Systems, devices, and methods for scheduling workflow for automated cell therapy manufacturing

Abstract

Described herein are systems, devices, and methods for high-throughput manufacturing of cellular products for biomedical applications using an automated system that executes parallel workflows. A method for scheduling cell processing cartridges for loading into a cell processing system may include determining a system configuration, determining a configuration for each of a plurality of cell processing cartridges in the system, and providing a loading schedule for loading a first cartridge of the plurality of cartridges into the system. A method for monitoring contention in a cell processing system that processes multiple cell samples in parallel may include loading the multiple cell samples into the system and determining contention for each of a plurality of processing instruments before and after processing operations are performed by the system. Contention may be based on the number of cell samples requiring an instrument during a period of time.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 438,925, filed January 13, 2023, which is incorporated herein by reference in its entirety for all purposes.

[0002] The devices, systems, and methods herein relate to high-throughput manufacturing of cellular products for biomedical applications using automated systems that execute parallel workflows. [Background technology]

[0003] Cell processing generally involves collecting and manufacturing cells for therapeutic use. For example, cell products can be used to achieve clinical responses in patients. Existing processing systems may define multi-step workflows that combine automated cell processing system equipment with tedious manual procedures performed in expensive biosafety cabinets and / or clean rooms. Furthermore, conventional systems can only operate with a single cell processing unit (e.g., a system configured to interface with a single cartridge carrying a single cell sample), resulting in low throughput. In contrast, automated (e.g., fully automated) multi-cartridge cell processing systems may require little or no operator interaction and may offer additional benefits such as reduced overhead, high-throughput manufacturing, end-to-end process flexibility, process robustness, and process scalability.

[0004] However, multi-cartridge systems can also experience contention within automated cell therapy systems due to overlapping requirements for system resources, leading to workflow delays or restarts. Excessive delays due to contention between critical parts of the workflow can result in unacceptable process outcomes that jeopardize sample viability and therefore patient treatment (e.g., timing of treatment, cost of treatment, etc.).

[0005] To optimize the high-throughput potential of multi-cartridge systems, it is important to manage and reduce contention within these systems. For example, tools for scheduling consumable cartridges into an automated cell manufacturing system and continuously monitoring the system and resource requirements of each cartridge being processed can ensure that patient samples are not adversely affected by contention issues resulting from parallel processing. Therefore, novel methods for managing and reducing contention within multi-cartridge automated cell processing systems may be desirable. Summary of the Invention

[0006] Described herein are systems, devices, and methods useful for cell processing, including high-throughput manufacturing of cellular products for biomedical applications using automated systems that execute parallel workflows.

[0007] A method for cell processing may first include determining a system configuration of a cell processing system configured to process multiple cartridges in parallel. Each of the multiple cartridges may be configured to carry a cell sample and be loaded into a work cell of the cell processing system. Next, the method may include determining a cartridge configuration for each of the multiple cartridges and providing a loading schedule for loading a first cartridge of the multiple cartridges into the work cell. The loading schedule may be based on the system configuration and the cartridge configuration for each of the multiple cartridges. The loading schedule may indicate one or more time periods when the first cartridge is not available for loading into the work cell. Additionally, the method may further include loading the first cartridge into the work cell based on the loading schedule. In some variations, the loading schedule may be provided via a user interface of the cell processing system. Determining the cartridge configuration may include padding data of the cartridge configuration to compensate for one or both of workflow process variability and cartridge loading variability. Furthermore, the method may include determining an amount of conflict within the cell processing system, and the loading schedule may be further based on the determined amount of conflict.

[0008] The system configuration may define the quantity of one or more subsystems of the cell processing system that may be contained within a work cell of the cell processing system. In some variations, the one or more subsystems may include one or more of a material handling system, a sterile liquid transfer system, a sterility system, a bioprocessing system, and a quality control system. In some variations, the system configuration may further define operating time constraints for at least one of one or more of the subsystems of the cell processing system.

[0009] The cartridge configuration may include one or both of a loading configuration and a workflow configuration. The loading configuration may include a length of time for loading the cartridge into the work cell. Further, the workflow configuration may include a simulated cell processing workflow for the cartridge, the simulated cell processing workflow being based on a process design plan for the cartridge and one or more sample intake parameters for the cartridge. The one or more sample intake parameters may include one or more of a sample cell type, a sample collection time, a sample transport time, a sample arrival time at a processing facility, a sample temperature, a patient age, a patient gender, a donor age, and a donor gender.

[0010] Further, in some variations, the plurality of cell processing cartridges may include at least one second cartridge, and the first cartridge may not be scheduled for processing in the cell processing system, and the at least one second cartridge may be scheduled for processing in the cell processing system. The method may further include scheduling the first cartridge for processing in the cell processing system based on the loading schedule.

[0011] Another method for cell processing may include initially loading multiple cell samples into a cell processing system for parallel processing, where the cell processing system may include multiple processing instruments. Next, the method may include determining an amount of contention for each of the multiple instruments before and after each of the multiple cell processing operations is performed by the cell processing system. The amount of contention may be based on the number of cell samples requiring the instrument during a time period. Finally, the method may include generating a notification, via a user interface of the cell processing system, indicating excessive contention if the number of cell samples requiring the instrument during the time period is greater than two. In some variations, the method may further include identifying prioritized cell samples for instrument use based on the instrument contention weight determined for each cell sample requiring the instrument during the time period, where the prioritized cell sample may have the highest instrument contention weight. For each cell sample, the instrument contention weight may be based on the current cell processing operation dwell time and the subsequent cell processing operation execution time. [Brief explanation of the drawings]

[0012] [Figure 1A] FIG. 1 is a block diagram of an exemplary variation of a cell processing system. [Figure 1B] FIG. 1B is a block diagram of an exemplary variation of a cartridge that may be used with the cell processing system of FIG. 1A. [Figure 1C] 1 shows a perspective view of an exemplary variation of a cell processing system. [Figure 1D] 1 shows a cross-sectional view of an exemplary variation of a work cell that may be used with the cell processing systems herein. [Figure 2] 1 is a flow chart illustrating two exemplary procedures for resolving conflicts in a cell processing system. [Figure 3] 1 is a flow chart illustrating an exemplary variation of a method for cell processing. [Figure 4] 1 is a flow chart illustrating an exemplary variation of another method for cell processing. [Figure 5]1 illustrates an exemplary variation of a cell processing workflow simulated by a cell processing system. [Figure 6A] 10 is an exemplary variation of a loading schedule for a cell processing cartridge provided by a cell processing system. [Figure 6B] 10 is an exemplary variation of a loading schedule for a cell processing cartridge provided by a cell processing system. [Figure 7A] 10 is an exemplary variation of a loading schedule for a cell processing cartridge provided by a cell processing system. [Figure 7B] 10 is an exemplary variation of a loading schedule for a cell processing cartridge provided by a cell processing system. DETAILED DESCRIPTION OF THE INVENTION

[0013] definition As used herein, sterility should be understood as a non-limiting description of several variations, optional features that provide advantages in the operation of certain systems and methods of the present disclosure. Maintaining sterility is typically desirable for cell processing, but may be achieved in a variety of ways, including, but not limited to, providing sterile reagents, media, cells, and other solutions, sterilizing the cartridge and / or cartridge components after loading (protecting the cellular product from destruction), and / or operating the system in a sterile enclosure, environment, building, room, etc. Such user- or system-performed sterilization steps may sterilize the cartridge or cartridge components and / or maintain the sterility of the cartridge or cartridge components.

[0014] As used in this disclosure, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. As used herein, "and" is used interchangeably with "or" unless expressly stated otherwise.

[0015] Throughout this application, the term "about" is used to indicate that a value includes the inherent variation of error for the device or method employed to determine the value, or the variation that exists between samples measured. Unless otherwise stated or clear from the context, the term "about" means within 10% above or below the reported numerical value (except where such numerical value would be greater than 100% or less than 0% of the possible values). When used in conjunction with a range or series of values, the term "about" applies to the endpoints of the range or each of the values ​​recited in the series of ranges, unless otherwise indicated. As used herein, the terms "about" and "approximately" are used interchangeably.

[0016] Unless the context clearly dictates otherwise, throughout this specification and the claims, words like "comprise," "comprising," and the like are to be construed in an inclusive sense, as opposed to an exclusive or exhaustive sense; that is, meaning "including, but not limited to." Words using the singular or plural also include the plural and singular, respectively. Furthermore, the words "herein," "above," "below," and words of similar import, when used in this application, refer to this application as a whole and not to any particular portions of this application.

[0017] Parallel processing of cartridges containing cell samples within a cell processing system may cause internal conflicts within the system due to resource contention (e.g., for reagents, components, and / or functions of the cell processing system). This conflict may cause one or more of the cartridges to delay or even restart the cell processing workflow, which may jeopardize sample viability and therefore patient treatment (e.g., treatment timing, treatment costs, etc.). Thus, as described herein, scheduling cartridges for parallel processing and resolving system conflicts due to parallel processing in real time may enable a multi-cartridge processing system to maintain high throughput without jeopardizing sample quality.

[0018] Scheduling multiple cartridges for processing can present challenges. For example, in some variations, scheduling may be based on allowing random access cartridge loading into the system cartridge. However, allowing random loading of cartridges can result in random, high-contention situations downstream of processing, which can jeopardize the viability of patient samples. As another example, cartridge processing scheduling based solely on conflict prevention without compensation for process deviations and / or loading variability can result in higher overall process variability and, therefore, longer time periods during which cartridges cannot be loaded into the cell processing system. Thus, scheduling the processing of multiple cartridges in an automated cell processing system can be difficult and can require a combination of inputs, conflict calculations, and feedback control to ensure that cartridges can be added to the system without inducing significant conflicts.

[0019] Thus, the present disclosure provides a "scheduler" application or tool that can be configured to schedule cartridge loading (e.g., asynchronous loading) into an automated cell processing system using a combination of inputs, contention calculations, and feedback control, and that can be used in conjunction with the automated cell processing system to minimize the risk of cell samples being adversely affected by parallel processing contention issues. Further modifications, features, and advantages of the present invention will become apparent from the following detailed description, and through the practice of the invention.

[0020] 1. Cell Processing System The cell processing systems herein may be fully integrated and configured to autonomously perform every step of the cell processing workflow.

[0021] The cell processing systems described herein may be configured to perform one or more cell processing steps within a work cell. The work cell may include a closed, automated environment that may be configured to maintain a sterile environment. The work cell may receive a cartridge therein and perform one or more cell processing steps on cells in a cell solution (e.g., a cell suspension) contained within the cartridge. For example, a cell processing system may include a work cell having multiple subsystems (each comprised of one or more instruments or components), each of which may be configured to independently perform one or more cell processing steps on cells and / or cell solutions, and a robot capable of moving cartridges within the work cell (e.g., between one or more bays configured to receive cartridges). The robot and / or other instruments may be configured to operate automatically, such that operator assistance may not be required at any point during the workflow. For example, a robot may receive a cartridge and move the cartridge between locations (e.g., instruments, bays, storage, feed-throughs) within the work cell according to a preprogrammed workflow, each location may be associated with one or more cell processing steps. After performing one or more cell processing steps of a pre-programmed workflow, the work cell may be configured to transfer the cartridge from the work cell (e.g., via a robot). Additionally or alternatively, at least a portion of the cell solution may be transferred to a second cartridge (e.g., via a fluidic device or fluid manifold).

[0022] The cell solutions (e.g., cell suspensions, cell samples) described herein may contain cells that can be processed for subsequent use in cell therapy. Cell solutions may include cells (e.g., allogeneic cells) in a fluid such as a medium (e.g., cell culture medium). Cell solutions may include cells from the same or different donors. Cells from the same donor may be divided among one or more cartridges so that separate cell processing steps are performed in each of the cartridges, increasing the overall throughput of the cell processing systems described herein. The cell solution may be transferred to the cartridge, e.g., by an operator, before loading the cartridge into the work cell. In some variations, the cartridge may be empty when loaded into the work cell so that the work cell can transfer the cell solution to the cartridge. In some variations, cells from two or more cartridges may be combined according to a predetermined ratio, which may correspond to an intended therapeutic treatment for a patient.

[0023] Additionally, the cell processing systems described herein may be advantageously configured to schedule parallel processing of multiple cell samples, as well as to manage contention within the system due to parallel processing by monitoring system contention due to a large number (e.g., greater than 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.) of cartridges requiring use of at least some of the subsystems (e.g., instruments of the subsystems) and resolving identified areas of high contention.

[0024] An exemplary cell processing system (CPS) for use with the automated devices, systems, and methods herein is shown in FIG. 1A. Shown therein is a block diagram of a cell processing system (CPS) 100, which may generally include a work cell 110, a cartridge 114 (which may be loaded into the work cell 110), and a controller 120. The work cell 110 may include one or more components and subsystems (having one or more components or instruments), including a feedthrough 111, a material handling system (MHS) 113, a reagent storage system (RVS) 118, a sterile liquid transfer system (SLTS) 115, a sterility system (SS) 117, a bioprocessing system (BPS) 119, a quality control system (QCS) 116, components 150, and a fluidics device 155. The cartridge 114 and fluidics device 155, which may be located outside the work cell 110 or may be used within the work cell 110, are shown in dashed lines. The cartridge 114 may be reusable or disposable. In general, work cell 110 may be configured for long term use. One advantage of the split modular / instrument design including work cell and cartridge may be that expensive components may be kept in subsystems of work cell 110, while less expensive components may reside in cartridge 114. Components such as component 150 may include one or more motors, sensors (e.g., cameras), heaters, lasers, pumps, etc.

[0025] Cartridge 114 may include one or more modules defined by a group of related components (mechanical and / or electrical) configured to perform specific cell processing operations in conjunction with work cell 110. Referring to Figure 1B, as shown, cartridge 114 may include one or more of a bioreactor module 150, an elutriation module 162, a pump module 164, an electroporation module 166, a cell sorting module 168 (e.g., magnetically activated cell sorting (MACS)), and a fluidic manifold 170.

[0026] FIG. 1C shows a perspective view of an exemplary variation of a CPS 100 including a work cell 110 and a cartridge 114. The cartridge 114 may be loaded into the work cell 110 via a feedthrough 111. In some variations, the feedthrough 111 may be the first of multiple feedthroughs 111. Generally, cell processing may involve moving a cartridge 114 configured to carry a cell sample between multiple components and subsystems of the work cell 110, as described herein. One or more work cell subsystems or modules (e.g., modules of the BPS 119, etc.) may be configured to interface with the cartridge 114 and perform processing steps on the cells in the cartridge 114. In some variations, multiple cell processing steps may be performed within the cartridge 114. For example, a robot 112 (e.g., a robotic arm) shown in FIG. 1C, which may be part of the MHS 113 of FIG. 1A, may be configured to move the cartridge 114 between subsystems of the work cell 110. Each module may be configured to perform a particular cell processing step when coupled (e.g., interfaced and / or engaged) with a corresponding instrument module in the cartridge 114. In some variations, each subsystem or module of the work cell 110 may include a receiving bay or dock for one of multiple cartridges 114, such that multiple cartridges 114 may be housed within the work cell 110 and multiple subsystems of the work cell 110 may be in use at any given time. Furthermore, each cartridge 114 may have a unique workflow or process design, and the work cell 110 may be configured to perform multiple different workflows in parallel.

[0027] In some variations, multiple cartridges 114 may be inserted into the work cell 110 and undergo one or more cell processing operations in parallel. For example, the work cell 110 may accept 1 to 30 cartridges 114 for processing, such as 1 to 16 cartridges (e.g., 1 cartridge, 2 cartridges, 3 cartridges, 4 cartridges, 5 cartridges, 6 cartridges, 7 cartridges, 8 cartridges, 9 cartridges, 10 cartridges, 11 cartridges, 12 cartridges, 13 cartridges, 14 cartridges, 15 cartridges, or 16 cartridges). As described herein, the performance of the work cell 110 may depend on its ability to resolve internal conflicts resulting from the multiplex processing of cell samples. Thus, the work cell 110 may have optimal performance at less than 100% cartridge capacity during multi-product manufacturing, such as about 50%-95% capacity, about 60%-90% capacity, about 70%-85% capacity, about 75%-80% capacity, about 80% capacity, or about 90% capacity. In other variations, the work cell 110 may function optimally at about 100% cartridge capacity during multi-product manufacturing.

[0028] 1A , the controller 120 of the CPS 100 may include one or more of a processor 122, a memory 124, a display 126, a user interface 128, a scheduler tool 130, and integration software 140 (e.g., an MES, an ERP, a LIMS). In some variations, the controller 120 may be configured to communicate (e.g., via a wired or wireless connection) with one or more components of the CPS 100 (e.g., the QCS 116), one or more remote devices (e.g., remote controls of mobile devices, etc.), and / or one or more additional CPSs 100 (e.g., a second controller 120 of a second CPS 100 and / or a third controller 120 of a third CPS 100, etc.). In one example, the first controller 120 of a first CPS 100 may be communicatively coupled to the second controller 120 of a second, proximate CPS 100 via a shared network. Thus, two CPSs 100 may be configured to jointly schedule and / or manage conflicts within a larger system during parallel processing of multiple cartridges. In some variations, using the scheduler tool 130, if a first CPS 100 identifies high conflicts within a work cell (e.g., two cartridges may require the same resource over a period of time) and is unable to resolve the conflict (e.g., neither of the two cartridges is determined to have a priority need for the resource over the other), the second CPS 100 may be able to retrieve one of the two conflicting cartridges and perform subsequent cell processing operations thereon. Such a scenario may arise, for example, when two cartridges 114 require the same resource in the work cell 110 over (at least partially) overlapping periods of time and the CPS 100 is unable to determine the relative priority of the two cartridges 114 (e.g., each cartridge is determined to have an equal need for the resource). Conflict monitoring and resolution during multi-product manufacturing is described in more detail herein with respect to FIGS. 2 and 4.

[0029] Any suitable cell processing workflow can be performed using the systems and devices described herein and can include steps such as proliferation, enrichment, selection, sorting, expansion, activation, transduction, electroporation, washing, etc., to meet desired specifications and / or quality (e.g., desired cell number) of the cell product. In some variations, a method of processing a solution containing a cell product includes digesting tissue using an enzymatic reagent to release a selected cell population into solution, enriching the cells using a CCE instrument, washing the cells using a CCE instrument, selecting cells in solution using a selection instrument, sorting cells in solution using a sorting instrument, differentiating or expanding the cells in a bioreactor, activating the cells using an activation reagent, electroporating the cells, transducing the cells using a vector, and finishing the cell product.

[0030] Typically, a cell processing workflow can take from about 9 days to about 2 weeks. The type, number, and length of cell processing operations (including repetitive operations) in a workflow can vary significantly for different cell samples. The workflow for each cell sample can depend on initial parameters such as cell type (e.g., autologous vs. allogeneic), sample collection time, sample transport time (e.g., to the facility running the CPS, such as the CPS 100), sample arrival time (e.g., at the facility running the CPS, such as the CPS 100), sample temperature (e.g., frozen vs. thawed), patient or donor age, and patient or donor gender. Estimated initial parameters, such as expected recovery from cell separation and / or expected recovery time, can also inform the process design for a cell sample. Furthermore, as discussed herein, variability in the manufacturing process (e.g., due to operator variability and / or competition between cell samples within a manufacturing unit) can alter the workflow for a given sample. Thus, during parallel processing of two or more cell samples (e.g., carried by two or more corresponding cartridges 114), CPS 100 may be configured to perform a unique workflow for each cell sample. That is, a workflow having a unique type and series of operations may be defined for each cell sample, and CPS 100 may synchronously process multiple cell samples according to the corresponding multiple unique workflows.

[0031] 1.1 Work Cell The work cell 110 may comprise a fully or at least partially enclosed housing within which one or more cell processing steps may be performed in a fully or at least partially automated process. Figure 1D shows a cross-sectional view of an exemplary variation of the work cell 110, including the feedthrough 111, material handling system (MHS) 113, reagent storage system (RVS) 118, sterile liquid transfer system (SLTS) 115, aseptic system (SS) 117, bioprocessing system (BPS) 119, quality control system (QCS) 116, components 150, and fluidics device 155.

[0032] The feedthrough 111 may be an entry and / or exit point for a cartridge (e.g., cartridge 114 in FIGS. 1A-1C) into the work cell 110. The feedthrough 111 may be configured to asynchronously receive multiple cartridges for simultaneous production of multiple products within the work cell 110. The feedthrough 111 may be operably coupled (e.g., via a wired or wireless connection) to an SS to sterilize the cartridge when it is docked within the feedthrough 111. In some variations, the work cell 110 may include multiple feedthroughs, such as 2-10 feedthroughs, 3-8 feedthroughs, or 4-6 feedthroughs. For example, the work cell 110 may include a first feedthrough 111.

[0033] The MHS 113 may be an automated transfer system having one or more mechanisms for transferring cartridges and fluidic devices throughout the work cell 110 (e.g., between the feedthrough, RVS, BPS, SLTS, etc.). In some variations, the MHS 113 may include a robotic arm (or multiple robotic arms) having at least one end for releasably coupling to a cartridge and / or fluidic device (e.g., fluidic device 155) for transfer. Thus, the MHS 113 may be configured to interact with one or more of the feedthrough 111, the RVS 118, the SLTS 115, and / or the BPS 119. Additionally, the MHS 113 may be communicatively coupled to one or more components of the cell processing system (e.g., the CPS 100 of FIGS. 1A-1C ), such as the controller 120.

[0034] RVS 118 may include one or more reagent reservoirs configured to store reagents in a fluidic device, such as fluidic device 155. In some variations, the reagent reservoirs may be refrigerated. Non-limiting examples of reagents stored in the reagent reservoirs of RVS 118 may include media, buffers, cytokines, proteins, enzymes, polynucleotides, transfection reagents, non-viral vectors, viral vectors, antibiotics, nutrients, cryoprotectants, solvents, cellular materials, and pharmaceutically acceptable excipients. Additionally or alternatively, waste products may be stored in the reagent reservoirs of RVS 118 or in fluidic device 155, which may be in the reagent reservoirs.

[0035] The RVS 118 can be communicatively coupled to the SS to enable sterilization of one or more fluidic devices therein. Additionally, the RVS 118 can be communicatively coupled to one or more components of the cell processing system (e.g., the CPS 100 of FIGS. 1A-1C), such as a controller (e.g., the controller 120 via the scheduler tool 130 of FIG. 1A) for reagent scheduling, inventory, and / or supply chain management. In some variations, the RVS 118 can include access points through which reagents can be delivered or exchanged during cell processing. For example, an operator can deliver reagents through an access point of the RVS 118 at any time during cell processing.

[0036] Fluidic device 155 may be a sterile liquid transfer device (SLTD). However, it should be understood that fluidic device 155 may be configured to transfer any fluid (including liquid), whether sterile or not. In general, fluidic device 155 can interact with SLTS 115, which may facilitate coupling between a cartridge (e.g., cartridge 114 in FIGS. 1A-1C) and fluidic device 155. Furthermore, SLTS 115 can perform all sterile liquid transfer operations in the system, including reagent addition and sampling. Thus, SLTS 115 may be an in-demand resource within work cell 110.

[0037] The work cell 110 may include one or more SLTSs 115, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 SLTSs 115. In some variations, the work cell 110 may include four SLTSs 115.

[0038] The SS 117 may be configured to sterilize the cartridges and fluidic devices 155 so that the work cell 110 may maintain an internal clean room environment. In some variations, the SS 117 may be configured to perform a sterilization procedure (e.g., vaporized hydrogen peroxide (VHP) treatment, ionized hydrogen peroxide decontamination) when the cartridges enter or exit the work cell (e.g., via the feedthrough 111) and / or when the fluidic devices 155 enter or exit the RVS 118.

[0039] The BPS 119 may include one or more work cell modules configured to interface and / or engage (electrically and / or mechanically) with corresponding cartridge modules to perform cell processing operations. The one or more work cell modules may include an elutriation module, a cell sorting module (e.g., a magnetically activated cell sorting module), an electroporation module, and a bioreactor. The work cell 110 may include one or more BPSs 119, such as 1-30 BPSs, 2-28 BPSs, 4-26 BPSs, 6-24 BPSs, 8-22 BPSs, 10-20 BPSs, 12-18 BPSs, or 14-16 BPSs (e.g., 16 BPSs). In some variations, the work cell 110 may perform optimal parallel processing of multiple cell samples (e.g., experience minimal contention) when fewer than all of the BPSs 119 (e.g., about 80% or about 90% of the number of BPSs 119) are engaged with the cartridge. For example, for a work cell with 16 BPS, the optimum capacity of the work cell may be 14 cartridges (each for processing in one of the 14 BPS).

[0040] The QCS 116 may be configured to perform automated sampling and analysis of cell samples (batches, cell products) during processing. In some variations, the QCS 116 may include an integrated cell culture analyzer configured to measure and / or estimate cell count and / or cell viability of the sample. Additionally or alternatively, sample containers may be collected from the work cell 110, and an operator or other system may perform the analysis. Furthermore, the QCS 116 may be configured to generate (e.g., automatically generate) and update records of cell samples as they progress through manufacturing. Batch records may be generated and / or updated via real-time process monitoring by the QCS 116. That is, initially, the QCS 116 may collect a sample (e.g., via the SLTS 115), analyze the sample, and update records associated with the sample. The QCS 115 may then (1) display the records to an operator (e.g., digitally via a display) and / or (2) send the records to a scheduler tool (e.g., scheduler tool 130 of FIG. 1A) so that real-time processing results can inform scheduling and / or conflict resolution within the system.

[0041] In some variations, one or more components and / or subsystems of the work cell 110 may include one or more fixed or operational time constraints, defined as the amount of time required for a component or subsystem to complete a task. Such fixed time constraints may affect the scheduling of multi-process cell manufacturing, as described herein. As an example, the MHS 113 may have one or more fixed time constraints for transferring cartridges and / or fluidic devices (e.g., via a robotic arm), such as a minimum time required to transfer a cartridge 114 or fluidic device 155 from a first subsystem of the work cell (e.g., from the feedthrough 111 or the RVS 118) to a second subsystem of the work cell (e.g., to the BPS 119).

[0042] 1.2 Cartridge The cell processing systems described herein may include one or more cartridges having one or more modules configured to interface with or releasably couple to one or more instruments in a work cell of the cell processing system. Generally, each cartridge 114 in a cell processing system may be used to manufacture a unique cell therapy product.

[0043] Some or all of the modules of a cell processing cartridge may, but need not, be integrated in a fixed configuration within the cartridge. For example, one or more of the modules may be configurable or movable within the cartridge (e.g., by a work cell operator, controller, and / or robot), allowing various cartridge formats to be assembled. For example, a cartridge may be a single closed unit with fixed components for each module, or the cartridge may include configurable modules coupled by configurable fluidic, mechanical, optical, and electrical connections. In some variations, one or more sub-cartridges, each containing a set of modules, may be used to perform various cell processing workflows. The modules may each be provided in a separate housing or may be integrated into a cartridge or sub-cartridge with other modules, and the modules may be arranged in any suitable configuration. For example, components for different modules may be interspersed with each other, such that each module may be defined by a set of connected components that collectively perform a predetermined function. However, the components of each module may or may not be physically grouped within the cartridge. In some embodiments, multiple cartridges may be used to process a single cell product through the transfer of the cell product from one cartridge to another cartridge of the same or different type, and / or by splitting the cell product among more cartridges and / or pooling multiple cell products into fewer cartridges.

[0044] As shown in FIG. 1B, cartridge 114 can be configured to carry (e.g., contain, immobilize, or encase) a cell solution (e.g., a cell suspension) for cell processing. Any number of cell processing steps can be performed on the cells within the cartridge. Accordingly, cartridge 114 can include one or more of a bioreactor module 160, an elutriation module 162, a pump module 164, an electroporation module 166, a cell sorting module 168 (e.g., magnetic-activated cell sorting (MACS)), and a fluidic manifold 170. In some variations, cartridge 114 can also include one or more of an additional sorting module (e.g., a fluorescence-activated cell sorting (FACS) module), an acoustic flow cell module, a microfluidic concentration module, a transduction module, and / or the like.

[0045] Fluid manifold 170 may be configured to transfer one or more fluids between one or more modules of cartridge 114. For example, fluid manifold 168 may transfer a fluid (e.g., a cell solution) from bioreactor module 150 to cell sorting module 168. In another example, fluid manifold 168 may transfer a fluid from cell sorting module 166 to any other module. In particular, fluid manifold 170 may transfer a fluid from cell sorting module 168 to any other module after a magnetic cell sorting process has been performed. Fluid manifold 170 may be configured to transfer sorted cells (e.g., magnetically tagged cells) to a first module and non-target cellular material to a second, different module.

[0046] The bioreactor module 160 can be configured to contain a cell solution. The bioreactor module 160 can include a mixing chamber in which the cell solution can be mixed with one or more reagents. The one or more reagents can include, for example, transduction reagents (e.g., lentiviral vectors and / or viruses) or magnetic particles configured to bind to specific types of cells.

[0047] The elutriation module 162 may be configured to perform an elutriation process, whereby cellular material may be separated according to size, shape, and / or density.

[0048] Pump module 164 may be configured to pump fluid in one or more directions along at least one fluid path. For example, pump module 169 may be configured to pump fluid to or from one or more of elutriation module 162, bioreactor module 160, fluid manifold 170, cell sorting module 168, and any other modules in cartridge 114.

[0049] The electroporation module 166 can be configured to facilitate intracellular delivery of macromolecules (ie, transfection by electroporation).

[0050] The cell sorting module 168 may be a magnetically activated cell sorting module that includes a flow cell and is configured to separate target cells (e.g., magnetically tagged cells) from non-target cell material. In some variations, the flow cell of the cell sorting module 168 may be used for the transduction step of the cell processing workflow.

[0051] A variety of materials may be used to construct the cartridge (including its modules) and cartridge housing, including metal, plastic, rubber, and / or glass, or combinations thereof. The cartridge, its components, and its housing may be fabricated by molding, machining, extrusion, 3D printing, or any combination thereof. The cartridge may contain commercially available components (e.g., tubing, valves, fittings) or may be attached to or integrated with custom components or devices. The cartridge housing may constitute an additional encapsulation layer that further protects the sterility of the cell product.

[0052] 1.3 Controller Referring back to FIG. 1A , the controller 120 may be configured to execute (e.g., via the processor 122) the scheduler tool 130 described herein. For example, a combination of software and hardware may be used to develop and update the scheduler tool. The software may include integration software 140, such as an MES, to aid in the execution of the scheduler tool 130. The hardware modules may include, for example, a general-purpose processor (or microprocessor or microcontroller), a field-programmable gate array (FPGA), an application-specific integrated circuit (ASIC), etc. The software modules (which execute on the hardware) may be expressed in various software languages ​​(e.g., computer code), including MATLAB, C, C++, Java, Python, Ruby, Visual Basic, and / or other object-oriented, procedural, or other programming languages ​​and development tools. Examples of computer code may include, but are not limited to, microcode or microinstructions, machine instructions such as those generated by a compiler, code used to create web services, and files containing high-level instructions executed by a computer using an interpreter. Additional non-limiting examples of computer code may include control signals, encryption code, and compression code.

[0053] Additionally, controller 120 may be communicatively coupled to one or more components of cell processing system 100, such as work cell 110, cartridge 114, and / or its subcomponents (e.g., one or more of MHS 113, RVS 118, SLTS 115, SS 117, BPS 119, QCS 116, and / or component 150). Memory 124 may store cell processing design plans, system instructions / commands, etc. Processor 122 may perform the calculations and methods described herein and may be configured to receive and store data using memory 124. Processor 122 may be any suitable processing device configured to operate and / or execute a set of instructions or code and may include one or more data processors, image processors, image processing units, physical processing units, digital signal processors, and / or central processing units. In some variations, controller 120 may include two or more controllers. In some variations, the user interface 128 may allow an operator of the cell processing system 100 to view, modify, or otherwise interact with the cell manufacturing workflow (e.g., a workflow that considers all cartridges being processed in the system) or an individual cell processing workflow for a single cartridge. In some variations, the user interface 128 may display recommendations for therapy modifications. The user interface 128 may be displayed on a suitable computing device that may include the integration software 140. In some variations, the display 126 may be configured to support the user interface 128. In some variations, the controller 120 may provide cell processing status notifications (e.g., digitally) via the user interface 128 (e.g., visual feedback, such as graphical and / or numerical feedback). In some variations, the controller 120 may be configured to automatically update one or more tools or processes (e.g., the scheduler tool 130) using data collected during the cell processing workflow.The data may include, for example, the actual execution time of a given cell processing operation, or cell sample characteristics (eg, cell count and / or cell viability) determined before or after a given cell processing operation.

[0054] 1.3.1 Scheduler Tools The scheduler tool 130 may generally be configured to schedule cell samples to an automated CPS (e.g., CPS 100) while managing system conflict issues through parallel processing so that the manufactured cell product meets all desired specifications (e.g., desired cell number and / or desired cell viability). The scheduler tool 130 may predict a cell production schedule that may orchestrate multiple processing for all of the system's multiple cartridges. For example, the scheduler tool 130 may generate a loading schedule that reduces or eliminates overlapping periods of need for a single work cell component or subsystem based on aggregate estimates of system operations, manual operations, cell processing workflows (specific to each cell sample in the system), and intake sample and patient / donor parameters. The schedule may be based on the minimum amount of workflow conflicts that are acceptable to process. Workflow conflicts may result from excessive or overlapping demands on cell processing resources that the system cannot meet. In some variations, high or excessive contention may be identified for system resources (e.g., one or more subsystems or components of the workcell 110) required for two or more cytological sample workflows in the same (e.g., at least partially overlapping) time period. The scheduler tool 130 may be configured to identify and (if possible) resolve areas (or predicted areas) of high contention by ranking the two or more workflows involved and identifying a prioritized workflow of the two, as described in detail herein. In some variations, the scheduler tool 130 may be configured to suggest steps for manual resolution of the conflict if it is determined that one or more cytological samples have equally (or substantially equally) weighted resource contention.

[0055] The schedule (loading schedule) may be used (e.g., automatically by CPS 100 and / or to notify an operator) to select asynchronous loading times for one or more cellular samples (e.g., cartridges carrying cellular samples) and / or to reschedule / reconfigure one or more ongoing processing operations to resolve internal conflicts. In some variations, the schedule may be a plot and / or list of exclusion times for loading proposed cartridges into work cells. In some variations, the scheduler tool 130 may automatically update the predicted loading schedule and / or conflict areas based on the system's real-time resource constraints.

[0056] In some variations, scheduler tool 130 may be an application configured to provide (e.g., visually and / or digitally display) cell processing information and / or receive user input. For example, scheduler tool 130 may provide one or both of a loading schedule for one or more cartridges and / or one or more conflict conditions or action items (e.g., for an operator to assist in resolving conflicts). For example, scheduler tool 130 may be accessed on one or both of display 126 and user interface 128. Additionally or alternatively, scheduler tool 130 may be accessed on a remote control, such as a mobile device, communicatively coupled to CPS 100 (e.g., to controller 120).

[0057] The scheduler tool 130 may be communicatively coupled to one or more components of the CPS, such as the MHS 113, the RVS 118, the SLTS 115, the SS 117, the BPS 119, and / or the QCS 116, via the controller 120. The scheduler tool 130 may be configured to receive and use real-time measurements of the system to inform scheduling and / or conflict resolution outputs. For example, the QCS 116 may provide measurements and / or estimates of cell count and / or cell viability to the scheduler tool 130, which may use the measurements and / or estimates to update one or more workflow simulation inputs (and, consequently, one or more outputs) of the scheduler tool 130.

[0058] I. Scheduling Cartridges for Loading The scheduler tool 130 may utilize a combination of mechanisms to determine when a cartridge, such as cartridge 114, can be safely loaded into a work cell of a cell processing system, such as work cell 110 of CPS 100. To do so, the scheduler tool 130 may include a feedback control system for predicting a cartridge loading schedule based on the environmental constraints of the CPS. The predictive schedule may organize the parallel processing of all cartridges scheduled for processing in the system and all proposed cartridges scheduled for processing in the system (each cartridge is associated with a unique cell processing workflow). Additionally, the scheduler may compensate for loading times and / or process variations by padding input data to limit potential downstream effects of loading and / or process variations.

[0059] The scheduler tool 130 may include one or more inputs for determining a cartridge loading schedule.

[0060] Non-limiting examples of inputs for scheduling cartridge loading, as discussed in detail herein, may include one or more of: (1) cell processing system configuration, (2) load window configuration (which may define the allowable variation in the nominal time a cartridge is loaded into the system), (3) scheduled cartridges and associated respective design plans and simulated workflows, (4) proposed (e.g., scheduled) cartridges and associated design plans and simulated workflows, and (5) intake sample parameters. In some variations, the system may determine debug configurations.

[0061] Intake or initial sample parameters may include data such as, but are not limited to, cell type (e.g., autologous vs. allogeneic), sample collection time, sample transport time (e.g., to the facility running the CPS, such as CPS 100), sample arrival time (e.g., at the facility running the CPS, such as CPS 100), sample temperature (e.g., frozen vs. thawed), patient / donor age, patient / donor gender, and / or additional patient / donor information (e.g., medical history). Estimated initial parameters, such as expected recovery from cell separation and / or expected recovery time, can also inform the process design for the cell sample. Initial sample parameters may be manually entered into the system (e.g., via user interface 128).

[0062] In some variations, the cell processing system may be configured to automatically generate one or more of the inputs, such as each of inputs 1-4 described above (e.g., via processor 122). In some variations, multiple cartridges (e.g., at least one, one or more, or two or more cartridges) may be analyzed simultaneously by scheduler tool 130 to determine when each of the cartridges may be input into the system.

[0063] The scheduler tool 130 can be configured to automatically determine one or more updated inputs at any time during the manufacturing process (e.g., before and after each operation of each cartridge in the system). For example, the cell processing system configuration can be updated using real-time resource constraints because one or more resources (e.g., one or more reagents, available BPS, etc.) may decrease as the manufacturing process continues. As another example, the scheduler tool 130 can be configured to calculate actual (e.g., realized) loading windows for one or more cartridges and use the calculated loading windows to reforecast the manufacturing plan or for operator or process feedback compensation, as described in detail herein.

[0064] Using one or more of the inputs described herein, the scheduler tool 130 may generate one or more outputs related to safely loading the proposed cartridges into the scheduler tool. The scheduler tool 130 may provide the output visually, such as graphically and / or numerically, via the display 126 and / or user interface 128. In some variations, an operator may edit one or more outputs to override decisions / suggestions made by the scheduler tool 130. In some variations, the scheduler tool 130 may prompt the operator to accept or reject the loading plan and / or conflict resolution plan. Non-limiting examples of such outputs may include one or more of: (1) a schedule of unavailable (excluded) times for loading; (2) a schedule of available times for loading; (3) a proposed time for loading the cartridge; and (4) a true / false result for one or more proposed cartridge loading times (e.g., indicating whether the proposed entry times are acceptable or not). The schedule output may further include an estimated time when one or more cartridges will be ejected from the system (eg, via the feedthrough 111).

[0065] In some variations, the scheduler tool 130 may be configured to periodically re-predict one or more outputs during the manufacturing process. For example, the scheduler tool 130 may re-predict the cartridge loading schedule (e.g., using updated data collected during the preceding processing event) before and after each cell processing operation for each cartridge in the system.

[0066] Additionally or alternatively, the scheduler tool 130 may be configured to provide a schedule for loading a fluidic device (e.g., fluidic device 155), such as for loading an SLTD into an RVS (e.g., RVS 118).

[0067] In some variations, the scheduler tool 130 may be further configured to output historical, real-time, and / or predicted system statistics. These statistics may include, for example, a robot operation summary (e.g., for the robot 112 of the MHS 113) and / or SLTD statistics.

[0068] The scheduler tool 130 may include one or more predictive models. Non-limiting examples of such models may include one or more of neural networks (e.g., CNNs), decision trees, linear regression, classification models, random forests, etc.

[0069] i. Input: Cell processing system configuration A cell processing system configuration may be defined by one or more of the following: the type and / or quantity of work cell equipment or subsystems, fixed timing constraints associated with the subsystems, the type and / or quantity of reagents stored within the system (e.g., within the RVS 118), etc. Fixed timing constraints may refer to timing constraints that are not workflow-specific. That is, fixed timing constraints may be timing constraints that are specific to the operation of a CPS subsystem or component. For example, a system configuration may have fixed timing constraints for fluid transfer between components (e.g., via the SLTS 115), cartridge and / or fluidic device transfer between work cells (e.g., via the MHS 113), sterilization of cartridges and / or fluidic devices (e.g., via the SS 117), etc. In some variations, a system configuration may include identifying one or more cartridges currently being processed by the system. Additionally, a system configuration may include a loading configuration, such as the number of hours, days, weeks, and / or months the system may operate and / or the number and / or length of operator shifts for operating the system.

[0070] Thus, the cell processing system configuration may define the real-time capabilities of the CPS based on the system's resource availability and fixed timing constraints. Generally, the more internal resources available, the more cartridges can be placed into the system, thereby increasing throughput. However, in some cases, adding equipment to the system may not affect critical processing paths (e.g., processing operations required by multiple cartridges over a shared time period) and therefore may not increase system throughput. Similarly, in some cases, adding equipment to the system to achieve internal redundancy (failure robustness) may not result in higher throughput.

[0071] ii. Input: Loading window configuration Although the scheduler tool 130 may be configured to identify an ideal loading time for a cartridge (e.g., a specified time of day, in minutes), in reality, it may be unlikely that an operator will enter the cartridge into the system at the exact specified time. Therefore, a loading window configuration may define an acceptable margin of error around a nominal time (e.g., a specific time such as 14:00) identified for a cartridge to enter the work cell. In particular, the loading window may include a symmetrical margin of error around the nominal identified time for loading. For example, a two-hour loading window may allow an operator to enter a proposed cartridge into the work cell at any time within one hour before or one hour after the identified loading time. That is, a nominal loading time of 12:00 with a two-hour loading window would allow an operator to load a cartridge into the work cell any time between 11:00 and 13:00.

[0072] Alternatively, in some variations, the loading window may have an asymmetric margin before and after the nominal identified loading time, for example, the loading window may be a period only before or only after the identified loading time.

[0073] The loading window can be on the order of seconds, minutes, or hours. In some variations, the loading window can be from 30 minutes to about 3 hours, e.g., from about 45 minutes to about 2.5 hours, from about 1 hour to about 2 hours, or from about 1.25 hours to about 1.75 hours. In some variations, the loading window can be less than 5 minutes, about 5 minutes, about 10 minutes, from about 5 minutes to about 10 minutes, about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.25 hours, about 1.5 hours, about 1.75 hours, about 2 hours, about 2.25 hours, about 2.5 hours, about 2.75 hours, about 3 hours, about 3.25 hours, about 3.5 hours, about 3.75 hours, about 4 hours, about 4.25 hours, about 4.5 hours, about 4.75 hours, about 5 hours, or more than 5 hours.

[0074] In general, a large loading window (e.g., on the order of hours, such as about 2, 3, 4, or 5 hours) may indicate that the scheduler tool 130 is not controlling or improving the overall cell processing plan, thereby limiting throughput by restricting the number of cartridges that can be loaded into the work cell. Conversely, a small loading window (e.g., on the order of seconds or minutes, such as about 2, 5, 10, or 30 minutes) may increase the likelihood that an operator will miss the loading window and have to reschedule proposed cartridges, which may also reduce throughput. Ideally, the loading window configuration input may allow for variability in cell sample (and / or cartridge) preparation while constraining the potential for reduced cell product throughput due to allowed variability in sample preparation.

[0075] In some variations, the loading time variation (actual loading time vs. scheduler-identified loading time) may be compensated for by the scheduler tool 130 (e.g., using feedback compensation) to limit the impact of loading time on overall process variability (e.g., to reduce overall process variability).

[0076] iii. Input: Scheduled cartridges and simulated workflow The scheduler tool 130 can evaluate scheduled (e.g., previously scheduled) cartridges for a work cell to determine when a proposed cartridge can be added to the system. All of the scheduled cartridges and their respective workflows (process design plans) may additionally be inputs for the scheduling tool. For example, the scheduler tool 130 may include one or more predictive models for simulating workflows for each of a plurality of currently scheduled cartridges. The one or more predictive models may be trained on results and / or estimates of past cell processing workflows and / or equivalent manual cell processing operations. For each scheduled cartridge, the one or more predictive models may receive data including, but not limited to, cell sample collection time, cell sample arrival time (e.g., at the facility running the CPS, such as CPS 100), initial cell count, expected recovery from cell separation, expected recovery time, cell sample temperature (e.g., frozen vs. thawed), patient / donor age, and patient / donor gender. The one or more predictive models may then simulate the workflow (e.g., including the schedule of cell processing operations and associated time estimates) for a given scheduled cartridge.

[0077] In some variations, the scheduler tool 130 may account for workflow variability (e.g., due to loading and / or process variations) by padding data for one or more of the simulated workflows. Padding scheduled cartridge data may involve the following steps: (1) predicting a nominal workflow based on loading at an ideal / planned time without process variations; (2) padding the simulated nominal workflow to account for potential variability within the loading window; and (3) padding the simulated nominal workflow to account for minimum and maximum variability in workflow behavior. This data padding may be performed for one or more or all of the simulated workflows of multiple scheduled cartridges.

[0078] Padding of the simulation data can take different forms, such as padding with or without variability compensation. In some variations, workflow variability compensation may allow loading window variability to be compensated for during a first extended (e.g., hours or days) cell processing operation. That is, loading window variability may be compensated for during an extended, such processing operation, which may take, for example, 4, 5, 6, 7, 8, 9, 10, or more than 10 days. Thus, loading window variability may only affect early processing operations (e.g., within the first day of a cell processing workflow) due to the cell sample undergoing an extended processing operation during which variability may be compensated for. Process variability compensation may be performed similarly to loading variability compensation, but may occur throughout the entire workflow.

[0079] An exemplary simulated workflow of the cartridge is described in Example 1 with reference to FIG. 5 herein.

[0080] iv. Input: Proposed cartridge simulated workflow The scheduler tool 130 may also include one or more predictive models for simulating the associated workflow of the proposed cartridge. The one or more predictive models may be trained on the results and / or estimates of past cell processing workflows and / or equivalent manual cell processing operations. Similar to the simulated workflow inputs for the scheduled cartridge, the workflow of the proposed cartridge may be modeled (e.g., via one or more predictive models) based on one or more intake parameters and the process design plan for the proposed cartridge. For example, the one or more predictive models may receive data including, but not limited to, cell sample collection time, cell sample arrival time (e.g., at the facility running the CPS, such as CPS 100), initial cell count, expected recovery from cell separation, expected recovery time, cell sample temperature (e.g., frozen vs. thawed), patient / donor age, and patient / donor gender. The one or more predictive models may then simulate the workflow for the proposed cartridge (e.g., including the schedule of cell processing operations and associated time estimates).

[0081] Additionally, as described above, the proposed cartridge workflow data may be padded to account for loading and / or process variations.

[0082] In general, a cartridge with a shorter process design (e.g., including fewer and / or more rapid cell processing operations compared to the average workflow) may have fewer conflicting issues than a cartridge with a longer process design (e.g., including more and / or longer cell processing operations compared to the workflow for a cell sample in another cartridge).

[0083] v. Output: Loading Schedule The scheduler tool 130 may determine a cartridge loading schedule for the proposed cartridges using one or more of the inputs described herein. For example, the scheduler tool 130 may identify and output one or more unavailable (or alternatively available) times (e.g., periods, such as a set of periods) for loading the proposed cartridge into the work cell (or for loading one or more of the multiple proposed cartridges). In some variations, the scheduler tool 130 may include one or more predictive models, such as one or more neural networks, configured to provide an output. In some variations, the output may include two or more schedules (e.g., multiple schedules), such as a schedule of unavailable loading times and a schedule of available loading times for the cartridges.

[0084] For example, the output may include a list or schedule of excluded times for loading the proposed cartridge. An excluded time may be one or more periods during which the proposed cartridge cannot be loaded into the work cell due to one or more subsystems operating at capacity and / or one or more subsystems having conflicts. For example, the set of excluded times (e.g., a closed set of excluded times) may include times when a scheduled cartridge is predicted to be loaded and / or times when a cell processing component or subsystem (e.g., SLTS 115 and / or BPS 119) is predicted to have high conflicts given the requirements of the scheduled workflow. In some variations, each excluded period in the set of excluded times may be a block of time that starts and ends at approximately the same times that a predicted conflicting event (e.g., scheduled cartridge loading) starts and ends.

[0085] The scheduler tool 130 may output the exclusion time schedule visually, such as graphically and / or numerically, via a display and / or user interface (e.g., display 126, user interface 128). In some variations, the schedule may be color-coded to support interpretation by an operator. In some variations, the exclusion time schedule may further identify the type of exclusion time. For example, the schedule may identify exclusion times covering scheduled cartridge loading windows differently (e.g., using different colors) from exclusion times covering periods of high contention. In some variations, the schedule may identify exclusion times covering periods of high contention for a first subsystem of the work cell (e.g., SLTS 115) as different from exclusion times covering periods of high contention for a second subsystem of the work cell (e.g., BPS 119), and may similarly function to identify exclusion times covering periods of high contention for any number of subsystems or components of the work cell. In some variations, the schedule may identify periods of acceptable contention (e.g., contention in which two or more workflows may require the same resource in close, but non-overlapping, time periods) for operator reference. Exemplary schedules of unavailable loading times for cartridges are described in Examples 2 and 3 herein with reference to Figures 6A-6B and 7A-7B, respectively.

[0086] Conversely, in some variations, the output may include a list or schedule of available times for loading the proposed cartridge. The available times may be one or more time periods during which the proposed cartridge may be loaded into the work cell. In some variations, the available times may include a set of time periods beginning at time zero (e.g., beginning before loading the first scheduled cartridge) and running indefinitely. Thus, the list of available times for loading the proposed cartridge may be less restrictive than the set of excluded times for loading the proposed cartridge.

[0087] In some variations, the output may include one or more recommended times for loading the proposed cartridge. Additionally, in some variations, the output may include a true / false result associated with at least one of the one or more recommended times for loading the proposed cartridge. The true / false result may indicate whether the proposed entry time is acceptable or not.

[0088] In some variations, the scheduler tool 130 may be configured to solve a "job shop" constraint satisfaction problem (CSP) considering all scheduled and proposed cartridges. The CSP may define the number of cell processing operations to be completed using a specific number and component ordering of work cells that will process the cartridges. Scheduling using a CSP may allow for efficient and flexible modeling of constraints and may handle complex and dynamic constraints that may arise during cell therapy manufacturing.

[0089] The scheduler tool 130 may solve the CSP to schedule an automated CSP by modeling the cell therapy manufacturing process as a set of jobs and the equipment used to execute the jobs as the resources required to complete the jobs. The output may include an optimal cartridge loading schedule that satisfies constraints, including one or more (e.g., all) of instrument availability, operational priority, operational criticality, maximum batch (e.g., cell sample) cell number, and maximum batch incubation time. The optimal schedule output optimizes resource utilization within the work cell, reducing the cost and time of cell processing cycles (e.g., meeting processing deadlines).

[0090] II. Managing System Conflicts The scheduler tool 130 can be used to monitor the progress of the manufacturing process and make real-time adjustments to ensure that all cell products meet required specifications and quality standards (e.g., meet predetermined thresholds of acceptable cell counts and / or cell viability). For example, system resource requirements and the workflow of the cell samples being processed can be continuously evaluated (e.g., based on the timing of cell processing events) to recalculate areas of conflict and / or re-predict areas of predicted conflict. In some variations, the scheduler tool 130 can determine conflict for each resource / instrument of the system by considering the processing requirements of each cartridge being processed before and after all cell processing operations are performed within the system.

[0091] The amount of contention can be determined from the number of cartridges (or associated workflows) simultaneously requiring system resources, or at least a portion of the resources. In some variations, system contention can be determined from the ratio of cartridges (or associated workflows) to required CPS subsystems and / or components during a given period. For example, the scheduler tool 130 can compare the number of competing cartridges and / or the contention ratio to a predetermined threshold of acceptable contention to quantify the contention of the identified subsystems and / or components. Generally, the lower the contention rate, the less contention exists in the system. Furthermore, for example, the length of overlap time between two cartridges requiring the same system resources can determine the amount of contention that exists. For example, two cartridges requiring the same SLTS within a 5-second overlap time can cause less contention than two cartridges requiring the same SLTS within a 30-minute overlap time. Furthermore, the amount of contention can depend on the dwell time for the current processing operation and / or the execution time for the subsequent processing operation for each of the competing cartridges for a given instrument. The residence time and / or run time of each cartridge may be used to determine the instrument contention weight of the cartridge, as described in detail herein.

[0092] In some variations, scheduler tool 130 may be configured to determine and provide a confidence estimate for one or more calculated conflict areas. Scheduler tool 130 and / or an operator may be able to configure and / or reconfigure a confidence threshold for comparison with one or more confidence estimates determined by scheduler tool 130.

[0093] In some variations, the scheduler tool 130 may be configured to recalculate system conflicts using updated data (e.g., collected during a previous processing operation) for one or more cartridges (e.g., processed, scheduled, or proposed cartridges) in the system to determine whether areas of conflict may arise due to differences between actual and simulated results. In some variations, the scheduler 130 may be configured to compare calculated operation execution times with corresponding simulated operation execution times to determine whether there is a significant difference between the two (e.g., a difference of more than about 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, or about 5%). Generally, the difference between calculated event times and simulated event times may be minimal when equipment conflicts are reduced or avoided through scheduling by the scheduler tool 130. In such cases, conflicts and associated deviations from simulated (ideal) results may be limited to small amounts (e.g., within about 5%, about 10%, about 15%, or about 20% of the simulated results) primarily as a function of robot interaction timing within the workcell (e.g., RVS 118 and / or SLTS 115 conflicts). Thus, deviations smaller than typical process variations (e.g., within about 15% of the predicted results) may have minimal impact on the reliability of the scheduler tool 130 output.

[0094] When high or excessive contention (e.g., periods of overlapping required resources and / or multiple cartridges requiring one or more resources) is identified (e.g., during contention recalculation before or after a given cell processing operation), the scheduler tool may suggest or automatically implement solutions (e.g., to an operator via the display 126 and / or user interface 128) for areas of high contention based on the priority constraints of the cell samples. For example, resolving the contention may involve rescheduling / reconfiguring the workflow of one or more cartridges (e.g., extending or shortening the period for which a cartridge resides in a subsystem).

[0095] Priority constraints may be evaluated based on the residence time for the current or completed cell processing operation and the execution time for the subsequent cell processing operation. Comparing the priority constraints of two or more cell samples may include determining an equipment conflict weight for each of the cell samples, where the cell sample with a greater conflict weight for a given equipment may be the cell sample with the highest priority constraint. The scheduler tool 130 can use this comparison to prioritize (or reprioritize) one or more cell samples requiring the same resource to ensure a high-quality cell product that meets the requirements of the manufacturing process. For example, if two different cell samples require SLTS, but one batch is constrained by the need for a viral vector (which must be used within 30 minutes of thawing), priority may be given to using that resource. Cell sample operations determined to have equally weighted resource conflicts may alert the operator with recommended possible solutions.

[0096] The dwell time may be the maximum amount of time allowed between a completed processing operation and a subsequent processing operation without affecting the quality of the cellular product. The run times may include minimum and maximum run times, which may be estimated times for completing subsequent processing operations with and without padding the time estimates (e.g., to account for process variability), respectively. The scheduler tool 130 may compare the dwell time for one or more cell samples with the minimum and maximum run times for one or more different cell samples to determine which samples should be prioritized and proceed with using competing resources.

[0097] For example, if the minimum and maximum execution times of a first cell sample are both shorter than the residence time of a second cell sample, the first cell sample may be assigned priority for proceeding with its subsequent processing steps (because the maximum execution time takes into account variations in the actual execution times of subsequent processing operations).

[0098] However, if the minimum run time of the first cell sample is greater than the residence time of the second cell sample, the scheduler tool 130 may proceed to evaluate the workflow of the first cell sample to determine that it can be delayed. If the first cell sample can be delayed, the second cell sample may be preferentially assigned to proceed with subsequent processing steps. If the first cell sample cannot be delayed (e.g., due to the use of a virus or lytic vector), the scheduler tool 130 may determine that the first and second cell samples have equally weighted resource competition. The scheduler 130 may then notify the operator (e.g., via the display 26 and / or the user interface 28) that the conflict between the first cell sample and the second cell sample cannot be resolved. The operator may then manually assign a priority to one of the first and second cell samples, may move one or both of the first or second cell samples to a different work cell (which may meet demand for required resources), and / or may manually perform a subsequent processing operation on one or both of the first and second cell samples.

[0099] Similarly, when the maximum run time of a first cell sample is equal (or substantially equal) to the residence time of a second cell sample, the scheduler tool 130 may determine that the first and second cell samples have equally weighted resource contention. The scheduler 130 may notify the operator (e.g., via the display 26 and / or the user interface 28) that the conflict between the first cell sample and the second cell sample is not resolved. The operator can then decide how to resolve the conflict.

[0100] Additionally, if the maximum run time of the first cell sample is greater than the residence time of the second cell sample, the second cell sample can be assigned priority for proceeding through its subsequent processing steps.

[0101] In some variations, the scheduler tool 130 may include a confidence model, which may be a model configured to provide a confidence estimate associated with one or more dwell times, minimum execution times, and / or maximum execution times determined by the scheduler tool 130. The scheduler tool 130 may provide such estimates graphically (e.g., confidence intervals) and / or numerically via the display 126 and / or user interface 128. For example, the scheduler tool 130 may be configured to provide a confidence estimate (e.g., confidence interval) associated with the minimum and maximum execution times for a given cell sample. One or both of the scheduler tool 130 and the operator can interpret the confidence estimate to determine, for example, how risky it may be to assign a priority to a first cell sample having a minimum execution time approximately equal to the dwell time of a second cell sample. In some variations, the scheduler tool 130 may be configured to automatically assign a priority to a second cell sample for proceeding to its subsequent processing operation if the confidence estimate of the minimum runtime for the first cell sample is less than about 95% or less than about 90%. As follows, in such variations, the scheduler tool 130 may be configured to automatically assign a priority to a second cell sample for proceeding to its subsequent processing operation if the confidence estimate of the minimum runtime for the first cell sample is greater than about 90% or greater than about 95%.

[0102] 2 is a flowchart illustrating an exemplary strategy for the scheduler tool 130 to evaluate and resolve conflicts between two cell samples. To perform both procedures 202, 204, the scheduler tool may be configured to calculate the minimum execution time (procedure 202) or maximum execution time (procedure 204) of a subsequent operation (operation A) of a first cell sample and the dwell time of the current (e.g., real-time) operation (operation B) of a second cell sample. While procedures 202, 204 outline a strategy for comparing the dwell time of operation B to the minimum or maximum execution time for operation A, in some variations, the scheduler tool 130 may be configured to compare the dwell time of operation B to both the minimum and maximum execution times of operation A, or to compare any combination of the dwell time, minimum execution time, and maximum execution time of operation B to any combination of the dwell time, minimum execution time, and maximum execution time of operation A.

[0103] To execute procedure 202, scheduler tool 130 may compare the minimum execution time of operation A with the dwell time of operation B. If the minimum execution time of operation A is within (e.g., less than or equal to) the dwell time of operation B, the scheduler tool may assign priority to the first cell sample to be processed in operation A. If the minimum execution time of operation A is not within (e.g., greater than or equal to) the dwell time of operation B, the scheduler tool may further evaluate operation A to determine whether the first cell sample can be dwelled. For example, if operation A includes introducing a virus or lytic vector into the first cell sample, operation A may not be delayed for more than 30 minutes of thawing the viral vector or within 45 minutes of thawing the lytic vector. Thus, if operation A is not delayed, scheduler tool 130 may notify the operator that the conflict between the first cell sample and the second cell sample cannot be resolved. Otherwise, if operation A may be delayed, scheduler tool 130 may assign priority to the second cell sample to be processed in operation B. When performing procedure 202, scheduler tool 130 may be configured to calculate a confidence estimate for the minimum execution time of operation A. If the confidence estimate for the minimum execution time is below a predetermined threshold, such as less than 90% (as shown in FIG. 5 ), scheduler tool 130 may be configured to assign priority to the first cell sample to be processed in operation A.

[0104] To perform procedure 204, scheduler tool 130 may compare the maximum execution time of operation A with the dwell time of operation B. If the maximum execution time of operation A is less than (or less than) the dwell time of operation B, scheduler tool 130 may be configured to assign a priority to a first cell sample to be processed in operation A. If the maximum execution time of operation A is greater than (or greater than) the dwell time of operation B, scheduler tool 130 may be configured to assign a priority to a second cell sample to be processed in operation B. If it is determined that the maximum execution time of operation A is equal to (or substantially equal to) the dwell time of the second cell sample, scheduler tool 130 may determine that the first and second cell samples have equally weighted resource contention. Scheduler 130 may then notify an operator that the conflict between the first cell sample and the second cell sample is not resolved. The operator can then decide how to resolve the conflict.

[0105] A practical example in which the scheduler tool 130 may use one or both of procedures 202 and 204 to resolve a conflict between a first cell sample and a second cell sample may involve a conflict between SLTSs (e.g., SLTS 115). In particular, in some cases, where there is only one available SLTS, operation A may involve the transfer of a lysis buffer in a first SLTD via the SLTS to a first sample in a first BPS, and operation B may involve the transfer of a wash buffer in a second SLTD via two SLTSs to a second sample in a second BPS. Thus, the area of ​​conflict may involve the single available SLTS. Operation A may have a minimum run time of about 20 minutes, a maximum run time of about 45 minutes, and a dwell time of about 30 minutes. Operation B may have a minimum run time of about 30 minutes, a maximum run time of about 45 minutes, and a dwell time of about 10 minutes. Thus, scheduler tool 130, via procedure 204, can determine that priority can be assigned to operation B, which has a dwell time that is shorter than the maximum execution time of operation A. In some cases, determining the priority between operations A and B can depend on the dissolution vector required for the remainder of operation A. For example, if operation A's dissolution vector is not thawed and / or has just been thawed (used within 45 minutes), operation B, with its smaller dwell time, minimum, and maximum execution times than operation A, can be assigned priority. However, via procedure 202, scheduler tool 130 can evaluate operation A to determine whether it can be delayed. If the dissolution vector must be thawed and used within approximately 30 to 45 minutes (operation B's minimum execution time), scheduler tool 130 can notify an operation to help resolve the conflict.

[0106] In variations in which more than two cell samples may (or are expected to) be involved in equipment contention, scheduler tool 130 may resolve the conflict (e.g., determine which cell sample, if possible, should be prioritized for proceeding to a subsequent processing operation) by (1) comparing the priority constraints of each of the more than two cell samples (as described above with respect to the first and second cell samples), and (2) stack-ranking each of the two or more cell samples based on their respective dwell, minimum run, and maximum run times. If two or more samples are determined to have equally weighted resource contention (e.g., cannot be ranked), scheduler tool 130 may indicate (e.g., via display 26 and / or user interface 28) that the conflict cannot be resolved. To resolve the conflict, an operator may then manually assign priorities to the two or more samples, move one or more of the cell samples to a different work cell (which can satisfy demand for the in-demand resource), or manually perform a subsequent processing operation on one or more of the cell samples.

[0107] In some cases, high contention can be resolved by simply adding a resource, such as fluid, to the system that is in demand during active manufacturing. For example, if two or more cartridges require a total amount of a reagent that is greater than the amount of the reagent currently stored in the system (e.g., in the RVS 118), the scheduler tool 130 can be configured to notify an operator (e.g., via an access point in the RVS 118) to add an amount of reagent to the system that is greater than or equal to the total amount required by the two or more cartridges to resolve the conflict.

[0108] 2. Methods for Cell Treatment In general, the systems described herein may perform one or more methods for cell processing, including one or more methods for scheduling and / or managing the processing of multiple cartridges. In some variations, one or more methods may be computer-implemented. For example, the methods described herein may be performed via a controller, such as controller 120 of FIG. 1A. The methods herein may generally include providing notifications (e.g., visual, audio, tactile, etc.) to an operator of the cell processing system (e.g., via a display, such as display 126, and / or a user interface, such as user interface 128) indicating (1) the output of scheduler tool 130 (e.g., a proposed cartridge loading schedule), (2) conflict status and / or changes being made to the workflow of one or more cartridges in the system to resolve, limit, or avoid conflicts between cartridges, or (3) manual decisions / actions required to advance the manufacturing plan (e.g., operator actions required to resolve conflicts). In some variations, the operator may optionally provide feedback to the CPS before, during, or after one or more steps of the methods described herein.

[0109] 3 provides a flowchart of an exemplary variation of a method 300 for cell processing. In particular, method 300 can be for scheduling proposed cartridges for cell processing. In some variations, a tool such as scheduler tool 130 of FIG. 1A can be configured to perform (e.g., automatically perform) method 300.

[0110] First, the method 300 may include determining 302 a cell processing system configuration. The CPS configuration may define the real-time and / or predictive capabilities of the CPS based on the system's resource availability and fixed timing constraints. The resources may include resources in the RVS (e.g., RVS 188), such as one or more of media, buffers, cytokines, proteins, enzymes, polynucleotides, transfection reagents, non-viral vectors, viral vectors, antibiotics, nutrients, cryoprotectants, solvents, cellular materials, and pharmaceutically acceptable excipients. The system's fixed timing constraints may include, for example, the time required for a robot of the MHS (e.g., robot 112 of MHS 113) to move a cartridge from one subsystem to another (e.g., from feedthrough 111 to BPS 119). As another example, the fixed timing constraints may include the time required for a SS (e.g., SS 117) to perform a sterilization procedure on the cartridge.

[0111] Next, method 300 may include determining 304 scheduled cartridge configurations, such as determining at least one, one or more, or a plurality of scheduled cartridge configurations. The scheduled cartridges may be cell processing cartridges (e.g., each carrying a cell sample and configured to interface with a CPS, such as cartridge 114) that have been previously scheduled for processing within the CPS. That is, the loading times (for loading the cartridges into the CPS) of the scheduled cartridges may already be defined prior to execution of method 300. Determining 304 may include identifying a first scheduled cartridge and / or a process design plan for the first scheduled cartridge, and may additionally include receiving one or more sample intake parameters for the cell sample carried by the first scheduled cartridge. Non-limiting examples of sample intake parameters may include one or more of the following: sample cell type, sample collection time, sample transport time, sample arrival time at the processing facility, sample temperature, patient age, patient gender, donor age, and donor gender. Determining 304 may involve modeling a workflow (e.g., via one or more predictive models) for the first scheduled cartridge based on the process design plan (workflow) and one or more sample intake parameters. In some variations, the simulated workflow may additionally or alternatively be based on real-time data (e.g., updated cell processing results). In some variations, one or more scheduled cartridges may be undergoing processing in real time, and any real-time estimates or measurements associated with the cartridges (e.g., realized cell processing operation runtime, cell count, cell viability estimates) may be used to determine and / or re-predict their associated scheduled cartridge configurations. In some variations, one or more scheduled cartridge configurations may be generated for viewing and / or editing by an operator (e.g., via a user interface, such as user interface 128).Determining 304 may be performed any number of times for each of a plurality of scheduled cartridges.

[0112] Next, method 300 may include determining 306 a proposed cartridge configuration. The proposed cartridge may be a cell processing cartridge that has not yet been scheduled for processing within the CPS. Determining 306 may include designing and / or identifying a process design plan for the proposed cartridge and, in addition, may include receiving one or more sample uptake parameters for a cell sample to be carried by the proposed cartridge (as listed above with respect to determining 304). Determining 306 may involve modeling a workflow for the proposed cartridge (e.g., via one or more predictive models) based on the process design plan (workflow) and the one or more sample uptake parameters. Additionally, or alternatively, the proposed cartridge configuration may include a loading configuration that defines an allowable time period during which an operator may load the proposed cartridge into the CPS. In some variations, the proposed cartridge configuration (e.g., simulated workflow and / or loading configuration) may be generated for viewing and / or editing by an operator (e.g., via a user interface, such as user interface 128). In some variations, determining 306 may be performed for each of a plurality of proposed cartridges.

[0113] Further, method 300 may include generating 308 (providing) a loading schedule for loading the proposed cartridge. The schedule may be generated based on the system configuration, the schedule, and the proposed cartridge configuration. Generating 308 may include displaying the schedule (e.g., in graphical and / or numerical form) via a display (e.g., display 126) and / or a user interface (e.g., user interface 128). The schedule may provide one or more exclusion times for the proposed cartridge, which may be periods during which the cartridge cannot be loaded into the CPS. Additionally, or alternatively, the schedule may provide one or more available times for loading the proposed cartridge into the system. Thus, generating 308 may include predicting system conflicts (e.g., cartridge conflicts for one or more subsystems or instruments of the system) caused by loading the proposed cartridge and reducing or resolving the predicted conflicts to create the schedule. Thus, the schedule may be an optimal schedule for loading the proposed cartridge that minimizes system conflicts and, therefore, sample viability risks. Managing system conflicts is described in more detail with respect to method 400 of FIG. 4, which may be used in conjunction with method 300.

[0114] Referring again to FIG. 3 , the method 300 may ultimately include loading 310 the proposed cartridge into the CPS (e.g., into the work cell 110) based on the loading schedule. That is, an operator may be instructed by the loading schedule to load the proposed cartridge into the system. For example, the operator may select a loading time that does not overlap with any of one or more unavailable loading times provided by the loading schedule to load the proposed cartridge into the system. In some variations, the loading schedule may identify an ideal time for loading the proposed cartridge, and the operator may load the proposed cartridge at this time (or within a loading window based on this time).

[0115] One example of a method for cell processing that includes scheduling proposed cartridges for cell processing may include first determining a system configuration for a cell processing system configured to process multiple cartridges in parallel. Each of the multiple cartridges may be configured to carry a cell sample and to be loaded into a work cell of the cell processing system. Next, the method may include determining a cartridge configuration for each of the multiple cartridges and providing a loading schedule for loading a first cartridge of the multiple cartridges into the work cell. The loading schedule may be based on the system configuration and the configuration for each of the multiple cartridges.

[0116] 4 provides a flowchart of an exemplary variation of a method 400 for cell processing. In particular, method 400 may be for monitoring and / or managing contention within a cell processing system (e.g., CPS 100) configured for parallel processing. In some variations, a tool such as scheduler tool 130 of FIG. 1A may be configured to perform (e.g., automatically perform) method 400.

[0117] First, method 400 may include determining 402 contention for an instrument of a cell processing system (e.g., CPS 100). An instrument may be a subsystem and / or component of the CPS, such as feedthrough 111, MHS 113, RVS 118, SLTS 115, SS 117, BPS 119, QCS 116, and at least a portion of one of components 150 (e.g., one or more motors, sensors, heaters, lasers, pumps, etc.). In some variations, determining 402 may be based on the number of cell samples having workflows requiring use of an instrument (e.g., at least a portion of an instrument) for the same period of time (e.g., an overlapping range of seconds, minutes, or hours). Some instruments may be configured to simultaneously handle (e.g., perform operations for or on) more cell samples than other instruments. Thus, instrument contention may be based on the specific number of cell samples in the instrument contention, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 cell samples. That is, high or excessive contention may be determined when the number of cell samples simultaneously requiring an instrument exceeds a predetermined threshold for the instrument (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 cell samples). In some variations, determining 402 may include determining contention for one or more instruments at once, such as for multiple instruments including all of the instruments in the system. In some variations, determining 402 may occur before and / or after a cell processing operation of the system, such as before and after every cell processing operation performed by the system. Thus, instrument contention may be continuously recalculated throughout the entire cell manufacturing process. In some variations, method 400 may include generating a notification of excessive contention in response to determining 402.

[0118] Once high or excessive contention is determined, method 400 may include evaluating 404 priority constraints for the cell samples (e.g., all of the cell samples) in the equipment contention. The priority constraints may be based on the operation dwell times (e.g., the current operation dwell time) and / or operation execution times (e.g., subsequent operation execution times, which may be minimum and / or maximum execution times) determined for each of the cell samples. As described herein (e.g., with respect to FIG. 2 ), evaluating 404 may include comparing one or more of the operation dwell times with one or more of the operation execution times for the cell samples. This may determine an equipment contention weight for each of the cell samples, which may define how the cell sample compares to all others (based on all of the cell sample priority constraints) in need of the equipment. The equipment contention weight may simply be the priority rank of the cell sample. For example, the cell sample with the greatest weight contention may be ranked as the sample with the highest (highest priority, number 1) need for the equipment. Optionally, method 400 may include reconfiguring / rescheduling the workflow for one or more cytological samples that were not identified as the highest priority (e.g., did not use the instrument when planned).

[0119] Next, method 400 may include identifying 406 one or more highest priority cell samples (priority samples for instrument use) based on evaluating 404. For example, identifying 406 may include generating / providing an indication of the highest priority cell samples or stack rank of the cell samples based on the weighted competition for the instrument. This indication may be provided in graphical and / or numerical form via a display (e.g., display 126) and / or a user interface (e.g., user interface 128). In some variations, identifying 406 may include indicating that the cell samples may not be prioritized (e.g., all have equal or substantially equal weighted competition). In such variations, method 400 may further include notifying or instructing an operator to help resolve the conflict, as described herein. In some variations, the operator may be able to manually reprioritize cell samples for processing via the instrument based on the priority information determined during evaluating 404.

[0120] If high or excessive contention is not determined, the method may not include evaluating 404 and may proceed to identifying 406 all cell samples in the system as priority cell samples (e.g., determining that all cell samples may proceed to be processed as scheduled / intended by that workflow).

[0121] In one example, a method for cell processing including monitoring and / or managing contention within a cell processing system configured for parallel processing may first include loading multiple cell samples into the cell processing system for parallel processing, where the cell processing system may include multiple processing instruments (e.g., subsystems). Next, the method may include determining an amount of contention for each of a plurality of instruments before and after each of a plurality of cell processing operations is performed by the cell processing system. The amount of contention may be based on the number of cell samples requiring the instrument during a time period. Finally, the method may include generating a notification, via a user interface of the cell processing system, indicating excessive contention if the number of cell samples requiring the instrument during the time period is greater than two. In some variations, the method may further include identifying prioritized cell samples for instrument use based on an instrument contention weight determined for each cell sample requiring the instrument during the time period, where the prioritized cell sample may have the highest instrument contention weight. For each cell sample, the instrument contention weight may be based on the current cell processing operation dwell time and the subsequent cell processing operation execution time.

[0122] The methods described above can be implemented in any of numerous ways. For example, at least some methods of the present technology may be implemented using hardware, firmware, software, or a combination thereof. When implemented in firmware and / or software, the firmware and / or software code can be executed on any suitable processor or collection of logical components, whether provided within a single device or distributed among multiple devices.

[0123] In this regard, various aspects described herein may be embodied as a computer-readable storage medium (or multiple computer-readable storage media) (e.g., computer memory, one or more floppy disks, compact disks, optical disks, magnetic tapes, flash memory, circuitry in a field programmable gate array or other semiconductor device, or other non-transitory or tangible computer storage medium) encoded with one or more programs that, when executed on one or more computers or other processors, perform methods that implement the various embodiments of the invention discussed above. The computer-readable medium or media may be transportable such that the program or programs stored thereon can be loaded into one or more different computers or other processors to implement the various aspects of the invention discussed above.

[0124] The terms "program" or "software" are used herein in a generic sense to refer to any type of computer code or set of computer-executable instructions that can be employed to program a computer or other processor to implement various aspects of the embodiments discussed above. Additionally, according to one aspect, it should be understood that one or more computer programs that, when executed, perform the methods disclosed herein need not reside on a single computer or processor, but may be distributed in a modular manner among several different computers or processors to implement various aspects of the invention disclosed herein.

[0125] Computer-executable instructions may be in many forms, such as program modules, executed by one or more computers or other devices. Generally, program modules include routines, programs, objects, components, data structures, etc. that perform particular tasks or implement particular abstract data types. Typically, the functionality of the program modules may be combined or distributed as desired in different variations.

[0126] Additionally, data structures may be stored on computer-readable media in any suitable form. For ease of explanation, data structures may be depicted as having fields that are related by location within the data structure. Such relationships may be achieved by allocating storage to fields that in turn have locations within the computer-readable media that convey the relationship between the fields. However, any suitable mechanism may be used to establish relationships between information within fields of a data structure, including the use of pointers, tags, or other mechanisms that establish relationships between data elements.

[0127] Finally, acts performed as part of the methods herein may be ordered in any suitable manner. Thus, although shown as sequential acts in exemplary embodiments, various methods can be constructed in which acts are performed in a different order than that illustrated, which may include performing some acts simultaneously. [Example]

[0128] Example 1 Figure 5 provides an example simulated workflow for a cell sample. The workflow is shown as plot 500. Each cell processing operation is represented as a bar on plot 500, with the length of the operation (execution time) correlating with the length of the corresponding bar. As shown, the workflow begins approximately 8:00 AM on December 25th. Several initial cell processing operations were scheduled between approximately 8:00 AM and 3:00 PM on December 25th (where a single operation is represented as a bar on the plot). Considering a ±1-hour loading window, a cartridge could be loaded into the system any time between 7:00 AM and 9:00 AM. Without compensation for loading variation, this ±1-hour window would affect the timing of all subsequent operations in the workflow. However, compensation can be applied to remove loading variation during the first extended processing step in the BPS. Here, compensation was removed between approximately 4:00 PM and 5:00 PM on December 26th. As a result, the cell processing step beginning at approximately 5:00 PM on December 27th, including all remaining cell processing operations, was not affected by variability in operator loading window timing until the end of the workflow.

[0129] Process variability compensation may be performed similarly to loading variability compensation, but may occur throughout the entire workflow. For example, as shown in plot 500, process variability that occurred between about 5:00 PM and about 7:00 PM on December 27th was compensated for during subsequent operations within the BPS, resulting in operations beginning between about 8:00 PM and about 9:00 PM on December 28th.

[0130] Example 2 6A-6B provide exemplary loading schedules 602, 604 for a cell processing system. The schedules 602, 604 show unavailable loading times for proposed cartridges. The unavailable times are indicated by bars, each with a length that correlates to the length of the unavailable loading period. Additionally, the light, medium, or dark shading of each bar indicates which subsystem or instrument in the work cell is at capacity, thus preventing the proposed cartridge from being loaded during that period. Dark bars represent the capacity of the BPS, medium bars represent feedthroughs in use or reserved for the scheduled cartridge, and light bars represent contention within the SLTS that restricts new input to the system.

[0131] The same simulated workflow was used for the scheduled cartridges to generate the plots of Figures 6A and 6B, but the proposed cartridge workflow was varied between a 14-day (Figure 3A) and a 7-day (Figure 3B) process. Thus, the 7-day proposed cartridge workflow used to simulate schedule 604 includes significantly less unavailable loading time, particularly between January 10 and January 25, when the manufacturing schedule of Figure 3A was essentially completely unable to receive the proposed cartridges.

[0132] Example 3 7A-7B provide additional exemplary loading schedules 702, 704 for a cell processing system. Similar to schedules 602, 604 in FIGS. 6A-6B, schedules 702, 704 provide unavailable loading times indicated by bars, each with a length corresponding to the length of the unavailable loading period. Furthermore, the light, medium, or dark shade of each bar indicates which subsystem or instrument in the work cell is at capacity, thus preventing the proposed cartridge from being loaded during that period. Dark bars represent the capacity of the BPS, medium bars represent feedthroughs in use or reserved for the scheduled cartridge, and light bars represent conflicts within the SLTS that restrict new input to the system. As shown in schedule 702, a proposed cartridge with a 7-day workflow was added to the system at approximately 9:30 AM on December 31, the available loading time. Therefore, schedule 702 was updated to incorporate the newly scheduled cartridge, as shown in FIG. 7B. There, updated schedule 704 shows a new cartridge loading window (represented by the medium-shade bar, from approximately 9:30 AM to approximately 1:00 PM on the 31st). Additionally, schedule 704 indicates that due to new cartridge workflow requirements, the BPS will reach and / or exceed capacity if another cartridge is loaded into the system between approximately 1:00 PM on December 31st and approximately 12:00 AM on January 7th. Additionally, to prevent another cartridge from being loaded before the target new cartridge (which would exceed the system's capacity when the target new cartridge is loaded), schedule 704 changed the status of a significant amount of potential loading time between December 25th and December 31st from available to unavailable.

[0133] While certain variations have been described and illustrated herein, those skilled in the art will readily envision various other means and / or structures for performing the functions and / or obtaining the results and / or one or more of the advantages described herein, and each such variation and / or modification is deemed to be within the scope of the inventive variations described herein. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary, and that the actual parameters, dimensions, materials, and / or configurations will depend on the particular application or applications in which the teachings of the present invention are used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific inventive variations described herein. Accordingly, it is to be understood that the foregoing variations are presented by way of example only and that, within the scope of the appended claims and their equivalents, the inventive variations may be practiced otherwise than as specifically described and claimed. The inventive variations of the present disclosure are directed to each individual feature and / or method described herein. In addition, any combination of two or more such features and / or methods, where such features and / or methods are not mutually inconsistent, is included within the inventive scope of the present disclosure.

Claims

1. 1. A method for cell treatment, comprising: determining a system configuration for a cell processing system configured to process a plurality of cartridges in parallel, each of the plurality of cartridges carrying a cell sample and configured to be loaded into a work cell of the cell processing system; determining a cartridge configuration for each of the plurality of cartridges; A method for cell processing, comprising: providing a loading schedule for loading a first cartridge of the plurality of cartridges into the work cell, the loading schedule being based on the system configuration and the cartridge configuration of each of the plurality of cartridges.

2. The method of claim 1 , wherein the loading schedule indicates one or more time periods that are unavailable for loading the first cartridge into the work cell.

3. The method of claim 1 , further comprising loading the first cartridge into the work cell based on the loading schedule.

4. The method of claim 1 , wherein the loading schedule is provided via a user interface of the cell processing system.

5. The method of claim 1 , wherein the system configuration defines a quantity of one or more subsystems of the cell processing system.

6. The method of claim 5 , wherein the one or more subsystems are contained within the work cell of the cell processing system.

7. The method of claim 5 , wherein the one or more subsystems include one or more of a material handling system, a sterile liquid transfer system, a sterility system, a bioprocessing system, and a quality control system.

8. The method of claim 5 , wherein the system configuration further defines operating time constraints for at least one of the one or more subsystems of the cell processing system.

9. The method of claim 1 , wherein the cartridge configuration comprises one or both of a loading configuration and a workflow configuration.

10. The method of claim 9 , wherein the loading configuration comprises a length of time for loading a cartridge into the work cell.

11. the workflow configuration includes a simulated cell processing workflow for a cartridge; 10. The method of claim 9, wherein the simulated cell processing workflow is based on a process design plan for the cartridge and one or more sample intake parameters for the cartridge.

12. 12. The method of claim 11, wherein the one or more sample intake parameters comprise one or more of sample cell type, sample collection time, transport time of the sample, arrival time of the sample at a processing facility, sample temperature, patient age, patient sex, donor age, and donor sex.

13. 10. The method of claim 1, wherein determining the cartridge configuration comprises padding the cartridge configuration data to compensate for one or both of workflow process variability and cartridge loading variability.

14. the plurality of cell processing cartridges includes at least one second cartridge; the first cartridge is not scheduled for processing within the cell processing system; The method of claim 1 , wherein the at least one second cartridge is scheduled for processing within the cell processing system.

15. 12. The method of claim 11, further comprising scheduling the first cartridge for processing in the cell processing system based on the loading schedule.

16. 10. The method of claim 1, further comprising determining an amount of competition within the cell processing system, wherein the loading schedule is further based on the determined amount of competition.

17. 1. A method for cell treatment, comprising: loading a plurality of cell samples into a cell processing system for parallel processing, the cell processing system including a plurality of processing devices; determining an amount of contention for each of the plurality of devices before and after each of a plurality of cell processing operations is performed by the cell processing system, the amount of contention being based on a number of cell samples requiring the device during a period of time; generating a notification via a user interface of the cell processing system indicating excessive contention if the number of cell samples requiring the instrument during the period is greater than two.

18. 18. The method of claim 17, further comprising identifying a priority cell sample among the plurality of cell samples for use of the instrument based on an instrument contention weight determined for each cell sample requiring the instrument during the period.

19. 20. The method of claim 18, wherein the prioritized cell sample comprises the highest weight of an instrument conflict.

20. 20. The method of claim 18, wherein for each cell sample, the instrument contention weight is based on a current cell processing operation dwell time and a subsequent cell processing operation execution time.

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