Monitoring system and method for biopharmaceutical products

Abstract

A monitoring system includes a manufacturing system having the ability to manufacture a plurality of biopharmaceutical products; at least one image capture device arranged to capture a scene comprising a manufacturing system; and a processing element connected to the at least one image capture device and arranged to process images captured by the at least one image capture device to track operator interactions and / or results of the operator interactions within the scene. The processing element is further arranged to compare a predefined workflow process scheme relating to the selected biopharmaceutical product with at least a portion of an interaction with a tracked operator of the manufacturing system and / or at least a portion of a result of the interaction with the tracked operator of the manufacturing system, and determining whether at least one preset criterion set by the workflow process scheme is satisfied based on the comparison.

Description

Technical Field

[0001] The present disclosure relates to systems for monitoring the manufacture of selected biopharmaceutical products.

[0002] The present disclosure further relates to a method for monitoring settings for manufacturing and / or settings for manufacturing of a selected biopharmaceutical product among a plurality of biopharmaceutical products. Background Art

[0003] The past decade has seen a major shift in the nature of products manufactured and sold by the innovative biopharmaceutical industry. Today's global biopharmaceutical portfolio reflects the greater prevalence of large molecule drugs, the expansion of the number of individualized or targeted products, and the rise of treatments for many rare diseases. These developments provide biopharmaceutical products with extremely limited production runs, high specific manufacturing requirements, and genotype-specific products. The ongoing shift in product mix provides a need for continuous improvement in the efficiency and effectiveness of production biopharmaceutical manufacturing.

[0004] Biopharmaceuticals (also known as biologics) such as therapeutic proteins, monoclonal antibodies, vaccines, etc. are complex molecules made by living cells or by living cells. They usually require parenteral administration by infusion or injection, thus requiring highly specialized manufacturing, special storage and manipulation, and close control, high-quality manufacturing and distribution networks to ensure safety and efficacy. The development of orphan drugs (i.e., drugs for diseases with a patient population of less than 200,000) has also been observed, and there has been a steady increase in the past decade. In addition, manufacturers are increasingly focusing on more complex diseases, for which there are very few or no effective treatments. The new treatments for these diseases are characterized by small batches of products.

[0005] Another important trend within biopharmaceuticals is the emergence of personalized medicine (i.e., products tailored to specific patient populations). Over time, manufacturing and product supply complexity will likely increase with the introduction of patient-level personalized medicine.

[0006] Biopharmaceutical products can be expected to be used for example for treatment or diagnosis. In order to ensure adequate product quality and well-controlled and auditable production conditions, cGMP (current good manufacturing practice) and QMS (quality management system) are usually required and applied. GMP processing environment is designed to comply with the guidelines recommended by specialized agencies (such as the Food and Drug Administration FDA) that control the authorization and licensing of the manufacture and sale of pharmaceutical products.

[0007] These drug combination trends promote the increase in the number and complexity of manufactured and commercially sold products. In addition, the above-mentioned trend and rapid market growth of biotherapeutics also imply the sharp increase in the number of small production batches during drug development before the product enters the market, especially for the production of clinical trial materials. Because the drug development process is generally characterized as a 'development funnel', wherein there is a significantly larger number of drug candidates that have undergone clinical trials compared to the number of successful and ultimately approved drugs. The production of bulk drugs during clinical trials and regular production requires high safety and throughput provided by the manufacturing system. However, the production of bulk drugs for clinical trials generally requires even higher flexibility in manufacturing methods and systems, to suit different requirements and production protocols, but still comply with strict cGMP and QMS requirements. For the background of all biopharmaceutical products subject to cost pressure, cost reduction during clinical manufacturing and drug development is equally important for the regular production of approved drugs. Therefore, a cost-effective and safe production system providing high throughput needs to adapt to frequent process changes, process and equipment reconfiguration and other modifications. In addition, some of the new medicines have increased the need for more complex manufacturing processes and more advanced equipment. Continuous and connected processing systems are emerging as a supplement or alternative to traditional batch manufacturing methods and may offer advantages in overall product and / or process quality, efficiency and throughput or cost.

[0008] In general, these drug combination trends indicate the need to have improved manufacturing creation flexibility without compromising quality, while creating operational efficiencies that can help reduce costs. A recent technological development used to reduce production costs, increase production throughput and quality, and reduce safety issues is to use single-use technology (SUT) for processing. Utilizing single-use technology equipment, wetted parts (such as fluid storage containers, pipelines, separation equipment, etc.) that contact process fluids and drug products during processing are provided as consumables, which are installed and used only for specific processes, and are thereafter disposed of. SUT consumables are typically produced, configured, and packaged in a clean room environment, and are pre-sterilized (such as by gamma irradiation) before use in a biomanufacturing process. In contrast to the traditional and fixed installation using stainless steel piping and stainless steel reactors and containers, SUT equipment and consumables simply provide greater flexibility in different process situations and configurations by rearranging (moving) equipment, installing, and replacing different consumables within the process. For example, a tank bin can be equipped with a clean and / or sterilized SUT fluid bag to provide a clean and encapsulated housing for fluids and their processing. The advantage of using single-use technology (SUT) fluid handling equipment is mainly that when the SUT equipment is used only for a single drug product, cross contamination between production batches and production campaigns is eliminated. The SUT equipment is discarded after use, which can be after a single run, batch or campaign including multiple runs and batches. When a pre-sterilized or bioburden-controlled SUT equipment is provided, initial cleaning and sterilization (e.g., by contacting the flow path with a sodium hydroxide solution) or disinfection can be avoided. When the SUT is used only for a single run or batch, even post-use cleaning can be omitted. With these features, the SUT equipment provides improved efficiency, safety and convenience. Today, SUT equipment can be used for most of all types of equipment and / or unit operations, among which are bioreactors for cell culture or fermentation, buffer bags for liquid storage, pipes and pumps for liquid transfer and filling operations, filters for separation, chromatographic columns and related systems. However, compared with traditional manufacturing using fixed stainless steel installations, the adaptation of single-use technology also implies a higher throughput and flow of materials (i.e., SUT consumables) in production processes and facilities. Furthermore, a large number of additional operating steps and operator interactions (work) are required to manipulate the material flows, as well as to install and remove disposable consumables before and after processing, and to document the materials, material flows, and their use in the process. The frequent changes associated with SUT consumables imply that new (recent) installations of process lines will be used and documented for each drug run, batch, or movement in the manufacturing process. The biopharmaceutical industry has rapidly adopted SUT for the reasons described above, but this adaptation is also characterized by at least some of the following challenges: Frequent installation of complete fluid paths required ·The large amount of material that will be handled by the operator and managed in planning, logistics and documentation Materials (i.e., consumables and commodities) are subject to in-process variation due to procurement variability and / or lack of standardization of single-use consumables Many manual interaction steps. Summary of the invention

[0009] It is an object of the present disclosure to provide solutions that seek to mitigate, alleviate or eliminate one or more of the above-mentioned deficiencies in the art and provide for improved biopharmaceutical manufacturing.

[0010] This object is achieved by a monitoring system for monitoring the manufacture of a selected biopharmaceutical product. The monitoring system comprises a manufacturing system having the capability to manufacture a plurality of biopharmaceutical products or a class of biopharmaceuticals in a plurality of predefined protocols or production scenarios, which may differ in their specific operating conditions, equipment / unit operation settings or processing systems (e.g. batch or continuous and connected processing). Unit operations are defined processing steps, such as reactors, filtration steps, chromatographic operations, etc. The monitoring system comprises: at least one image capture device, the at least one image capture device being arranged to capture a scene including the manufacturing system; and a processing element, the processing element being connected to the at least one image capture device and being arranged to process images captured by the at least one image capture device to track operator interactions and / or results of operator interactions within the scene. The processing element is further arranged to compare a predefined workflow process scheme associated with the selected biopharmaceutical product with at least a portion of the tracked operator interactions with the manufacturing system and / or at least a portion of the results of the tracked operator interactions with the manufacturing system. The processing element is further arranged to determine, based on the comparison, whether at least one preset criterion set by the workflow process scheme is met.

[0011] The use of predefined workflow process scenarios associated with specific selected biopharmaceutical products and comparison with at least a portion of tracked user-operator interactions with the manufacturing system and / or at least a portion of the results of tracked operator interactions with the manufacturing system enables improved manufacturing flexibility without compromising quality while creating operational efficiencies that can help reduce costs. Quality applies in this article to multiple or all parts of the process, such as inspection prior to installation (i.e., inspection of the so-called bill of materials BOM, including materials required to achieve the installation setting), installation of the installation setting, installation procedures, approval / inspection of the installation setting and installation procedures, the processing itself, and disassembly of the installation setting.

[0012] All of the above may be included in the above-mentioned predefined workflow process scheme. Verification and documentation may be obtained. Thus, the predefined workflow process scheme comprises at least the data of the traditional batch protocol, but it may further comprise other processes, i.e. the extended batch protocol as is evident from the above. The predefined workflow process scheme may also comprise the data of the batch record, thus comprising data related to the approval and verification of the batch protocol / extended batch protocol.

[0013] Therefore, the terms 'batch record' (BR, eBR - electronic batch record) and batch protocol are equivalent to a "predefined workflow process scheme". The protocol is the instructions and the record is the complete protocol as the documented proof and result of the executed process.

[0014] The monitoring system as disclosed herein supports (and refines) electronic protocols and records, thereby allowing processing elements to communicate in ways that would otherwise be impossible, and is efficient in its flexibility, agility, adaptability, and learning capabilities.

[0015] Deviations from the installation arrangement as indicated by the predetermined protocol may be detected. The installation setup may include a check prior to installation (so-called check of the bill of materials) and / or installation of the installation setup and / or removal of the installation setup. Deviations from the installation setup that adversely affect the final biopharmaceutical product may lead to a determination that the manufacturing system is not correctly setup.

[0016] Additionally, deviations from installation procedures as indicated by a predetermined protocol may be detected. Deviations from installation procedures that adversely affect the final biopharmaceutical product may lead to a determination that the manufacturing system was not properly configured.

[0017] Furthermore, deviations from installation settings and / or installation procedures and other deviations known to adversely affect the final biopharmaceutical product can then be recorded. The characteristics of the final biopharmaceutical product thus manufactured can be recorded in association with the recorded deviations. A detailed analysis of the impact of different procedure deviations can then be obtained, which in turn can be used to further improve the installation procedures of the predetermined scheme. Accordingly, the deviations in the final biopharmaceutical product thus produced can even be reduced over time.

[0018] The monitoring system and the way it works with the electronic work instructions also allow to provide some flexibility in using different external devices (e.g. consumables) that produce the same functionality of the assembled final system. The monitoring system allows to guide the operator through this operation following an electronic batch protocol. Thus, flexibility handles material procurement variability; the system is able to self-learn and improve instructions and autonomy in electronic inspection during changes and repeated use of new configurations.

[0019] Further embodiments of the invention are defined in the dependent claims.

[0020] The objects of the present disclosure are also obtained by a method for monitoring settings for manufacturing and / or settings for manufacturing and / or disassembly after manufacturing of a selected biopharmaceutical product. The method includes the following steps: capturing an image of a scene including a manufacturing system, wherein the manufacturing system has the capability to manufacture a plurality of biopharmaceutical products and has a plurality of first connector elements for connecting to an external device; processing the captured image to track operator interactions and / or results of operator interactions within the scene; comparing at least a portion of the tracked operator interactions and / or at least a portion of the results of the tracked operator interactions with the manufacturing system to a predefined workflow process scheme associated with the selected biopharmaceutical product; and determining, based on the comparison, whether at least one preset criterion set by the workflow process scheme is met.

[0021] According to the method, the stored data can be used in subsequent steps, wherein the manufacturing process is improved based on learning based on the at least semi-autonomous model, whereby the production of the final biopharmaceutical product can be refined and potential deviations in the final biopharmaceutical product can be reduced for each biopharmaceutical product manufactured.

[0022] The object of the present disclosure is also obtained by a computer program product, which includes at least one non-transitory computer-readable storage medium having computer-executable program code instructions stored therein. The computer-executable program code instructions include program code instructions configured to perform the method as described above when executed.

[0023] In addition to the above advantages (which are naturally also applicable to the method and computer program product embodiments), the present disclosure also provides the advantage of improved process robustness and the possibility of accelerating vertical expansion to commercial production of biopharmaceutical products. Additional advantages include increased flexibility and reduced production lead time. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 is a block diagram illustrating an example of a monitoring system.

[0025] Figure 2 It is a graphic Figure 1 A block diagram of an example of a user interface suitable for use in a monitoring system.

[0026] Figure 3 Schematic diagram illustrating examples of production records for selected biopharmaceutical products.

[0027] Figure 4 Schematic diagram illustrating an example of a manufacturing facility scenario.

[0028] Figure 5 Schematic diagram illustrating an example of a timeline for identification of external devices and other equipment within a facility.

[0029] Figure 6 is a flow chart illustrating an example of a method for monitoring settings for manufacturing and / or settings for manufacturing of a selected biopharmaceutical product among a plurality of biopharmaceutical products.

[0030] Figure 7 A diagrammatic scheme illustrating different levels of providing manufacturing support compliant with the ISA95 standard.

[0031] Figure 8 Illustrate an example of a timeline of high-level workflow operations and activities and the instructions associated with them. DETAILED DESCRIPTION

[0032] Figure 1 A system 100 for monitoring the manufacture of a selected pharmaceutical product is disclosed.

[0033] When it comes to the manufacture of biopharmaceutical products, the process is important for the final biopharmaceutical product in terms of the type, configuration and installation of the manufacturing system, as well as the detailed processing system for the operating parameters. Therefore, the installation procedures for setting up the manufacture can have an impact on the final biopharmaceutical product, because errors or imperfect installations can cause fluid leakage, failure or changes in the processing steps and their results. For example, the regulatory and / or legal requirements for the production of biopharmaceuticals approved by the FDA (Food and Drug Administration) require strict control and documentation of the settings, installation and use of equipment, such as for operator interaction and automatic process control. Operating procedures (such as batch protocols) and records (such as batch records) are basic concepts in the development and production of biopharmaceuticals, including approval and monitoring from regulatory agencies. The system as defined herein is also useful in monitoring the settings for the installation of the manufacture and the procedures for setting the installation for the manufacture.

[0034] The monitoring system is suitable for the manufacture of a variety of biopharmaceutical products. The monitoring system is suitable for handling small batch runs that require frequent changes and may require equipment reconfiguration and updating.

[0035] Furthermore, as described above, the system is suitable for handling manufacturing using manufacturing processes in which increasing complexity and / or more advanced equipment may be used.

[0036] The system allows for improved manufacturing flexibility without compromising quality, while creating operational efficiencies that can help reduce costs.

[0037] Monitoring system 100 includes manufacturing system 110. The manufacturing system is suitable for the manufacture of a selected biopharmaceutical product among a plurality of biopharmaceutical products. In nature, the manufacturing system is selected based on the biopharmaceutical product to be manufactured. In nature, the same or similar configuration of the manufacturing system can be used for the production of several biopharmaceutical products.

[0038] The manufacturing system 110 may include a liquid chromatography system, which is preferably configured to operate with at least one column and is configured for purification of a sample including a target product using a predefined process. The manufacturing system may include one or more manufacturing devices. Each manufacturing device may be suitable for the pharmaceutical product to be manufactured. Each manufacturing device may be provided with an installation and configuration to adapt to the results of the manufacturing device. Examples for typical manufacturing devices are devices for fluid transfer, fluid filling, fluid or buffer preparation, devices for cell culture or fermentation (e.g., bioreactors), devices for cell collection or purification, devices for chromatography or membrane adsorption, filtration or buffer exchange devices, etc. Manufacturing devices can be combined to achieve an integrated system that runs multiple processing steps.

[0039] A manufacturing system can be defined as one or more unit operations that include installations and configurations that are used to adapt to the results of the unit operations. Examples for typical unit operations are fluid transfer, fluid or buffer preparation operations, cell culture operations using bioreactors, cell collection or purification operations, chromatography or membrane adsorption operations, filtration or buffer exchange operations, etc. A manufacturing system can include unit operations that are combined so as to implement an integrated system that runs multiple processing steps, and the regulations, instructions, documentation, and operator guides of the manufacturing system can be suitable for this aspect. In addition, a manufacturing system and its components can be suitable for batch processing and / or continuous and connected processing systems. Therefore, different manufacturing devices are arranged to perform different types of unit operations.

[0040] The monitoring system has procedures, instructions, documentation and operator guides that can be adapted to the manufacturing system in this regard. In addition, the monitoring system and its components can be adapted to batch processing and / or continuous and connected processing systems.

[0041] The monitoring system 100 may further include a user interface 160. The biopharmaceutical product may then be selected via the user interface.

[0042] The monitoring system further comprises at least one image capture device 130 arranged to capture a scene comprising the manufacturing system. The at least one image capture device may be arranged to capture an image of substantially the entire scene.

[0043] The at least one image capture device 120 may include a camera, a thermal camera, and / or a three-dimensional camera arranged to record an image within a field of view. The camera may be arranged to generate a time series of images. At least one of the cameras may be a video camera. At least a portion of the image may be time stamped.

[0044] Additional sensor elements may be provided to obtain additional position information, for example as distance or coordinates. The sensor elements may include radar and / or lidar and / or GPS receivers, etc. The additional sensor element(s) may be arranged at the image capture device or arranged in a known relationship to it. The additional sensor element(s) may be arranged to provide redundancy and / or additional spatial resolution to the images captured by the image capture device.

[0045] The monitoring system 100 further comprises a processing element 150 connected to the at least one image capture device. The processing element 150 is arranged to process images captured by the at least one image capture device to track operator interactions and / or results of operator interactions within a scene.

[0046] The processing element 150 is further connected to the memory 170. The memory includes a plurality of workflow process schemes. Each scheme is associated with a specific biopharmaceutical product or product batch. The predetermined workflow process scheme associated with a specific biopharmaceutical product or product batch may include one or more components. The predetermined workflow process scheme associated with a specific selected biopharmaceutical product may include components involving at least a portion of the tracked user operator interactions with different components of the manufacturing system and / or at least a portion of the results of the tracked operator interactions with different components of the manufacturing system (e.g., installation of installation settings, installation procedures, processing itself, and removal of installation settings). The predetermined workflow process scheme may also include processes that may not necessarily be connected to the manufacturing system itself, such as inspections before installation (so-called inspections of the bill of materials).

[0047] Thus, the predefined workflow process scheme may include processes and data typically included in a traditional batch processing protocol, but it may further include other processes and data, ie, an extended batch processing protocol as is apparent from the above description.

[0048] The predetermined workflow process scheme may also include approval / verification of installation settings and installation procedures. Thus, the predetermined workflow process scheme may also include data of batch records, thus including data related to approval and verification of batch protocols / extended batch protocols.

[0049] The workflow process protocol and / or its components may be permanently stored in memory or checked in for the manufacture of a particular biopharmaceutical product.

[0050] The processing element 150 is further arranged to compare a predefined workflow process scheme associated with the selected biopharmaceutical product with at least a portion of the tracked operator interactions with the manufacturing system and / or at least a portion of the results of the tracked operator interactions with the manufacturing system.

[0051] The processing element 150 is further arranged to determine, based on the comparison, whether at least one preset criterion set by the workflow process scheme is met.

[0052] Thus, deviations from the installed settings as indicated by the predetermined protocol may be detected.Deviations from the installed settings that adversely affect the final biopharmaceutical product may lead to a determination that the manufacturing system was not correctly configured.

[0053] Additionally, deviations from installation procedures as indicated by a predetermined protocol may be detected. Deviations from installation procedures that adversely affect the final biopharmaceutical product may lead to a determination that the manufacturing system was not properly configured.

[0054] In addition, deviations from installation settings and / or installation procedures and other deviations known to adversely affect the final biopharmaceutical product can then be recorded. The characteristics of the final biopharmaceutical product thus manufactured can be recorded in association with the recorded deviations. A detailed analysis of the impact of different procedure deviations can then be obtained, which in turn can be used to further improve the installation procedures of the predetermined scheme. Accordingly, the deviations in the final biopharmaceutical product thus produced can even be reduced over time. For example, machine learning can be used for analysis. This will be described in more detail below.

[0055] The predetermined workflow process scheme defines in different embodiments a plurality of predetermined interconnections between a plurality of first connector elements 111 of the manufacturing system 110 and at least one second connector element 121 of at least one external device 120 connectable to the manufacturing system 110. The processing element 150 may then be arranged to process the image and / or information obtained by the additional sensor element or by operator input in order to: identify the interconnections between the first and second connector elements 111, 121 in the image; compare each identified interconnection with a predetermined interconnection defined by the predetermined workflow process scheme; and determine based on the comparison which operator interaction results meet at least one preset criterion. Thus, according to these embodiments, it is then determined whether the manufacturing system is connected to the respective external device. Thus, according to these embodiments, it is then determined whether the manufacturing system is connected to the respective external device. Furthermore, when the manufacturing system comprises a plurality of manufacturing devices, the same may apply to the interconnections between different manufacturing devices of the manufacturing system.

[0056] The processing element 150 has the capability to guide the operator to avoid deviations, such as establishing an incorrect interconnection. When working with single-use consumables and, for example, with disposable sterile connectors, incorrectly established interconnections may not be reversible without a violation of the sterility or sterilization state of the assembly and thereby compromising quality during setup and production. Therefore, correction of a faulty interconnection in an assembly may require replacement and reinstallation of a larger subassembly and, in the worst case, a complete fluid line.

[0057] The processing element 150 further has the capability to guide the operator to correct and resolve moderate deviations in accordance with predetermined solutions and actions determined and presented by the processing element, and the processing element 150 does so in a proactive manner. This increases overall efficiency in manufacturing because minor deviations addressed and corrected by means of the monitoring system can produce approved and verified results that are compatible with predetermined protocols. Independent follow-up by supervisors and / or formal investigations can be avoided or at least facilitated by means of the actions, corrections, and documentation provided by the monitoring system.

[0058] The monitoring system can analyze the causes, effects, and resolution of the deviations to further improve the installation procedures and / or prevent future deviations according to the predetermined plan. It can also analyze and propose improvements or alternatives to the predetermined plan. In this regard, intelligent or learning systems can be used. This will be discussed in more detail later.

[0059] Accordingly, deviations in the final biopharmaceutical product thus produced may even be reduced over time.

[0060] The at least one external device 120 may include consumables and / or sensor elements and / or electronics and / or a power supply.

[0061] The consumables may be flow paths, including, for example, wetted fluid lines, bags, connectors, and sensors. The consumables may be single-use flow paths that may be installed and interchanged for different biopharmaceutical products, product batches, and / or production campaigns. The external device may also include reusable hardware configured with consumables, which may be single-use consumables.

[0062] Thus, a comparison of a predefined workflow process scheme associated with a selected biopharmaceutical product and at least a portion of the tracked operator interactions with the manufacturing system and / or at least a portion of the results of the tracked operator interactions can be performed, for example, for the connection of hoses for consumables and for the connection of cables. Furthermore, the comparison is performed in addition or in lieu of installed sensors that extend into the manufacturing device for sensing characteristics associated with the manufactured biopharmaceutical product and / or the manufacturing device itself.

[0063] Thereby, it may be determined that the manufacturing system is supplied with consumables, and / or is connected to an electrical device, and / or is connected to a power supply, and / or that the sensor(s) are installed according to a predetermined workflow process scheme.

[0064] The predetermined workflow process scheme may further include characteristics of an external device 120 connected to the manufacturing system 110 for the manufacture of the selected biopharmaceutical product. The processing element 150 may then be arranged to obtain information related to at least one connected external device, compare the obtained information with the characteristics of the connected external device obtained from the predetermined workflow process scheme, and determine whether a preset criterion related to the characteristics of the external device (the external device is connected to the manufacturing system) set by the predetermined workflow process scheme is met.

[0065] Thus, it can be determined that the manufacturing system is supplied with correct consumables, and / or is connected to the correct electrical device, and / or is connected to the correct power supply, and / or (one or more) correct sensors are installed. In addition, it can be determined that the external devices (such as consumables) of the manufacturing system are connected in the correct order and configuration. This increases safety because the determination implies that the correct product is delivered by a system with an expected property. By determining the correct configuration and the compliance with the operating procedures through the monitoring system and also determining the operator interaction and behavior that meet the operating procedures, the error made by the operator, the error in the setting or other deviations can be detected and corrected and first omitted, which has great value for the inspection of the correct production setting before the manufacturing system is defined so that the manufacturing system can subsequently process fluids and drugs of interest. The above also relates to, for example, the disassembly of the processing itself and / or the system.

[0066] In various embodiments of the present disclosure, the processing element 150 is arranged to detect at least one of the connected external devices 120 in the image, and to obtain information related to at least one of the connected external devices based on the detection in the image. The information may be obtained from a barcode, QR code and / or plain text on the connected external device and / or detected characteristics of the connected external device itself (e.g., shape and / or outline and / or color and / or appearance (translucent, opaque, reflective, etc.)).

[0067] Accordingly, the captured image can be used to detect the external device. Therefore, as soon as a new external device enters the scene, this can be detected by processing the image.

[0068] Furthermore, any information in the captured image relating to characteristics of the connected external device may be used by the system to derive information relating to the corresponding external device.

[0069] The processing element 150 may be arranged to obtain information related to at least one connected external device 120 by receiving external device data via wireless or wired communication. In the illustrated example, the manufacturing system includes a receiver 140, which is arranged to receive wirelessly transmitted data. However, such a receiver may be located at other locations within the facility. The operator may even carry an electronic user device with such functionality. The external device data received by the receiver 140 is transmitted to the processing element 150. The external device data related to at least one connected external device may include identification code data. For example, the identification code data may be transmitted from an RFID tag 122 associated with the external device 120.

[0070] Accordingly, the corresponding external device can be detected by receiving external device data (eg identification code data for identifying a separate external device). Thus, as soon as a new external device enters the scene, this can be detected by receiving external device data (eg identification code data).

[0071] Furthermore, received external device data associated with the respective connected external devices may be used by the monitoring system to derive information associated with the respective external devices.

[0072] Furthermore, the determination that the manufacturing system is supplied with the correct consumables and / or connected to the correct electrical device and / or connected to the correct power supply and / or the correct sensor(s) are installed may alternatively or additionally be based on tracking of the operator(s) within the scenario. Thus, multiple ways of determining that the correct external device is connected may provide redundancy in the determination. Thus, multiple sources underlying the determination may be used to improve reliability.

[0073] The processing element 150 may additionally or alternatively be arranged to obtain information related to the at least one external device 120 through operator input via the user interface 160 .

[0074] The processing element 150 may be arranged to track operator interactions with at least one external device, compare the tracked operator interactions with at least one external device with a predefined workflow process scenario involving operator interactions with at least one external device, and determine whether at least one preset criterion set by the predefined workflow process scenario is met based on the comparison.

[0075] Accordingly, not only are operator interactions with the manufacturing system and / or their results tracked, but operator interactions with the external device(s) and / or their results are also tracked.

[0076] The processing element 150 may be arranged to track the operator when connecting the respective interconnecting element to its corresponding external device, and / or when installing the respective external device. Thus, the processing element may be arranged to track the operator when connecting to the external device hoses, cables, etc. connected to the manufacturing system. The processing element may further be arranged to track other procedures for installing the respective external device.

[0077] The comparison to the predetermined protocol involving the selected biopharmaceutical product may then include comparing the procedure as determined based on the image to the procedure as indicated by the predetermined workflow process protocol involving the selected biopharmaceutical product.

[0078] The scene captured by the at least one image capture device may at least partially include a biopharmaceutical manufacturing facility, the biopharmaceutical manufacturing facility including a manufacturing system. The processing element 150 may be arranged to process the image captured by the at least one image capture device to determine at least one of the following: Prior to initiating setup for manufacturing of a selected biopharmaceutical product, determining that the biopharmaceutical manufacturing facility is in a state ready to initiate setup for manufacturing. Thus, the predefined workflow process scheme may include a set of criteria that, when met, defines that the facility is ready to initiate setup for manufacturing. In a GMP (Good Manufacturing Process) processing environment with processes running in a dedicated production area or room, a fundamental aspect of determining the readiness of the setup manufacturing system is to verify the bill of materials (BOM) included by the batch processing protocol. The bill of materials typically includes (single-use) consumables, buffers, containers required to configure the manufacturing system. The bill of materials may also include hardware and other components required to execute the process, such as sampling devices, etiquettes, etc.

[0079] The monitoring system and its processing element 150 can determine that the correct BOM is delivered to the scene by checking the identification code, shelf life validity, etc. In the case of any variability detected for the batch protocol in the BOM, the monitoring system can determine whether the alternative components (such as connectors or fluid bag variants) are compatible with the predetermined batch protocol or the changes in the predetermined batch protocol. The scene can be defined as a complete operating area, such as a room, facility or area. However, for certain operations or events, such as when the specific operating steps, specific equipment and / or specific components included in the BOM guide and monitor operator interaction, the monitoring system and its processing element 150 can focus on a smaller area of ​​the scene. For example, the connection of a specific pipeline to the inlet connection of a chromatography system can focus on only sensing, monitoring and documenting the BOM and (one or more) operator's equipment, components and items that are particularly relevant to establishing the connection between the pipeline and the system inlet.

[0080] The monitoring system may also provide assistance and guidance in updating or modifying batch protocols and obtaining approval or providing guidance to valid operators or QA initiating approval of modified batch protocols or new revisions of batch protocols. The system may perform or provide assistance in risk analysis of said revisions.

[0081] Whether an external device present in the facility has been moved or exchanged during setup for manufacturing / processing or during manufacturing / processing. If it is detected that an external device has been moved or exchanged during setup for manufacturing or during manufacturing in a manner that does not conform to a predefined workflow process protocol and / or in a manner that may compromise the quality of the manufactured biopharmaceutical product, it may be determined that at least one of the pre-set criteria is not met.

[0082] Operator movement within the facility while set for manufacturing or during manufacturing. If an operator is detected moving around the facility or interacting with the manufacturing system while set for manufacturing or during manufacturing in a manner inconsistent with or without predefined workflow processes and / or in a manner that may compromise the quality of the manufactured biopharmaceutical product, it may be determined that at least one of the preset criteria is not met. For example, it may be detected that an unauthorized person has been in the facility while set for manufacturing or during manufacturing.

[0083] The processing element 150 may be further arranged to provide instructions regarding verification of the process for those operator interactions and / or for the results of those operator interactions determined to satisfy at least one pre-set criterion set by the workflow process schema.

[0084] Thus, the processing element 150 is arranged according to this example to first determine that the process meets preset criteria set by the workflow process scheme, and then to perform a check to verify the determination that the process meets the preset criteria set by the workflow process scheme.

[0085] This process requires redundancy in nature. Thus, for example, if the determination is made using (one or more) first sources, then (one or more) other sources are used for verification. It is possible that some of the preset standards can be verified, while for other preset standards, redundancy is lacking and therefore verification cannot be performed. In conventional prior art systems, a first operator can complete an operation step (e.g., the connection of two fluid lines) and use a signature in a batch record to confirm this action. For important or critical actions, a second operator verifies the correctness and completion of the operation step and verifies the document proof provided by the first operator by checking and providing a second signature in the batch record. In the monitoring system proposed herein, both the first and second operator signatures can be omitted, as long as the system can obtain sufficient information about the correctness, completion and document proof of the step through its image analysis and sensing features (which may include machine vision and machine inspection technology). Any intermediate state (where one or both of the two operators are completely or partially relieved of any identification, document proof or verification action) will provide improvements in accuracy, speed and quality in setting or operating a manufacturing system.

[0086] In using this inspection process, automatic / computer-aided inspection is provided. This increases safety as the inspection implies that the correct product is delivered by the system with the expected properties.

[0087] exist Figure 2 In the diagram, the diagram is suitable for Figure 1 An example of a monitoring system user interface 260 for the monitoring system is shown.

[0088] The user interface 260 includes a user input element 261. The user input element 261 may include, for example, a keyboard, a touch screen, etc. The user input element 261 may be arranged to receive operator input for selecting a biopharmaceutical product for manufacture. The user input element 261 may be arranged to receive an operator input such as a Figure 1 The user input element 261 may be arranged to receive operator input related to other information about the settings for manufacturing and / or the manufacturing settings themselves, which information may be used for comparison with predefined workflow process protocols involving the selected biopharmaceutical product.

[0089] The user interface 260 further comprises in the illustrated example at least one display element 162. The at least one display element is arranged to display instructions for setting up the manufacture of the selected biopharmaceutical product, operating states and / or conditions of a component or system, and / or projections, predictions or indications of future conditions of the system or its components. Figure 1The processing element 150 may be arranged to feed instructions related to the next or current step to the display, and / or feed feedback information related to the execution of the previous step to the operator based on the tracking of the operator in the images captured by at least one image capture device.

[0090] At least one display element 162 may include an augmented reality display, for example formed in glasses worn by an operator. Other technologies may be used alternatively or in addition, such as light guide systems and / or projection, tactile feedback, audio, etc.

[0091] In another example, at least one display element 162 may include an electronic ink (e-ink) display. The information displayed on the e-ink display can be changed according to user interaction steps, process states, etc., with the advantage that little or no further energy must be provided to the readable display between events that change information. In other examples, the display element and / or the sensor can be powered by an energy harvesting device. Energy harvesting technology (such as recycling of electromagnetic radiation or solar panels that harvest indoor light) can be used to eliminate the need for batteries at the wireless connection device.

[0092] Figure 3 Schematic diagram as compared to Figure 1 and Figure 2 The contents stored in the memory 370 of the monitoring system for manufacturing multiple biopharmaceutical products. The memory 370 permanently or temporarily stores workflow process schemes associated with corresponding biopharmaceutical products. The predetermined workflow process scheme associated with each product may include at least one of the following: Identify which steps are to be performed to set the data for manufacturing data identifying the sequence and / or timing of steps used to set up the fabrication process (for those steps where this is relevant) data identifying the procedures used to perform each step, and data identifying which external devices are to be connected to the manufacturing system, data identifying the configuration of the interconnection between the manufacturing system and the external devices, data identifying characteristics of the manufacturing facility in a steady state that initiates setup for manufacturing, Identify data present in the facility that permits the movement of external devices and / or devices within the facility and / or the exchange of devices within the facility, Data identifying permitted operator movement within the facility, such as the number of operators permitted or required in the facility and / or the identities of authorized operators permitted in the facility and / or the timings at which operators are permitted in the facility and / or the areas permitted for operators in the facility, where permitted areas may be associated with authorization levels for individual operators, etc.

[0093] exist Figure 3 In the example of FIG. 371 , a production record 371 related to a biopharmaceutical product is shown, and Figure 3 An excerpt of such a record showing specific steps for connecting a fluid line to an inlet of a flow path in a chromatography system. The production record 371 includes recorded data associated with the predetermined workflow process scheme. The production record 371 may be included in a predetermined workflow process scheme 372 associated with a selected biopharmaceutical product.

[0094] In the illustrated example, the predetermined workflow process scheme defines a plurality of activity steps x.1, x.2, x.3. The illustrated activity steps illustrate the connection of buffer containers and corresponding fluid lines to an inlet of a chromatography system.

[0095] The first step x.1 defines that a predetermined solution with a predetermined part number should be obtained. The production record 371 comprises in the illustrated example an area 373 for storage of supporting images or video movies showing the execution of the first step or its results. The supporting images or video movies may or may not be annotated.

[0096] The production record 371 further includes an area 374 for recording a signature that the step has been performed. The signature may be provided by the operator who has performed the step or by another person. The signature may instead be computer generated based on a comparison between the captured image and a predetermined workflow process protocol, optionally in combination with other information obtained from additional sensor elements.

[0097] The production record 371 further includes an area 375 for recording a verification that the first step has been successfully performed. The verification may be provided by someone other than the person providing the signature that the step was performed. The verification may instead be computer generated based on a comparison between the captured image and a predetermined workflow process protocol, optionally in combination with other information obtained from additional sensor elements.

[0098] The same applies to the subsequent steps: Supporting images / video(s) and / or information from additional sensor elements (whether annotated or not) may be stored in area 373, An electronic or manual signature may be provided in area 374 for a signature indicating that a step has been performed. • A manual or electronic check may be provided in area 375 for checking that the step has been successfully performed.

[0099] In addition, the production record 371 includes a record of the connections and external devices and their characteristics according to the predetermined workflow process scheme. In the illustrated example, the record includes ·Entry Number—System Solution Part Number - Buffer Solution batch number - buffer Solution Expiration Date - Buffer Solution ID, fluid lines and connectors Connector type Additionally, for each record, there may be a signature and verification, as described above. Additionally, for each record, there may be supporting images / videos and / or other information derived from additional sensor elements (whether annotated or not), as described above.

[0100] Thus, the illustrated production record 371 includes data indicating which tracked operator interactions and / or results thereof satisfy at least one preset criterion set by the workflow process schema and / or verification data indicating which processes were verified.

[0101] As described above, the illustrated production record also includes images / video and / or other information obtained from additional sensor elements (whether or not annotated), which at least in part serves as the basis for data and / or verification data indicating which tracked operator interactions or their results meet at least one preset criterion set by the workflow process solution.

[0102] The proposed monitoring system obtains data which can be used to determine whether at least one pre-set criterion set by the workflow process scheme is met and possibly used for verification. The obtained data can be stored.

[0103] The tests performed and the amount of data stored are typically at least at the minimum level requirements defined by the manufacturer, regulatory agency, and / or regulatory agency (eg, FDA).

[0104] The resulting data may be further stored for use in troubleshooting, for data and workflow analysis, and to improve understanding and models of cause and effect relationships, for example by applying mechanical or statistical modeling and data analysis across all or portions of the manufacturing process (including manufacturing setup and BOM).

[0105] The proposed monitoring system allows for a set of computer-assisted or automated verification of the manufacturing system of selected biopharmaceutical products.

[0106] Computer-aided / automated testing results in minimizing downtime in setting up a manufacturing system for the manufacture of a new biopharmaceutical product.

[0107] Figure 4 A scenario 400 is disclosed in which an operator is setting up the manufacture of a selected biopharmaceutical product. The setting up of the manufacture and the subsequent manufacture of the biopharmaceutical product may be performed by, for example Figure 1 , Figure 2 and Figure 3Any of the disclosed monitoring systems is supported.

[0108] The manufacture of biopharmaceutical products is typically carried out under current good manufacturing practices cGMP. The manufacture typically involves one or more unit operations for upstream production (i.e., bioreactors) and / or downstream product purification. The manufacture typically relies on single-use technologies as much as possible across the manufacturing process. This means the use of disposable consumables, hoses, etc. Thus, the facilities and equipment used for the manufacture of biopharmaceutical products can be easily cleaned before launching the manufacture of a new biopharmaceutical product, for example by discarding and replacing the used consumables that have come into product contact during the completion of the process.

[0109] An image capture device 430 in the form of a camera is arranged to capture a scene 400. The scene 400 may cover a manufacturing facility for the manufacture of biopharmaceutical products. The manufacturing facility may be a secluded space in such a room. The image capture device may be arranged to capture the entrance to the scene. Typically, the entrance to the scene may be a transfer and / or inspection area 447 for introducing materials (e.g., materials according to a BOM).

[0110] BOM inspection may be performed in transfer and / or inspection areas adjacent to clean production and handling zones. BOM inspection may be performed on tables, benches or shelves where incoming materials for the BOM are inspected. Image capture devices and / or other sensor elements may be used for inspection of 'registered materials' prior to installation.

[0111] A manufacturing system including at least one manufacturing device 410 is arranged in scene 400 .

[0112] A plurality of external devices 420 are arranged within the scene. The external devices 420 may include external devices including a flow kit 446 and consumables mounted to a manufacturing device (e.g., a chromatography system and / or a bioreactor). The external devices may include a buffer bin and / or container that may be connected to a manufacturing system.

[0113] In the illustrated example, flow kit 446 is installed in front of manufacturing apparatus 410, which takes the form of a chromatography system, such as Ready system (GE Healthcare). Flow kit 446 has a first connection element 111. In the illustrated example, the first connection element 111 includes a fluid inlet, a fluid outlet, and a connection 111 to an external device 420, which takes the form of a chromatography column, such as a Ready To Process column (GE Healthcare). The connection element 111 can take the form of a sterile connector, such as a ReadyMate connector (GE Healthcare).

[0114] At least some of the first connector elements 111 of the manufacturing device 410 and at least one second connector element 121 of at least one external device 420 are mutually connectable. The connector elements 111, 121 can be expected to be directly connected to each other via interconnection / interconnection elements (such as hoses, cables, etc.). In the example shown, the second connector element 121 of the external device 420 in the form of a column is expected to be connected to the corresponding first connector element 111 of the manufacturing device 410.

[0115] The connector element 111 may be suitable for connection to an external device 420 (eg, a consumable). The connector element 111 may be suitable for electrical communication and may, for example, form electrical contacts.

[0116] In the example shown, the manufacturing device 410 includes a receiver 440, which is arranged to receive wireless transmission data related to at least one of (one or more) external devices, the manufacturing device 410, the reader and other devices in the scene. However, this receiver 440 can be located at other locations in the facility as an alternative or supplement, and provide data to the monitoring system. In the example shown, the operator carries an electronic user device 441 with this receiver 440. Wireless transmission data can be transmitted from an RFID tag 422 or other transmitter element 445, for example, which is associated with (one or more) external devices and / or manufacturing devices 410 and / or other devices and / or materials (such as connectors, fluid lines, fluid bags, flow kits, columns, filters, etc.) in the scene. RFID tags or other transmitter elements can be arranged for short-range communication. In one example, when the transmitter and receiver are in the same room, communication is obtained in characteristics. Communication can be obtained by Bluetooth, WiFi, RFID, NFC, etc.

[0117] For example, the external device may include a memory or have access to at least a portion of a memory including the following data: Part Number ·batch number ·Date of Expiry ID Characteristics of the external device (e.g., type, unit operation(s), consumables, probes, etc., other details related to the composition / function of the external device, size, etc.) Connector type The state / status of the connection (wrapping, unwrapping and preparing for a "ready to connect" connection, faulty or correct state before connecting, faulty or correct state in an established connection) Appropriate interconnect components (clamp type, etc.) for connecting to external devices The sensor type(s) associated with the external device Environmental data to which the external device has been subjected, such as temperature At least a portion of the above data may be delivered to the receiver 440 upon request and / or when communication is established and / or sensor signals are obtained by any sensor associated with the external device. The receiver 440 may be a wireless receiver or sensor, supplementing traditional wired sensors and wired transmission of data.

[0118] For example, a manufacturing device may include a memory or have access to a memory including data such as: Part Number ·batch number Connector type(s) ID Characteristics of the manufacturing unit (e.g. type (chromatograph, bioreactor), other details related to the composition / function of the manufacturing unit, size, etc.) At least a portion of the above-described data may be communicated to receiver 440 upon request and / or when communication is established.

[0119] Other equipment may include interconnecting elements for making connections of the device to external devices. Interconnecting elements may include hoses, cables, clamps, etc. Other equipment may include memory or have access to memory including data such as: ID Characteristics of the equipment (e.g. type of equipment (cable, hose clamp, etc.), other details related to the composition / function of the equipment, size, etc.) The sensor type(s) associated with the device At least a portion of the above data may be communicated to the receiver 440 upon request and / or when communication is established and / or sensor signals are obtained by any sensor associated with equipment above the device.

[0120] Accordingly, the corresponding external device and / or other equipment can be detected by receiving external device data (e.g., identification code data for identifying a separate external device). Thus, as soon as a new external device and / or other external device enters the scene, this can be detected by receiving external device / other equipment data (e.g., identification code data).

[0121] In addition, the state change sensed by the sensor of the corresponding external device and / or other device can be detected by receiving the external device / other device data (including the state data). Therefore, once the state change of the sensor of the external device and / or other device is sensed, this can be detected by receiving the external device / other device data.

[0122] Furthermore, received external device data / other equipment data related to the respective connected external devices may be used by the monitoring system to derive information related to the respective external devices / other equipment.

[0123] In addition, tags or labels (e.g., RFID tags 422) associated with (one or more) external devices and / or manufacturing devices 410 and / or other equipment and / or materials within the scene and the information contained by the tags or labels can also be changed and updated to reflect changes in the state, condition, or use of the components. Information can be written to the tag to update its content.

[0124] In the example shown in the drawing, one of the operators 444 holds a further device 442, for example in the form of a clamp, such as a pipe clamp (the pipe is not shown). The further device is associated with a sensor 443 and a transmitter element 445 associated with a memory (not shown).

[0125] In addition, the operator in the scene can also be tracked by a camera device. Thus, it can be recorded which external devices and / or other external devices connected to the manufacturing device the operator interacts with.

[0126] Thus, operators entering the facility and moving within the scene are tracked, and their interactions with the equipment / other devices of the facility can be tracked.

[0127] Information redundancy can be used to verify that the detected event has occurred. For example, if a sensor detects a change in state, the image from the image capture device can be used to verify the timing and / or position of the change in state of the sensor, and the position of the operator in the image at that timing can be used to verify that the operator performs activities on the device / external device associated with the sensor. In addition, the image can be processed to track the operator's manipulation in detail to ensure that the operator connects the device / external device in the correct manner and / or in accordance with the predetermined requirements of sequence and / or timing. In addition or alternatively, the received information related to the device / external device can be used to ensure that the correct device / external device is involved in the connection activity. In addition or alternatively, image processing can be used to ensure that the correct device / external device is involved in the connection activity. Image processing can be applied at various levels of detail and complexity, including machine vision and machine inspection methods, which may include recognition of written text and information on labels, barcodes, and OCR code information, etc., to eliminate the need for operators to read, process and / or document this information in batch records, for example.

[0128] In another example, when image processing detects that a new external device and / or other equipment has entered the facility, the data received by the receiver 440 can be used to confirm this. In addition, the image can be processed to track operator manipulation in detail to ensure that the operator enters the other equipment / external equipment into the facility at the timing of the reception of data via the receiver. Further or in addition, image processing can also be used to confirm that the characteristics of the other equipment / external equipment are consistent with the characteristics of the other equipment / external equipment as determined by the data received by the receiver 440.

[0129] Figure 5 A scheme is disclosed that shows a timeline for identification of external devices including consumables and reusable hardware, as well as operators and other equipment within a scene. The timeline for identification allows detection, inspection, monitoring, verification and documentation of the device / external device / and the operator, their interaction with the device / external device and the results of this interaction.

[0130] The external devices of this illustrative example include consumables of the manufacturing device. Other equipment includes a clamp in the example shown, which here includes wireless detection of the clamp state, which indicates open or closed valves and fluid lines when the operator closes the clamp and the clamp clamps the fluid line.

[0131] In the example shown, a 20L bag 1 consumable is identified at a timing along a timeline. The timing of the identification may be recorded. In the example shown, the position of the identified 20L bag 1 is recorded. In the example shown, the position includes the recorded angular position of the 20L bag 1. The angular position may be given relative to a predetermined reference direction. The position further includes a distance in the example shown. The distance may be given relative to a predetermined reference point. The angular position and distance may be determined based on an image captured by an image capture device.

[0132] Angular position and distance from the image capture device (camera) can be converted into and represented by Cartesian 2- and 3-dimensional coordinates, and the scene can be reconstructed and displayed in mixed reality involving virtual and / or augmented reality displays.

[0133] Furthermore, the characteristics of the 20L bag object may be recognized through processing of the captured image to determine that the recognized object is the 20L bag 1 .

[0134] Furthermore, in the example shown, the operator 9 is identified at a timing along the timeline. The timing of the identification may be recorded. In the example shown, the position of the identified operator is recorded. In the example shown, the position comprises the recorded angular position of the operator 9. The angular position may be given relative to a predetermined reference direction. The position further comprises a distance in the example shown. The distance may be given relative to a predetermined reference point. The angular position and the distance may be determined based on the image captured by the image capture device.

[0135] In addition, in the example shown, the 100L bag 2 is identified at the next timing along the timeline. The timing of the identification can be recorded. In the example shown, the position of the identified 100L bag 2 is recorded. In the example shown, as described above, the position is recorded as the angular position of the object. The position further includes the distance in the example shown. The angular position and the distance can be determined based on the image captured by the image capture device.

[0136] Apart from Figure 5 In addition to the representation of the data shown, of course any information obtained on parameters with spatial and temporal resolution, including the position, status and action of operators, external devices, other equipment and other objects in the scene, can be presented, evaluated and documented in a variety of different formats and graphical representations.

[0137] Furthermore, the characteristics of the 100L bag 2 object may be identified through processing of the captured image to determine that the identified object is a 100L bag.

[0138] In addition, the RFID reader reads the RFID tag associated with the 100L bag at the timing of identifying the 100L bag 2. Thus, redundancy and / or other information, such as the identification code of the 100L bag, can be obtained.

[0139] Readings of RFID bags may be associated with operator interactions (eg, activation of a reader), and readings may be associated with a tracked operator and / or reader location in time and space.

[0140] In addition, at another timing, pipeline x 3 is identified. The timing of identification can be recorded. In the example shown, the position of the identified pipeline x 3 is recorded. In the example shown, as described above, the position can be recorded as an angular position and a distance using an image captured by a camera. In addition, at the timing of identifying pipeline x 3, an RFID reader reads an RFID tag associated with pipeline x 3. Thus, redundancy and / or other information, such as an identification code of pipeline x 3, can be obtained. In addition, at the timing of identifying pipeline x 3, a connection sensor senses that pipeline x 3 has been connected. The connection sensor can be one or more sensor components that are attached to one or two connectors involved in the established connection, thereby providing wired or wireless sensor feedback. However, the connection sensor can be provided by other sensing means, such as an identification code of at least one of the connectors that can be identified and an image analysis and machine vision capability that can identify the successful conduct and completion of the connection process. Therefore, additional information that can provide redundancy related to the establishment of a manufacturing system is obtained.

[0141] At yet another timing, bag B 4 is identified. The timing of identification can be recorded. In the example shown, the position of the identified bag B 4 is recorded. In the example shown, as described above, the position can be recorded as an angular position and a distance using an image captured by a camera. In addition, at the timing of identifying bag B 4, a barcode reader reads a barcode. The barcode reader can be carried by an operator, for example. Alternatively, the barcode is identifiable from the captured image. The barcode can be present on the pipe itself or its packaging.

[0142] Thereafter, at the next timing, the pipe y 5 is identified. The timing of the identification can be recorded. In the illustrated example, the position of the identified bag y 5 is recorded. In the illustrated example, as described above, the position can be recorded as an angular position and a distance using an image captured by a camera. In addition, at the timing of identifying the pipe y 5, the connection sensor senses that the pipe y 5 has been connected. Therefore, additional information related to the setting of the manufacturing system that can provide redundancy is obtained.

[0143] Additionally, a clamp sensor state change is detected at pipe y 5. The clamp sensor detects whether the pipe clamp (characteristically a manual pinch valve) is in an open position or a closed position. Information related to the position of the operator can be used to provide additional information about the position of the operator in the pipe clamp when the clamp sensor state change is detected.

[0144] Thereafter, at yet another timing, the column XY 6 is identified. The timing of the identification can be recorded. In the example shown, the position of the column XY 6 is recorded. In the example shown, as described above, the position can be recorded as an angular position and a distance using an image captured by a camera. In addition, at the timing of identifying the column XY 6, a barcode reader reads a barcode associated with the column XY 6. Alternatively, the barcode is identifiable from the captured image. The barcode may exist on the column XY 6 itself.

[0145] At the next timing, the jig 7 is recognized. The timing of recognition can be recorded. In the example shown, the position of the recognized jig 7 is recorded. In the example shown, as described above, the position can be recorded as an angular position and a distance using an image captured by a camera.

[0146] In practice, the clamp 7 may be identified at the timing of activation of a clamp activation signal from a clamp sensor associated to the clamp 7. The clamp sensor activation signal may be transmitted upon detection of a connected clamp. Tracking of the operator may then be used to identify the clamp 7 in the image for use in determining the position of the clamp 7. At the timing of the clamp sensor activation signal, the operator is characteristically at the position of the clamp 7. Therefore, the image captured at the timing of activation of the clamp sensor signal is characteristically used to determine the position of the clamp 7 manipulated by the operator.

[0147] As an alternative or in addition, the clamp 7 can be identified as being in an open or closed state by means of information obtained by an image capture device and evaluated by a processing unit.

[0148] Furthermore, at the timing of identifying the jig 7, the RFID reader reads the RFID tag associated with the jig 7. Thus, redundancy and / or other information, such as an identification code of the jig 7, can be obtained.

[0149] At the next timing, the pipe connection 8 is identified. The timing of the identification can be recorded. In the example shown, the position of the identified pipe connection 8 is recorded. In the example shown, as described above, the position can be recorded as an angular position and a distance using an image captured by a camera.

[0150] In practice, the pipe connection 8 may be identified at the timing of activation of a clamp activation signal from a clamp sensor associated with the pipe connection 8. The clamp sensor activation signal may be transmitted upon detection of a clamp in connection with the connection. Tracking of the operator may then be used to identify the pipe connection 8 in the image for use in determining the position of the pipe connection 8. At the timing of the clamp sensor activation signal, the operator is characteristically at the position of the pipe connection 8. Thus, the image captured at the timing of activation of the clamp sensor signal is characteristically used to determine the position of the pipe connection 8 manipulated by the operator.

[0151] Additionally or alternatively, the pipe connection 8 may be identified at the timing of activation of a pipe connection signal from a sensor of the pipe connection 8. The pipe connection sensor signal may be transmitted upon detection of the connection. Tracking of the operator may then be used to identify the pipe connection 8 in the image for use in determining the position of the pipe connection 8. At the timing of the pipe connection sensor signal, the operator is characteristically at the position of the pipe connection 8. Thus, the image captured at the timing of detection of the pipe connection sensor signal is characteristically used to determine the position of the pipe connection 8 manipulated by the operator.

[0152] The monitoring system may track, control, and advise the user on the optimal physical positioning and orientation of objects and components within the manufacturing space and scene 400. For example, the monitoring system may propose a floor plan for the positioning of the components and instruct the user to arrange the components according to the proposed floor plan. The floor plan may be changed throughout the process to obtain the best utilization of space within the clean room and / or the best execution of the manufacturing process. The monitoring system may further include a machine learning and optimization component so that the floor plan is further optimized, for example, by analyzing process performance, user interaction, and space utilization from previous batches.

[0153] The monitoring system may further allow for the integration of robots into the workflow, and it may optimize the interaction of robots and users within the manufacturing system, process, facility, and / or overall workflow. For example, an automated self-driving material transport vehicle may be controlled in concert with manual user interaction, and the integration and coordination of all resources may be optimized and improved through machine learning and analytics-based AI.

[0154] Tubing and bags are single-use and disposable products in nature. Figure 5 The described approach or similar approaches may be applicable, for example, in the set-up of a chromatography system having a buffer bag on the inlet side and another buffer bag on the outlet side.

[0155] As above relative to Figure 5 The described timeline scheme for identifying external devices and other equipment within a scene can be used to determine whether at least one preset criterion set by the workflow process scheme according to the present disclosure is met. Figure 5 The described timeline scheme for identifying external devices and other equipment within a scene can also be used for inspection according to the present disclosure. Figure 5 The described timeline scheme for identifying external devices and other equipment within a scene can also be used for inspection according to the present disclosure. Figure 5 The described timeline scheme for identification of external devices and other equipment within a scene may also be used to improve manufacturing processes in accordance with the present disclosure. Process improvements and / or optimizations may be provided, for example, through a 'time-lapse' feature that compresses, streamlines, or filters events according to one or more objectives, which may vary depending on the type of analysis. For example, a time-lapse feature may focus only on the display, review, and / or analysis of user interactions with a certain component. These specific interactions may then be reviewed in detail to improve the efficiency, safety, or robustness of the process.

[0156] exist Figure 6 , a method 10 of monitoring settings for manufacturing and / or setting for manufacturing and / or disassembly following manufacturing of a selected biopharmaceutical product is illustrated.

[0157] The method comprises a step of capturing an image of a scene comprising a manufacturing system (S1). The manufacturing system has the capability of manufacturing a plurality of biopharmaceutical products. The manufacturing system may have a plurality of first connector elements for connecting to an external device.

[0158] The method further comprises a step of processing the captured images to track operator interactions and / or results of operator interactions within the scene (S3). The method further comprises a step of comparing at least a portion of the tracked operator interactions and / or at least a portion of the results of the tracked operator interactions with the manufacturing device to a predefined workflow process scheme associated with the selected biopharmaceutical product (S5). The method further comprises a step of determining whether at least one preset criterion set by the workflow process scheme is met based on the comparison (S6).

[0159] The method may further comprise the step of also obtaining information related to at least one connected or connectable device or other equipment (S2). At least part of the obtained information may then be used in a comparison with the characteristics of the connected external device obtained from the predetermined workflow process scheme (S5) and in a determination as to whether preset criteria related to the characteristics of the external device (which is connected to the manufacturing device) set by the predetermined workflow process scheme are met (S5).

[0160] The method may further include a step (S4) of providing visual, tactile and / or audio assistance for the setting for manufacturing. The visual assistance may be displayed on a screen or presented as an augmented reality presentation, for example, formed within glasses worn by the operator. The visual / verbal assistance may be based on the tracking of the operator and possible tracking of a predefined workflow process scheme that identifies which activity the operator is involved in. Visual / verbal support is then provided based on the identified activity. For example, data for support is stored in association with each activity of the predetermined workflow process scheme.

[0161] Feedback to the operator may be provided in relation to the activity performed. The operator may then have the opportunity to redo the activity or at least learn for next time. The level of operator guidance and feedback may then be contextually adjusted based on the operator's ability level, experience, and request for a certain level and detail in guidance.

[0162] Thus, as will be appreciated from the above, determinations as to whether preset criteria are met may be made continuously as the operator(s) work on the set-up for manufacturing of the selected biopharmaceutical product. Alternatively, determinations may be made once the set-up for manufacturing is complete.

[0163] In summary, the method of monitoring the setting of manufacturing and / or setting the manufacturing of a selected biopharmaceutical product among a plurality of biopharmaceutical products determines which preset criteria set by the workflow process scheme are met and which preset criteria are not met or at least cannot be determined whether they are met. For those potential preset criteria that are not met or at least cannot be determined whether they are met, a report can be provided by the system. Those criteria can be manually checked.

[0164] It may be advantageous to include a measure of precision and therefore reliability in the determination provided by the processing element 150 as to whether the corresponding preset criteria are met. Based on the precision and reliability in the determination, the system may autonomously determine that the preset criteria are met when the precision and reliability in this determination are high. In other cases, when the information is insufficient to allow autonomous determination and the reliability is determined to be insufficient, additional operator input may be requested. In some cases, the system 150 may learn from repeated execution or from additional data and knowledge bases, such as improving image data in memory, so that the accuracy is improved for subsequent processes, so that more autonomous determinations are made by the system and / or less additional user input is required. For example, if a predetermined workflow process scheme indicates that a particular valve should be opened, the reliability measure may, for example, indicate that the valve is open, the valve is closed, or the state of the valve is undefined. Therefore, the reliability measure may indicate CORRECT, FAULT, or UNDEFINED. Alternatively, the reliability measure may include a percentage. The reliability measure may be based on the quality of the available data, the number and / or type of sources used for determination as to whether the preset criteria are met, etc.

[0165] Furthermore, in the event that it has been determined that the preset criteria have been met, an inspection indication may be provided (S7). The inspection indication is preferably derived using other information (information used for the determination that the preset criteria have been met). Data related to the inspection may then be stored (S7). Once the setup for manufacturing is complete, the inspection is performed on the characteristics.

[0166] It may be advantageous to add a reliability measure to the check in the same or similar manner as described above with respect to the determination as to whether a corresponding preset criterion is met.

[0167] Data related to the inspection may be stored (S8). Thus, information serving as a basis for conducting the inspection may be stored.

[0168] Data related to the determination as to whether preset criteria set by the workflow process scenario are met may be stored.

[0169] Other data obtained during the setup of manufacturing may also be stored.

[0170] In addition, any corrections made within the scene, such as those made during production, may also be stored. Corrections may include external devices and / or other equipment being moved or damaged. This may be useful in possible subsequent troubleshooting.

[0171] After inspection and approval of the installation, the processing of the biological product is carried out, which is usually some kind of fluid processing (bioreactor, chromatography, filtration). Here, many operator interactions are required, such as sampling of fluids, actuation of tubing clamps, etc.

[0172] Disassembly of the manufacturing system after processing is also a step in which the operator must follow the protocol that can be provided by the monitoring system. The interactions and results are also monitored, verified and documented in this step.

[0173] The stored data can be used in a later step, ie, improving the manufacturing process S9. Thus, the production of the final biopharmaceutical product can be refined, and potential deviations in the final biopharmaceutical product can be reduced for each biopharmaceutical product manufactured.

[0174] In detail, the visual / audio aid may be improved based on a (statistical) analysis of previous operator activities for setting up the manufacturing and the characteristics of the final biopharmaceutical product manufactured thereby.

[0175] The decision made by the system can also be improved by having the operator carefully review the UNDEFINED results in the determination and / or verification as to whether the predetermined preset criteria are met in this improvement step, and indicating whether the preset criteria are met and whether to conduct a verification if it is indicated as system "undefined".

[0176] Machine learning can be used for this improvement step S9. Learning can be used to refine one or more steps in the process, such as steps S2, S3 and S6.

[0177] The method may be implemented by a computer program product comprising at least one non-transitory computer-readable storage medium storing computer-executable program code instructions, wherein the computer-executable program code instructions include program code instructions configured to perform the method when executed.

[0178] By recording and documenting portions of a batch process, learning and system intelligence can be used to refine, update and improve batch protocols, for example during 'technical scheduling.' Additionally, the resulting information (i.e., mixed reality output and batch protocols) can be used for operator training purposes, troubleshooting, data analysis, etc.

[0179] Figure 7 A diagrammatic scheme illustrating different levels of manufacturing support that is compliant with the ISA95 standard. Level 0 shows the physical production process. In level 1, the components of the physical production process (e.g., sensors, pumps, etc.) are defined. The physical process is sensed by sensors, and the production process can be manipulated. Level 2 involves automation systems. Level 2 can be defined as a factory or unit operation level. In level 2, monitoring and supervisory control and automatic control of the process are obtained. By implementing levels 1 and 2, manufacturing control is achieved. Manufacturing control involves basic control, supervisory control, process sensing, and process manipulation.

[0180] Level 3 is the manufacturing execution system MES level. In the example shown, in level 3, batch records are controlled to produce the expected final product. Batch records are expected to be used for workflow and / or recipe control. Batch records can be maintained, and / or the production process can be optimized. The use of predetermined workflow process schemes as disclosed herein allows manufacturing support mainly at this level, that is, control, execution and documentation of batch records. In order to fully utilize the monitoring system as described herein, batch records are preferably managed electronically, and workflow instructions and input and feedback to electronic batch records (eBR) by sensors, for example, are transmitted electronically. This level 3 may represent the manufacturing operations management level. This level covers dispatched production and / or detailed production scheduling and / or reliability assurance.

[0181] However, at least part of the workflow can be defined at level 2. This will be relative to Figure 8 Further discussion.

[0182] Level 4 is the Enterprise Resource Planning (ERP) level. Level 4 is the Business Planning and Logistics level. This level involves factory production scheduling and business management.

[0183] Figure 8 An example of a protocol for the manufacture of a predetermined biopharmaceutical product is shown.

[0184] The scenario includes, in the example shown, a high-level workflow 80 for the manufacture of a predetermined biopharmaceutical product. In the example shown, the high-level workflow 80 begins with a material transfer and / or BOM check 81. Thereafter, an installation step 83 is performed for the installation of the manufacturing system. Thereafter, the installation is verified 83. Then, an automatic process 84 is performed, which may employ manual interaction. Thereafter, a sampling step 85 is performed for sampling manual activities. Thereafter, the scene of manufacturing is cleaned 86. At this step, the single-use product is disposed of. Steps may be added and / or removed from this high-level workflow 80.

[0185] In addition, the solution may include instructions 90, 100 for the manufacture of a predetermined biopharmaceutical product. The instructions include, for example, a standard operating procedure SOP and / or an electronic batch record eBR. The instructions may belong to level 2 or level 3 or a combination of different levels that provide manufacturing support in accordance with the (International Society of Automation) ISA95 standard, such as relative Figure 7 described.

[0186] In the example shown, the level 3 instructions 90 include instructions for line cleaning (91). This instruction is characteristically a precursor to or can be understood as the initiation of material transfer and / or BOM check (81).

[0187] In the example shown, level 3 instructions include other instructions 92 for consumables and / or equipment and / or fluids and / or brands. This instruction is material transfer and / or BOM check 81 and / or installation 82 in nature.

[0188] In the example shown, the level 3 instructions include other instructions 93 for bag installation and / or bag filling. This instruction belongs to installation 82 and / or inspection 83 in nature.

[0189] In the example shown, level 3 instructions include other instructions 94 for final installation prior to fluid processing. This instruction is of a testing 83 and / or automatic processing 84 nature.

[0190] In the example shown, level 3 instructions include other instructions for the collection of a fluid sample 95. This instruction is of an automated process 84 and / or a manual activity 85 for sampling in nature.

[0191] In the example shown, level 3 instructions include other instructions for product manipulation 96. This instruction is a sampling manual activity 85 in nature.

[0192] In the example shown, level 3 instructions include other instructions for disposal of consumables 97. The consumables may be of SUT type (Single Use Technology). This instruction belongs to cleaning 86 in nature.

[0193] Furthermore, in the example shown, the Level 2 instructions 100 include instructions for flow path installation (e.g., chromatography system) 101. This instruction is characteristically material transfer and / or BOM check 81 and / or installation 82, and can be called or referenced by the Level 3 eBR as a standard operating procedure (SOP), such as defined, executed, documented, and maintained by the chromatography system and its control system or a different workflow management system.

[0194] Furthermore, in the example shown, the Level 2 instructions 100 include instructions 102 for connection of the bag to the chromatography system. This instruction pertains in nature to installation 82 and / or verification 83. This instruction, its execution and documentation may again be called or referenced by the Level 3 eBR as a standard operating procedure (SOP).

[0195] Furthermore, in the example shown, the level 2 instructions 100 include instructions 103 for the execution of process automation and / or data logging. This instruction belongs to the automatic processing 84 in nature.

[0196] Additionally, in the example shown, the level 2 instructions 100 include instructions for documentation and / or data management 104. This instruction may include or be a component of the manual sampling activity 85 and / or the cleaning activity 86.

[0197] This scheme for the manufacture of predetermined biopharmaceutical products is apparent through the above-mentioned example.High-level workflow 80 and / or instructions 90,100 may be added or removed.Instructions may further be appropriately selected to belong to level 2 or level 3.Level 2 activities may be understood as SOP (standard operating procedure), which may be managed by an independent electronic workflow system.This level 2 workflow management system may provide instructions, guidance and correction of operators, document proof results, provide the above-mentioned features of intelligent sensing, learning and workflow improvement capabilities.Level 2 workflow management system may be provided by instrument or system (e.g., chromatographic system and control software thereof) or by independent independent systems and software.

Claims

1. A system (100) for monitoring settings for manufacturing and / or setting for manufacturing of a biopharmaceutical product, the system comprising: A manufacturing system (110) for manufacturing the biopharmaceutical product, at least one image capture device (130) arranged to capture an image of a scene including the manufacturing system, and a processing element (150) connected to the at least one image capture device and arranged to process images captured by the at least one image capture device to track operator interactions and / or results of operator interactions within the scene, Wherein the processing element (150) is further arranged to: obtaining information related to at least one external device (120) connected to the manufacturer's system, wherein the at least one external device (120) includes at least one single-use consumable, comparing at least a portion of the obtained information associated with the at least one external device with characteristics of the external device defined in a predetermined workflow process protocol, and Based on the comparison, it is determined whether a preset criterion set by the predetermined workflow process scheme related to the characteristic of the at least one external device connected to the manufacturing device is met.

2. The system (100) according to claim 1, wherein: The processing unit is further arranged to determine that a facility for the manufacturing is ready for the settings for manufacturing and / or that the settings are used for the manufacturing, wherein the facility for the manufacturing comprises at least one external device.

3. The system (100) according to claim 1 or 2, wherein: The processing element is further arranged to provide visual, tactile and / or auditory aids for setting up for manufacturing.

4. The system (100) according to any preceding claim, wherein: The processing element is further arranged to provide an indication that the process is validated for those operator interactions and / or for the results of those operator interactions determined to satisfy the at least one pre-set criterion set by the workflow process scheme.

5. A system (100) according to any preceding claim, wherein the information relating to the at least one external device connected to the manufacturer system is obtainable from a barcode and / or plain text on the connected external device and / or a detection characteristic of the connected external device itself; or The processing element (150) is arranged to obtain information related to the at least one connected external device (120) by receiving identity data, wherein the identity data may be transmitted from an RFID tag associated with the external device (120); or The processing element (150) is arranged to obtain information related to the at least one external device (120) by operator input via a user interface (160).

6. The system (100) according to any preceding claim, wherein: The at least one external device (120) further comprises a sensor element and / or an electronic device and / or a power supply device.

7. The system (100) according to claim 6, wherein: The processing element (150) is arranged to track operator interactions with at least one external device, compare the tracked operator interactions with the at least one external device with the predetermined workflow process scheme involving the operator interactions with the at least one external device, and determine whether at least one preset criterion set by the predetermined workflow process scheme is met based on the comparison.

8. A method (10) for monitoring settings for manufacturing and / or setting settings for manufacturing of a biopharmaceutical product using a system (100) as claimed in any preceding claim, the method comprising the steps of: capturing (S1) an image of a scene including a manufacturing system (110), wherein the manufacturing system (110) has the capability to manufacture a plurality of biopharmaceutical products, obtaining (S2) information related to at least one external device connected to the manufacturer system, wherein the at least one external device includes at least one disposable consumable, processing the captured images (S3) to track operator interactions and / or results of operator interactions within the scene, comparing at least a portion of the obtained information related to the at least one external device with characteristics of the external device defined in a predetermined workflow process scheme (S5), and Based on the comparison, it is determined (S6) whether a preset criterion set by a predefined workflow process scheme related to the characteristic of the at least one external device connected to the manufacturing device is met.

9. The method according to claim 8, further comprising the steps of: determining that the facility for said manufacturing is ready for said settings for manufacturing and / or that the settings are used for said manufacturing, wherein, The facility for said manufacturing comprises at least one external device.

10. The method according to claim 8 or 9, further comprising the following steps: Machine learning is used to refine one or more steps of the method.

11. The method according to any one of claims 8-10 further comprises the step of providing an indication that the process is validated for those operator interactions and / or for those operator interactions that are determined to satisfy at least one preset criterion set by the workflow process scheme.

12. According to the method of any one of claims 8 to 11, the step of obtaining the information related to the at least one external device connected to the manufacturer system comprises: obtaining the information related to the at least one external device from a barcode and / or plain text on the connected external device and / or a detection characteristic of the connected external device itself; or obtaining information associated with the at least one connected external device (120) by receiving identity data, wherein the identity data may be communicated from an RFID tag associated with the external device (120); or Information related to the at least one external device (120) is obtained through operator input via a user interface (160).

13. The system (100) according to any one of claims 8 to 12, wherein: The at least one external device (120) further comprises a sensor element and / or an electronic device and / or a power supply device.

14. The system (100) according to claim 13 further comprises the following steps: tracking operator interactions with the at least one external device, comparing the tracked operator interactions with the at least one external device with the predetermined workflow process scheme involving the operator interactions with the at least one external device, and determining whether at least one preset criterion set by the predetermined workflow process scheme is met based on the comparison.

15. A computer program product comprising at least one non-transitory computer-readable storage medium having computer-executable instructions stored therein, the computer-executable instructions being configured to perform the method according to claims 8-14 when executed.

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