Systems and methods for pharmaceutical products

Abstract

The present disclosure relates to a biological fluid treatment system and method. The system includes a fluid treatment device having at least one fluid path, a pump for applying pressure within the at least one fluid path, a valve arranged along the fluid path, and a first actuator configured to control the valve to achieve a desired opening state of the fluid path. The biological fluid treatment system further includes a process interface including a pump driver for driving the pump of the fluid treatment device, and a process control element including a pump control system configured to control at least the pump driver and a valve control system configured to control the first actuator. The system is modular. The fluid treatment device is included in a fluid treatment device module having a predetermined fluid treatment device configuration. The process interface has a predetermined process interface configuration. The process control element is configured to receive information related to the predetermined process interface configuration of the process interface module and / or the predetermined fluid treatment device configuration of the fluid treatment device module, and to control the at least one pump driver and / or valve based on the received information related to the predetermined fluid treatment device configuration and the predetermined process interface configuration.

Description

[Technical Field]

[0001] The present disclosure relates to a biological fluid treatment system comprising a fluid treatment device, a treatment interface, and a treatment control element.

[0002] The present disclosure also relates to a method for setting up a biological fluid treatment system comprising a fluid treatment device, a treatment interface, and a treatment control element. [Background technology]

[0003] Biopharmaceuticals, also known as biologics, are a broader category of complex molecules intended for therapeutic or diagnostic use. Biologics are typically produced by living tissues or cells, such as vaccines, recombinant therapeutic proteins, and monoclonal antibodies. These products are typically obtained by culturing host cells in bioreactors that produce the drug substance of interest and then perform liquid processing steps, such as cell culture clarification, filtration, and chromatography steps. Biologicals often require parenteral administration via infusion or injection. This requires a tightly controlled, high-quality manufacturing and distribution network, including highly specialized manufacturing, specialized storage, and handling, to ensure the drug's efficacy and safety.

[0004] The past decade has seen a remarkable shift in the nature of products manufactured and marketed by the innovative biopharmaceutical industry. Today's global biopharmaceutical portfolio reflects a dramatic expansion in the number, variety, and specificity of biologics. One example of this expansion is the emergence of personalized medicine, which targets products for specific patients, patient populations, or individual patients. These developments result in biopharmaceuticals with limited production runs, highly specific manufacturing requirements, and genotype-specific products. Another factor reducing the volume and scale of production of these products while increasing the number of formulations and manufacturing processes required is the expiry of patent rights on successful biopharmaceuticals, thereby opening up a growing market for many generic biopharmaceuticals, known as biosimilars. Managing the cost, quality, and speed of delivering these new, improved, and more cost-effective treatments to patients requires continuous improvements in the efficiency and effectiveness of biopharmaceutical manufacturing and related technologies.

[0005] With regard to the manufacture of biopharmaceuticals, the manufacturing process as such is critical to the characteristics and quality of the produced drug product. The manufacturing process includes the sequence and design of processing steps and operating parameters, but also the processing setup regarding the type, configuration, and installation of the manufacturing system, as well as general manufacturing practices. Practices for manufacturing setup, for example, by installing and qualifying manufacturing systems and components, can affect the final biopharmaceutical product. For example, incorrect or incomplete installation can cause contamination, fluid leaks, malfunctions, or variations in processing steps and their results. Furthermore, product and patient safety can depend on adherence to good manufacturing and hygienic practices regarding hygiene, for example, for the sterile containment and management of fluids during processing or sampling, and for cleaning equipment and facilities.

[0006] The application of current good manufacturing practices (cGMP) and quality management systems (QMS) is typically necessary to ensure adequate product quality through well-controlled and auditable production conditions. A cGMP processing environment is designed to comply with guidelines recommended by agencies that govern the approval and licensing of pharmaceutical manufacturing and sales, such as the Food and Drug Administration (FDA). Regulatory and / or legal requirements for biopharmaceutical production, such as FDA approval, mandate that equipment setup, installation, and use, including operator interaction and automated process control, be strictly controlled and documented. Batch records (BRs) or electronic batch records (eBRs) are fundamental in biopharmaceutical production and for regulatory approval and monitoring. Batch records control, monitor, and document procedures and results and typically refer to established standard protocols and standard operating procedures (SOPs) managed through a QMS that describe, for example, the operation, use, maintenance, and documentation of subcomponents or steps.

[0007] The drug development process is typically characterized by a "development funnel" in which a significantly larger number of drug candidates undergo clinical trials than the number of drugs that are successful and ultimately approved. Therefore, the trend toward an increased number and variety of drug products and treatments available to patients is accompanied by a significant increase in the number of clinical trials and the number of production runs to provide clinical trial materials. Clinical trial materials are typically manufactured under the same strict cGMP and QMS requirements that apply to the final, routine production of approved drugs. Therefore, given the cost pressures facing the healthcare sector and the need to deliver new and improved treatments to patients faster and more cheaply, this is particularly true for the production of clinical-phase materials, where improvements in biomanufacturing technologies can be utilized.

[0008] Continuously connected processing methods are now becoming a desirable addition to or alternative to the conventional batch manufacturing methods traditionally applied in the biopharmaceutical industry, in that they can offer advantages in terms of product and / or overall process quality, efficiency, throughput, or cost. Continuously connected processes involve increased complexity in the design and automation of manufacturing equipment, including process control and monitoring. Therefore, additional and improved process monitoring and process analytical technologies (PAT) are desired and are currently being developed and applied where appropriate.

[0009] Another need in biopharmaceutical manufacturing is the emergence of decentralized local production of drug substances, so-called "local production." The trend toward personalized medicine and decentralized local manufacturing, coupled with an increasing number of drug products, calls for improved biopharmaceutical manufacturing technologies that allow for a more modular and flexible design and deployment of production capacity, facilities, and equipment. Modular designs allow for the duplication and expansion of production capacity not only within a specific manufacturing site and facility, but also across different manufacturing sites and countries. Furthermore, there is a need to rapidly implement and deploy manufacturing technologies to meet specific production needs without the overhead costs and financial risks of excessive capital expenditures and investments. Therefore, improved manufacturing technologies enable a LEAN approach to biopharmaceutical production.

[0010] Another need in biopharmaceutical manufacturing is improved safety for patients, production personnel, and the environment. Drug products must be free of contamination, and production techniques should help avoid the risk of product contamination with, for example, microorganisms, product carryover between different drug production processes, and other undesirable contaminants that may adversely affect patient health or drug efficacy.

[0011] Protection of personnel operating biopharmaceutical manufacturing processes is important when infectious, toxic, or otherwise harmful materials are handled, for example, in the production of certain vaccines or antibody-drug conjugates (ADCs). Thus, improved manufacturing techniques are needed to improve drug, patient, and operator safety, for example, by enabling closed handling and containment of processed fluids and materials.

[0012] One recent development that addresses the aforementioned needs for reducing production costs, increasing production throughput and quality, and improving safety in biomanufacturing is represented by single-use technology (SUT), which has been rapidly adopted in the biopharmaceutical industry. With single-use processing technologies and equipment, wetted parts that come into contact with process fluids and drug products during processing, such as fluid storage vessels, tubing, and separation devices, are installed and used for a specific process, product, or for a limited time only, and then provided in a clean, ready-to-use condition, providing consumables that are to be disposed of.

[0013] SUT consumables are typically produced, constructed, and packaged in a cleanroom environment to avoid contamination with microorganisms, particulates, and the like. SUT wetted parts are further cleaned and provided in a pre-sterilized state, thereby enabling aseptic and / or sterilization processes, thereby reducing the aforementioned risks associated with product, operator, or patient safety. Typically, SUT wetted parts undergo a sterilization gamma irradiation process prior to use in a biomanufacturing process and, upon doing so, are deployed as “pre-sterilized” at the point of use. This may involve providing the consumable with a formal, verified sterility marking after the sterilization process, or alternatively, providing consumables that have undergone sterilization but are provided without a formal sterility marking. Under controlled and rigorous manufacturing conditions, SUT consumables may be deployed non-sterile and / or subjected to processes that control the state and condition of the consumable. This allows the level of microbial contamination, commonly referred to as “bioburden,” or the level of contamination or presence of contaminants or particles to be controlled and maintained within a predefined level.

[0014] The primary benefit of using single-use technology (SUT) fluid handling equipment is the elimination of cross-contamination between production batches and campaigns when the SUT equipment is used for only a single formulation. SUT equipment is disposed of after use, which may be after a single production run, batch, or a campaign involving multiple production runs and batches. When SUT equipment is provided in a pre-sterilized state or bioburden-controlled by other means, initial cleaning and disinfection (e.g., by contacting the fluid lines with sodium hydroxide solution) or sterilization can be avoided. This enables a LEAN manufacturing approach, as time-consuming, expensive, non-value-added steps can be eliminated. Even post-use cleaning can be eliminated when SUT is used for only a single production run or batch. Eliminating the cleaning procedure and required cleaning fluids further reduces the clean water, fluid handling, and waste disposal required to prepare the cleaning solution in the first place, thereby reducing the size and complexity of the facility.

[0015] Single-use equipment may include fluid connectors that enable sealed processing, thereby protecting process fluid lines and / or operators and the environment from contamination or exposure to hazardous materials. Alternatively, the fluid connectors may include sterile connection features, thereby tightly and completely closing the fluid line. When using a sterile connector or disconnector, the sterility of a fluid line, two connected lines or components, or two disconnected lines or components may be maintained, provided that the fluid lines or components involved in the operation are kept sterile. These features allow SUT equipment to not only enable more efficient processing, but also reduce facility classification and containment requirements, thereby reducing costs and the risk of contamination or infection of process fluids and formulations and / or the process environment, facility, or operators.

[0016] SUT systems offer greater flexibility in (re)configuring manufacturing facilities and designing them to accommodate different processes and products, i.e., through reducing the need for fixed installations compared to traditional processing systems and installations, which required auxiliary systems for, for example, CIP and SIP. Thus, today, SUT equipment and SUT processing methods are available or made available for the majority of all types of equipment and / or unit operations, especially bioreactors for cell culture or fermentation, buffer bags for liquid storage, tubing and pumps for liquid transfer and filling operations, filters, chromatography columns, and related systems for separations.

[0017] These features enable SUT equipment to offer improved efficiency, safety, and convenience compared to traditionally installed facilities and systems. Traditionally, processing equipment and systems are typically constructed of stainless steel and / or plastic and are not produced under controlled (or cleanroom) conditions that reduce bioburden. Traditional systems are typically cleaned-in-place (CIP) and sometimes sterilized-in-place (SIP), requiring ancillary equipment, instruments, and fluids, as well as substantial time for validation, execution, and quality control of CIP and SIP procedures. The size, cost, and complexity of facilities relying on traditional equipment and installed facilities are significantly greater than those employing SUT. SUT facilities and processes can be planned, constructed, and launched in significantly less time than traditional manufacturing techniques, reducing the capital investment and financial risks associated with a typically highly dynamic portfolio of drug products, as well as the risks and uncertainties associated with drug candidate testing and approval and product demand.

[0018] Although the biopharmaceutical industry is rapidly adopting SUT for many reasons, there remains a need for further improvements to current SUT systems and installations to further increase the efficiency and effectiveness of production biopharmaceutical manufacturing. These needed improvements involve improved design as well as improved methods for using SUT systems. Summary of the Invention [Problem to be solved by the invention]

[0019] There are still challenges that need to be overcome to adapt to single-use technology, some of which are common to both conventional and SUT systems.

[0020] One challenge with current system, subsystem, and component designs is limited flexibility to achieve different process and system configurations, both at the system supplier and at the point of use, particularly in biopharmaceutical manufacturing. Typically, systems are built or adapted by the system supplier for a specific processing task and then provided to the end user for use limited to that specific task and application. Today, both traditional and SUT systems, by design, have very limited reconfiguration capabilities at the point of use and therefore performed by the user. Due to this lack of configurability, different dedicated systems and products are typically required today to perform different unit operations, such as performing either a chromatography unit operation or a filtration unit operation. Therefore, new systems, particularly new SUT systems, are needed that offer greater flexibility and configurability, particularly at the point of use, with reduced cost and lead time. [Means for solving the problem]

[0021] This is accomplished using a biological fluid treatment system comprising a fluid treatment device including at least one fluid path, a pump for applying pressure within the at least one fluid path, a valve configured along the fluid path, and a first actuator configured to control the valve to achieve a desired opening state of the fluid path. The biological fluid treatment system further comprises a process interface including a pump driver for driving the pump of the fluid treatment device, and a process control element including a pump control system configured to control at least the pump driver and a valve control system configured to control the first actuator. The system is modular. The fluid treatment device is included in a fluid treatment device module having a predetermined fluid treatment device configuration. The process interface is included in a process interface module having a predetermined process interface configuration. The process control element is configured to receive information related to the predetermined process interface configuration of the process interface module, receive information related to the predetermined fluid treatment device configuration of the fluid treatment device module, and control the at least one pump driver and / or valve based on the received information related to the predetermined fluid treatment device configuration and the predetermined process interface configuration.

[0022] Thus, the processing control element is arranged to control various system setups.

[0023] The modular design allows for easy and robust (re)configuration of the system to accommodate different unit operations, preferably at the point of use.

[0024] The solution according to the present disclosure allows to design a compact system, in which the appearance of dead volume can be minimized.

[0025] The fluid treatment device may be prefabricated, thus reducing or even eliminating the need for the user to connect hoses, thus reducing installation time.

[0026] Furthermore, the process control elements for different types of activities may be the same so that if a process control element is made unavailable, another process control element may be substituted as the process control element may be generic.

[0027] Additionally, and with regard to validation requirements, the use of general purpose processing control elements is beneficial.

[0028] Physical separation of the process control elements from the fluid processing devices allows for greater flexibility in accommodating different system capacities, such as flow path ID, flow rate, or processing volume. Separation of the fluid control elements and fluid processing devices also allows for greater flexibility in accommodating different unit operations, such as single column (batch chromatography) or multiple column chromatography, filtration, etc.

[0029] This flexibility is particularly advantageous in bioprocessing when small-volume production scenarios for biologics are planned and when greater facility and equipment flexibility is a competitive advantage. Having process control elements that can be used for multiple unit operations and processes helps reduce CAPEX requirements, as the control elements can be used for different operations and processes, as opposed to today's technology, where completely different systems must be purchased. Other benefits include reduced complexity in servicing the equipment and a smaller overall footprint within the facility.

[0030] In small-scale production facilities, capital investment and the number of process control elements can be reduced without compromising overall processing time and throughput. Indeed, the same process control element can be used for different types of processes. The process control element is used in a first process and unit operation with a first fluid processing device having a first fluid processing configuration, while, for example, a second fluid processing device having a second fluid processing configuration and configured for a second manufacturing process may already be in the process of setting up fluid lines for processing and connecting devices to the second fluid processing device. The process control element is then deployed after completion of the first manufacturing process and connected to the second fluid processing device for processing with the second fluid processing device configuration.

[0031] In various embodiments, the fluid treatment device module includes its own structural support.

[0032] The modularity of this system, as described above, provides an entirely new, LEAN way of operating and utilizing equipment in biomanufacturing. When a fluid handling device has structural support that is not dependent on the structural support provided by a process control element, the fluid handling device can be utilized in a biomanufacturing process to establish fluid connections with external devices before pairing with a process control element for automated processing. As an example, assembly and configuration of fluid lines in an SUT biomanufacturing system, and therefore consumable setup, are time-consuming activities that must be performed prior to automated processing. To complete this setup of consumables, the fluid handling device must be connected and assembled with necessary external devices, such as auxiliary fluid storage and / or fluid transfer equipment and / or separation devices. A new and improved method of deploying a system in accordance with the present invention is to connect a reusable (and expensive) process control element after fluid line assembly and / or fluid connections, if any, with the fluid handling element and external device are completed or initiated. As a result, the process control element is primarily used in actual product processing and is not blocked in non-value-adding assembly and preparation steps.

[0033] The same may be true for the processing interface if it is provided as a separate modular unit and separate from the processing control element.

[0034] For example, preparatory steps for a subsequent processing step may be performed while the processing control element is employed in another processing step. The same advantages apply to disassembly and disposal of used wetted parts and consumables after processing. As a result, processing control elements may be used with considerable flexibility in processes and facilities, allowing for rapid changeover between processing steps and processes.

[0035] In some embodiments, the processing interface may be provided as a separate modular unit and connected after the fluid line assembly and / or fluid connections, if any, with the fluid treatment elements and external devices are completed or initiated, thereby allowing the processing interface to be utilized with greater flexibility and lean efficiency in processes and facilities, and because the processing interface is not occupying non-value-adding assembly and preparation steps.

[0036] In SUT systems, compared to traditional manufacturing employing conventional systems, issues arise from the frequent changeover and replacement of materials, i.e., SUT consumables. In one aspect, this creates an issue of warehouse space required to store consumables at biomanufacturing company facilities. In another aspect, packaging and labeling of SUT consumables must comply with hygienic storage and transportation requirements. For example, traditional cardboard boxes are prone to mold and / or spores and are therefore unsuitable for storage. Furthermore, they are strictly excluded for further material transfer within biomanufacturing facilities. The fluid treatment device module with its unique structural support enables improved (re)packaging, labeling, and handling so that fluid treatment devices can be stored, transported, and ultimately deployed to biomanufacturing companies in a safe and robust manner.

[0037] Today, frequent changes associated with SUT consumables require new (fresh) installations of process fluid lines to be used, installed, qualified, and documented for each production run, batch, or campaign. This means that numerous items and extended bills of materials (BOMs) are handled at the point of use in biomanufacturing bioequipment. This also necessitates a more sophisticated material flow and handling suite, including managing, documenting, and qualifying said materials. During actual processing, this requires significantly intensified and time-consuming handling of materials by operators, with potential errors, deviations, and delays that, in the worst case scenario, can affect the overall quality and efficiency of manufacturing. The increased number of operational steps and operator interactions that occur with this extended BOM is reflected by the expanded batch protocol and by the more complex work instructions that appear in manufacturing batch protocols and records compared to traditional manufacturing. Thus, the above system allows for a reduction in the complexity of material flow, BOMs, work instructions, and batch records.

[0038] Modular biological fluid processing systems can operate fluid processing devices, FPDs, designed for "traditional" cleaning and (re)use. The modular system concept may thereby provide standardization of a "one size fits all" system platform where modules are designed according to their intended use for either single or multiple cycles, batches, campaigns, and / or processes.

[0039] The modularity of the system concept according to the invention further allows for the fluid treatment device, FPD, to be used and removed from the system and process control element, PCE, for example, to perform maintenance on the process control element or to clean and sterilize the fluid treatment device. These activities can be performed elsewhere, for example, in another room, facility, or at another site, company, or supplier. The removed fluid treatment device can be reused with the same or a different process control element after maintenance, cleaning, or sterilization. This allows the system concept according to the invention to improve the deployment and use of conventional and hybrid systems as well.

[0040] In a further application scenario, structurally self-sufficient fluid processing devices (consumables) can be stored between campaigns, enabling new use cases when the design and material selection for the consumables support long-term use. This storage is noteworthy, especially for SUT processing and to avoid the risk of cross-contamination between different processes. By being able to separate the fluid processing device from the process control elements and optionally the process interface, the fluid processing device, potentially together with other fluid processing devices such as columns or filters, can be stored between production campaigns, while the process control elements and / or process interface can be utilized in other processes.

[0041] In a further application, the process control elements and / or process interfaces may be removed from the fluid line assembly containing the fluid treatment device after processing, for example, thereby keeping the fluid line assembly intact and ready for future processes and batches, while the process control elements and / or process interfaces may be utilized for a different process and batch, or in another part of the facility or plant. This alternative may be attractive when operating equipment in a traditional manner, including cleaning, intermediate storage, and reuse of fluid treatment equipment and wetted parts.

[0042] In a further application, the system and process control elements can be utilized in continuous processing operations. Continuous processing generally refers to operation over a longer time span than a typical batch process. These are typically designed so that there is no or very limited fluid retention volume between two adjacently connected operational steps, such as two adjacently connected unit operations, and such bioreactors have filtration or chromatography steps that process the output from the bioreactor. For operation in continuous processes, the FPD can be adapted differently compared to batch processes to specifically suit the process. For example, the chromatography step and FPD can be designed to operate alternately with two columns, where the first column is loaded by applying a feed to the system, the second column is eluted, and then regenerated for a new loading step, and then the second column is loaded while the first column is eluted and then regenerated for a new cycle. A continuous chromatography system and its FPD may be adapted to run two, three, four, or more columns for continuous processing, where two or more of the columns are typically connected in series for a specific time period within a column loading step, allowing for higher column volume utilization and therefore higher productivity. Ideally, the modular process control element and / or process interface unit of the basic system can accommodate a wide range of different FPD variations, allowing for flexibility in achieving continuous operation and different configurations of the FPD and connected external components and external fluid processing devices.

[0043] In one embodiment, the modular system is adapted to allow operation of two or more unit operations in either batch or continuous mode, and in either conventional or SUT mode, and the process control elements may allow for connecting two or more process interfaces and fluid processing device modules.

[0044] In another embodiment, the modular system and its process control elements can be expanded with modules that allow for an increase in the number or type of components, e.g., valves, pumps, or sensors, internal or external to the process control element. In another embodiment, the modular system and its process interfaces can be expanded with modules that allow for an increase in the number or type of interfaces to components, e.g., valves, pumps, or sensors, internal or external to the process interface.

[0045] The present disclosure also relates to a process control element for use in a biological fluid processing system as disclosed herein.

[0046] The present disclosure also relates to a fluid treatment device for use in a biological fluid treatment system as disclosed herein.

[0047] The present disclosure also relates to a method for setting up a biological fluid treatment system. The method includes providing a fluid treatment device including at least one fluid path, a pump for applying pressure within the at least one fluid path, valves arranged along the fluid path, and a first actuator arranged to control the valve to assume a desired opening state of the fluid path. The method further includes providing a process control element, connecting the fluid treatment device to the process control element, and controlling at least one pump driver for controlling the pump and / or the valve based on received information related to a predetermined fluid treatment device configuration and a predetermined process interface configuration. [Brief explanation of the drawings]

[0048] [Figure 1a] 1 is a schematic diagram illustrating an example of a prior art design for a biological fluid treatment system. [Figure 1b] 1 is a schematic diagram illustrating an example of a prior art design for a biological fluid treatment system. [Figure 2] 1 is a schematic diagram illustrating an example of a modular fluid treatment system according to the present invention. [Figure 3] FIG. 3 is a schematic block diagram illustrating the modular design of the fluid biological fluid treatment system of FIG. 2. [Figure 4] FIG. 3 is a schematic workflow diagram for the biological fluid processing system of FIG. 2. [Figure 5a] 3A-3C illustrate different setups of the modular fluid processing system of FIG. 2. [Figure 5b] 3A-3C illustrate different setups of the modular fluid processing system of FIG. 2. [Figure 5c] 3A-3C illustrate different setups of the modular fluid processing system of FIG. 2. [Figure 5d] 3A-3C illustrate different setups of the modular fluid processing system of FIG. 2. [Figure 6a] FIG. 1 illustrates an example of a modular design for fluid treatment devices of a modular fluid treatment system. [Figure 6b] FIG. 1 illustrates an example of a modular design for fluid treatment devices of a modular fluid treatment system. [Figure 6c] FIG. 1 illustrates an example of a modular design for fluid treatment devices of a modular fluid treatment system. [Figure 6d] FIG. 1 illustrates an example of a modular design for fluid treatment devices of a modular fluid treatment system. [Figure 7] FIG. 2 illustrates an example of a valve and a first valve actuator according to an example of the invention. [Figure 8] 1 is a schematic flow chart illustrating an example of a method for setting up a biological fluid treatment system. DETAILED DESCRIPTION OF THE INVENTION

[0049] 1a and 1b illustrate a prior art fluid treatment system 1. FIG.

[0050] Fluid treatment system 1 comprises a fluid treatment section 2. Fluid treatment section 2 is characterized by wetted parts, i.e., parts that come into contact with the process fluid. The wetted parts include wetted parts and / or consumables of the system. In the example shown, fluid treatment section 2 comprises fluid connections 3 to external fluid treatment components and possibly other external components. In the example shown, fluid treatment section 2 further comprises at least one valve 4, at least one pump 5, and at least one sensor 6.

[0051] The fluid treatment system 1 further comprises an external fluid treatment component 7. The external fluid treatment component 7 comprises an external wetted part / consumable arranged to contact the process fluid. In the illustrated example, the external fluid component 7 comprises a fluid supply vessel 8 and / or a fluid treatment device 9 and / or a fluid receiving vessel 10.

[0052] Fluid treatment system 1 further comprises a non-wetted system portion 11. The non-wetted system portion comprises a portion 11 of fluid treatment system 1 that does not contact fluid. The non-wetted system portion 11 comprises a process interface, such as, for example, an actuator 12 and / or a drive 13. The non-wetted system portion 11 further comprises a process control element. The process control element comprises, for example, a valve control system 14 and / or a pump control system 15 and / or a sensor control system 16. The process control element may further comprise a power supply 17. The non-wetted system portion further comprises a human machine interface, HMI 18, a processing element 19, and a memory 20.

[0053] The present invention addresses prior art processing systems, such as those described with respect to Figures 1a and 1b, and further addresses the processes and workflows involved.

[0054] Additionally, the present invention contemplates conventional and / or hybrid systems of SUT processing systems, where these hybrid systems are characterized by a mix and / or combination between the SUT and conventional systems, subsystems, or components.

[0055] 2 discloses an example of a modular biological fluid treatment system 200. The modular biological fluid treatment system 200 may include all or some of the components as described with respect to FIG.

[0056] The biological fluid treatment system may be, for example, an SUT biological fluid treatment system, but may also be a conventional biological fluid treatment system or a hybrid biological fluid treatment system.

[0057] The modular biological fluid treatment system 200 is preferably designed with three modules in mind, where a common treatment control element 124 may be paired with one or more treatment interfaces 123_1, ..., 123_n having at least two different treatment interface configurations for operating the various fluid treatment devices 122_1, ..., 122_n, and the fluid treatment devices 122, or the modules they comprise, may differ in terms of unit operations and / or configurations (P&IDs) and / or capacity / size, e.g., flow rate ranges, tubing and component sizing, liquid hold-up volumes, pressure ratings, etc.

[0058] The SUT fluid processing system may be, for example, an SUT chromatography system built for process scale-up and production in early clinical stages. The illustrated system is intended for use with ready-to-use disposable fluid processing devices 122_1,...,122_n that are deployed as consumables and disposed of after processing.

[0059] The fluid treatment devices 122_1, ..., 122_n may be structurally self-sufficient flow path systems. The structurally self-sufficient fluid treatment devices may be provided as cabinets. The cabinets may be configured to contain fluids from potential leaks in the fluid treatment devices.

[0060] The structurally self-sufficient fluid treatment devices 122_1, ..., 122_n may have different fluid treatment device configurations, for example, in terms of functions and unit operations. The fluid treatment devices 122_1, ..., 122_n may further comprise fluid treatment devices such as columns, filters, reactors, etc. The fluid treatment devices may further comprise a device for fluid storage and / or a transfer device such as a hose.

[0061] The processing interfaces 123_1, ... 123_n provide the physical and / or mechanical interfaces required by the fluid processing devices 122_1, ... 122_n. As is clear from the above, different fluid processing devices may require different physical and / or mechanical interfaces in terms of location, size, number, etc.

[0062] Each processing interface 123_1,...,123_n typically includes at least one pump driver, such as a motor having a rotating shaft, coupled to a pump chamber in the fluid processing device to engage the pump chamber and enable pumping of fluid. In some configurations of fluid processing devices, a single pump may be sufficient, but the size and capacity of the pump, and therefore the size of the pump driver required in the processing interface, may vary. In other embodiments of fluid processing devices, the location or number of interfaces between the pump drivers and the pump chambers of the fluid processing device may vary. Thus, a modular system allows for the deployment of different, possibly dedicated, processing interface modules to utilize different fluid processing devices along with the processing control element 124. Alternatively, the modular biological fluid processing system 200 may be constructed using at least one single processing interface module, but this module allows for the processing interface to be reconfigured for use with different fluid processing devices along with the processing control element. For example, pump drivers may be replaced with drivers of higher or lower capacity and size, or pump drivers may be added, removed, or rearranged to accommodate the different requirements of different fluid processing devices.

[0063] The modular biological fluid treatment system 200 has electrical connections between components of the fluid treatment device, such as sensors, and the treatment control element 124. The electrical connections may be established directly between the fluid treatment device and the treatment control element. However, the electrical connections may also or alternatively be established via a treatment interface. In the latter example, the treatment interface also comprises the electrical connections. This may be advantageous because the cables connecting with the fluid treatment device can be kept short. Alternatively, the cables may be omitted by interfacing and establishing electrical contacts between the fluid treatment device and the treatment interface when docking the fluid treatment device to the treatment interface.

[0064] The modular biological fluid treatment system 200 may further include a pneumatic connection between a component of the fluid treatment device, such as a valve and its first actuator, and the treatment control element. The pneumatic connection may be established directly between the fluid treatment device and the treatment control element. Alternatively, or in addition, the pneumatic connection may be established via a treatment interface. The latter may be advantageous because the air line (air tubing) to be connected to the fluid treatment device may be kept short. Alternatively, the air line (air tubing) may be omitted by interfacing and establishing a pneumatic contact between the fluid treatment device and the treatment interface when docking the fluid treatment device to the treatment interface.

[0065] The use of multi-connectors may be preferred, for example, to combine electrical and / or pneumatic connections on one or more connectors to reduce the number of user interactions and connections that must be made when connecting process control elements, process interfaces, and fluid processing devices. Multi-connectors may also help to prevent user interactions because the layout of the multi-connector is predefined.

[0066] Furthermore, the assignment and purpose of individual connections or connection points on a multi-connector may be changed when connecting different fluid processing devices and / or processing interfaces with the processing control element. This allows for great flexibility in modifying the fluid processing devices and processing interfaces, for example, when upgrading the fluid processing device in the future or customizing the fluid processing device with new and / or different components. A general-purpose I / O interface may be provided with connections for transmitting general-purpose signals used for controlling and / or monitoring electrical or pneumatic components. The general-purpose I / O interface may be utilized differently among different combinations of processing control elements, processing interfaces, and fluid processing devices. Also, an excessive number of connections for such general-purpose signals may be provided on the connection interfaces and / or multi-connectors within the fluid processing devices and / or processing interfaces and / or processing control elements, such that all available I / O connections and interface functions are not used at all in some configurations. Thus, connections between fluid processing devices and / or processing interfaces and / or processing control elements may be implemented through the use of multi-connector, general-purpose I / O interfaces, and these connections are reconfigured by changing their functional assignments when connecting different fluid processing devices and processing interfaces to the processing control elements.

[0067] The modular design of the process control elements, process interfaces, and fluid processing devices, and in some cases the use of universal connectors, allows a wide variety of different fluid processing devices, e.g., different fluid processing devices configured for different unit operations such as chromatography or filtration, to be utilized with the process control elements 124. In this regard, interchangeability of the fluid processing devices 122 provides flexibility to accommodate different fluid processing tasks.

[0068] In another aspect, the universal connector provides the flexibility to "proof" the system and its process control element 124 by allowing new fluid process device and process interface configurations to be added and used with the universal process control element 124 without having to physically upgrade or modify the process control element 124. Instead, functions (and connections) can be reallocated by deploying firmware updates or different software configurations.

[0069] Furthermore, the modular design and, in some cases, the connection of submodules via universal connectors allow the modular biological fluid treatment system 200 to be used with various types of fluid treatment devices for different use cases, such as, for example, conventional biological treatment systems or SUT biological treatment systems. For example, the process control element 124 and processing interfaces configured for the operation of a chromatography unit and corresponding fluid treatment device may be used with an SUT fluid treatment device in one manufacturing setup or facility, while equivalent fluid treatment devices and processing interfaces, and alternatively, the same fluid treatment elements and processing interfaces, may be utilized in another manufacturing instance with similar fluid treatment devices, but in a conventional setup that includes pre- and / or post-treatment cleaning of the fluid treatment device, thereby enabling reuse of the fluid treatment device. The modular design and connection via universal connectors thus allow for the use of a “one-size-fits-all” system platform that enables different use cases for the system by allowing for the adaptation of different fluid treatment devices provided for different use cases. One fluid treatment device provided for conventional use may, for example, include a pump module or other components in the flow paths that provide longer operation and lifespan compared to the SUT fluid treatment device and its flow paths. Fluid treatment devices provided for conventional applications may include different wetted materials that are compatible with harsh and prolonged cleaning fluids and cleaning regimes, and may provide other types of fluid connectors and inlets and outlets.

[0070] For end users, the modular design of modular biological fluid treatment system 200 and its connection via universal connectors allows for the flexibility to change operational modes on demand, for example, from conventional bioprocessing to SUT bioprocessing or vice versa, thereby eliminating the need to invest in multiple different systems and products, not only reducing capital expenditures but also reducing maintenance complexity, footprint within manufacturing facilities, etc.

[0071] Thus, modular biological fluid treatment system 200, in one example, is a single-use technology (SUT) system. SUT systems are characterized primarily by the manner and purpose for which their wetted parts are used. With SUT systems, the wetted parts are used exclusively for the production of a particular biological product or a particular product class. SUT wetted parts may be replaced after a specific period of time, for example, after the completion of a production batch, campaign, or other requirements. Because replacing used SUT wetted parts typically results in the disposal of these parts, SUT is often described as disposable technology and SUT wetted parts are described as disposable.

[0072] Upon replacement and installation of a new SUT wetted part, the condition of the installed wetted part is known with respect to hygiene and contamination levels and / or functionality of the wetted part. For example, a pre-sterilized clean wetted part may be installed. After replacement of the SUT wetted part, additional production batches and / or campaigns with the same or different biological product may be run using the newly installed wetted part. The design of the SUT system, including the wetted part, preferably facilitates easy replacement of the wetted part.

[0073] Modular biological fluid treatment system 200, as described above in one example, is a conventional system. Conventional systems are characterized primarily by the manner and purpose for which the system and its wetted parts are used. In conventional systems, wetted parts are typically not replaced between production runs with different biological agents or classes of biological agents. Instead, extensive thorough cleaning is continued to avoid cross-contamination and carryover between batches of different agents. Of course, conventional systems are used exclusively for the production of specialized formulations, e.g., in routine production, thereby eliminating the risk of cross-contamination and carryover between different formulations.

[0074] When producing material for drug product clinical trials where many different formulations need to be produced in small quantities, cleaning of wetted parts is necessary, even though it involves tedious cleaning procedures, cleaning validation, and QC after the cleaning step.

[0075] The design of conventional systems that include wetted parts typically does not facilitate easy replacement of the wetted parts.

[0076] In one example, fluid processing system 200 is a hybrid system. A hybrid system is characterized by a mix of system components, or rather subsystems, where at least one subsystem is characterized and used as an SUT subsystem and at least another subsystem is characterized and used as a conventional system. Hybrid systems may be used, for example, when the technology to build a complete SUT system is unavailable. Hybrid systems may be useful when a subsystem that is difficult to clean is deployed as an SUT subsystem, while other subsystems that are easier to clean may be conventional. One example for a hybrid system is a chromatography unit operation comprising a chromatography system with SUT wetted parts connected to SUT fluid supply and fluid receiving vessels and bags, but with a conventional chromatography column as the fluid processing device. All wetted parts except the column may be deployed as SUT consumables and pre-sterilized, but the column may be washed after a conventional column packing operation because a particular chromatography resin and a particular column and packed bed dimension combination are not available in the form of an SUT column. Although the example of a conventional chromatography column describes external fluid processing components, there may be some components or modules of the fluid processing device that are not available in the SUT technology, or the available SUT components do not provide the required functionality of the conventional technology, such as, for example, a required particular sensor. Thus, conventional technology may be combined with the SUT for hybrid processing devices and systems.

[0077] FIG. 3 shows an example of a modularly designed fluid treatment system 200 .

[0078] The fluid treatment system includes a fluid treatment device, FPD 122, with wetted parts that contact the process fluid, a process interface, PI 123, and a process control element, PCE 124. In one example, the process control element 124 can operate at least two different types of fluid treatment devices 122 or fluid treatment devices of different designs, preferably one at a time. Some embodiments of a modular biological fluid treatment system 200 have been described with respect to FIG. 2.

[0079] The fluid treatment device 122, as described above, is characterized by wetted parts, i.e., parts that come into contact with the process fluid. The wetted parts include the wetted parts and / or consumables of the system.

[0080] The fluid treatment device 122 comprises at least one fluid pathway. The at least one fluid pathway may comprise a fluid conduit (not shown) arrangement having at least one inlet and one outlet. The fluid treatment device 122 may comprise a fluid connection 103 arranged to connect the fluid conduit (not shown) arrangement to an external fluid treatment component. The fluid treatment arrangement may be formed within the fluid treatment core.

[0081] The fluid processing device 122, or fluid processing core, comprises at least one valve 104 controlled by a corresponding first actuator 125, the valve / actuator arrangement being configured to control flow in said at least one fluid path, the valve being arranged in said fluid path and the first actuator being configured to control the valve to assume a desired opening state of said fluid path.

[0082] The fluid treatment device 122 further comprises at least one pump 105 arranged to control flow in the at least one fluid path. The fluid treatment device 122 further comprises at least one sensor 106 arranged to monitor at least one condition of the process fluid of the fluid treatment device 122.

[0083] At least one valve 104 with a corresponding first actuator 125, at least one pump 105, and at least one sensor 106 are operably connected to a processing control element 124 via a processing interface 121 or via a direct connection.

[0084] The fluid treatment device 122 is designed as a replaceable flow path. The fluid treatment device 122 may form a cabinet that provides sufficient structural support for the mounting and / or assembly with the components that supply, transport, treat, and / or receive process fluids. This structural support for the cabinet may be achieved either by the structure of the fluid treatment device itself or by providing support structures for the fluid treatment device or portions thereof. Sufficient structural support is thereby provided to allow connection of external devices even when the fluid treatment device is not connected to the process control element 124.

[0085] To establish a unit operation for a manufacturing step, it is typically necessary to connect the fluid processing device 122 to an external fluid processing component 107. The external fluid processing component 107 comprises an external wetted part / consumable configured to contact the process fluid. The external fluid processing component 107 includes, for example, at least one fluid supply vessel 108 and / or at least one fluid receiving vessel 110, and / or a fluid processing device 109, which may be, for example, a chromatography column or a filter.

[0086] The modular biological fluid treatment system 200 further comprises a non-wetted system portion 111. The non-wetted system portion comprises the portion 111 of the fluid treatment system 100 that does not contact fluid. The non-wetted system portion 110 comprises a process interface 123 and a process control element 124.

[0087] The process control element 124 may, for example, comprise a valve control system 114 with the second actuator 112, and / or a pump control system 115, and / or a system 116 for monitoring and / or controlling the at least one sensor of the fluid processing device and / or other sensors of the system 200. The process control element 124 may further comprise a power source 117.

[0088] The valve control system 114 is arranged to control at least one first actuator 125 and associated valve 104 in the fluid treatment device 122 .

[0089] The valve control system 114 is, for example, pneumatically controlled. In one example, the valve control system 114 is configured to control a fluid pressure (liquid or gas) to operate the valve between a fully open and a fully closed position. The valve control system may be configured to control the fluid pressure to control the valve to an intermediate position between a closed and an open position. This allows the valve to function as an ON / OFF valve and / or a pressure control valve. The pressure control valve or flow control valve is controlled to limit the fluid pressure or fluid flow of the process fluid by partially closing the valve between a fully open and a fully closed state.

[0090] Valve control system 114, in the illustrated example, includes a second actuator, which may include, for example, a solenoid valve or a motor-driven valve for regulating air pressure in pneumatic conduits connected to the first actuator and associated valve.

[0091] One or more connector units (not shown) may be provided to allow connection and disconnection of multiple pneumatic conduits within the valve control system, thereby connecting and disconnecting the second actuator to the first actuator. The connector units may be arranged, for example, at the fluid processing device and / or connect the processing control element to the fluid processing device and / or connect the processing control element to the fluid processing device via the processing interface.

[0092] In one example, the valve 104 of the fluid processing device 122 comprises a diaphragm valve. A pneumatic connection provides an easy-to-use and flexible method of interfacing a cost-effective diaphragm valve and its first actuator 125 in the fluid processing device 122 to a second actuator and pneumatic valve control in the process control element 124. Alternatively, the diaphragm valve and corresponding first actuator 125 are controlled by a second actuator 112 in the process control element 124 and a mechanical, hydraulic, or electrical controller.

[0093] The pump control system 115 is arranged to control at least one pump 105 in the fluid treatment device 122. The system 116 for monitoring and / or controlling the sensors 106 is arranged to monitor / control at least one sensor in the fluid treatment device and / or potentially other sensors of the system.

[0094] To enable flexible modular design of the process control element, PCE 124 and the fluid processing device, FPD 122, and also to enable user-friendly interactive operation, the number of mechanical contact points between the process control element 124 and the fluid processing device, FPD 122 may be minimized.

[0095] The mechanical interfaces to the fluid treatment elements 122 include an interface to a pump driver 113 and possibly an interface between a reusable reader 121 for the sensors. The pump driver 113 is typically configured to drive one to three pumps. The reader 121 may include at least one flow meter transmitter positioned adjacent to the fluid path and adapted to mate with a transmitter, such as an electromagnetic flow measurement device, or a UV light source positioned adjacent to and mating with a UV cell in the fluid path. These interfaces are preferably included in the treatment interface 123.

[0096] The pump drive 113 may be a stand-alone unit that fits into the processing interface, PI 123. The processing interface, PI 123, may be provided with configuration slots, for example, for varying the physical location of the pump drive or for accommodating various pump drive sizes or numbers. In another embodiment, the processing interface 123 is modular and may comprise multiple processing interfaces or a mobile, stand-alone skid that includes a processing interface and a separate component, e.g., one or more pumps. A separate pump drive 113 or a pump drive within a separate processing interface may be required when providing a large-scale, high-volume system. For such systems, the processing interface (alternatively, the pump drive) may be provided as a floor-mounted skid, preferably movable on wheels. However, for small-scale, low-volume systems, the processing interface may be compact and lightweight, for example, so that it can be positioned on a bench. The fluid processing device may also be positioned on the bench.

[0097] There are electrical and / or fluid connections between the processing control element 124 and the pump driver. These connections may be established through the processing interface 123. Alternatively, these connections may be established directly between the processing control element 123 and the pump driver.

[0098] The processing interface typically includes a pump drive 113, as described above. The pump drive may include, for example, a motor having a rotating shaft that is coupled to a pump chamber in the fluid processing device, thereby engaging the pump chamber and enabling pumping of fluid.

[0099] The process control element 124 may be adaptable and configurable for different process interface 123 configurations and / or different fluid processing device 122 configurations. For example, the process control element 124 may be configured in one configuration to form a chromatography system with a fluid processing device 122 that includes the flow paths, functions, and components of a chromatography system, and in another configuration to form a filtration system with a fluid processing device 122 that includes the flow paths, functions, and components of a filtration system.

[0100] For example, a second valve actuator in the processing control element 124 may be capable of operating at least two different or similar first actuators, which may be arranged in at least two different fluid processing devices, and the second actuator may be arranged to operate both of them, one at a time.

[0101] The sensors and / or valves and / or pumps of the fluid processing device 122 may be in electrical communication with the processing control element 124. This communication may be performed wirelessly or at least partially wired, either directly or through a processing interface.

[0102] The system biological fluid treatment system 200 allows for operation of at least one of a plurality of fluid treatment devices that differ in terms of the unit operations provided (e.g., batch chromatography, multi-column chromatography, filtration, etc.), differ in terms of the particular instrumentation configurations (P&IDs) provided (e.g., number and location of inlets / outlets, number of pumps and sensors, etc.), and / or differ in terms of capacity ranges (e.g., flow rates, volumes, pressure ratings). To be adaptable to the operation of one of a plurality of fluid treatment devices, the treatment interface is interchangeable, configurable, or reconfigurable to match the fluid treatment device to the treatment control elements.

[0103] For example, in one configuration for a chromatography system, the fluid processing device may be configured with a specific number of inlets, e.g., six inlets, where the inlets are intended to be connected to an external fluid supply container or SU bag. The fluid processing device and its flow paths may further be configured with a connection to at least one fluid processing device, which may be, for example, a chromatography column or a membrane adsorber for accommodating separation tasks in which solutes in the inlet fluid are adsorbed onto the column. The fluid processing device may also be configured with its flow paths and a specific number of outlet conduits and connections, e.g., four outlets, for connection to fluid-receiving containers or single-use bags. In other configurations of the fluid processing device, a different number of inlets and outlets may be provided, and other fluid processing devices, such as filters in a filtration process, may be connected. In other configurations of the fluid processing device, the fluid processing device may be omitted or unnecessary, for example, when the fluid processing device is intended only for fluid transfer from a fluid supply container to a fluid-receiving container.

[0104] External fluid processing components to be connected to the fluid processing device, such as fluid supply or fluid receiving conduits or vessels and / or separation or reaction devices, e.g., filters or chromatography columns, may be attached to and / or assembled with the fluid processing device prior to connecting the fluid processing device to the processing interface and / or processing control elements.

[0105] Additionally, the fluid processing devices, processing interfaces, and / or processing control elements may themselves be formed by multiple sub-modules.

[0106] The non-wetted system portion 111 may further include a human machine interface, HMI 118 .

[0107] The software implemented processing control element controls reside in the processing element 119 and memory 120 .

[0108] In particular, the process control element is configured to receive information related to a predetermined process interface configuration of the process interface module and / or a predetermined fluid process device configuration of the fluid process device module, and to control at least one of the pump drivers and / or valves based on the received information related to the predetermined fluid process device configuration and / or the predetermined process interface configuration.

[0109] The processing control element may comprise or be connected to a user interface for inputting information relating to a given fluid processing device configuration and / or a given processing interface configuration.

[0110] The processing control element may include or be connected to a receiver configured to receive information relating to a given fluid processing device configuration and / or a given processing interface configuration, and the received information may be communicated, for example, from an RFID tag associated with the processing interface module and / or the fluid processing device module.

[0111] For example, different technologies may be deployed to store, access, and / or communicate information on and / or between modules of fluid processing system 200, the system itself, and / or external monitoring and / or control systems, such as manufacturing execution systems or factories, systems for scheduling, workflow, or material flow. Examples of such technologies are machine vision, which may be enhanced by machine learning and / or artificial intelligence, and various augmented and / or mixed reality instruction tools, including optical waveguide technology. Other examples of tagging and sensing technologies that may be used are barcodes, QR codes, LADAR, etc.

[0112] In different examples, information regarding the configuration of the fluid treatment device and / or processing element when identified may be obtained from a database or the like. The identification may be obtained, for example, by a sensor such as at least one of those exemplified above. Information regarding the configuration of the fluid treatment device and / or processing element may include information regarding the modules of the system, material flows, local scheduling, and / or data from the manufacturer.

[0113] In the example shown, the receiver is included in the data communication interface 121 .

[0114] The received information may include identification information of the fluid processing device module and / or identification information of the processing interface module.

[0115] In FIG. 4, an example workflow scheme for the setup, production, and post-production takedown for the production of biopharmaceuticals using a biological fluid handling system as disclosed herein is shown.

[0116] The scheme includes a high-level batch recording workflow 40 in the example shown.

[0117] The workflow schemes include workflow steps related to fluid processing, divided into a first scheme illustrating a workflow 50 for handling external fluid processing components and a second scheme illustrating a workflow 60 for handling a biological fluid processing system.

[0118] In the example shown, a high-level batch record workflow 40 begins with line clearance 41. This is followed by material transfer and / or BOM inspection step 42. An installation and validation step 43 is then performed for installation and validation of the manufacturing system. Automated processing 44 is then performed, possibly with manual interaction. A product handling and sampling step 45 is then performed for product handling and sampling of manual activities. This is followed by a process line demolition step 46. This is followed by a material unloading and process line cleaning step 47, in which single-use products are disposed of. Steps may be added and / or removed from this high-level workflow 40, and / or the time requirements for performing the steps may differ.

[0119] A first scheme illustrating a workflow 50 for handling external fluid handling components includes a step for bag installation 51. The workflow 50 for handling external fluid handling components further includes a step 52 for bag filling, which refers to an example of a process that requires large volumes of liquids and buffers and therefore requires filling of bags at the point of use.

[0120] A second scheme illustrating a workflow 60 for handling a biological fluid processing system includes a step 61 for connecting a filled bag to a fluid processing device. Additionally, the workflow 60 for handling a biological fluid processing system may also include a step 62 for installing a processing interface and / or processing control elements. The fluid processing device is then connected or installed 63 to the processing interface and / or processing control elements.

[0121] As is evident from the workflow steps related to fluid processing, the first scheme illustrating a workflow 50 for handling external fluid processing components includes a step 53 of configuring fluid lines in cooperation with connecting a bag to a fluid processing device. Furthermore, the first scheme illustrating a workflow 50 for handling external fluid processing components includes a step 54 of final checks in cooperation with connecting a bag to a fluid processing device 61, a possible step 62 of installing a processing interface and / or processing control element, and installing the fluid processing device on the processing interface and / or processing control element.

[0122] A second scheme illustrating a workflow 60 for handling a biological fluid processing system then includes a processing step 64. The processing may be preferably performed in an automated manner, either fully automated or semi-automated. Data records relating to the processing may be obtained.

[0123] Furthermore, the first scheme illustrating a workflow 50 for handling external fluid processing components may include a step 55 of cleaning, such as, for example, column cleaning, which may be performed during processing 64 and / or in post-processing cases.

[0124] A second scheme illustrating a workflow 60 for handling a biological fluid processing system includes, after processing 64, a step 65 of disconnecting the fluid processing device from the processing interface and / or processing control elements. The workflow 60 for handling a biological fluid processing system may further include a step 66 of removing the processing interface and / or processing control elements. The workflow 60 for handling a biological fluid processing system further includes a step 67 of disconnecting external fluid processing components from the fluid processing device.

[0125] Additionally, the first scheme illustrating the workflow 50 for handling external fluid handling components further includes a step 55 of disposing of the single-use technology, SUT, and consumables, if any.

[0126] The batch record workflow 40 and / or workflow steps related to fluid processing can be associated with instructions and data for the manufacture of a given biopharmaceutical. Instructions include, for example, standard operating procedures, SOPs, and / or electronic batch records, eBRs. Instructions belong to either Level 2 or Level 3, or a combination of different levels, which provide manufacturing support aligned with the ISA95 standard (ISA, International Society of Instrumentation and Control Engineers).

[0127] For example, the instructions may include instructions for line clearance 41, which may characteristically precede or be considered as the initialization of material transfer and / or BOM inspection 42.

[0128] These instructions may include instructions regarding consumables and / or equipment and / or fluid transfer and / or etiquette, which may be characteristically pertaining to material transfer and / or BOM inspection 42 and / or installation 43.

[0129] These instructions may include, in a corresponding manner, instructions for automated processing 44, product handling and sampling 45, process line removal 46, and material transfer and line cleaning 47.

[0130] These schemes for the manufacture of a given biopharmaceutical are, as will be apparent from the above, merely exemplary. High-level workflows and / or instructions may be added or removed. Also, the timeline in Figure 4 is merely exemplary.

[0131] In summary, the modularity of the system allows for the fluid treatment devices to be installed and disconnected from the treatment control elements / treatment interfaces in separate steps immediately before / after treatment. Thus, the fluid treatment devices and treatment elements may be utilized and / or prepared separately prior to installation and / or disconnection of the fluid treatment devices when the treatment elements are contained at least partially in separate units. Thus, the steps and processes of deploying the modules of the system may be performed in parallel, and overall utilization of the modules may be significantly improved, for example, because the control unit is not locked during setup for treatment and / or post-treatment cleaning.

[0132] 5a, 5b, 5c, and 5d illustrate different setups of the modular fluid processing system 200. Different possibilities for arranging the process control element, PCE 124, the process interface, PI 123, and the fluid processing device, FPD 122 are illustrated.

[0133] The modular fluid treatment system 200 and / or its modules may be designed for complete three-dimensional modularity and 3D utilization of configurability and expansion.

[0134] The fluid treatment device may be mounted on a simple frame or skid, thereby providing mobility. Mobility may be achieved using wheels attached to the frame or skid. The fluid treatment device may further be mounted on a frame or skid to provide structural support and stability for the cabinet, e.g., to avoid the risk of tipping; i.e., when the fluid treatment device is connected to surrounding fluid lines (tubes, bags, and tanks). The processing control element 124 may be designed with one or more rigid connection interfaces to the processing interface 123 and / or fluid treatment device 122. A rigid connection interface is considered here to be a connector or multi-connector that provides the electrical and / or pneumatic and / or mechanical interfaces necessary for communication, control, etc. in the operation of the complete system, and the connection requires the sub-modules (processing control element, processing interface, and / or fluid treatment device) to assume a predefined physical orientation relative to each other. Typically, the rigid connection interface is a connector positioned on or attached to the wall of the cabinet containing the sub-modules. A rigid connection interface is therefore designed to have no or very limited flexibility in the connection, as opposed to a flexible connection interface in which a connector is provided at the end of a flexible cable, connecting line, or harness comprising said flexible cable and / or connecting line. This allows the sub-modules to be connected to have a high degree of variability in their relative physical positions and / or distances towards each other, due to the flexibility of the cables, connecting lines, and harnesses between the two sub-modules. In one embodiment of the present invention, a flexible connection interface is utilized between a processing control element and a processing interface module.

[0135] An advantage of utilizing a flexible connection interface, particularly between the process control element and the process interface, is that the process control element can be positioned a distance from the process interface and fluid processing device so as not to interfere with the setup of the fluid processing components. For example, it may be preferable to position external fluid processing components, such as vessels and fluid processing devices, a short distance away from the fluid processing device, which can help reduce fluid hold-up volume and increase processing efficiency. The process control element and its cabinet can be positioned further away from the fluid processing device, so that the size and volume of the process control element's cabinet do not interfere with the fluid line assembly.

[0136] Furthermore, when the connection of the external fluid processing component to the fluid processing device is to be made before connecting the fluid processing device to the processing control element, the flexible connection interface and the ample length of its flexible cables and connecting lines can be utilized to connect the fluid processing device and processing control element without the need for rearrangement of the external fluid processing component to enable said connection.

[0137] Also, the cables and connections between the processing control element and the processing interface may be arranged so that the processing control element is not in close proximity to the processing interface but is obtained over a longer distance, for example, the processing control element and the processing interface may be in different rooms.

[0138] A modular biological fluid processing system may also preferably provide a modular and mobile solution that can provide some control, monitoring, and / or documentation functionality when using the fluid processing device and / or processing interface while not connected to a processing control element. Such a solution may be used as a complement to, or in place of, other functionality provided by, the processing control element and / or the HMI, processing element (computer), or memory included in or interacting with the processing control element. One example of a solution providing control, monitoring, and / or documentation functionality is when an external fluid processing device is connected to the fluid processing device while the fluid processing device is not connected to a processing control element. Here, for example, it may be desirable to provide readers for identifying tags and labels on fluid lines and connectors, or to provide interfaces to wireless readers or sensors. For example, a wireless reader for reading a tubing clamp sensor for monitoring the open / closed position of a tubing clamp (a manual valve in a fluid line to a bag) can be used to manage fluid with or adjacent to a fluid treatment device while the fluid treatment device is not yet connected to a process control element, and the valves in the fluid treatment device may not yet be controllable because the second valve actuator of the process control element is not yet connected to the first valve actuator in the fluid treatment device. In another embodiment of the invention, external solutions providing control, monitoring, and / or documentation functions may be utilized while the fluid treatment device is connected to a process control element and / or process interface, or both before and during full assembly of the process control element, process interface, and fluid treatment device modules to form a biological treatment system. As a result, the functionality of the fluid treatment system as a whole is not impaired when utilizing modules of the system in several workflow steps before or after utilizing all modules of the system required for processing.Additionally, in the pre-processing and / or post-processing workflow steps, support modules may be added to the system that provide functionality required in the pre-processing and / or post-processing.

[0139] 6a-6d show an example for a modular design of a fluid treatment device 922. In the example shown, inlet / outlet manifolds that connect to an external fluid treatment device are provided as sub-modules. Thus, the inlet / outlet manifolds can be designed as modules of the fluid treatment device. Providing the fluid treatment device as sub-modules can be advantageous. These sub-modules can then be used at the point of use, thereby improving ergonomics in connecting external fluid treatment devices to the inlets and outlets of the fluid treatment device. Another advantage of providing sub-modules for a fluid treatment device, particularly in providing modularity with respect to the number of inlets and outlets, is improved flexibility and configurability at the point of use. As such, a modular design can, of course, aid in the production of the fluid treatment device in the first place.

[0140] In the example shown, the fluid processing device 922 is designed as a flow path for a chromatography system, comprising an inlet manifold 930 configured to connect to one or more fluid supply vessels. The fluid processing device 922 further comprises an outlet manifold 931 configured to connect to one or more fluid receiving vessels. The fluid processing device further comprises a column manifold 932 configured to connect to a chromatography column. The inlet and outlet manifolds 930, 931 as well as the column manifold 932 are connected to a fluid flow path core 933, which typically comprises one or more pumps, sensors, and valves.

[0141] Typically, there is only one fluid conduit between the fluid path core 933 and the outlet manifold 931. Thus, connecting the fluid path core 933 with the outlet manifold 931 is simple for the operator at the point of use, as only a single fluid connection is established. Aseptic (sterile) connectors could be used, if necessary, to maintain the sterility of the SUT assembly. Thus, providing the outlet manifold as a module and connecting the outlet connection to a fluid receiving vessel before connecting the outlet manifold to the fluid path core may provide advantages in workflow in terms of ergonomics and improved user interaction, allowing the outlet manifold to be provided pre-connected to one or more outlet connections and fluid receiving vessels, etc.

[0142] On the inlet side of the fluid pathway core 933, typically one or two inlet manifolds 930 are connected to one or two pumps within the fluid pathway core. Again, the one or two connections can be easily established by the operator at the point of use for convenience in separately providing and / or deploying the inlet modules.

[0143] The fluid treatment device further comprises connections for connecting the fluid path core 933 to a treatment interface of a fluid treatment system.

[0144] In Figures 6b, 6c, and 6d, the modular manifolds are designed so that two or more manifolds can be connected to increase the number of inlets and / or outlets by mounting the manifolds adjacent to each other.

[0145] The modular manifold can be expanded "on demand" by adding another modular manifold during pre-processing installation, during a process step, or between process steps, for example, by adding fluid lines to additional fluid supply or receiving vessels, or by adding another fluid treatment device when the first fluid treatment device has insufficient capacity.

[0146] When manifolds are used as sub-modules, the pneumatic control valve system of the first actuator is equally modular in design, with control from the valve control system of the process control element operating the manifold and corresponding valves in the fluidic core 933. In particular, the routing and connections of the pneumatic control lines are modular and designed for easy assembly and operation with fail-safe mechanisms.

[0147] Having modular inlet and outlet manifolds at the point of use can improve ergonomic flexibility. When setting up a manufacturing process for production, it can be useful to establish multiple connections between the inlets and outlets of a fluid treatment device before connecting the inlet and / or outlet manifolds to the fluid treatment device, for example, when connecting external tubing to the manifolds using a welding machine. The inlet and outlet manifolds are moved to the welding machine for the welding operation, and a single fluid connection between each manifold and the fluid pathway core 933 can then be established, for example, using a standardized sterile connector.

[0148] Another advantage of deploying modular inlet and outlet manifolds at the point of use is that it provides greater flexibility and configurability.

[0149] The fluid inlet interface may be formed on one side and the fluid outlet interface may be formed on another side, such as the opposite side of the cabinet, thereby minimizing the risk of incorrect installation.

[0150] In Figure 7, an example of a first actuator and valve arrangement 11" of a fluid treatment device is shown. Thus, in the exemplary valve arrangement 11" shown, the first actuator is contained within the valve.

[0151] The valves may be provided, for example, as pinch valves and / or diaphragm valves, each comprising a first actuator that moves a wetted component of the valve to a desired open state, which may be achieved by pinching the wall of a tube or displacing the diaphragm of a diaphragm valve.

[0152] The valve arrangement 11" can be designed in a compact and cost-effective manner in which a first actuator is designed as a chamber 74 with flexible walls that displace to vary the volume of the chamber in response to a fluid pressure established by a second actuator in the process control element. The fluid can be a liquid, but a pneumatic system using a compressed gas, e.g., compressed air, is preferred.

[0153] The valve arrangement is formed in the example shown by a valve seat and a flexible diaphragm 73, which also represents a flexible wall within the chamber of the first actuator.

[0154] The valve arrangement 11'' can control the fluid flow of the process fluid in a single-use flow path. Typical sizing of the fluid path is 1 to 32 mm in diameter, although smaller and larger fluid paths are also feasible.

[0155] In instances where the first actuator is pneumatic, the fluid treatment device may comprise a "pneumatic distributor" that controls the pressurization of (pneumatic) valves that control the flow of process fluid in the conduits of the single-use consumables. The "pneumatic distributor" is again a control valve arrangement that is fed by a common compressed air source.

[0156] In another embodiment, the diaphragm of the first actuator can be connected to the diaphragm of a diaphragm valve via a mechanical element (a pin or actuator member) or to a pinching actuator that pinches tubing. In another embodiment, the first actuator can engage a lever or the lever of a rocker valve.

[0157] In other embodiments, a double diaphragm may be used to ensure seal integrity and avoid contamination of either the process fluid or the pneumatic fluid in the event of any leaks.

[0158] Specifically, in the example shown, the diaphragm 73 is driven directly by compressed air via a conduit 49 which is connected to the process control element.

[0159] The valve arrangement 11'' is designed so that displacement of the walls of a first actuator chamber 74 affects the closure (or opening) of a fluid path 75 adjacent to the first actuator. In one example, the first actuator pneumatic chamber 74 is adjacent to a fluid conduit 75 for a process fluid, which is designed for use with a valve seat 71 and a flexible diaphragm 73, which also represents a flexible wall element within the first actuator pneumatic chamber. Pressurizing the first actuator chamber to a pressure greater than the pressure of the process fluid causes the diaphragm to press against the valve seat in the process fluid conduit, thereby closing the valve. Conversely, applying a pneumatic control pressure to the first actuator chamber that is less than the pressure of the process fluid actively opens the valve, drawing the diaphragm toward or into the first actuator chamber. Thus, the walls of the chamber are pneumatically controlled by applying and regulating fluid pressure to the chamber walls.

[0160] The valve arrangement 11'' has a small hold-up volume and minimal backmixing compared to standard valve arrangements used in conventional systems. Furthermore, this valve arrangement can be a cost-effective, disposable component with low mechanical complexity, providing great flexibility in spatial positioning and configurability of the fluid processing device, enabled by the first actuator design. Traditionally, first actuators in pneumatic systems are designed as hydraulic cylinders with movable pistons and movable seals, thereby requiring precision in the dimensions of the hydraulic cylinder and piston. Hydraulic cylinders are used, for example, in pinch valve actuators (first actuators) in AKTA-enabled systems. The first actuator design described herein allows for very compact designs of fluid processing devices, particularly in fluid processing devices with multiple valves. Three-dimensional valve configurations in fluid processing devices are made possible, as well as positioning of valves within a fluid processing module or cabinet, previously impossible to apply with conventional first actuators that require adjacent positioning of the valves. A compact design is advantageous for fluid processing operations, for example, because it allows for minimal hold-up volume. In filtration, i.e., cross-flow filtration for example, a small hold-up volume allows for more efficient processing and a higher concentration of the final product. Another advantage of compact flow paths and fluid processing devices is the small volume of consumables, which improves ease of handling and reduces the volume required for storage and transportation of consumables.

[0161] 8 relates to a method 80 for setting up a biological fluid treatment system, the method comprising step S2 of providing a fluid treatment device comprising at least one fluid path, a pump for applying pressure within the at least one fluid path, valves arranged along the fluid paths, and a first actuator arranged to control the valves to assume a desired opening state of the fluid paths.

[0162] The method further comprises a step S4 of providing a processing control element.

[0163] The method further includes a step S5 of connecting the fluid processing device to a processing control element. Further, the fluid processing device may be connected to a processing interface. The processing interface may include a pump driver for driving a pump of the fluid processing device. In one example, at least a portion of the processing interface is provided within a separate processing interface module.

[0164] The method further includes receiving information S6 relating to the predetermined fluid processing device configuration and / or the predetermined processing interface configuration, which may be received after connecting S5 or before connecting, preferably when the processing control element is within short communication distance from the processing interface and fluid processing element.

[0165] The method further includes a step S7 of controlling at least one pump driver for controlling pumps and / or valves based on the received information relating to the predetermined fluid processing device configuration and / or the predetermined processing interface configuration.

[0166] The method may further comprise the step S1 of providing an external fluid component and the step S3 of connecting said external fluid component to the fluid treatment device before connecting the fluid treatment device to the treatment interface and / or treatment control element.

[0167] The modularity of the system allows for the fluid treatment devices to be installed / removed from the treatment control elements / treatment interfaces in separate steps immediately before / after treatment. Thus, the fluid treatment devices and treatment elements may be utilized and / or prepared separately prior to installation and / or disconnection of the fluid treatment devices when the treatment elements are contained at least partially in separate units. Thus, the steps and processes of deploying the modules of the system may be performed in parallel, and overall utilization of the modules may be significantly improved, for example, because the control unit is not locked during setup for treatment and / or post-treatment cleaning.

[0168] Additionally, automatic control S7 of at least one pump driver for controlling pumps and / or valves based on received information related to a predetermined fluid processing device configuration and / or a predetermined processing interface configuration further reduces setup time for processing.

[0169] Furthermore, the system is highly flexible because the process control elements control based on the configuration of the process interface and / or the configuration of the fluid processing device. Thus, each configuration is associated with a corresponding process control. The process control associated with each configuration can be adapted at any time by software. [Explanation of symbols]

[0170] 1. Prior Art Fluid Treatment Systems 2. Fluid processing section 3 Fluid Connections 4 valves 5. Pump 6 sensors 7 External Fluid Handling Components 8 Fluid supply container 9 Fluid Processing Devices 10 Fluid receiving vessel 11 System non-wetted parts 11'' First Actuator and Valve Arrangement 12 Actuators 13 Drive unit 14 Valve Control System 15 Pump Control System 16 Sensor Control System 17 Power supply 18 Human Machine Interface, HMI 19 Processing Elements 20 memory 40 High-Level Batch Recording Workflow 41 Line Clearance 49 Conduit 50 Workflows 60 Workflows 71 Valve seat 73 Diaphragm 74 Chamber 75 Fluid Path 80 methods 100 Fluid Treatment System 103 Fluid Connection 104 Valve 105 Pump 106 Sensors 107 External Fluid Handling Components 108 Fluid supply container 109 Fluid Processing Devices 110 Fluid receiving vessel 111 System non-wetted parts 112 Second Actuator 113 Pump drive unit 114 Valve Control System 115 Pump Control System 116 System 117 Power supply 118 Human Machine Interface, HMI 119 Processing Elements 120 memory 121 Processing Interface 122 Fluid Processing Devices 122_1, ..., 122_n Various fluid processing devices 123 Processing Interface 123_1, ..., 123_n processing interfaces 124 Common Processing Control Elements 125 First Actuator 200 Modular Biological Fluid Treatment Systems 922 Fluid Processing Devices 930 Inlet Manifold 931 Outlet Manifold 932 Column Manifold 933 Fluid Flow Path Core

Claims

Claim 1: A biological fluid processing system (200) for the production of a biological product, comprising:

1. A fluid treatment device comprising: at least one fluid pathway; a pump for applying pressure within said at least one fluid path; a valve disposed along the fluid path; and a fluid treatment device comprising a first actuator arranged to control the valve to a desired opening state of the fluid path; a processing interface including a pump driver for driving the pump of the fluid processing device; a process control element comprising a pump control system configured to control at least the pump drive and a valve control system configured to control the first actuator; the system is modular, and the fluid treatment device, the treatment interface, and the treatment control element are physically separable; the fluid treatment device is included in a fluid treatment device module having a predetermined fluid treatment device configuration; the processing interface has a predetermined processing interface configuration; The processing control element receiving information relating to the predetermined processing interface configuration and / or the predetermined fluid processing device configuration of the fluid processing device module; configured to control the at least one pump driver and / or the valve based on the received information related to the predetermined fluid processing device configuration and / or the predetermined processing interface configuration; The biological fluid treatment system (200) is characterized in that the first actuator is included in the valve and is designed so that displacement of a wall of a chamber of the first actuator affects the open state of the fluid path.

2. 10. The system of claim 1, wherein the process control element comprises or is connected to a user interface for inputting information relating to the predetermined fluid process device configuration and / or the predetermined process interface configuration.

3. 3. The system of claim 1, wherein the processing interface is included in a processing interface module having the predetermined processing interface configuration, and the processing control element is arranged to receive information relating to the predetermined processing interface configuration of the processing interface module.

4. 4. The system of claim 1, wherein the processing control element comprises or is connected to a receiver configured to receive information relating to the predetermined fluid processing device configuration and / or the predetermined processing interface configuration, and wherein the received information may be transmitted from an RFID tag associated with the processing interface module and / or fluid processing device module, and / or the received information may be obtained via machine vision.

5. The system of claim 1 , wherein the received information includes an identification of the fluid treatment device module and / or an identification of the treatment interface module.

6. The system of claim 1 , wherein the fluid treatment device module includes its own structural support.

7. 7. The system of claim 1, wherein the valve is a diaphragm valve.

8. 8. A system according to any one of claims 1 to 7, wherein the first actuator is arranged to move a wetted component of the valve to adopt the desired open state of the valve.

9. 9. The system of claim 1, wherein the valve and first actuator are formed using a valve seat and a flexible diaphragm, the diaphragm also representing the flexible wall within the chamber of the first actuator.

10. 10. The system of claim 1, wherein the walls of the chamber are pneumatically controlled.

11. 11. The system of claim 1, wherein the walls of the chamber are pneumatically controlled by applying a fluid pressure to the walls of the chamber and adjusting the fluid pressure.

12. 12. The system of claim 1, wherein the processing control element comprises a second actuator for controlling the first actuator.

13. 13. The biological fluid treatment system of claim 1, wherein at least one of the fluid treatment devices is a single-use product of technology.

14. A process control element for use in a biological fluid treatment system according to any one of claims 1 to 13.

15. A fluid treatment device for use in a biological fluid treatment system according to any one of claims 1 to 13.

16. A method for setting up a biological fluid treatment system according to claim 1, comprising: providing a fluid treatment device (S2), at least one fluid pathway; a pump for applying pressure within said at least one fluid path; a valve disposed along the fluid path; and a step (S2) of providing a first actuator configured to control the valve to assume a desired opening state of the fluid path; providing a processing control element (S4); connecting the fluid treatment device to a treatment interface and to the treatment control element (S5); and (S7) controlling at least one pump driver to control the pumps and / or the valves based on the received information relating to a predetermined fluid processing device configuration and a predetermined processing interface configuration; The first actuator is contained within the valve and is designed such that displacement of a wall of a chamber of the first actuator affects the open state of the fluid path.

17. 17. The method of claim 16, further comprising the steps of: providing an external fluid component (S1); and connecting the external fluid processing component (S3) to the fluid processing device before connecting the fluid processing device to the processing interface and / or processing control element.

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