned as “Review Required,” at step 4, the software system 120 may simulate "Variables to Solve" combinations that fulfil all criteria at 710.

[0085] In another embodiment, the software system 120 may adjust the "Variables to Solve" at 710 and returns "Process Plan" at 704.

[0086] In yet another embodiment, the software system 120 may, at 710, simulate suggestions of "Variables to Solve" and "Input & Adjust" combinations that fulfil all criteria. In this embodiment, the software system 120 may promptthe human operator to decide on the recommended "Input & Adjust' combinations.

[0087] In another embodiment, the software system 120 may highlight or identify the parameters when the status returns as “Review Required,” so that the user may be able to focus on these parameters to facilitate the review. In one embodiment, the software system 120 may employ machine learning mechanisms to assist the evaluation process.

[0088] As discussed above, the software system 120 may provide the GUI for the user to provide instructions to decide the execution of the process plan as part of the process at 710.

[0089] It is to be understood that the software system 120 may repeat 704, 706 and 710 until the process plan status returns “OK” to 708.

[0090] Once the status of the process plan is the “OK” or ready state, the software system 120 may conduct equipment checks or evaluations or configure hardware equipment at 712. For example, the user or human operator may configure the integrated System, including Hardware, PLC, HMI, SCADA, and Software. In this process, the user may also get the hardware systems and parts (e.g., those equipment identified as part 122 in FIG. 1) ready, activated, or energized. In another embodiment, the Culture Seed Train Input Module and the Culture Medium Input Module may be configured. In another embodiment, the required Input Cell Mass for Batch 1 into the Culture Seed Train Input Module may be prepared. Further, the Culture Medium Input Module for a perpetual supply of the required volume of the medium may also be prepared and configured.

[0091] At 714, the user or the Human operator may press the "Start" button or may initiate or cause the software system 120 to execute the system 100 for Batch 1. In response, the software system 120 may transmit or send a first signal to control the Hardware to start culturing.

[0092] In one example, at 714, the sensors and detectors in Hardware may measure and collect Fundamental Culture Data, e.g. cell viability, density, temperature, pH, dissolved oxygen, waste level, etc. In another embodiment, the sensors and detectors in Hardware may further measure and collect all data required for the Monitoring Parameters.

[0093] In another embodiment, the software system 120 may analyze the data and check whether the ending condition in the Apparatus as per the Process Plan is reached. Once the ending condition is reached, the software system 120 may send a second signal to actuate hardware to move culture from the current Apparatus to the next.

[0094] In another embodiment, the software system 120 may further trigger the Culture Medium Input Module to fill the next Apparatus to the volume required.

[0095] At 716, the software system 120 may send a third signal to Hardware to trigger or commence the Culture Seed Train Input Module and the Culture Medium Input Module for Batch 2.

[0096] In another embodiment, the software system 120 may, at a preconfigured amount of time before the end of the previous Batch, subsequent signals to the user or human operator to prepare for Batch 2. In this embodiment, the user or human operator may prepare and input the required Input Cell Mass for Batch 2 into the Culture Seed Train Input Module. In this process, the user or human operator may configure or check the setup of the Culture Medium Input Module for a perpetual supply of the required volume of the medium.

[0097] At 718, the software system 120 may repeat the above, depending on the process plan, for the Intermediary Apparatus for Batch 1.

[0098] At 718, the software system 120 may repeat the above, depending on the process plan, for the Starting Apparatus for Batch 2.

[0099] Further, per the process plan, the software system 120 may trigger a similar process, depending on the process plan, at 714 to 718, which may eventually lead to the final apparatus for Batch 1

[0100] At 722, the software system 120 may send signals to Hardware to trigger the Harvest Processing System for harvest of Batch 1. Further at 724, the software system 120 may send signals to Hardware to trigger the Harvest Processing System for harvest of Batch 2.

[0101] In one embodiment, the software system 120 may further trigger Batch 2, Batch 3, to Batch N and Batch N+1 to the Starting Apparatus, the Intermediary Apparatus, the Final Apparatus, and the Harvest ProcessingSystem for harvest. In essence, the software system 120 may enable the hardware 122 to conduct in a loop.

[0102] FIG. 5 may be a high-level illustration of a portable computing device 801 communicating with a remote computing device 841 but the application may be stored and accessed in a variety of ways. In addition, the application may be obtained in a variety of ways such as from an app store, from a website, from a store Wi-Fi system, etc. There may be various versions of the application to take advantage of the benefits of different computing devices, different languages and different API platforms.

[0103] In one embodiment, a portable computing device 801 may be a mobile device that operates using a portable power source 855 such as a battery. The portable computing device 801 may also have a display 802 which may or may not be a touch sensitive display. More specifically, the display 802 may have a capacitance sensor, for example, that may be used to provide input data to the portable computing device 801. In other embodiments, an input pad 804 such as arrows, scroll wheels, keyboards, etc., may be used to provide inputs to the portable computing device 801. In addition, the portable computing device 801 may have a microphone 806 which may accept and store verbal data, a camera 808 to accept images and a speaker 810 to communicate sounds.

[0104] The portable computing device 801 may be able to communicate with a computing device 841 or a plurality of computing devices 841 that make up a cloud of computing devices 811. The portable computing device 801 may be able to communicate in a variety of ways. In some embodiments, the communication may be wired such as through an Ethernet cable, a USB cable or RJ6 cable. In other embodiments, the communication may be wireless such as through Wi-Fi (802.11 standard), Bluetooth, cellular communication or near field communication devices. The communication may be direct to the computing device 841 or may be through a communication network such as cellular service, through the Internet, through a private network, through Bluetooth, etc. FIG. 6 may be a simplified illustration of the physical elements that make up a portable computing device 801 and FIG. 5 may be a simplified illustration of the physical elements that make up a server type computing device 841 .

[0105] FIG. 5 may be a sample portable computing device 801 that is physically configured according to be part of the system. The portable computing device 801 may have a processor 850 that is physically configured according to computer executable instructions. It may have a portable power supply 855 such as a battery which may be rechargeable. It may also have a sound and video module 860 which assists in displaying video and sound and may turn off when not in use to conserve power and battery life. The portable computing device 801 may also have volatile memory 865 and non-volatile memory 870. It may have GPS capabilities 880 that may be a separate circuit or may be part of the processor 850. There also may be an input / output bus 875 that shuttles data to and from the various user input devices such as the microphone 806, the camera 808 and other inputs, such as the input pad 804, the display 802, the speakers 810, and the sensors 811 etc. It also may control of communicating with the networks, either through wireless or wired devices. Of course, this is just one embodiment of the portable computing device 801 and the number and types of portable computing devices 801 is limited only by the imagination.

[0106] As a result of the system, better information about the actual bioprocess may be provided to a user at a point of sale. The information may be user specific and may be required to be over a threshold of relevance. As a result, users may make better informed decisions. The system is more than just speeding a process but uses a computing system to achieve a better outcome.

[0107] The physical elements that make up the remote computing device 841 may be further illustrated in FIG. 6. At a high level, the computing device 841 may include digital storage such as a magnetic disk, an optical disk, flash storage, non-volatile storage, etc. Structured data may be stored in the digital storage such as in a database. The server 841 may have a processor 1000 that is physically configured according to computer executable instructions. It may also have a sound and video module 1005 which assists in displaying video and sound and may turn off when not in use to conserve power and battery life. The server 841 may also have volatile memory 1010 and non-volatile memory 1015.

[0108] The database 1025 may be stored in the memory 1010 or 1015 or may be separate. The database 1025 may also be part of a cloud of computing device 841 and may be stored in a distributed manner across a plurality of computing devices 841. There also may be an input / output bus 1020 that shuttles data to and from the various user input devices such as the microphone 806, the camera 808, the inputs such as the input pad 804, the display 802, and the speakers 810, sensors 811 , etc. The input / output bus 1020 also may control of communicating with the networks, either through wireless or wired devices. In some embodiments, the application may be on the local computing device 801 and in other embodiments, the application may be remote 841. Of course, this is just one embodiment of the server 841 and the number and types of portable computing devices 841 is limited only by the imagination.

[0109] The claimed system and method may address several technical problems and challenges, some of which are described. In one aspect, embodiments of the invention reduce a new insurance product configuration and testing time and IT development dramatically while allowing insurance professionals to intuitively configure digitized insurance products without computer programming. Aspects of the invention provide tools that enable insurance providers to build more competitive insurance products with intuitive feedback from claims experience with short conception-to-market turnaround time. Furthermore, aspects of the invention further provide instant processing of claims while reducing fraud, waste and abuse.

[0110] The user devices, computers and servers described herein may be general purpose computers that may have, among other elements, a microprocessor (such as from the Intel Corporation, AMD or Motorola); volatile and non-volatile memory; one or more mass storage devices (i.e., a hard drive); various user input devices, such as a mouse, a keyboard, or a microphone; and a video display system. The user devices, computers and servers described herein may be running on any one of many operating systems including, but not limited to WINDOWS, UNIX, LINUX, MAC OS, or Windows (XP, VISTA, etc.). It is contemplated, however, that any suitable operating system may be used for the present invention. The servers may be a cluster of web servers, which may each be LINUX based and supported by a load balancer thatdecides which of the cluster of web servers should process a request based upon the current request-load of the available server(s).

[0111] The user devices, computers and servers described herein may communicate via networks, including the Internet, WAN, LAN, Wi-Fi, other computer networks (now known or invented in the future), and / or any combination of the foregoing. It should be understood by those of ordinary skill in the art having the present specification, drawings, and claims before them that networks may connect the various components over any combination of wired and wireless conduits, including copper, fiber optic, microwaves, and other forms of radio frequency, electrical and / or optical communication techniques. It should also be understood that any network may be connected to any other network in a different manner. The interconnections between computers and servers in system are examples. Any device described herein may communicate with any other device via one or more networks.

[0112] In one embodiment, the remote computing device 841 and the portable computing device 801 may execute the exemplary flow illustrated in FIG. 4.

[0113] The example embodiments may include additional devices and networks beyond those shown. Further, the functionality described as being performed by one device may be distributed and performed by two or more devices. Multiple devices may also be combined into a single device, which may perform the functionality of the combined devices.

[0114] The various participants and elements described herein may operate one or more computer apparatuses to facilitate the functions described herein. Any of the elements in the above-described Figures, including any servers, user devices, or databases, may use any suitable number of subsystems to facilitate the functions described herein.

[0115] Any of the software components or functions described in this application, may be implemented as software code or computer readable instructions that may be executed by at least one processor using any suitable computer language such as, for example, Java, C++, Phython or Perl using, for example, conventional or object-oriented techniques.

[0116] The software code may be stored as a series of instructions or commands on a non-transitory computer readable medium, such as a randomaccess 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.

[0117] It may be understood that the present invention as described above may 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 may know and appreciate other ways and / or methods to implement the present invention using hardware, software, or a combination of hardware and software.

[0118] The above description is illustrative and is not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of the disclosure. The scope of the invention should, therefore, be determined not with reference to the above description but instead should be determined with reference to the pending claims along with their full scope or equivalents.

[0119] One or more features from any embodiment may be combined with one or more features of any other embodiment without departing from the scope of the invention. A recitation of "a", "an" or "the" is intended to mean "one or more" unless specifically indicated to the contrary. Recitation of "and / or" is intended to represent the most inclusive sense of the term unless specifically indicated to the contrary.

[0120] One or more of the elements of the present system may be claimed as means for accomplishing a particular function. Where such means-plus- function elements are used to describe certain elements of a claimed system it will be understood by those of ordinary skill in the art having the present specification, figures and claims before them, that the corresponding structure is a general purpose computer, processor, or microprocessor (as the case may be) programmed to perform the particularly recited function using functionality found in any general purpose computer without special programming and / or by implementing one or more algorithms to achieve the recited functionality. As would be understood by those of ordinary skill in the art that algorithm may be expressed within this disclosure as a mathematical formula, a flow chart, anarrative, and / or in any other manner that provides sufficient structure for those of ordinary skill in the art to implement the recited process and its equivalents.

[0121] While the present disclosure may be embodied in many different forms, the drawings and discussion are presented with the understanding that the present disclosure is an exemplification of the principles of one or more inventions and is not intended to limit any one of the inventions to the embodiments illustrated.

[0122] The present disclosure provides a solution to the long-felt need described above. Further advantages and modifications of the abovedescribed system and method will readily occur to those skilled in the art. The disclosure, in its broader aspects, is therefore not limited to the specific details, representative system and methods, and illustrative examples shown and described above. Various modifications and variations can be made to the above specification without departing from the scope or spirit of the present disclosure, and it is intended that the present disclosure covers all such modifications and variations provided they come within the scope of the following claims and their equivalents.

Claims

CLAIMSWhat is claimed is:

1. A computerized system for a perpetual automated bioprocessing production comprising: receiving from a user information relating to cell culture, apparatuses, or parameters relevant to the bioprocessing production via a user interface; defining, via a processor, a set of relationships among parameters for the bioprocessing production; in response to the received user information, determining a process plan by the processor; in response to the received user information, calculating combinations of variable parameters that standardize a duration of the cell culture in the apparatuses from a regular batch onwards to achieve just-in-time lock-step cell culture flow from a starting apparatus to one or more final apparatuses; outputting, via the user interface, the process plan to the user for further confirmation instructions; evaluating, by the processor, all parameters associated with the process plan; energizing, via the processor, a series of hardware components as a function of the evaluated process plan; and in response to an initiation instruction from the user received via the user interface, sending signals to the series of hardware components for execution of the process plan.

2. The computerized system of claim 1 , further comprising determining, by the processor, a set of user-configurable inputs, a set of user non-configurable inputs, and a set of flexible parameters.

3. The computerized system of claim 1 , wherein the bioprocessing production comprises a cell-cultivated meat production.

4. The computerized system of claim 1 , further comprising defining, via the processor, one or more intermediary apparatuses positioned between the starting apparatus, and one or more final apparatuses, wherein the starting apparatus, the one or moreintermediary apparatuses, and the one or more final apparatuses comprise at least one bioreactor.

5. The computerized system of claim 4, wherein the processor is further configured to re-arrange the one or more intermediary apparatuses and the one or more final apparatuses as a function of the evaluated process plan.

6. The computerized system of claim 5, wherein the processor is further configured to dynamically determine a number of the one or more intermediary apparatuses as a function of the evaluated process plan.

7. The computerized system of claim 6, wherein the processor is further configured to dynamically determine a number of the one or more final apparatuses as a function of the evaluated process plan.

8. The computerized system of claim 4, wherein the processor is configured to define and execute the starting apparatus, the one or more intermediary apparatuses, and the one or more final apparatuses for a first batch of bio-materials for the bioprocessing production as a result of the process plan.

9. The computerized system of claim 8, wherein the processor is further configured to define a second set of starting apparatus, a second set of one or more intermediary apparatuses, and a second set of one or more final apparatuses for a second batch of bio-materials for the bioprocessing production concurrently as the result of the process plan.

10. The computerized system of claim 8, wherein the processor is further configured to execute the second set of one or more intermediary apparatuses, and the second set of one or more final apparatuses for the second batch of bio-materials for the bioprocessing production concurrently as the result of the process plan.

11. The computerized system of claim 4, wherein the processor is configured to execute the starting apparatus, the one or more intermediary apparatuses, and theone or more final apparatuses for one or more batches of bio-materials concurrently in a lock-step arrangement as a result of the process plan.

12. The computerized system of claim 1 , wherein the user information may include user instructions containing with a formula to calculate the combination of adjustable parameters to achieve same duration at the at all bioreactors.

13. The computerized system of claim 12, wherein the user instructions comprise a spreadsheet.

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