Self-coordinated management of biopharmaceutical devices

Abstract

A System for performing a bioprocess comprising of the following modular system components of a bioprocess machine with a digital controller for controlling the bioprocess machine; and at least one physical or software-based auxiliary device for being coupled to the bioprocess machine with a digital controller for controlling the auxiliary device; wherein the digital controllers each comprising a machine to machine communication tool (MtoM) configured for connecting to a network, a discovery negotiation pairing (DNP) manager configured for cooperating over the network for establishing a paired condition between either the bioprocess machine and the at least one physical or software-based auxiliary device and / or between the physical or software-based auxiliary devices,and a capability manager configured to organize capabilities of the paired bioprocess machine and / or the auxiliary devices which is characterized in that the digital controllers each comprising a communicating finite state-machines (CFM) tool which is configured to exchange system data with each other and enables each component to work autonomously regarding the capabilities of the paired components to perform the workflow of the bioprocess.

Description

[0001] SELF-COORDINATED MANAGEMENT OF BIOPHARMACEUTICAL

[0002] DEVICES

[0003] The hereby described invention discloses a system and a method for performing a bioprocess using modular process analytical technology system components.

[0004] Technical Field

[0005] The invention relates to the field of process analytical technology (PAT) for monitoring and control of biopharmaceutical production processes, such as for monoclonal antibodies, vaccines, and recombinant proteins.

[0006] Background and description of the prior art

[0007] In biopharmaceutical production facilities, process analytical technology (PAT) devices are used to monitor and control critical process parameters and quality attributes. To implement effective process control, scientists and engineers need to coordinate workflows across multiple interconnected PAT devices. PAT involves real-time measurements and analysis of critical quality attributes and process parameters to ensure consistent product quality.

[0008] Currently, this requires access to centralized systems like DCS, SCADA, or Process Orchestration Layers. However, these solutions are expensive, require significant expertise, and represent an additional centralized system to implement and maintain. At worst, operators are left to manually propagate setpoints between devices. Furthermore existing batch control systems can coordinate devices, but require significant expertise and cost. They are also centralized systems requiring separate configuration. The prior art technologies lack capabilities to enable modular bioprocess devices to directly interoperate and coordinate in a distributed fashion based on process analytics.

[0009] Some biopharmaceutical production facilities utilize modular processing equipment for different unit operations connected via a batch control system. As described in the prior art WO 2023 / 046605 A1 modular automation systems with interconnected manufacturing units or devices having digital controllers are known in the field of analytical technology (PAT) for monitoring and control of biopharmaceutical production processes. The prior art describes an automated Manufacturing Execution System (MES) with orchestration capabilities to coordinate modular units and execute manufacturing workflows and recipes.

[0010] However, such biopharmaceutical facilities have unique requirements compared to typical manufacturing plants. The production processes involve complex biological systems and sensitive protein molecules. Realtime process adjustments and tight coordination between analytical measurements and control of process equipment is critical. This has created a need for improved capabilities to integrate and orchestrate operations across modular bioprocessing equipment.

[0011] Therefore, there is a need for improved distributed control architectures and automation technologies that can meet the demands of interconnected analytical and processing equipment in modern biopharmaceutical production facilities.

[0012] The task of this patent application is now to address these challenges and to ease the configuration and integration of multiple PAT tools without requiring additional centralized systems. This will allow biopharmaceutical manufacturers to more readily implement process analytical technology and effectively coordinate devices to improve process monitoring and control. Summary of the invention

[0013] This task has been solved by a System for performing a bioprocess comprising of the following modular system components of a bioprocess machine with a digital controller for controlling the bioprocess machine; at least one physical or software-based auxiliary device for being coupled to the bioprocess machine with a digital controller for controlling the auxiliary device; wherein the digital controllers each comprising a machine to machine communication tool (MtoM) configured for connecting to a network, a discovery negotiation pairing (DNP) manager configured for cooperating over the network for establishing a paired condition between either the bioprocess machine and the at least one physical or software-based auxiliary device and / or between the physical or software-based auxiliary devicesand a capability manager configured to organize capabilities of the paired bioprocess machine and / or the auxiliary devices; and the digital controllers each comprising a communicating finite state-machines (CFM) tool which is configured to exchange system data with each other and enables each component to work autonomously regarding the capabilities of the paired components to perform the workflow of the bioprocess. The central piece of the invention is a communicating finite state-machines (CFM) implementation that is deployed on each system component. This enables the individual system components to work autonomously while still achieving a distributed workflow. After DNP pairing, the system components start to synchronize themselves so as to overall execute the said workflow. The DNP manager hereby can either establish a paired condition between the bioprocess machine and the available auxiliary devices and / or between the auxiliary devices, if more than one auxiliary device is available. The system data exchanges are thereby the content of messages of CFM. They are conveying process' events like start / stop of phases. They may also contain data like the identifier of a sampling. The messages of CFM are implemented as OPC UA Events and / or data monitoring. The events and data subscriptions are initiated as the outcome of the DNP capability pairing as further described. Advantageous and therefore preferred further developments of this invention emerge from the associated subclaims and from the description and the associated drawings.

[0014] One of those preferred further developments of the disclosed system comprise that after the DNP pairing, the components start to synchronize themselves to overall execute the bioprocess workflow. This provides the effect of an automated coordination.

[0015] Another one of those preferred further developments of the disclosed system comprise that the CFM tool is either hard-coded in the respective digital controller at design- or production-time in which case the DNP manager will be used to match the exchanged system data on actual process-related events, or deployed and configured by an external configuration software hosted by a Working Engineering Station in which case the external configuration software is used to match the exchanged system data on actual process-related events. This allows for an flexibility in implementation. As mentioned the system data exchanges are preferably the digital embodiment of, but not limited to, process-related events like the start of a process phase, or the end of a sampling associated with the sampling identifier.

[0016] Another one of those preferred further developments of the disclosed system comprise that the bioprocess workflow is defined in the external configuration software, so that the software splits and lower down the workflow into a configuration dedicated to each individual system component. This leads in the end to a centralized orchestration with decentralized execution. Another one of those preferred further developments of the disclosed system comprise that the configuration will be based on a CFM decomposition theory and knowledge of the system components, in particular of existing MTP configurations, an Asset Administration Shell, a signal description and / or a device shape, as an input. That allows an automated configuration generation tailored to each device. A CFM decomposition is defined as the inverse operation of composition. It means out of one CFM S_c, one can find S_a and S_b such that the composition of S_a x S_b is S_c. The composition of CFM is defined as: given two (or more) CFM S_a and S_b, the output S_(axb) is a unique CFM that behaves as the parrallel execution of S_a and S_b. The composition takes into account all the possible interleaving of communication between the composed CFM.

[0017] Another one of those preferred further developments of the disclosed system comprise that the MtoM tool is configured to transfer data in form of process- related events as a system data exchange and transforms it, so that the CFM tool can interpret it as CFM messages input. If some process-related events are already exposed by the bioprocess machine and / or auxiliary device as data (eg OPC UA Variables), M2M bridges could be leveraged to transfer those data and later be transformed as system data exchange, for the selfcoordinated service management to interpret as CFM messages input.

[0018] Another one of those preferred further developments of the disclosed system comprise that the at least one software-based auxiliary device is hosted either by a remote computer which transfers the created software-based auxiliary device to its respective digital controller or is hosted directly as a local instance on said respective digital controller. That allows flexibility and modularity in the system components.

[0019] Another one of those preferred further developments of the disclosed system comprise that the digital controller of the bioprocess machine and the auxiliary device each includes a file containing a description of each provided and consumed capability. This enables an automated discovery and matching between devices.

[0020] Another one of those preferred further developments of the disclosed system comprise that the DNP manager of the bioprocess machine and the auxiliary device are configured for cooperating over the network for establishing a paired condition. That leads to an automated handshaking and coupling of components.

[0021] Another one of those preferred further developments of the disclosed system comprise that the system includes a plurality of auxiliary devices and the DNP manager of each bioprocess machine is configured for establishing a paired condition simultaneously with and / or between the auxiliary devices. While it is possible and within the described invention that only one auxiliary device exists which is then paired to the bioprocess machine, the usual use case includes a plurality of auxiliary devices and paired conditions between them and / or with the bioprocess machine.

[0022] Another one of those preferred further developments of the disclosed system comprise that the system include a first bioprocess machine, a second bioprocess machine and a plurality of auxiliary devices, and the DNP manager of at least one auxiliary device is configured for establishing a paired condition either with the first bioprocess machine or with the second bioprocess machine.

[0023] Another one of those preferred further developments of the disclosed system comprise that each MtoM communication tool is configured for connecting to a network with an Internet Protocol, such as Ethernet, Wi-Fi, Bluetooth or cellular 5G. This allows leveraging standard robust networking protocols. Another solution of the given task is a method for operating a system as previously described, comprising the following steps of Importing a device description, e.g. a MTP file or device shape; Describing the workflow of the desired bioprocess in a visual way; Automatically generating a distributed self-coordinated artifact to create a self-coordination subsystem for each of the system components; Automatically generating a configuration in form of a user instructions list and / or an automated way of pairing the system components; Deploying these configurations on the system components via the network; and Manually or automatically activating the self-coordination subsystem on each configured system component to enable them to execute their bioprocess workflow according to the deployed configuration. The idea is that as an outcome of a decomposition algorithm, there is a list of the DNP capabilities to be paired. This list could be transformed as a user instructions list for for the user to manually execute. This same list could be also provided to another software that could automatically do the pairing without a manual user intervention.

[0024] Another one of those preferred further developments of the disclosed method comprise that the workflow of the desired bioprocess is described in a visual way via a BPMN editor. The Business Process Model and Notation (BPMN) is a widespread and known process modeling standard and therefore most possible users are familiar with it which makes it a preferred solution to display the desired bioprocess to the user who can then continue with the generated a worker instructions list.

[0025] Another one of those preferred further developments of the disclosed method comprise that for automatically generating a distributed self-coordinated artifact the following method steps are performed: The bioprocess workflow is first encoded as a finite state-machine with each state allocated to a unique bioprocess machine; Then heuristics and other algorithms are applied to split the finite state-machine into several communicating finite state-machines (CFM) each dedicated to one bioprocess machine; Recomposing of the CFM and validating them by comparing them to the initial bioprocess workflow; and Converting the split, individual CFM into artifacts which can be ingested by the local configurable self-coordinated service management of the respective bioprocess machine.

[0026] Another one of those preferred further developments of the disclosed method comprise that for manually activating the self-coordination subsystem on each configured system component after deployment of the configurations on the system components according to a production line plan, the lab scientist or the process engineer then plugs the horizontal network cable so that the network auto discovery occurs and DNP-pairs the system components as per the user instructions list on local hmi of the system components

[0027] Detailed description of the invention

[0028] The method and system according to the invention and functionally advantageous developments of those are described in more detail below with reference to the associated drawings using at least one preferred exemplary embodiment. In the drawings, elements that correspond to one another are provided with the same reference numerals.

[0029] The drawings show:

[0030] Figure 1 : a schematic of an example of the invented system

[0031] Figure 2: a schematic of an example of the service management workflow

[0032] One exemplary preferred embodiment of the invented method will be described in the following. The steps itself are performed divergent in every exemplary embodiment dependent on the different conditions. In the chosen preferred embodiment Figure 1 shows an example of a preferred embodiment of the invented system. It is based on the system as disclosed by the mentioned prior art document WO 2023 / 046605 A1 and in this preferred embodiment discloses a bioprocess machine and two bioprocess auxiliary devices. All such system components comprise of a fluid treater, which is in a further preferred embodiment a bioreactor for the bioprocess machine and e.g. a pump for the auxuliar devices. They further comprise of a digital controller, wherein the digital controller comprises of a device shape file with a configuration and three tools: a machine to machine communication tool (MtoM) for connecting to a network, a discovery negotiation pairing (DNP) manager for cooperating over the network for establishing a paired condition between the bioprocess machine and / or the at least one physical or software-based auxiliary device and a capability manager configured to organize capabilities of the paired bioprocess machine and / or the auxiliary devices. Core of this invention is now the Configurable self-coordinated service-manager. A further novel system component is the Working Engineer Station which has a Configuration software stored which can be used to configure the bioprocess machine and / or the auxiliary devices.

[0033] This system can now be used in a preferred way which is disclosed in Figure 2 as well as described further in the following chapters.

[0034] Depending on if there is a preset configuration not sufficient or not existing a lab scientist or the process engineer will from a working engineering station to perform the following steps:

[0035] 1 ) imports devices description, e.g. MTP file or device shape

[0036] 2) describes its expected workflow in a visual way (like BPMN editor as in Figure 2 of the working example 3) automatically generate distributed self-coordinated artifact for each of the concerned devices a. To achieve this, the services workflow is first encoded as a finite state-machine with each state allocated to a unique bioprocess machine. b. Then, heuristics and other algorithms are applied to split it into several communicating finite state-machines (CFM) each dedicated to one bioprocess machine. In the case of preset bioprocess machine, the CFM of this machine is exactly the preset one. c. Finally, those CFM are recomposed and compared to initial workflow to ensure correctness. d. Once split, the individual CFM are converted to artifacts that local configurable self-coordinated service management can ingest.

[0037] 4) Automatically generate a worker instructions list and / or an automated way of pairing devices

[0038] 5) Push those configurations on devices, eg through OPC UA ComGW

[0039] Once devices installed as per production line plan, the lab scientist or the process engineer then: a. plug the horizontal network cable so that network auto discovery occurs. b. DNP-pair the devices as per the worker instructions list on local hmi of said devices (or from generated sw) c. manually or automatically activate the self-coordination subsystem on one of the said devices. The devices then execute following their configuration, overall ensuring the expected workflow execution.

Claims

Patent claims1. System for performing a bioprocess comprising of the following modular system components: a bioprocess machine with a digital controller for controlling the bioprocess machine; and at least one physical or software-based auxiliary device for being coupled to the bioprocess machine with a digital controller for controlling the auxiliary device; wherein the digital controllers each comprising a machine to machine communication tool (MtoM) configured for connecting to a network, a discovery negotiation pairing (DNP) manager configured for cooperating over the network for establishing a paired condition between either the bioprocess machine and the at least one physical or software-based auxiliary device and / or between the physical or software-based auxiliary devices, and a capability manager configured to organize capabilities of the paired bioprocess machine and / or the auxiliary devices; characterized in that the digital controllers each comprising a communicating finite statemachines (CFM) tool which is configured to exchange system data with each other and enables each component to work autonomously regarding the capabilities of the paired components to perform the workflow of the bioprocess.

2. System according to claim 1 characterized in that after the DNP pairing, the components start to synchronize themselves to overall execute the bioprocess workflow.

3. System according to any of the previous claims characterized in that the CFM tool is either hard-coded in the respective digital controller at designor production-time in which case the DNP manager will be used to match the exchanged system data on actual process-related events, or deployed and configured by an external configuration software hosted by a Working Engineering Station in which case the external configuration software is used to match the exchanged system data on actual process-related events.

4. System according to claim 3 characterized in that the bioprocess workflow is defined in the external configuration software, so that the software splits and lower down the workflow into a configuration dedicated to each individual system component.

5. System according to claim 4 characterized in that the configuration will be based on a CFM decomposition theory and knowledge of the system components, in particular of existing MTP configurations, and / or an Asset Administration Shell, and / or a signal description, and / or a device shape, as an input.

6. System according to any of the previous claims characterized in that the MtoM tool is configured to transfer data in form of process-related events as a system data exchange and transforms it, so that the CFM tool can interpret it as CFM messages input.

7. System according to any of the previous claims characterized in that the at least one software-based auxiliary device is hosted either by a remote computer which transfers the created software-based auxiliary device to its respective digital controller or is hosted directly as a local instance on said respective digital controller.

8. System according to any of the previous claims characterized in that the digital controller of the bioprocess machine and the auxiliary device each includes a file containing a description of each provided and consumed capability.

9. System according to any of the previous claims characterized in that the DNP manager of the bioprocess machine and the auxiliary device are configured for cooperating over the network for establishing a paired condition.

10. System according to any of the previous claims characterized in that the system includes a plurality of auxiliary devices and the DNP manager of each bioprocess machine is configured for establishing a paired condition simultaneously with and / or between the auxiliary devices.11 . System according to any of the previous claims characterized in that each MtoM communication tool is configured for connecting to a network with an Internet Protocol, such as Ethernet, Wi-Fi, Bluetooth or cellular 5G.

12. Method for operating a system according to claims 1 to 11 , the following steps comprising:• Importing a device description, e.g. a MTP file or device shape;• Describing the workflow of the desired bioprocess in a visual way;• Automatically generating a distributed self-coordinated artifact to create a self-coordination subsystem for each of the system components ;• Automatically generating a configuration in form of a user instructions list and / or an automated way of pairing the system components;• Deploying these configurations on the system components via the network; and• Manually or automatically activating the self-coordination subsystem on each configured system component to enable them to execute their bioprocess workflow according to the deployed configuration.

13. Method according to claim 12 characterized in that the workflow of the desired bioprocess is described in a visual way via a BPMN editor.

14. Method according to claims 12 to 13 characterized in that for automatically generating a distributed self-coordinated artifact the following method steps are performed:• The bioprocess workflow is first encoded as a finite state-machine with each state allocated to a unique bioprocess machine;• Then heuristics and other algorithms are applied to split the finite statemachine into several communicating finite state-machines (CFM) each dedicated to one bioprocess machine.• Recomposing of the CFM and validating them by comparing them to the initial bioprocess workflow;Converting the split, individual CFM into artifacts which can be ingested by the local configurable self-coordinated service management of the respective bioprocess machine.

15. Method according to claims 12 to 14 characterized in that for manually activating the self-coordination subsystem on each configured system component after deployment of the configurations on the system components according to a production line plan, the lab scientist or the process engineer then plugs the horizontal network cable so that the network auto discovery occurs and DNP-pairs the system components as per the user instructions list on local hmi of the system components.

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