Bioprocessing system and process utilizing transfer modules

Abstract

A bioprocessing system comprising a central control unit (1), at least two bioprocessing units (2a, 2b), wherein each bioprocessing unit of the at least two bioprocessing units comprises at least one flow path (3a, 3b) comprising an inlet (4a, 4b) and an outlet (5a, 5b) and wherein at least two selected bioprocessing units of the at least two bioprocessing units are connected in series by a fluid connection (6) of the outlet of an upstream bioprocessing unit (2a) of the two selected bioprocessing units and the inlet (4b) of a downstream bioprocessing unit (2b) of the two selected bioprocessing units, thereby forming a line of serially connected at least two bioprocessing units, a client control module (7a, 7b) per each bioprocessing unit of the at least two bioprocessing units, wherein each client control module is connected to the central control unit and wherein each client control module is configured to interact with the bioprocessing unit connected to said client control module, and a transfer module 8 associated with each fluid connection (6) between each of the at least two selected bioprocessing units in the line of serially connected at least two bioprocessing units, wherein each of the transfer modules (8) comprises an upstream set of parameters characterizing the upstream bioprocessing unit of each fluid connections (6) and a downstream set of parameters characterizing the downstream bioprocessing unit (2b) of each fluid connection, wherein the upstream set of parameters comprises at least an upstream status parameter characterizing the status of the upstream bioprocessing unit (2a) and the downstream set of parameters comprises at least a downstream status parameter characterizing the status of the downstream bioprocessing unit; and wherein each of the transfer modules (8) comprises at least one algorithm to compute a decision statement from said upstream set of parameters and / or the downstream set of parameters, wherein the decision statement comprises adjusting the flow rate of the fluid in the fluid connection (6) associated with said transfer module (8).

Description

[0001] Bioprocessing System and Process utilizing Transfer Modules

[0002] Technical Field

[0003] The present invention is concerned with a bioprocessing system, preferably a downstream bioprocessing system, and a respective bioprocessing process utilizing transfer modules.

[0004] Background of the Invention

[0005] Downstream bioprocessing refers to the recovery and the purification of biosynthetic products from natural sources such as animal tissue, plant tissue, or fermentation broth, thereby recycling salvageable components from these resources.

[0006] Downstream bioprocessing is an essential step in the manufacture of pharmaceuticals such as antibiotics, hormones (e.g., insulin and human growth hormone), antibodies (e.g., infliximab and abciximab), vaccines, antibodies, and enzymes used in diagnostics, industrial enzymes, natural fragrance, and flavour compounds.

[0007] It is widely accepted to categorize downstream bioprocessing into four stages, which are applied to transform a product from its natural or post-synthetic state as a component of a tissue, cell, or fermentation broth into the pure form of the product, thereby owing to high purity standards depending on the further intended use of the product, e.g., in medicine or analytics. These four stages are generally recognized as removal of insoluble (sometimes also regarded as midstream bioprocessing), product isolation, product polishing, and product formulating.

[0008] Removal of insoluble (midstream bioprocessing) involves the capture of the product as a solute in a particulate-free liquid. Hence, e.g., cells, cell debris, or other particulate matter must be separated from a liquid comprising the product. Typically, the removal of insoluble is achieved by filtration, centrifugation, sedimentation, precipitation, flocculation, electro-precipitation, and / or gravity settling. Additional operations such as grinding, homogenization, or leaching, required to recover products from solid sources such as plant and animal tissues, are usually included in this group.

[0009] Product isolation comprises the removal of components having physical and chemical properties varying considerably from the properties of the product. In downstream bioprocessing, this mostly includes the removal of water. As such, product isolation reduces the volume of the material to be processed and further concentrates the product. Typically, product isolation is achieved by solvent extraction, adsorption, ultrafiltration, and / or precipitation.

[0010] Product polishing is dedicated to separate the products from components having very close physical and chemical properties. Hence, product purification involves expensive steps, which require sensitive and sophisticated equipment. This stage constitutes a major part of the entire downstream bioprocessing process. Typical steps used in product purification are chromatography steps (e.g., affinity, size exclusion, hydrophobic interaction, reversed phase, ion-exchange) as well as crystallization and fractional precipitation.

[0011] Product formulating describes final processing steps typically yielding packaging of the product in a stable and easily form. Crystallization, desiccation, lyophilization, and spray drying are typical unit operations. Depending on the product and its intended use, product formulation may also include operations to sterilize the product.

[0012] Certain operations combine two or more of the described stages. For example, expanded bed adsorption accomplishes removal of insolubles and product isolation in a single step. As another example, affinity chromatography can isolate and polish in a single step.

[0013] In industrial application it is desired to achieve downstream bioprocessing in an efficient and cost-reduced manner. Therefore, processes have been developed, which connected operation steps as described above, which transport the product in a liquid phase to facilitate the transportation from one step to the other. Furthermore, the outputs of several preceding operational steps can be collected as a combined input for a subsequent step. This is due to the concentration effect usually achieved by each step. In the beginning of a downstream bioprocess, the volume liquid per product is very high, wherein during purification the concentration of the product is significantly enhanced. Hence, at least a part of the downstream bioprocess can typically be set up in a tree-like structure, whereas at the beginning of the downstream bioprocess many operational units are present in the first step, whereas the number of operational units usually gets fewer and fewer with each step downstream in the process.

[0014] However, also inverse designs are conceivable, in which the output of an operational step is split up or at least connected to more than one subsequent operational step. This could be used, e.g., to provide fallback operational steps, i.e. , parallel operational steps, in the subsequent operation. Another use case is the acceleration of generally time-intensive operational steps. Furthermore, it could also be provided to achieve a flexible design and attribute idle subsequent operational steps with preceding steps, which are ready to provide a batch of processed bioprocessing liquid.

[0015] It is a general desire to develop semi-continuous downstream bioprocesses, which are able to overcome the shortcomings of batch-wise driven downstream bioprocessing. Such a design allows for continuous operation within a certain parameter window and thus to produce more efficiently and cost sensitive.

[0016] Controlling and automation of bioprocessing is already known in the prior art. However, mostly the upstream processes are addressed, such as in US 2023 / 077294 A1 , US 2022 / 259532 A1 , US 2022 / 010261 A1 , or EP 3 839 036 A1. Other attempts were made, which have been used to automate the process of parameter optimization in bioprocessing, i.e., also downstream bioprocessing, as found i.e., in US 2021 / 269888 A1 , US 2021 / 263482 A1 and US 2019 / 154713 A1 . Even visualization of flow pathways in downstream bioprocessing has been implemented, cf. US 2021 / 109490 A1 . The aforementioned documents are hereby also further incorporated herein by reference to the maximum permissible extent possible.

[0017] Summary of the Invention

[0018] However, to achieve a semi-continuous downstream bioprocess, which is able to be remotely or automatically controlled, it is particularly important to control the interaction between the operational steps keeping in mind the certain configurations as set out above. Such a controlled semi-continuous downstream bioprocess is desirable as it lifts the downstream bioprocessing to another level of efficiency. Neither of the prior art as cited above addresses this problem.

[0019] Thus, the object of the present invention is to provide a downstream bioprocessing system and / or process, which can be run in semi-continuous mode independently from the complexity of the process itself, and which achieves improved safety, efficiency, and reliability.

[0020] It has now surprisingly been found out that this object is achieved by a bioprocessing system comprising a central control unit, at least two bioprocessing units, wherein each bioprocessing unit of the at least two bioprocessing units comprises at least one flow path comprising an inlet and an outlet and wherein at least two selected bioprocessing units of the at least two bioprocessing units are connected in series by a fluid connection of the outlet of an upstream bioprocessing unit of the two selected bioprocessing units and the inlet of a downstream bioprocessing unit of the two selected bioprocessing units, thereby forming a line of serially connected at least two bioprocessing units, a client control module per each bioprocessing unit of the at least two bioprocessing units, wherein each client control module is connected to the central control unit and wherein each client control module is configured to interact with the bioprocessing unit connected to said client control module, and a transfer module associated with each fluid connection between each of the at least two selected bioprocessing units in the line of serially connected at least two bioprocessing units, wherein each of the transfer modules comprises an upstream set of parameters characterizing the upstream bioprocessing unit of each fluid connections and a downstream set of parameters characterizing the downstream bioprocessing unit of each fluid connection, wherein the upstream set of parameters comprises at least an upstream status parameter characterizing the status of the upstream bioprocessing unit and the downstream set of parameters comprises at least a downstream status parameter characterizing the status of the downstream bioprocessing unit; and wherein each of the transfer modules comprises at least one algorithm to compute a decision statement from said upstream set of parameters and / or the downstream set of parameters, wherein the decision statement comprises adjusting the flow rate of the fluid in the fluid connection associated with said transfer module.

[0021] It has been further found out that above-mentioned object can be achieved by a bioprocessing unit, comprising an inlet, an outlet, a client control module, configured to be connected to a central control unit and configured to interact with the bioprocessing unit, and a set of parameters characterizing the bioprocessing unit.

[0022] It has been also further found out that above-mentioned object can be achieved by a bioprocessing process for separating a target species from a raw fluid mixture, the process comprising the steps of (A) providing a raw fluid mixture comprising the target species; (B) purifying the raw fluid mixture yielding a fluid volume comprising the target species; (C) collecting the target species from the fluid volume; wherein step (B) comprises at least one series of sets of steps, said set comprising the steps of providing at least two bioprocessing units, wherein each bioprocessing unit comprises at least one flow path comprising an inlet and an outlet and wherein at least two selected bioprocessing units of the at least two bioprocessing units are connected in series by a fluid connection of the outlet of an upstream bioprocessing unit of the two selected bioprocessing units and the inlet of a downstream bioprocessing unit of the two selected bioprocessing units, thereby forming a line of serially connected at least two bioprocessing units; introducing an input fluid mixture comprising the target species into the upstream bioprocessing unit; monitoring an upstream set of parameters characterizing said upstream bioprocessing unit, monitoring a downstream set of parameters characterizing said downstream bioprocessing unit, and calculating a decision statement therefrom, wherein the decision statement comprises adjusting the flow rate of the fluid in a fluid connection between said upstream bioprocessing unit and the downstream bioprocessing unit, depending on the calculated decision statement, adjusting the flow rate of the fluid in the fluid connection between said upstream bioprocessing unit and said downstream bioprocessing unit, producing upon starting the fluid connection an output fluid volume at the outlet of the downstream bioprocessing unit, transferring the output fluid volume as input fluid volume to a subsequent set of steps of the series of sets of steps directly following the set of steps or, if the set of steps is the last set of steps in the series of sets of steps, as fluid volume to step (C), wherein the input fluid mixture is the raw fluid mixture, if the set of steps is the first set of steps in the series of set of steps.

[0023] It has been even further found out that above-mentioned object can be achieved by a process for setting up a bioprocessing system, the process comprising the steps of providing an upstream bioprocessing unit comprising an inlet, an outlet, and an upstream set of parameters characterizing said upstream bioprocessing unit; providing an upstream client control module configured to interact with the upstream bioprocessing unit; providing a downstream bioprocessing unit comprising an inlet, an outlet, and a downstream set of parameters characterizing said downstream bioprocessing unit and the status thereof; providing a downstream client control module configured to interact with the downstream bioprocessing unit; providing a central control unit; connecting the outlet of the upstream bioprocessing unit to the inlet of the downstream bioprocessing unit using a fluid connection; connecting the upstream client control module and the downstream client control module with the central control unit; transferring the upstream set of parameters from the upstream bioprocessing unit to the upstream client control module; Transferring the upstream set of parameters from the upstream client control module to the central unit; transferring the downstream set of parameters from the downstream bioprocessing unit to the downstream client control module; transferring the downstream set of parameters from the downstream client control module to the central unit; providing a transfer module associated with said fluid connection; and configuring the transfer module to comprise at least one algorithm to compute a decision statement from said upstream set of parameters and downstream set of parameters, wherein the decision statement comprises adjusting the flow rate in the fluid connection associated with said transfer module.

[0024] An advantage of the present invention is that complex bioprocessing systems and processes can be run at high efficiency and without manual intervention. Furthermore, bioprocessing systems are provided, which are able to set themselves up in a quasiindependent manner.

[0025] Brief Description of the Drawings

[0026] Figure 1 shows a schematic view of the bioprocessing system of one preferred embodiment of the present invention comprising a synchronous fluid connection (6).

[0027] Figure 2 shows a schematic view of the bioprocessing system of one preferred embodiment of the present invention comprising an asynchronous fluid connection (6) with a scale as measurement unit (14).

[0028] Figure 3 shows a schematic view of an asynchronous fluid connection (6), in which the critical maximum volume (16) of the surge vessel (15) is smaller than the sum of the critical delivering volume (17) and the inverse critical receiving volume (18).

[0029] Figure 4 shows a schematic view of an asynchronous fluid connection (6), in which the critical maximum volume (16) of the surge vessel (15) is larger than the sum of the critical delivering volume (17) and the inverse critical receiving volume (18).

[0030] Figure 5 shows a schematic view of the bioprocessing system of one preferred embodiment of the present invention including a merging branch (9).

[0031] Figure 6 shows a schematic view of the bioprocessing system of one preferred embodiment of the present invention including a splitting branch (9).

[0032] Figure 7 shows a schematic view of the bioprocessing system of one preferred embodiment of the present invention including a splitting branch (9) and a merging branch (9’) thereby leading to a parallel bioprocessing step.

[0033] Figure 8 shows a schematic view of the bioprocessing system of the example of the present invention.

[0034] Definitions

[0035] The term “fluid volume" as used herein denotes a volume comprising a fluid and preferably the target species. Preferably, the fluid is a liquid. More preferably, the fluid is a liquid comprising, preferably consisting of, a solvent. Even more preferably, the solvent is selected from water-based buffer solutions, such as phosphate, acetate, citrate, or tris(hydroxymethyl)aminomethane, and mixtures thereof with other solvents such as ethanol. The solvents can comprise additives such as polymers, e.g., PEG and / or dextran, salts, e.g., ammonium sulphate, sodium chloride etc., detergents, and / or stabilizers. Some affinity stationary phases (membranes or beads) may require more complex mixtures. For instance, Immobilized Metal Chelate Affinity Chromatography (IMAC) requires the addition of an organic compound such as imidazole.

[0036] The term “target species" as used herein denotes the product to be isolated. Usually, the target species is a substance naturally occurring in animal or plant tissue, is produced by naturally occurring microorganisms or enzymes, and / or is produced by modified, preferably genetically modified, microorganisms or enzymes. As such, the target species can be, but is not limited to, antibodies, proteins, viruses, organic substances, DNA molecules, RNA molecules, shorter nucleotides molecules, exosomes, cells (such as used in cell therapy), or specific target molecules.

[0037] The term “raw mixture" as used herein denotes a mixture of various contaminants, solvents, and at least one target species. The mixture can be a natural product, such as animal or plant tissue, which already has been brought in contact with at least one solvent, or a mixture from a bioreactor. Preferably, the raw mixture is a mixture from a bioreactor comprising microorganisms, such as yeasts, bacteria, and / or fungi, cells, viruses, tissue, target species, and / or solvents.

[0038] The term “flow-through mode" as used herein denotes a chromatography method, in which impurities in a raw mixture are bound to the chromatography matrix, while the target species is not bound, thereby separating the target species in the dilute.

[0039] The term “bind / elute mode" as used herein denotes a chromatography method, in which the target species in a raw mixture is bound to the chromatography matrix, while the impurities are not bound. The impurities are washed from the column with the dilute and the column is subsequently flushed with an elute, which removes the target species from the chromatography column, thereby separating the target species in the elute.

[0040] The term “bioprocessing unit" as used herein denotes a unit, which receives a fluid volume comprising a target species and usually contaminants and which outputs a fluid volume comprising the target species and usually less contaminants. Preferably, the bioprocessing unit is selected from the list consisting of chromatographic devices, including columns and membranes, filters, centrifuges, extraction devices, and two- phase separation devices. In the present invention differentiation is made between “synchronous bioprocessing units” and “asynchronous bioprocessing units”, wherein the difference lies within the time dependence of the input process (receiving) and the output process (delivering). Hence, a synchronous bioprocessing unit is a unit, wherein the input process (receiving) and the output process (delivering) occur at substantially the same time. Hence, a synchronous bioprocessing unit is a bioprocessing unit, in which the input process will inevitably lead to an output process. Thus, the target species will travel continuously through the synchronous bioprocessing unit during operation. In contrast, in the asynchronous bioprocessing unit the input process (receiving) and the output process (delivering) occur at different times. Hence, an asynchronous bioprocessing unit is a bioprocessing unit, in which the input process will not inevitably lead to an output process. Thus, the target species will not travel continuously through the asynchronous bioprocessing unit during operation. Instead, the asynchronous bioprocess unit provides means for a status, wherein at least a part of the target species can be stored for a certain time. Examples for synchronous bioprocessing units are chromatography devices suitable for flow-through mode and filters. Examples for asynchronous bioprocessing units are chromatography devices suitable for bind / elute mode.

[0041] The term “fluid connection" as used herein denotes the connection between an output of an upstream bioprocessing unit and an input of a downstream bioprocessing unit. It might also denote the connection with another fluid connection, thereby forming branched fluid connections. The fluid connection between two or more bioprocessing devices might be a “synchronous fluid connection" or an “asynchronous fluid connection" , wherein the difference lies within the time dependence of the input process (delivered by the upstream bioprocessing unit) and the output process (received by the downstream bioprocessing unit). Hence, a synchronous fluid connection is a fluid connection, wherein the input process and the output process occur at the same time. Hence, a synchronous fluid connection is a fluid connection, in which the input process will inevitably lead to an output process. Thus, the target species will travel continuously through the fluid connection during transfer. In contrast, in the asynchronous fluid connection the input process (delivered by the upstream bioprocessing unit) and the output process (received by the downstream bioprocessing unit) occur at different times. Hence, an asynchronous fluid connection is a fluid connection, in which the input process will not inevitably lead to an output process. Thus, the target species will not travel continuously through the fluid connection unit during transfer. Instead, the asynchronous fluid connection provides means for a status, wherein at least a part of the target species can be stored for a certain time. Examples for synchronous fluid connections are direct connections. Examples for asynchronous fluid connections are buffered connections, i.e. , comprising a surge vessel in the fluid connection. The term “off-line analysis" as used herein denotes an analysis step, wherein the sample is taken out of the bioprocessing unit or a transportation line in sterile conditions and analysed in a laboratory after physical pre-treatments (e.g., filtration and dilution). Preferably, the preparation and handling require clear Standard Operating Procedures (SOPs) as well as skilled personnel. Together with the complexity involved in manual handling, the major disadvantage of off-line measurement is the time delay, which results in lower measurement frequency. Due to these issues off-line measurements are usually not considered true PAT (Process Analytical Technology) unless there are no other measurement possibilities (e.g., HPLC for product titter or mass spectroscopy for product quality). Off-line laboratory measurements are commonly used to monitor and validate the accuracy of the in-line / on-line process analysers.

[0042] The term “at-line analysis" as used herein denotes an analysis step, wherein the sample is removed from the bioprocessing unit or a transportation line and is analysed in close proximity to the production process, either manually or by using automated sampling devices. Similar to off-line measurement, sterile conditions must be maintained for accurate results. At-line measurement is most common for parameters which cannot be measured accurately in-line or on-line. Advantages of at-line measurement include shortened time delay (relative to off-line), and the possibility for automated control.

[0043] The term "on-line analysis" as used herein denotes an analysis step, wherein the sample is diverted from the bioprocessing unit or a transportation line by a branching and may be returned to the bioprocessing process after analysis. The sample is automatically measured in the by-pass by process sensors. The advantages of this method can be found in the simple sterilization and the straightforward access to the sample in stationary conditions. The implementation of such a solution requires a specifically designed or modified bioprocessing process, in particular bioprocessing unit and / or transportation line.

[0044] The term “in-line analysis" as used herein denotes an analysis step, wherein the measurement occurs directly in the bioprocessing unit or the transportation line with a process sensor. Preferably, the generated measurements are sent in real-time to the control system. Process parameters such as pH, ORP (redox potential), dissolved oxygen, dissolved CO2, temperature, and / or conductivity are commonly measured by in-line analysis. Moreover, also measurements allowing for detection of specific molecules can be measured by in-line analysis, such as LIV / VIS absorbance / transmittance, fluorescence emission, and refractive index. The term “unique id" as used herein denotes an information, which is unique in the address space used for the object to be identified. Hence, it is assured that the id is never used for two objects in the same address space.

[0045] As used in this specification and in the appended claims, the singular forms of “a“ and “an" also include the respective plurals unless the context clearly dictates otherwise. In the context of the present invention, the terms “about" and “approximately" denote an interval of accuracy that a person skilled in the art will understand to still ensure the technical effect of the feature in question. The term typically indicates a deviation from the indicated numerical value of ±10 %, preferably ±8 %, more preferably ±5 %, even more preferably ±2 %. It is to be understood that the term “comprising" and “encompassing" is not limiting. For the purposes of the present invention the term “consisting of‘ is considered to be a preferred embodiment of the term “comprising of‘. If hereinafter a group is defined to comprise at least a certain number of embodiments, this is meant to also encompass a group which preferably consists of these embodiments only. Furthermore, the terms “first" , “second", “third" or “(a)“, “(b)", “(c)", “(d)" etc. and the like in the description and in the claims, are used for distinguishing between similar elements and not necessarily for describing a sequential or chronological order. It is to be understood that the terms so used are interchangeable under appropriate circumstances and that the embodiments of the invention described herein are capable of operation in other sequences than described or illustrated herein. In case the terms “first", “second", “third" or “(a)", “(b)", “(c)“, “(d)", “i“, “K“ etc. relate to steps of a method or use or assay there is no time or time interval coherence between the steps, i.e. the steps may be carried out simultaneously or there may be time intervals of seconds, minutes, hours, days, weeks, months or even years between such steps, unless otherwise indicated in the application as set forth herein above or below. It is to be understood that this invention is not limited to the particular methodology, protocols, reagents etc. described herein as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention that will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.

[0046] As used herein the term “does not comprise", “does not contain", or “free of’ means in the context that the composition of the present invention is free of a specific compound or group of compounds, which may be combined under a collective term, that the composition does not comprise said compound or group of compounds in an amount of more than 0.8% by weight, based on the total weight of the composition. Furthermore, it is preferred that the composition according to the present invention does not comprise said compounds or group of compounds in an amount of more than 0.5% by weight, preferably the composition does not comprise said compounds or group of compounds at all.

[0047] When referring to compositions and the weight percent of the therein comprised ingredients it is to be understood that according to the present invention the overall amount of ingredients does not exceed 100% (± 1 % due to rounding).

[0048] Detailed Description

[0049] The present invention is related to a downstream bioprocessing system and process being able to make autonomous decisions of the transfer of fluid volumes in between connected bioprocessing steps or units. Usually, downstream bioprocessing processes are not continuous processes. This is due to the character of the process, which is defined by the connection of several at least two bioprocessing units or steps, which themselves usually are designed to deliver the product batch-wise. Hence, usually, the downstream bioprocessing processes are set up in a semi-continuous manner. As such the product is delivered in fluid volumes from one operational step of the bioprocessing process to a subsequent operational step of the bioprocessing process. Thereby, the steps can be connected directly in a 1 : 1 fashion or in a tree-like structure, thereby either receiving fluid volumes from more than one preceding operational step or delivering fluid volumes to more than one subsequent operational step. Furthermore, the connection itself can be a synchronous (i.e., direct) connection or an asynchronous connection, which normally comprises a storage vessel. Finally, also the at least two bioprocessing units or steps can be quasi synchronous, i.e., in flow-through mode, or asynchronous, i.e., in bind / elute mode. Hence, these requirements result in a complex problem to be solved, the complexity of which scales with the complexity of the system or process used.

[0050] In the following, the bioprocessing system and the bioprocessing unit of the present invention are described followed by the bioprocessing process of the present invention and a process for setting up a bioprocessing system of the present invention.

[0051] Bioprocessing system

[0052] The present invention relates to a bioprocessing system exemplified in Figures 1 or 2, preferably a downstream bioprocessing system, comprising a central control unit (1), at least two bioprocessing units (2a, 2b), wherein each of the at least two bioprocessing units (2a, 2b) comprises at least one flow path (3a, 3b) comprising an inlet (4a, 4b) and an outlet (5a, 5b) and wherein at least two selected bioprocessing units of the at least two bioprocessing units are connected in series by a fluid connection (6) of the outlet (5a) of an upstream bioprocessing unit (2a) of the two selected bioprocessing units and the inlet (4b) of a downstream bioprocessing unit (2b) of the two selected bioprocessing units, thereby forming a line of serially connected bioprocessing units, a client control module (7a, 7b) per each of the at least two bioprocessing units (2a, 2b), wherein each client control module (7a, 7b) is connected to the central control unit (1) and wherein each client control module (7a, 7b) is configured to interact with the at least two bioprocessing units (2a, 2b) connected to said client control module (7a, 7b), and a transfer module (8) associated with each fluid connection (6) between each of the at least two selected bioprocessing units in the line of serially connected at least two bioprocessing units, wherein each of the transfer modules (8) comprises an upstream set of parameters characterizing the upstream bioprocessing unit (2b) of each fluid connections (6) and a downstream set of parameters characterizing the downstream bioprocessing unit (2b) of each fluid connection (6), wherein the upstream set of parameters comprises at least an upstream status parameter characterizing the status of the upstream bioprocessing unit (2a) and the downstream set of parameters comprises at least a downstream status parameter characterizing the status of the downstream bioprocessing unit (2b); and wherein each of the transfer modules (8) comprises at least one algorithm to compute a decision statement from said upstream set of parameters and / or the downstream set of parameters, wherein the decision statement comprises adjusting the flow rate of the fluid in the fluid connection (6) associated with said transfer module.

[0053] The central control unit (1) can be any device for receiving, sending, and storing data as well as calculating using said data. Hence, preferably, the central control unit (1) is a computer, preferably a computer connected to a network. However, the central control unit (1) could also be any other electronic device, which is able to carry out the operations as described herein. Hence, the operations of the central control unit (1) could be either implemented by hardware, such as in electronic circuits, or could be implemented by software and configured to run on a computer. In one preferred embodiment of the present invention, the central control unit (1) is a dedicated computer, i.e., server, which is connected via network to all client control modules (7a, 7b) and / or all bioprocessing units (2a, 2b). In an alternative preferred embodiment of the present invention, the central control unit (1) could be provided by at least one of the at least two bioprocessing units (2a, 2b). This embodiment has the advantage that the bioprocessing system does not necessarily need a dedicated computer. It is also possible that the central control (1) unit is provided by the connected at least two bioprocessing units (2a, 2b) thereby providing a decentralized central control unit (1). This embodiment has the further advantage that also no dedicated computer is necessary, but the computing capabilities are improved.

[0054] Likewise, the transfer module (8) could also be either provided in hardware or in software. However, preferably, the transfer module (8) is implemented in software and configured to run on the central control unit (1). The transfer module (8) comprises an upstream set of parameters characterizing the upstream bioprocessing unit (2b) of each fluid connections (6) and a downstream set of parameters characterizing the downstream bioprocessing unit (2b) of each fluid connection (6). Hence, the transfer module (8) is associated with the upstream bioprocessing unit (2a) and the downstream bioprocessing unit (2b).

[0055] In parallel, the client control modules (7a, 7b) can also be either provided in hardware or in software. Thus, preferably, each client control module (7a, 7b) is provided by the associated bioprocessing unit (2a, 2b). Thereby, preferably, the client control module (7a, 7b) is implemented in software and configured to run on the at least two bioprocessing units (2a, 2b). However, most preferably, the client control module (7a, 7b) is implemented in software and configured to run on the central control unit (1).

[0056] In an especially preferred embodiment of the present invention, the transfer module (8) and each client control module (7a, 7b) are implemented in software and are configured to run on the central control unit (1). This has the advantage that only one computer is used, and the computing unit is centralized. Furthermore, such unit could be run in the cloud, further enhancing flexibility and stability. In such an embodiment, preferably, each of the at least two bioprocessing units (2a, 2b) is connected to the central control unit (1), preferably by network.

[0057] In another especially preferred embodiment of the present invention, each client control module (7a, 7b) runs on a dedicated computer, which is connected to the respective bioprocessing unit (2a, 2b) and to a local network. Thereby, one of these dedicated computers is also at the same time the central control unit (1). This embodiment achieves best reliability in case of a failure of one of the computers.

[0058] Thereby, preferably, at least one of the at least two bioprocessing units (2a, 2b) is suitable for being configured by the user by setting at least a part of the set of parameters characterizing the at least two bioprocessing units (2a, 2b) prior to setting up the bioprocessing system. This information might be entered by an enter field in form of a small screen or a LCD device in combination with buttons, a pointing device or even a keyboard. Hence, preferably, the at least two bioprocessing units (2a, 2b) furthermore comprise an input device suitable for setting at least a part of the set of parameters characterizing the at least two bioprocessing units (2a, 2b) prior to setting up the bioprocessing system, wherein the input device is selected from the group consisting of a touch screen or touch LCD device, a screen or LCD device in combination with buttons, a screen or LCD device in combination with a pointing device, or a screen or LCD device in combination with a keyboard. Alternatively, the this information could be provided by prepared scripts, preferably by Al generated scripts.

[0059] Preferably, the set or parameters characterizing the at least two bioprocessing units (2a, 2b) comprises the information of the type of the bioprocessing unit, i.e., whether it is a synchronous or asynchronous bioprocessing unit. The same holds true for the type of fluid connection (6), which could be synchronous or asynchronous. In particular the information of the type of the fluid connection (6) is preferably provided by the user as defined before.

[0060] Preferably, in the bioprocessing system according to the present invention, each of the transfer modules (8) is configured to retrieve data from the connected client control modules (7a, 7b). Furthermore, preferably, in the bioprocessing system according to the present invention, each of the transfer modules (8) is configured to send data to the connected client control modules (7a, 7b). Thereby, at least one parameter of the upstream set of parameters or the downstream set of parameters is sent or received, i.e., updated. Hence, preferably, the transfer module (8) is configured to update on the upstream client control module (7a) at least one parameter of the upstream set of parameters characterizing the upstream bioprocessing unit (2a), which is connected to the fluid connection (6) associated with said transfer module (8), and / or is configured to update on the downstream client control module (7b) at least one parameter of the downstream set of parameters characterizing the downstream bioprocessing unit (2b), which is connected to the fluid connection (6) associated with said transfer module (8). This ensures that the transfer module (8) is suitable for controlling the associated client control modules (7a, 7b). The parameter, which can be updated by the transfer module (8) is preferably the status parameter of the at least two bioprocessing units (2a, 2b) of the associated client control module (7a, 7b). Such a status parameter can be either ‘running’, ‘waiting’, or ‘failed’, wherein ‘waiting’ can include the information such as ‘ready to receive’ or ‘ready to deliver". It might alternatively or additionally be the flow rate within the at least two bioprocessing units (2a, 2b) associated with the client control module (7a, 7b). By updating this status parameter, the transfer module (8) is suitable for starting or stopping the at least two bioprocessing units (2a, 2b) via its associated client control module (7a, 7b) or otherwise modifying the flow rate thereof. Likewise, also preferably, the upstream client control module (7a) is configured to update on the transfer module (8) at least one parameter of the upstream set of parameters characterizing the upstream bioprocessing unit (2a), which is connected to the fluid connection (6) associated with said transfer module (8), and / or the downstream client control module (7b) is configured to update on the transfer module (8) at least one parameter of the downstream set of parameters characterizing the downstream bioprocessing unit (2b), which is connected to the fluid connection (6) associated with said transfer module (8). This ensures that the transfer module (8) is suitable for knowing about the current state of the bioprocessing device (2a, 2b) of the respective client control module (7a, 7b).

[0061] Preferably, in the bioprocessing system according to the present invention, each of the at least two bioprocessing units (2a, 2b) is configured to send data to the connected client control module (7a, 7b). Furthermore, preferably, in the bioprocessing system according to the present invention, each of the at least two bioprocessing units (2a, 2b) is configured to send data to the connected client control module (7a, 7b). Preferably, the client control module (7a, 7b) is configured to read at least one parameter from the connected at least two bioprocessing units (2a, 2b). Also preferably, the client control module (7a, 7b) is configured to write at least one parameter from the connected at least two bioprocessing units (2a, 2b).

[0062] Usually, the status parameter of the at least two bioprocessing units (2a, 2b) depends on other measurement values retrievable from the at least two bioprocessing units (2a, 2b), such as flow rates, valve positions, loading / elution states of columns, breakthrough states of columns, quality of the target species, etc. These parameters are typically measured on the at least two bioprocessing units (2a, 2b) and are communicated to the client control module (7a, 7b). Hence, preferably, the at least two bioprocessing units (2a, 2b) are configured to measure measurement parameters and to send these measurement parameters to the connected client control module (7a, 7b). Preferably, said measurement parameters are selected from the list consisting of flow rates, valve positions, loading / elution states of columns, break-through of columns, quality of the target species, and mixtures thereof. From these measurement parameters, the status of the bioprocessing unit can be derived. For example, if a bind / elute chromatography device reaches full loading of a column, it will stop processing and reach a ‘waiting’ status with the additional information ‘ready to deliver". The transfer module (8) can then set the status to ‘running’ or otherwise tell the client control module (7a, 7b) to start processing again, if the at least one algorithm of the transfer module (8) computes such a decision statement, which is explained further below. The client control module (7a, 7b) will then set the appropriate parameters of the at least two bioprocessing units (2a, 2b) to let it continue processing. Nevertheless, in another embodiment of the invention, the respective computation of the status parameter from the measurement values does not occur within the client control module (7a, 7b), but rather already in the at least two bioprocessing units (2a, 2b), or even in the transfer module (8). However, it is preferred, that the at least one upstream status parameter characterizing the status of the upstream bioprocessing unit (2a) and the at least one downstream status parameter characterizing the status of the downstream bioprocessing unit (2b) are determined in the client control module (7a, 7b). Thus, preferably, the upstream bioprocessing unit (2a) is configured to determine the upstream status parameter and the downstream bioprocessing unit (2b) is configured to determine the downstream status parameter, the upstream client control module (7a) is configured to determine the upstream status parameter and the client control module (7b) is configured to determine the downstream status parameter, or the transfer module (8) is configured to determine the upstream status parameter and the downstream status parameter. However, preferably, the upstream client control module (7a) is configured to determine the upstream status parameter and the client control module (7b) is configured to determine the downstream status parameter.

[0063] Furthermore, preferably, the upstream set of parameters comprises at least one parameter selected from the list consisting of a volume flow rate of the upstream bioprocessing unit (2a), a critical volume of the upstream bioprocessing unit (2a), and a product quality of the upstream bioprocessing unit (2a), and / or wherein the downstream set of parameters comprises at least one parameter selected from the list consisting of a volume flow rate of the downstream bioprocessing unit (2b), a critical volume of the downstream bioprocessing unit (2b), and a product quality of the downstream bioprocessing unit (2b). Generally, in case the transfer module should only be able to decide whether to start or stop the at least two bioprocessing units (2a, 2b) via the client control module (7a, 7b), it is sufficient that each set of parameters comprises the respective status parameter of the associated at least two bioprocessing units (2a, 2b). In such a scenario, it is only necessary for the transfer module (8) to know the current status of the at least two bioprocessing units (2a, 2b). As stated above, the status parameter could be either ‘running’, ‘waiting’, or ‘failed’, wherein ‘waiting’ can include the information such as ‘ready to receive’ or ‘ready to deliver". However, in case the transfer module (8) should be able to adjust the flow rate of the at least two bioprocessing units (2a, 2b), the current flow rate within the at least two bioprocessing units (2a, 2b) needs to be available by the transfer module (8).

[0064] If the one of the at least two bioprocessing units (2a, 2b) is an asynchronous bioprocessing unit, it can be beneficial to know the critical volume of the asynchronous bioprocessing unit. If the fluid connection (6) of the bioprocessing system according to the present invention is an asynchronous fluid connection, it preferably comprises a buffer vessel (15). Preferably, the surge vessel (15) has at least one measurement unit (14).

[0065] The filling status of the surge vessel (15) should not exceed a critical maximum volume (16), otherwise loss of target species can be expected. Furthermore, if the filling status of the surge vessel (15) is below a critical delivering volume (17), the downstream bioprocessing unit (2b) cannot be started, as the surge vessel (15) might run dry during operation of the downstream bioprocessing unit (2b). If the filling status of the surge vessel (15) is above the critical delivering volume (17), the downstream bioprocessing unit (2b) can be started (cf. Figure 3, (I)). Moreover, if the filling status of the surge vessel (15) is above a critical receiving volume (18), the upstream bioprocessing unit (2a) cannot be started as otherwise the critical maximum volume (16) of the surge vessel (15) might be exceeded during operation of the upstream bioprocessing unit (2a). Finally, if the filling status of the surge vessel (15) is below a critical receiving volume (18) the upstream bioprocessing unit (2a) can be started (cf. Figure 3, (III)). Hence, in case of a preferred embodiment of the present invention according to Figure 3, in which the critical delivering volume (17) is larger than the critical receiving volume (18), the surge vessel (15) comprises a volume, in which the upstream bioprocessing unit (2a) can be started, but the downstream bioprocessing unit (2b) not (cf. Figure 3, (III)), a volume, in which the downstream bioprocessing unit (2b) can be started, but the upstream bioprocessing unit (2a) not (cf. Figure 3, (I)), wherein these two volumes do not overlap with each other, and a volume where neither of the upstream nor downstream bioprocessing units (2a, 2b) can be started (cf. Figure 3, (II). Likewise, in case of another preferred embodiment of the present invention according to Figure 4, in which the critical delivering volume (17) is smaller than the critical receiving volume (18), the surge vessel (15) comprises a volume, in which the upstream bioprocessing unit (2a) can be started, but the downstream bioprocessing unit (2b) not (cf. Figure 4, (VI)), a volume, in which the downstream bioprocessing unit (2b) can be started, but the upstream bioprocessing unit (2a) not (cf. Figure 4, (IV)), wherein these two volumes do not overlap with each other, and a volume where both the upstream and the downstream bioprocessing units (2a, 2b) can be started (cf. Figure 4, (V)).

[0066] In another preferred embodiment of the present invention, the critical delivery volume (17) and the critical receiving volume (18) of the surge vessel could be dynamically adjusted depending on the flow rate from the upstream bioprocessing unit (2a) or the flow rate to the downstream bioprocessing unit (2b). Hence, in case the flow rate from the upstream bioprocessing unit (2a) is higher than the flow rate to the downstream bioprocessing unit (2b), the critical receiving volume (18) could be lowered. Likewise, in case the flow rate from the upstream bioprocessing unit (2a) is lower than the flow rate to the downstream bioprocessing unit (2b), the critical delivering volume (17) could be lowered.

[0067] The measurement unit (14) of the surge vessel (15) of the fluid connection preferably is configured to communicate with at least one of the at least two bioprocessing units (2a, 2b), a client control module (7a, 7b), or the transfer module (8). Preferably, the measurement unit (14) of the surge vessel (15) of the fluid connection is configured to communicate with a client control module (7a, 7b), preferably the upstream client control module (7a). Most preferably, the client control module (7a, 7b) is configured to add the value provided by the measurement unit (14) of the surge vessel (15) of the fluid connection to the respective set of parameters, most preferably, the upstream client control module (7a) is configured to add the value provided by the measurement unit (14) of the surge vessel (15) of the fluid connection to the upstream set of parameters.

[0068] Preferably, the measurement unit (14) of the surge vessel (15) is selected from the list consisting of a scale, a swimmer, an input batch counter, a light barrier, and a liquid level sensor. Preferably, the liquid level sensor is selected from the list consisting of a vibrating point sensor, a rotating paddle sensor, an admittance-type sensor, a magnetic float sensor, a mechanical float sensor, a pneumatic sensor, a conductive sensor, a state dependent frequency sensor, an ultrasonic sensor, a capacitance sensor, an optical sensor, and a microwave sensor.

[0069] The transfer module (8) comprises at least one algorithm to compute a decision statement from said upstream set of parameters and / or the downstream set of parameters, wherein the decision statement comprises adjusting the flow rate of the fluid in the fluid connection (6) associated with said transfer module. Preferably, the upstream set of parameters comprises the upstream status parameter of the bioprocessing unit (2a), and / or the downstream set of parameters comprises the downstream status parameter of the bioprocessing unit (2b), and the transfer module (8) is configured to compute a decision statement by the at least one algorithm from said upstream set of parameters and / or the downstream set of parameters, wherein the decision statement comprises starting or stopping the fluid connection (6) associated with said transfer module (8).

[0070] Preferably, the upstream set of parameters comprises the upstream status parameter of the bioprocessing unit (2a) and / or an upstream flow rate of the bioprocessing unit (2a), and / or the downstream set of parameters comprises the downstream status parameter of the bioprocessing unit (2b), and / or a downstream flow rate of the bioprocessing unit (2b), and the transfer module (8) is configured to compute a decision statement by the at least one algorithm from said upstream set of parameters and / or the downstream set of parameters, wherein the decision statement comprises adjusting the flow rate of the fluid in the fluid connection (6) associated with said transfer module (8).

[0071] Starting or stopping the fluid connection (6) depends on the type of the fluid connection (6), i.e. , whether it is a synchronous or asynchronous connection. Preferably, the fluid connection (6) is an asynchronous connection and starting or stopping the fluid connection (6) comprises starting the upstream bioprocessing unit (2a), starting the downstream bioprocessing unit (2b), or starting the upstream and the downstream at least two bioprocessing units (2a, 2b). Also preferably, the fluid connection (6) is a synchronous connection and starting or stopping the fluid connection (6) comprises starting the upstream and the downstream at least two bioprocessing units (2a, 2b), preferably at the same time.

[0072] In the bioprocessing system according to the present invention, the transfer module (8) preferably comprises at least one condition used by the at least one algorithm to compute a decision statement from said set of parameters. Preferably, the at least one condition comprises at least one in-condition with reference to a parameter of the upstream set of parameters and / or at least one out-condition with reference to a parameter of the downstream set of parameters. Even more preferably, the at least one in-condition comprises a condition with reference to the upstream status parameter and / or wherein the at least one out-condition comprises a condition with reference to the downstream status parameter. Preferably, the at least one condition is provided to the transfer module upon creation. Hence, the transfer module (8) preferably is configured to receive the at least one condition upon creation. In an alternative embodiment of the present invention, the transfer module (8) is selected from a list of preselected transfer modules, each of which has several predefined conditions. Alternatively, and preferably, the conditions are provided by the client control modules (7a, 7b) connected to the transfer module (8). Hence, most preferably, the upstream client control module (7a) is configured to send at least one in-condition to the transfer module (8) and / or the downstream control module (7b) is configured to send at least one out-condition to the transfer module (8). Thereby, preferably, the in-condition is part of the upstream set of parameters and / or the out-condition is part of the downstream set of parameters.

[0073] Preferably, the in-condition comprises the condition that the upstream status parameter of the upstream bioprocessing unit (2a) is ‘waiting’ and ‘ready to deliver". Moreover, preferably, the out-condition comprises the condition that the downstream status parameter of the downstream bioprocessing unit (2b) is ‘waiting’ and ‘ready to receive’. Most preferably, the fluid connection (6) is a synchronous connection, the in-condition comprises the condition that the upstream status parameter of the upstream bioprocessing unit (2a) is ‘waiting’ and ‘ready to deliver", and the out-condition comprises the condition that the downstream status parameter of the downstream bioprocessing unit (2b) is ‘waiting’ and ‘ready to receive’.

[0074] In an alternative preferred embodiment, the in-condition comprises the condition that the upstream status parameter of the upstream bioprocessing unit (2a) is ‘waiting’ and ‘ready to deliver" and the condition that the filling status of the surge vessel (15) is below the critical receiving volume (18). In another alternative preferred embodiment, the out-condition comprises the condition that the downstream status parameter of the downstream bioprocessing unit (2b) is ‘waiting’ and ‘ready to receive’ and the condition that the filling status of the surge vessel (15) is above the critical delivering volume (17). More preferably, in the alternative preferred embodiment, the fluid connection (6) is an asynchronous fluid connection, the in-condition comprises the condition that the upstream status parameter of the upstream bioprocessing unit (2a) is ‘waiting’ and ‘ready to deliver" and the condition that the filling status of the surge vessel (15) is below the critical receiving volume (18). Also more preferably, in the alternative preferred embodiment, the fluid connection (6) is an asynchronous fluid connection, the out-condition comprises the condition that the downstream status parameter of the downstream bioprocessing unit (2b) is ‘waiting’ and ‘ready to receive’ and the condition that the filling status of the surge vessel (15) is above the critical delivering volume (17).

[0075] As set out before, typically, a bioprocessing process, in particular a downstream bioprocessing process, is not a linear process, but comprises branches. Branching can be applied in terms of a tree-like structure, in which the preceding bioprocessing steps have a higher number than the subsequent bioprocessing steps. This can be implemented to achieve faster concentration of the target species. Furthermore, branches can be used to implement parallel steps of the same type. This can be beneficial to either speed up time-intensive steps or to provide redundancy in production systems. Another advantage of parallel steps of the same type can be dynamic adjustment of capacities. E.g., if a volume happens to have a high product content, then it can be rerouted to a larger column, if present as a parallel step. Likewise, if a volume has a low product content, it can be rerouted to a smaller column, if present as a parallel step. Branching can also be implemented as interconnections of multiple production lines. In such case, if in one of the multiple production lines a bioprocessing unit enters a failure state, the volumes produced preceding the failed bioprocessing unit can be redirected to one or more parallel production lines.

[0076] Hence, preferably, in the bioprocessing system according to the present invention, the fluid connection (6) comprises at least one branching (9). The branching can be selected from the list consisting of a valve having at least two outlets, i.e. , a two-way valve, a connector having at least two outlets, i.e., a Y-connector, and a surge vessel. Most preferably, the branching is a vent having at least two outlets, preferably a Y-vent. The advantage of a vent is that it can open or close the branching. Hence, most preferably, the branching is an electronically actuated vent. Most preferably, the electronically actuated vent is connected to the at least two bioprocessing units (2a, 2b), the client control module (7a, 7b), and / or the transfer module (8). The branching (9) can be configured to be an outlet or an inlet or both.

[0077] In a preferred embodiment of the present invention, the branching (9) leads to an analysis unit (10), preferably to an off-line analysis unit. This embodiment has the advantage that the system can control the quality of the intermediate product without disturbing production.

[0078] In another preferred embodiment of the present invention according to Figure 5, the at least two bioprocessing units (2a, 2b) comprise at least three bioprocessing units (2a, 2b, 2c), and wherein the inlet (4b) of the downstream bioprocessing unit (2b) is additionally connected to the outlet (5c) of a second upstream bioprocessing unit (2c) by a second fluid connection (6’), preferably by a branching (9) to the fluid connection (6). This embodiment allows for merging the flow paths of target species to one downstream bioprocessing unit.

[0079] In another preferred embodiment of the present invention according to Figure 6, the at least two bioprocessing units (2a, 2b) comprise at least three bioprocessing units (2a, 2b, 2c), and wherein the outlet (5a) of the upstream bioprocessing unit (2a) is additionally connected to the inlet (4c) of a second downstream bioprocessing unit (2c) by a second fluid connection (6”), preferably by a branching (9) to the fluid connection (6). This embodiment allows for splitting up the flow path of a target species to enter at least one more downstream bioprocessing unit.

[0080] Likewise, in another preferred embodiment of the present invention according to Figure 7, the at least two bioprocessing units (2a, 2b) comprise at least four bioprocessing units (2a, 2b, 2c, 2d), wherein at least three selected bioprocessing units of the at least four bioprocessing units (2a, 2b, 2c, 2d) are connected in series by a first and a second fluid connection (6, 6”’) of the inlets (4a, 4b) and the outlets (5b, 5c), thereby forming a line of serially connected bioprocessing units (2a, 2b, 2c), wherein each of the first and the second connections (6, 6”’) comprises a branching (9, 9’), wherein the branching (9) of the first fluid connection (6) is fluidly connected to the inlet (4d) of a selected fourth bioprocessing unit (2d) of the at least four bioprocessing units (2a, 2b, 2c, 2d) via fluid connection (6’) and wherein the branching (9’) of the second fluid connection (6”’) is fluidly connected to the outlet (5d) of the selected fourth bioprocessing unit (2d) of the at least four bioprocessing units (2a, 2b, 2c, 2d) via fluid connection (6”). Such an embodiment enables parallelization of bioprocessing steps (i.e. , 2b and 2c). As such, time-intensive operations can be sped up and / or redundancy can be enhanced.

[0081] The at least two bioprocessing units (2a, 2b) are devices, which receive a fluid volume comprising a target species and usually contaminants and which output a fluid volume comprising the target species and usually less contaminants. The at least two bioprocessing units (2a, 2b) each comprise an inlet (4a, 4b), and outlet (5a, 5b) and a flow path (3a, 3b) connecting the inlet (4a, 4b) and the outlet (5a, 5b). Preferably, the at least two bioprocessing units (2a, 2b) are selected from the list consisting of chromatographic devices, including columns and membranes, filters, centrifuges, extraction devices, and two-phase separation devices. Preferably, each of the at least two bioprocessing units (2a, 2b) comprises at least one pump (11a, 11 b) and at least one separation device (12a, 12b) connected to the at least one flow path (3a, 3b) of the bioprocessing unit. In a preferred embodiment of the invention the at least one separation device (12a, 12b) is selected from the list consisting of a liquid chromatography separation device, a filter, a centrifugal, an extractor, an electrophoresis apparatus, and an acoustic wave separation device, preferably selected from the list consisting of a chromatography separation device and a filter. Preferably, at least one of the at least two bioprocessing units (2a, 2b) comprises more than one separation device (12a, 12b), preferably at least three separation devices. Such an embodiment can achieve higher efficiency and loadings in comparison to bioprocessing units having only one separation device.

[0082] Preferably, the at least one separation device (12a, 12b) is a liquid chromatography device. More preferably, the liquid chromatography device selected from the list consisting of liquid-liquid, liquid-solid, and ion exchange chromatography devices, preferably selected from the list consisting of an ion exchange chromatography device, a size exclusion chromatography device, a hydrophobic interaction chromatography device, and an affinity chromatography device. Preferably, the liquid chromatography device is selected from the list consisting of a liquid chromatography column and a liquid chromatography membrane. Generally, ideally, at least one of the at least two bioprocessing units (2a, 2b) comprises at least two liquid chromatography devices (12, 12’), preferably liquid chromatography columns.

[0083] Preferably, in the bioprocessing system according to the present invention, at least one of the at least two bioprocessing units (2a, 2b) comprises at least one analysis unit (13a, 13b). Such a unit has the advantage that no external analysis unit is needed, and that the status parameter of the associated bioprocessing unit (2a, 2b) can be easily maintained. Preferably, the analysis unit (13a, 13b) comprises at least one detector selected from the list consisting of an ultraviolet light absorption (UV) detector, a visible light absorption (VIS) detector, a photo diode array (PDA) detector, a refractive-index detector, an evaporative light scattering detector, a multi-angle light scattering detector, a mass spectrometer, a conductivity detector, a fluorescence detector, a chemiluminescence detector, an optical rotation detector, and an electrochemical detector. More preferably, the analysis unit (13a, 13b) is an in-line analysis unit, an online analysis unit, or an at-line analysis unit. Further preferably, the analysis unit (13) is configured to send a measured value to the client control module (7a, 7b) of the bioprocessing unit (2a, 2b). This allows for real-time control of the state of the target species and of the bioprocessing unit.

[0084] In an especially preferred embodiment of the bioprocessing system according to the present invention, the central control unit (1) is configured to automatically create and configure the transfer module (8) upon connection of the at least two selected bioprocessing units (2a, 2b) by a fluid connection (6) and connection of each client control (7a, 7b) unit per each of the at least two selected bioprocessing units (2a, 2b) with the central control unit (1). Hence, based on the information, which is received by the central control unit (1) about the at least two bioprocessing units (2a, 2b), particularly the parameters characterizing the upstream bioprocessing unit (2b) and parameters characterizing the downstream bioprocessing unit (2a), the central control unit (1) is able to negotiate the conditions and / or algorithms for the transfer module (8). Hence, usually, the central control unit (1) runs a master module (1a), which controls the transfer modules (8) and the client control modules (7a, 7b). This implementation has the advantage that setting up a bioprocessing system does not require profound knowledge of setting up a transfer module. Hence, the setup process of setting up a bioprocessing system of the present invention is significantly facilitated.

[0085] Preferably, each client control module (7a, 7b) is configured to provide said set of parameters characterizing the at least two bioprocessing units (2a, 2b) associated with said client control module (7a, 7b), an identification information associated with said at least two bioprocessing units (2a, 2b), and a connection information associated with said fluid connection (6), and wherein the central control unit (1) is configured to create and configure after reception of said set of parameters, said identification information and said connection information the transfer module (8) associated with said fluid connection (6). Preferably, the identification information comprises a unique id. Also preferably, the connection information comprises a unique id.

[0086] In the following, bioprocessing units for certain operations are listed, which are preferably useful to be implemented in the bioprocessing system of the present invention.

[0087] Preferred bioprocessing units include bioprocessing units suitable for carrying out common steps in bioprocessing, preferably downstream bioprocessing, such as dilution, pH adjustments, conductivity adjustments, additions, concentration, bioburden reduction, and mixtures thereof.

[0088] Furthermore, preferred bioprocessing units for the bioprocessing system according to the present invention are bioprocessing units suitable for cell harvesting, preferably by depth filtration, normal flow filtration, tangential flow filtration, continuous centrifugation, extraction, and mixtures thereof.

[0089] Also bioprocessing devices suitable for cell disruption, either chemically or physically, are preferred. Further preferred bioprocessing units for the bioprocessing system according to the present invention are bioprocessing units suitable for clarification, preferably by depth filtration, normal flow filtration, tangential flow filtration, continuous centrifugation, sterile filtration, such as 0.2 pm filtration with sterile grade filters, extraction, and mixtures thereof.

[0090] Other preferred bioprocessing units for the bioprocessing system according to the present invention are bioprocessing units suitable for capturing, preferably by gel chromatography, membrane chromatography, extraction, adsorption, and mixture thereof.

[0091] Also preferred bioprocessing units for the bioprocessing system according to the present invention are bioprocessing units suitable for intermediate purification / polishing, preferably by gel chromatography, membrane chromatography, adsorption, and mixtures thereof.

[0092] Moreover, preferred bioprocessing units for the bioprocessing system according to the present invention are bioprocessing units suitable for polishing, preferably by gel chromatography, membrane chromatography, charged filtration, tangential flow filtration, and mixtures thereof.

[0093] Other preferred bioprocessing units for the bioprocessing system according to the present invention are bioprocessing units suitable for formulation, preferably by gel chromatography, tangential flow filtration, ultrafiltration, and mixtures thereof.

[0094] Also preferred bioprocessing units for the bioprocessing system according to the present invention are bioprocessing units suitable for viral filtration, preferably by nanofiltration.

[0095] Finally, further preferred bioprocessing units for the bioprocessing system according to the present invention are bioprocessing units suitable for virus inactivation, preferably by chemical treatment or heating.

[0096] In the following, especially preferred embodiments of bioprocessing systems are described in detail. While the following description aims at describing certain bioprocessing units used and certain combinations of bioprocessing units used, it should be understood that each embodiment described in the following comprises all features of the most general embodiment as described above, even if these features are not described explicitly in the following.

[0097] In a first especially preferred embodiment, the at least two bioprocessing units (2a, 2b) comprise at least six bioprocessing units, which are described in the following, preferably serially connected in the order as provided in the following. It should be further understood that this embodiment is not limited to the actual number of bioprocessing units. Hence, some of the bioprocessing units as provided herein might be present more than once in the bioprocessing system, thereby forming a tree-like structure and / or parallel bioprocessing units.

[0098] Generally, the first especially preferred embodiment of the bioprocessing system of the present invention is directed towards monoclonal antibody (mAb) purification and, thus, to a system suitable for removing host cell proteins (HCP), DNA, and other contaminants while maintaining the integrity of the product. It is important to effectively remove aggregates, which can be very toxic and reduce mAb therapeutic efficacy.

[0099] Hence, the first bioprocessing unit of the bioprocessing system according to the first especially preferred embodiment of the present invention is a bioprocessing unit suitable for clarification, such as a depth filtration bioprocessing unit, a normal flow filtration bioprocessing unit, or a continuous centrifugation bioprocessing unit.

[0100] Furthermore, the second bioprocessing unit of the bioprocessing system according to the first especially preferred embodiment of the present invention is a bioprocessing unit suitable for affinity capturing, such as an affinity chromatography bioprocessing unit (e.g., Cytiva MabSelect Sure or MabSelect PrismA resins or any other Protein A- based resin) or an affinity membrane bioprocessing unit (e.g., Sartorius Sartobind Rapid A affinity membrane or any other Protein A-based membrane).

[0101] Moreover, the third bioprocessing unit of the bioprocessing system according to the first especially preferred embodiment of the present invention is a bioprocessing unit suitable for conditioning, such as a viral inactivation bioprocessing unit, or a pH / conductivity adjustment bioprocessing unit.

[0102] The fourth bioprocessing unit of the bioprocessing system according to the first especially preferred embodiment of the present invention is a bioprocessing unit suitable for polishing, such as a multimodal chromatography bioprocessing unit (e.g., Cytiva Capto adhere or Capto adhere ImpRes), an anion exchanger chromatography (AIEX) bioprocessing unit (e.g., Cytiva Capto Q resin), or an anion exchanger membrane bioprocessing unit (e.g., Pall Mustang Q).

[0103] Furthermore, the fifth bioprocessing unit of the bioprocessing system according to the first especially preferred embodiment of the present invention is a bioprocessing unit suitable for tangential flow filtration. Finally, the sixth bioprocessing unit of the bioprocessing system according to the first especially preferred embodiment of the present invention is a bioprocessing unit suitable for sterile filtration, such as a 0.2 pm filtration bioprocessing unit with sterile grade filters.

[0104] In the bioprocessing system and, thus, the bioprocessing process defined by this bioprocessing system, the affinity capturing bioprocessing unit / process step and the polishing bioprocessing unit / process step are the two most important steps. The first provides a concentration of mAb molecules, while the second is run in flow-through mode (mAbs pass the column without binding. Only impurities, such as aggregates, HOP or DNA, bind).

[0105] In a second especially preferred embodiment the at least two bioprocessing units (2a, 2b) comprise at least eight bioprocessing units, which are described in the following, preferably serially connected in the order as provided in the following. It should be further understood that this embodiment is not limited to the actual number of bioprocessing units. Hence, some of the bioprocessing units as provided herein might be present more than once in the bioprocessing system, thereby forming a tree-like structure and / or parallel bioprocessing units.

[0106] Generally, the second especially preferred embodiment of the bioprocessing system of the present invention is directed towards adeno associated virus (AAV) purification.

[0107] The first bioprocessing unit of the bioprocessing system according to the second especially preferred embodiment of the present invention is a bioprocessing unit suitable for cell lysis nuclease.

[0108] Hence, the second bioprocessing unit of the bioprocessing system according to the second especially preferred embodiment of the present invention is a bioprocessing unit suitable for clarification, such as a depth filtration bioprocessing unit, a normal flow filtration bioprocessing unit, or a continuous centrifugation bioprocessing unit.

[0109] Furthermore, the third bioprocessing unit of the bioprocessing system according to the second especially preferred embodiment of the present invention is a bioprocessing unit suitable for tangential flow filtration.

[0110] Moreover, the fourth bioprocessing unit of the bioprocessing system according to the second especially preferred embodiment of the present invention is a bioprocessing unit suitable for affinity capturing, such as an affinity chromatography bioprocessing unit (e.g., Cytiva Capto AVB resin, Thermofisher Poros Capture Select AAVX resin) or a cation exchanger chromatography (CIEX) bioprocessing unit. The fifth bioprocessing unit of the bioprocessing system according to the second especially preferred embodiment of the present invention is a bioprocessing unit suitable for dilution.

[0111] The sixth bioprocessing unit of the bioprocessing system according to the second especially preferred embodiment of the present invention is a bioprocessing unit suitable for AIEX polishing, such as an anion exchanger chromatography (AIEX) bioprocessing unit (e.g., Cytiva Capto Q resin).

[0112] Furthermore, the seventh bioprocessing unit of the bioprocessing system according to the second especially preferred embodiment of the present invention is a bioprocessing unit suitable for tangential flow filtration.

[0113] Finally, the eighth bioprocessing unit of the bioprocessing system according to the second especially preferred embodiment of the present invention is a bioprocessing unit suitable for sterile filtration, such as a 0.2 pm filtration bioprocessing unit with sterile grade filters.

[0114] In the bioprocessing system and, thus, the bioprocessing process defined by this bioprocessing system, the affinity capturing bioprocessing unit / process step and the AIEX polishing bioprocessing unit / process step are the two most important steps. The first provides a concentration of AAV, while the second provides an effective separation of full and empty adeno-associated virus capsids (viral particles with no viral genome).

[0115] In a third especially preferred embodiment the at least two bioprocessing units (2a, 2b) comprise at least seven bioprocessing units, which are described in the following, preferably serially connected in the order as provided in the following. It should be further understood that this embodiment is not limited to the actual number of bioprocessing units. Hence, some of the bioprocessing units as provided herein might be present more than once in the bioprocessing system, thereby forming a tree-like structure and / or parallel bioprocessing units.

[0116] Generally, the third especially preferred embodiment of the bioprocessing system of the present invention is directed towards adeno virus (AdV) purification. Adeno viruses are used as viral vectors for gene therapy or vaccines and as oncolytic viruses. Because of this wide application range, adeno virus production volumes can vary significantly. Hence, the interest in scalable platforms for industrial adenovirus production is increasing.

[0117] The first bioprocessing unit of the bioprocessing system according to the third especially preferred embodiment of the present invention is a bioprocessing unit suitable for cell lysis nuclease. This bioprocessing unit preferably is suitable for a process, in which the adeno viruses are released from the infected cells (upstream culture) and cell DNA is chopped down in smaller fragments with benzonase.

[0118] Hence, the second bioprocessing unit of the bioprocessing system according to the third especially preferred embodiment of the present invention is a bioprocessing unit suitable for clarification, such as a depth filtration bioprocessing unit, a normal flow filtration bioprocessing unit, or a continuous centrifugation bioprocessing unit.

[0119] Furthermore, the third bioprocessing unit of the bioprocessing system according to the third especially preferred embodiment of the present invention is a bioprocessing unit suitable for tangential flow filtration.

[0120] The fourth bioprocessing unit of the bioprocessing system according to the third especially preferred embodiment of the present invention is a bioprocessing unit suitable for capturing, such as an anion exchanger chromatography (Al EX) bioprocessing unit in bind / elute mode (e.g., Cytiva Q Sepharose XL or Cytiva Capto Q ImpRes).

[0121] Moreover, the fifth bioprocessing unit of the bioprocessing system according to the third especially preferred embodiment of the present invention is a bioprocessing unit suitable for polishing, such as size exclusion chromatography bioprocessing unit (e.g., Cytiva Sepharose 4 Fast Flow) or multimodal chromatography bioprocessing unit (e.g., Cytiva Capto Core 700).

[0122] Furthermore, the sixth bioprocessing unit of the bioprocessing system according to the third especially preferred embodiment of the present invention is a bioprocessing unit suitable for tangential flow filtration.

[0123] Finally, the seventh bioprocessing unit of the bioprocessing system according to the third especially preferred embodiment of the present invention is a bioprocessing unit suitable for sterile filtration, such as a 0.2 pm filtration bioprocessing unit with sterile grade filters.

[0124] In the bioprocessing system and, thus, the bioprocessing process defined by this bioprocessing system, the capturing bioprocessing unit / process step and the polishing bioprocessing unit / process step are the two most important steps. In the first step, negatively charged adeno viruses bind to the AIEX resin, while in the second step they flow through the chromatographic resin.

[0125] In a fourth especially preferred embodiment the at least two bioprocessing units (2a, 2b) comprise at least seven bioprocessing units, which are described in the following, preferably serially connected in the order as provided in the following. It should be further understood that this embodiment is not limited to the actual number of bioprocessing units. Hence, some of the bioprocessing units as provided herein might be present more than once in the bioprocessing system, thereby forming a tree-like structure and / or parallel bioprocessing units.

[0126] Generally, the fourth especially preferred embodiment of the bioprocessing system of the present invention is directed towards lentvirus (LV) purification. Lentviruses (LV) are enveloped RNA viruses belonging to the retroviridae family with a particle size of -80-100 nm. LV are one of the most efficient gene transfer vectors and integrate the RNA into the host cell DNA. LV is commonly used for Chimeric Antigen Receptor (CAR) T cell therapy to successfully treat cancer. Purification of lentiviral vector is very challenging due to low stability of this enveloped virus that is sensitive to low pH, high salt, temperature, and shear forces for example.

[0127] The first bioprocessing unit of the bioprocessing system according to the fourth especially preferred embodiment of the present invention is a bioprocessing unit suitable for harvest nuclease.

[0128] Hence, the second bioprocessing unit of the bioprocessing system according to the fourth especially preferred embodiment of the present invention is a bioprocessing unit suitable for clarification, such as a depth filtration bioprocessing unit, a normal flow filtration bioprocessing unit, or a continuous centrifugation bioprocessing unit.

[0129] Furthermore, the third bioprocessing unit of the bioprocessing system according to the fourth especially preferred embodiment of the present invention is a bioprocessing unit suitable for tangential flow filtration.

[0130] The fourth bioprocessing unit of the bioprocessing system according to the fourth especially preferred embodiment of the present invention is a bioprocessing unit suitable for + / - capturing, such as an anion exchanger chromatography (AIEX) bioprocessing unit in bind / elute mode (e.g., Cytiva Capto DEAE resin, Pall Mustang Q membrane).

[0131] Moreover, the fifth bioprocessing unit of the bioprocessing system according to the fourth especially preferred embodiment of the present invention is a bioprocessing unit suitable for polishing, such as a multimodal chromatography bioprocessing unit (e.g., Cytiva Capto Core 700 resin). Furthermore, the sixth bioprocessing unit of the bioprocessing system according to the fourth especially preferred embodiment of the present invention is a bioprocessing unit suitable for tangential flow filtration.

[0132] Finally, the seventh bioprocessing unit of the bioprocessing system according to the fourth especially preferred embodiment of the present invention is a bioprocessing unit suitable for sterile filtration, such as a 0.2 pm filtration bioprocessing unit with sterile grade filters.

[0133] In the bioprocessing system and, thus, the bioprocessing process defined by this bioprocessing system, the capturing bioprocessing unit / process step and the polishing bioprocessing unit / process step are the two most important steps. In the first step, a concentration of LV and an efficient purification of the viral particles is provided, whereas the second step, which is operated in flow-through mode, the viruses do not bind to the chromatography resin, while only the impurities bind.

[0134] In a fifth especially preferred embodiment the at least two bioprocessing units (2a, 2b) comprise at least five bioprocessing units, which are described in the following, preferably serially connected in the order as provided in the following. It should be further understood that this embodiment is not limited to the actual number of bioprocessing units. Hence, some of the bioprocessing units as provided herein might be present more than once in the bioprocessing system, thereby forming a tree-like structure and / or parallel bioprocessing units.

[0135] Generally, the fifth especially preferred embodiment of the bioprocessing system of the present invention is directed towards exosome purification. Exosomes are a class of cell-derived extracellular vesicles of endosomal origin and are typically 30-150 nm in diameter. Enveloped by a lipid bilayer, exosomes are released into the extracellular environment containing a complex cargo of contents derived from the original cell, including proteins, lipids, mRNA, miRNA and DNA. These naturally-equipped nanovesicles can be therapeutically targeted or engineered as drug delivery systems.

[0136] The first bioprocessing unit of the bioprocessing system according to the fifth especially preferred embodiment of the present invention is a bioprocessing unit suitable for tangential flow filtration.

[0137] The second bioprocessing unit of the bioprocessing system according to the fifth especially preferred embodiment of the present invention is a bioprocessing unit suitable for chromatographic purification, such as a multimodal chromatography bioprocessing unit (e.g., Cytiva Capto Core 700 resin) or a size exclusion chromatography bioprocessing unit (e.g., Cytiva Sephacryl S-400 HR). Moreover, the third bioprocessing unit of the bioprocessing system according to the fifth especially preferred embodiment of the present invention is a bioprocessing unit suitable for chromatographic purification, such as an ion exchanger chromatography bioprocessing unit (e.g., Cytiva Capto Q or Cytiva Fibro Q or Pall Mustang Q).

[0138] Furthermore, the fourth bioprocessing unit of the bioprocessing system according to the fifth especially preferred embodiment of the present invention is a bioprocessing unit suitable for tangential flow filtration.

[0139] Finally, the fifth bioprocessing unit of the bioprocessing system according to the fifth especially preferred embodiment of the present invention is a bioprocessing unit suitable for sterile filtration, such as a 0.2 pm filtration bioprocessing unit with sterile grade filters.

[0140] In the bioprocessing system and, thus, the bioprocessing process defined by this bioprocessing system, the two chromatographic purification bioprocessing unit / process steps are the two most important steps. In the first step, the exosomes flow through the beads, whereas smaller particles / impurities enter the pores in the beads. Furthermore, preferably, the ion exchange chromatography bioprocessing unit is an anion exchanger working in bind / elute mode.

[0141] In a sixth especially preferred embodiment the at least two bioprocessing units (2a, 2b) comprise at least nine bioprocessing units, which are described in the following, preferably serially connected in the order as provided in the following. It should be further understood that this embodiment is not limited to the actual number of bioprocessing units. Hence, some of the bioprocessing units as provided herein might be present more than once in the bioprocessing system, thereby forming a tree-like structure and / or parallel bioprocessing units.

[0142] Generally, the sixth especially preferred embodiment of the bioprocessing system of the present invention is directed towards plasmid DNA (pDNA) purification. A plasmid is a small, extrachromosomal DNA molecule within a cell that is physically separated from chromosomal DNA and can replicate independently. They are most commonly found as small circular, double-stranded DNA molecules in bacteria. While chromosomes are large and contain all the essential genetic information for living under normal conditions, plasmids are usually very small and contain only additional genes that may be useful in certain situations or conditions. Artificial plasmids are widely used as vectors in molecular cloning and are in principle used for the cell and gene therapy industry. For instance, they are used to produce mRNA or AAVs used in gene therapy. The first bioprocessing unit of the bioprocessing system according to the sixth especially preferred embodiment of the present invention is a bioprocessing unit suitable for cell lysis and flocculation. In this bioprocessing unit / step destruction of bacteria (E-Coli) occurs to extract the plasmids and flocculation of cell debris.

[0143] Hence, the second bioprocessing unit of the bioprocessing system according to the sixth especially preferred embodiment of the present invention is a bioprocessing unit suitable for clarification, such as a depth filtration bioprocessing unit, a normal flow filtration bioprocessing unit, or a continuous centrifugation bioprocessing unit.

[0144] Furthermore, the third bioprocessing unit of the bioprocessing system according to the sixth especially preferred embodiment of the present invention is a bioprocessing unit suitable for tangential flow filtration.

[0145] The fourth bioprocessing unit of the bioprocessing system according to the sixth especially preferred embodiment of the present invention is a bioprocessing unit suitable for normal flow filtration.

[0146] Moreover, the fifth bioprocessing unit of the bioprocessing system according to the sixth especially preferred embodiment of the present invention is a bioprocessing unit suitable for chromatographic purification, such as a size exclusion chromatography bioprocessing unit (e.g., Cytiva Sepharose 6 FF).

[0147] The sixth bioprocessing unit of the bioprocessing system according to the sixth especially preferred embodiment of the present invention is a bioprocessing unit suitable for chromatographic purification (e.g., Cytiva Plasmid Select Xtra or Capto Plasmid Select).

[0148] The seventh bioprocessing unit of the bioprocessing system according to the sixth especially preferred embodiment of the present invention is a bioprocessing unit suitable for AIEX polishing, such as an anion exchanger chromatography (AIEX) bioprocessing unit (e.g., Cytiva Source 30 Q).

[0149] Furthermore, the eighth bioprocessing unit of the bioprocessing system according to the sixth especially preferred embodiment of the present invention is a bioprocessing unit suitable for tangential flow filtration.

[0150] Finally, the ninth bioprocessing unit of the bioprocessing system according to the sixth especially preferred embodiment of the present invention is a bioprocessing unit suitable for sterile filtration, such as a 0.2 pm filtration bioprocessing unit with sterile grade filters. In the bioprocessing system and, thus, the bioprocessing process defined by this bioprocessing system, three chromatographic steps are involved: size exclusion chromatography, removal of open circular (OC) pDNA, and anion exchanger chromatography. In the size exclusion chromatography, the large pDNA flows through the beads, whereas smaller RNA enters the pores in the beads. In the OC pDNA removal step, the OC and SC (supercoiled conformation) pDNA conformations are eluted selectively, whereas the AIEX polishing is used to fine purify the SC pDNA in a bind-elute mode.

[0151] In a seventh especially preferred embodiment the at least two bioprocessing units (2a, 2b) comprise at least eight bioprocessing units, which are described in the following, preferably serially connected in the order as provided in the following. It should be further understood that this embodiment is not limited to the actual number of bioprocessing units. Hence, some of the bioprocessing units as provided herein might be present more than once in the bioprocessing system, thereby forming a tree-like structure and / or parallel bioprocessing units.

[0152] Generally, the seventh especially preferred embodiment of the bioprocessing system of the present invention is an alternative approach directed towards plasmid DNA (pDNA) purification.

[0153] The first bioprocessing unit of the bioprocessing system according to the seventh especially preferred embodiment of the present invention is a bioprocessing unit suitable for cell lysis and flocculation. In this bioprocessing unit / step destruction of bacteria (E-Coli) occurs to extract the plasmids and flocculation of cell debris.

[0154] Hence, the second bioprocessing unit of the bioprocessing system according to the seventh especially preferred embodiment of the present invention is a bioprocessing unit suitable for clarification, such as a depth filtration bioprocessing unit, a normal flow filtration bioprocessing unit, or a continuous centrifugation bioprocessing unit.

[0155] Furthermore, the third bioprocessing unit of the bioprocessing system according to the seventh especially preferred embodiment of the present invention is a bioprocessing unit suitable for tangential flow filtration.

[0156] The fourth bioprocessing unit of the bioprocessing system according to the seventh especially preferred embodiment of the present invention is a bioprocessing unit suitable for normal flow filtration.

[0157] Moreover, the fifth bioprocessing unit of the bioprocessing system according to the seventh especially preferred embodiment of the present invention is a bioprocessing unit suitable for chromatographic purification, such as an anion exchange membrane bioprocessing unit in bind / elute mode (e.g., Pall Mustang Q XT140).

[0158] The sixth bioprocessing unit of the bioprocessing system according to the seventh especially preferred embodiment of the present invention is a bioprocessing unit suitable for chromatographic purification (e.g., Cytiva Plasmid Select Xtra or Capto Plasmid Select).

[0159] Furthermore, the seventh bioprocessing unit of the bioprocessing system according to the seventh especially preferred embodiment of the present invention is a bioprocessing unit suitable for tangential flow filtration.

[0160] Finally, the eighth bioprocessing unit of the bioprocessing system according to the seventh especially preferred embodiment of the present invention is a bioprocessing unit suitable for sterile filtration, such as a 0.2 pm filtration bioprocessing unit with sterile grade filters.

[0161] In the bioprocessing system and, thus, the bioprocessing process defined by this bioprocessing system, only two chromatographic steps are involved: AIEX chromatography and removal of OC pDNA. The anion exchanger chromatography is run using a charged membrane instead of a chromatographic resin, and the normal the classical OC pDNA removal step as in the previous process.

[0162] In an eighth especially preferred embodiment, the at least two bioprocessing units (2a, 2b) comprise at least six bioprocessing units, which are described in the following, preferably serially connected in the order as provided in the following. It should be further understood that this embodiment is not limited to the actual number of bioprocessing units. Hence, some of the bioprocessing units as provided herein might be present more than once in the bioprocessing system, thereby forming a tree-like structure and / or parallel bioprocessing units.

[0163] Generally, the eighth especially preferred embodiment of the bioprocessing system of the present invention is directed towards messenger RNA (mRNA) purification. Messenger RNAs are single-stranded nucleic acids transcribed from DNA. When used as a preventative vaccine or a therapeutic drug, mRNA is typically delivered to the cell’s cytoplasm where it directs production of protein-based antigens. By mimicking the actions of natural mRNAs, therapeutical mRNAs use cells as natural “bioreactors” to produce clinically relevant proteins, thus avoiding challenges associated with some protein-based therapeutics. The upstream bioprocessing unit is a bioprocessing unit suitable for in vitro transcription, i.e. , a stirred tank bioreactor. Thereby, mRNA is produced by incubating DNA template with an RNA polymerase - usually the T7-RNA-Polymerase - and nucleotides (NTPs) in a cell-free in vitro transcription (IVT) process.

[0164] The first bioprocessing unit of the bioprocessing system according to the eighth especially preferred embodiment of the present invention is a bioprocessing unit suitable for tangential flow filtration.

[0165] Furthermore, the second bioprocessing unit of the bioprocessing system according to the eighth especially preferred embodiment of the present invention is a bioprocessing unit suitable for affinity capturing, such as an affinity chromatography bioprocessing unit (e.g., a highly specific chromatographic resin or membrane based on Oligo-DT ligands).

[0166] The third bioprocessing unit of the bioprocessing system according to the eighth especially preferred embodiment of the present invention is a bioprocessing unit suitable for tangential flow filtration.

[0167] The fourth bioprocessing unit of the bioprocessing system according to the eighth especially preferred embodiment of the present invention is a bioprocessing unit suitable for polishing, such as a multimodal chromatography bioprocessing unit (e.g., Cytiva Capto Core 700 resin) or a hydrophobic interaction chromatography (HIC) bioprocessing unit (e.g., Cytiva Butyl Sepharose 4 Fast Flow).

[0168] Furthermore, the fifth bioprocessing unit of the bioprocessing system according to the eighth especially preferred embodiment of the present invention is a bioprocessing unit suitable for tangential flow filtration.

[0169] Finally, the sixth bioprocessing unit of the bioprocessing system according to the eighth especially preferred embodiment of the present invention is a bioprocessing unit suitable for liquid nanoparticle encapsulation of the purified mRNA.

[0170] In a ninth especially preferred embodiment, the at least two bioprocessing units (2a, 2b) comprise at least five bioprocessing units, which are described in the following, preferably serially connected in the order as provided in the following. It should be further understood that this embodiment is not limited to the actual number of bioprocessing units. Hence, some of the bioprocessing units as provided herein might be present more than once in the bioprocessing system, thereby forming a tree-like structure and / or parallel bioprocessing units. Generally, the ninth especially preferred embodiment of the bioprocessing system of the present invention is directed towards oligo synthesis. DNA oligonucleotides can be manufactured via chemical synthesis using a fully automated oligonucleotide synthesizer like the Cytiva AKTA oligosynt. However, the resulting oligo molecule needs to go through a purification procedure to achieve product quality as required for pharmaceutical / therapy use.

[0171] Hence, the upstream bioprocessing unit is a bioprocessing unit suitable oligonucleotide synthesis.

[0172] The first bioprocessing unit of the bioprocessing system according to the ninth especially preferred embodiment of the present invention is a bioprocessing unit suitable for cleavage and protection. Preferably, the first bioprocessing unit of the bioprocessing system according to the ninth especially preferred embodiment of the present invention is suitable for ester hydrolysis of the linker and simultaneous removal of the product from the solid support, both of which are carried out by treatment with concentrated aqueous ammonia.

[0173] Furthermore, the second bioprocessing unit of the bioprocessing system according to the ninth especially preferred embodiment of the present invention is a bioprocessing unit suitable for normal flow filtration (NFF) and tangential flow filtration (TFF) to remove solid matter and adopt concentration and buffer.

[0174] The third bioprocessing unit of the bioprocessing system according to the ninth especially preferred embodiment of the present invention is a bioprocessing unit suitable for polishing, such as an anion exchanger chromatography (AIEX) bioprocessing unit (e.g., Cytiva Capto Q resin).

[0175] The fourth bioprocessing unit of the bioprocessing system according to the ninth especially preferred embodiment of the present invention is a bioprocessing unit suitable for desalting and concentration, i.e., either size exclusion chromatography (for small scale) (e.g., Sephacryl S-300 HR) or tangential flow filtration (for large scall).

[0176] The fourth bioprocessing unit of the bioprocessing system according to the ninth especially preferred embodiment of the present invention is a bioprocessing unit suitable for polishing, such as a multimodal chromatography bioprocessing unit (e.g., Cytiva Capto Core 700 resin) or a hydrophobic interaction chromatography (HIC) bioprocessing unit (e.g., Cytiva Butyl Sepharose 4 Fast Flow). Finally, the fifth bioprocessing unit of the bioprocessing system according to the ninth especially preferred embodiment of the present invention is a bioprocessing unit suitable for sterile filtration, such as 0.2 pm filtration with sterile grade filters.

[0177] In an alternative embodiment of the ninth especially preferred embodiment of the present invention, the third bioprocessing unit is preceded by two more bioprocessing units, wherein the first of these two bioprocessing units is suitable for chromatography purification (i.e., HIC or RPC), and the second of these two bioprocessing units is suitable for Detritylation (acid pH).

[0178] The key element in this alternative embodiment of the ninth especially preferred embodiment of the present invention is that the hydrophobic protective trityl group (DMTr) is retained after the upstream bioprocessing unit and used as a handle for hydrophobic interaction chromatography (HIC) (e.g., Cytiva Phenil Sepharose 6 FF) or reverse-phase chromatography (RPC) (e.g., Cytiva Source 30 RPC) purification. The trityl group is then easily removed by lowing pH using a strong acid solution. Then the polishing step is achieved using a regular anion exchange chromatography resin.

[0179] Bioprocessing unit

[0180] The present invention further relates to a bioprocessing unit (2), comprising an inlet (4), an outlet (5), a client control module (7), configured to be connected to a central control unit (1) and configured to interact with the bioprocessing unit (2), and a set of parameters characterizing the bioprocessing unit (2).

[0181] Preferably, the set of parameters comprises at least one parameter selected from the list consisting of a volume flow rate of the bioprocessing unit (2), a critical volume of the bioprocessing unit (2), and a product quality of the bioprocessing unit (2). This embodiment allows for bioprocessing systems according to the present invention, which is able to adjust the flow rate of the fluid connection (6) by the transfer module (8). Furthermore, it allows asynchronous fluid connections and enhanced product quality.

[0182] Preferably, the bioprocessing unit (2) comprises at least one pump (11) and at least one separation device (12) connected to the at least one flow path of the bioprocessing device (2).

[0183] The bioprocessing unit (2) is a device, which receives a fluid volume comprising a target species and usually contaminants and which outputs a fluid volume comprising the target species and usually less contaminants. The bioprocessing unit (2) comprises an inlet (4), and outlet (5) and a flow path (3) connecting the inlet (4) and the outlet (5). Preferably, the bioprocessing unit (2) is selected from the list consisting of chromatographic devices, including columns and membranes, filters, centrifuges, extraction devices, and two-phase separation devices. Preferably, the bioprocessing unit (2) comprises at least one pump (11) and at least one separation device (12) connected to the flow path (3) of the bioprocessing unit.

[0184] In a preferred embodiment of the invention the at least one separation device (12) is selected from the list consisting of a liquid chromatography separation device, a filter, a centrifugal, an extractor, an electrophoresis apparatus, and an acoustic wave separation device, preferably selected from the list consisting of a chromatography separation device and a filter. Preferably, the bioprocessing unit (2) comprises more than one separation device (12, 12’), preferably at least three separation devices. Such an embodiment can achieve higher efficiency and loadings in comparison to bioprocessing units having only one separation device.

[0185] Preferably, the at least one separation device (12, 12’) is a liquid chromatography device. More preferably, the liquid chromatography device selected from the list consisting of liquid-liquid, liquid-solid, and ion exchange chromatography devices, preferably selected from the list consisting of an ion exchange chromatography device, a size exclusion chromatography device, a hydrophobic interaction chromatography device, and an affinity chromatography device. Preferably, the liquid chromatography device is selected from the list consisting of a liquid chromatography column and a liquid chromatography membrane. Generally, ideally, the bioprocessing unit (2) comprises at least two liquid chromatography devices (12, 12’), preferably liquid chromatography columns.

[0186] Preferably, in the bioprocessing system according to the present invention, the bioprocessing unit (2) comprises at least one analysis unit (13). Such a unit has the advantage that no external analysis unit is needed, and that the status parameter of the bioprocessing unit (2) can be easily maintained. Preferably, the analysis unit (13) comprises at least one detector selected from the list consisting of an ultraviolet light absorption (UV) detector, a visible light absorption (VIS) detector, a photo diode array (PDA) detector, a refractive-index detector, an evaporative light scattering detector, a multi-angle light scattering detector, a mass spectrometer, a conductivity detector, a fluorescence detector, a chemiluminescence detector, an optical rotation detector, and an electrochemical detector. More preferably, the analysis unit (13) is an in-line analysis unit, an on-line analysis unit, or an at-line analysis unit. Further preferably, the analysis unit (13) is configured to send a measured value to the client control module (7) of the bioprocessing unit (2). This allows for real-time control of the state of the target species and of the bioprocessing unit.

[0187] In an especially preferred embodiment of the present invention, the bioprocessing unit (2) is further configured to provide said set of parameters characterizing the bioprocessing unit (2), an identification information associated with the bioprocessing unit (2), and a connection information associated with a fluid connection (6) to a further connected bioprocessing unit (2). Preferably, the identification information comprises a unique id. Also preferably, the connection information comprises a unique id.

[0188] Bioprocessing process

[0189] The present invention further relates to a bioprocessing process for separating a target species from a raw fluid mixture, the process comprising the steps of:

[0190] (A) providing a raw fluid mixture comprising the target species;

[0191] (B) purifying the raw fluid mixture yielding a fluid volume comprising the target species;

[0192] (C) collecting the target species from the fluid volume; wherein step (B) comprises at least one series of sets of steps, said set comprising the steps of, providing at least two bioprocessing units (2a, 2b), wherein each bioprocessing unit comprises at least one flow path (3a, 3b) comprising an inlet (4a, 4b) and an outlet (5a, 5b) and wherein at least two selected bioprocessing units of the at least two bioprocessing units (2a, 2b) are connected in series by a fluid connection (6) of the outlet (5a) of an upstream bioprocessing unit (2a) of the two selected bioprocessing units (2a, 2b) and the inlet (4b) of a downstream bioprocessing unit (2b) of the two selected bioprocessing units (2a, 2b), thereby forming a line of serially connected at least two bioprocessing units (2a, 2b); introducing an input fluid mixture comprising the target species into the upstream bioprocessing unit (2a); monitoring an upstream set of parameters characterizing said upstream bioprocessing unit (2a), monitoring a downstream set of parameters characterizing said downstream bioprocessing unit (2b), and calculating a decision statement therefrom, wherein the decision statement comprises adjusting the flow rate of the fluid in a fluid connection (6) between said upstream bioprocessing unit (2a) and the downstream bioprocessing unit (2b), depending on the calculated decision statement, adjusting the flow rate of the fluid in the fluid connection (6) between said upstream bioprocessing unit (2a) and said downstream bioprocessing unit (2b), producing upon starting the fluid connection (6) an output fluid volume at the outlet of the downstream bioprocessing unit (2b), transferring the output fluid volume as input fluid volume to a subsequent set of steps of the series of sets of steps directly following the set of steps or, if the set of steps is the last set of steps in the series of sets of steps, as fluid volume to step (C) wherein the input fluid mixture is the raw fluid mixture, if the set of steps is the first set of steps in the series of set of steps.

[0193] Preferably, the decision statement comprises an upstream decision statement and a downstream decision statement. Hence, preferably, the decision statement comprises a statement, which results in an adjustment of the flow rate of the upstream bioprocessing unit (2a), and a statement, which results in an adjustment of the flow rate of the downstream bioprocessing unit (2b). Hence, preferably, the step of adjusting the flow rate of the fluid in the fluid connection (6) comprises the step of adjusting the flow rate of the upstream bioprocessing unit (2a) based upon the upstream decision statement and the step of adjusting the flow rate of the downstream bioprocessing unit (2b) based upon the downstream decision statement.

[0194] Most preferably, in the process according to the present invention, the step of adjusting the flow rate of a bioprocessing unit comprises, preferably consists of, starting or stopping said bioprocessing unit.

[0195] Preferably, the upstream set of parameters comprises at least one parameter selected from the list consisting of a volume flow rate of the upstream bioprocessing unit (2a), and a product quality of the upstream bioprocessing unit (2a), and / or the downstream set of parameters comprises at least one parameter selected from the list consisting of a volume flow rate of the downstream bioprocessing unit (2b), and a product quality of the downstream bioprocessing unit (2b).

[0196] Preferably, the step of calculating a decision statement comprises computing at least one condition with respect to at least one parameter of said set of parameters. More preferably, the step of calculating an upstream decision statement comprises computing at least one in-condition with respect to at least one parameter of said upstream set of parameters, and / or wherein the step of calculating a downstream decision statement comprises computing at least one out-condition with respect to at least one parameter of said downstream set of parameters.

[0197] Preferably, the at least one in-condition comprises a reference to a parameter of the upstream set of parameters and / or the at least one out-condition comprises a reference to a parameter of the downstream set of parameters. Even more preferably, the at least one in-condition comprises a reference to the upstream status parameter and / or wherein the at least one out-condition comprises a reference to the downstream status parameter. Hence, preferably, the in-condition is part of the upstream set of parameters and / or the out-condition is part of the downstream set of parameters.

[0198] Preferably, the in-condition comprises the condition that the upstream status parameter of the upstream bioprocessing unit (2a) is ‘waiting’ and ‘ready to deliver". Moreover, preferably, the out-condition comprises the condition that the downstream status parameter of the downstream bioprocessing unit (2b) is ‘waiting’ and ‘ready to receive’. Most preferably, the fluid connection (6) is a synchronous connection, the in-condition comprises the condition that the upstream status parameter of the upstream bioprocessing unit (2a) is ‘waiting’ and ‘ready to deliver", and the out-condition comprises the condition that the downstream status parameter of the downstream bioprocessing unit (2b) is ‘waiting’ and ‘ready to receive’.

[0199] In an alternative preferred embodiment, the in-condition comprises the condition that the upstream status parameter of the upstream bioprocessing unit (2a) is ‘waiting’ and ‘ready to deliver" and the condition that the filling status of the surge vessel (15) is below the critical receiving volume (18). In another alternative preferred embodiment, the out-condition comprises the condition that the downstream status parameter of the downstream bioprocessing unit (2b) is ‘waiting’ and ‘ready to receive’ and the condition that the filling status of the surge vessel (15) is above the critical delivering volume (17). More preferably, in the alternative preferred embodiment, the fluid connection (6) is an asynchronous fluid connection, the in-condition comprises the condition that the upstream status parameter of the upstream bioprocessing unit (2a) is ‘waiting’ and ‘ready to deliver" and the condition that the filling status of the surge vessel (15) is below the critical receiving volume (18). Also more preferably, in the alternative preferred embodiment, the fluid connection (6) is an asynchronous fluid connection, the out-condition comprises the condition that the downstream status parameter of the downstream bioprocessing unit (2b) is ‘waiting’ and ‘ready to receive’ and the condition that the filling status of the surge vessel (15) is above the critical delivering volume (17). Process for setting up a bioprocessing system

[0200] The present invention further relates to a process for setting up a bioprocessing system, the process comprising the steps of

[0201] Providing an upstream bioprocessing unit (2a) comprising an inlet (4a), an outlet (5a), and an upstream set of parameters characterizing said upstream bioprocessing unit (2a);

[0202] Providing an upstream client control module (7a) configured to interact with the upstream bioprocessing unit (2a);

[0203] Providing a downstream bioprocessing unit (2b) comprising an inlet (4b), an outlet (5b), and a downstream set of parameters characterizing said downstream bioprocessing unit (2b) and the status thereof;

[0204] Providing a downstream client control module (7b) configured to interact with the downstream bioprocessing unit (2b);

[0205] Providing a central control unit (1);

[0206] Connecting the outlet (5a) of the upstream bioprocessing unit (2a) to the inlet (4b) of the downstream bioprocessing unit (2b) using a fluid connection (6);

[0207] Connecting the upstream client control module (2a) and the downstream client control module (2b) with the central control unit (1);

[0208] Transferring the upstream set of parameters from the upstream bioprocessing unit (2a) to the upstream client control module (7a);

[0209] Transferring the upstream set of parameters from the upstream client control module (7a) to the central unit (1);

[0210] Transferring the downstream set of parameters from the downstream bioprocessing unit (2b) to the downstream client control module (7b);

[0211] Transferring the downstream set of parameters from the downstream client control module (7b) to the central unit (1);

[0212] Providing a transfer module associated with said fluid connection; and

[0213] Configuring the transfer module to comprise at least one algorithm to compute a decision statement from said upstream set of parameters and downstream set of parameters, wherein the decision statement comprises adjusting the flow rate in the, preferably starting or stopping the, fluid connection (6) associated with said transfer module. Preferably, wherein the central control unit (1) is configured to automatically set up the transfer module (8) depending on the upstream set of parameters and downstream set of parameters.

[0214] Examples

[0215] In the following an example is provided to further elucidate the present invention. References are made to Figure 8. In the example, the bioprocessing system comprises five different bioprocessing units, which are connected in series. Bioprocessing unit C1 is a normal flow filtration unit run on an AKTA Go with a non-standard flow path, which is connected to bioprocessing unit 02 via an asynchronous fluid connection comprising a surge vessel, which has a scale from Mettler Toledo as measurement unit. Bioprocessing unit 02 is a capture chromatography step and is run on an AKTA POO 75 utilizing an asynchronous column valve position option, wherein the column valve positions on the two column valves are not set using position 1 , 2, or 3, but instead it is set individually for each column valve. Hence, bioprocessing unit 02 is an asynchronous bioprocessing unit. 02 is connected via a synchronous transfer to bioprocessing unit 03, which is a conditioning bioprocessing unit and is run on a AKTA pure using a non-standard flow path. 03 is connected via an asynchronous fluid connection to 04. The asynchronous fluid connection comprises a batch counter as measurement unit, wherein a 1 :1 ratio of batches should be achieved. 04 is the polishing step, i.e. , a chromatography step, which achieves the final purity, and is run on a AKTA pure using a non-standard flow path. This bioprocessing unit is connected via a final asynchronous fluid connection to the bioprocessing unit 05. The asynchronous fluid connection comprises a batch counter as measurement unit, wherein a 8: 1 ratio should be achieved. 05 is a tangential flow filtration bioprocessing unit and is run on a AKTA Avant using a non-standard flow path

[0216] Each AKTA bioprocessing unit is connected via its Unicorn API to a computer (indicated by the rectangle ‘virtual’), in which the client control modules (client 1-5) and a master layer comprising the transfer module are running as python programs (ORBIT) on Microsoft Windows. With each bioprocessing unit, one client control module is associated. Furthermore, with each fluid connection, one transfer module is associated. The scale is connected to the computer using a serial port (RS232).

[0217] C1 is a continuous normal flow filtration step which adjusts its flow to the subsequent surge vessel according to a PI regulator implemented in software on client 1 based on the fluid level in the beaker. The PI regulator is designed to keep the volume in the surge vessel constant. 02 is a bind-elute capture step which takes material from the beaker as batches. The transfer module 1 manages the transfer in between C1 and C2. The in-condition of transfer module 1 is:

[0218] • C1 is in state “Ready to deliver”

[0219] The out-conditions of transfer module 1 are:

[0220] • critical delivering volume in the surge vessel has been reached

[0221] • C2 is in state “Ready to receive”

[0222] Even if C1 is continuously delivering to the beaker it still has the same checkpoints as the other clients where it will set its state to “Ready to deliver” and pause while waiting for permission to continue. However, as can be seen in the in-condition of the transfer module 1 , C1 will be allowed to continue as soon as its state is “Ready to deliver”. The flow of C1 will be regulated using the PI regulator based on the fluid level of the surge vessel. The PI regulator keeps the surge vessel from overflowing, which is the reason C1 is allowed to always deliver.

[0223] As the second fluid connection is a synchronous connection, the conditions of the transfer module 2 are less complex. The upstream bioprocessing unit is C2, which is a bind-elute capture step, and which delivers its output as batches. The downstream bioprocessing unit is C3, which is a conditioning step, and which takes in its input as batches.

[0224] The in-conditions of transfer module 2 are:

[0225] • C3 is in state “Ready to receive”

[0226] • C2 is in state “Ready to deliver”

[0227] The out-conditions of transfer module 2 are:

[0228] • C3 is in state “Ready to receive”

[0229] • C2 is in state “Ready to deliver”

[0230] Since this is a synchronous (direct) transfer, the in- and out-conditions have to be identical to make sure that both C2 and C3 are allowed to continue at the same time.

[0231] The upstream bioprocessing unit of transfer module 3 is C3, which is a conditioning step, and which delivers its output as batches. The downstream bioprocessing unit of transfer module 3 is C4, which is a flow-through polishing step, and which takes its input as batches.

[0232] The in-conditions of transfer module 3 are:

[0233] • The critical maximum volume of the surge vessel has not been reached.

[0234] • C3 is in state “Ready to deliver” The out-conditions of transfer module 3 are:

[0235] At least one batch delivered by C3 is currently present in the surge vessel.

[0236] C4 Is in state “Ready to receive”

[0237] Since C4 is a flow-through step, a specific setup of the “Ready to receive” / ”Ready to deliver” status parameters is needed. Right after setting the state to “Ready to receive” and waiting for permission to continue, the client does not go ahead and load like the other clients but instead sets its state to “Ready to deliver” to make sure that it also can deliver to the subsequent fluid connection before continuing.

[0238] The upstream bioprocessing unit of transfer module 4 is C4, which is a flow-through polishing step that delivers its output as batches. The downstream bioprocessing unit of transfer module 4 is C5, which is a tangential flow filtration step that takes its input as batches.

[0239] The in-conditions of transfer module 5 are:

[0240] • The critical maximum volume of the surge vessel has not been reached.

[0241] • C4 is in state “Ready to deliver”

[0242] Out Conditions:

[0243] • At least eight batches delivered by C4 are currently present in the surge vessel.

[0244] • C5 is in state “Ready to deliver”

[0245] Since C5 needs more fluid to perform TFF than C4 delivers in one batch, it has to wait for eight batches to be delivered from C4 before C5 is given permission to load.

[0246] Generally, the bioprocessing devices run in circle command routes, which are usual command programs programmed by the client control unit via the Unicorn API. Hence, a bioprocessing unit, which is an asynchronous bioprocessing unit e.g. suitable for bint / elute capture chromatography is programmed to pre-conditioning the column, load a sample, run the capture program until the loading of the column has been finished, and eventually washing the loaded column. Now the bioprocessing module reports to the client control module and waits the client control module sends the go command. The client control module, on the other hand, received the go command from the transfer module beforehand. Now, the bioprocessing module carries out the remaining commands of the circle command route, which is eluting the column, and preconditioning the column to be ready for loading. Then, again, it reports to the client control module and waits for the go command to load the next sample. In various embodiments, a process is controlled by allowing transfers between unit operations (e.g. equipment) when pre-defined criteria are fulfilled, and delaying fluid transfers when the criteria are not fulfilled. In a chain of process steps this means that only the process steps that are allowed by the transfer modules / objects are executed. The transfer module algorithm can thus be made agnostic as to the configuration of any upstream and downstream bioprocessing units, and only considers generic parameters relating to the transfer of fluid in the transfer / no transfer decision.

[0247] Such embodiments thus provide a modular way of handling process progression, in which a limited number of transfer objects can take care of liquid flows in almost any process, independent of equipment and product specific operating conditions.

[0248] Advantageously, self-adjusting functionality can thus be provided for bioprocessing operations. Additionally, various embodiments may be used in connected processes, and in single use formats, to avoid errors and prolong the time a connected process set up can be operated.

[0249] A set of standard generic modules may thus be provided that can be used anywhere in a process. Such transfer objects / modules may drive, adjust, and control a process flow based on certain parameters that often (but not always) are generated by hardware used in the process set-up. The final end process can thus be automatically selfcontrolled and run only when the appropriate run criteria are met.

[0250] Various embodiments of the present invention can also be applied to bioprocessing units performing processes both in a cyclical and / or a steady-state manner. This is thus advantageous in that it can be applied to a more general set-up than can various conventional systems.

Claims

Claims:

1. A bioprocessing system, comprising: a central control unit (1), at least two bioprocessing units (2a, 2b), wherein each at least two bioprocessing units (2a, 2b) of the at least two bioprocessing units comprises at least one flow path (3a, 3b) comprising an inlet (4a, 4b) and an outlet (5a, 5b) and wherein at least two selected bioprocessing units of the at least two bioprocessing units are connected in series by a fluid connection (6) of the outlet (5a) of an upstream bioprocessing unit (2a) of the two selected bioprocessing units and the inlet (4b) of a downstream bioprocessing unit (2b) of the two selected bioprocessing units, thereby forming a line of serially connected at least two bioprocessing units, a client control module (7a, 7b) per each at least two bioprocessing units (2a, 2b) of the at least two bioprocessing units, wherein each client control module (7a, 7b) is connected to the central control unit (1) and wherein each client control module (7a, 7b) is configured to interact with the at least two bioprocessing units (2a, 2b) connected to said client control module (7a, 7b), and a transfer module (8) associated with each fluid connection (6) between each of the at least two selected bioprocessing units in the line of serially connected at least two bioprocessing units, wherein each of the transfer modules (8) comprises an upstream set of parameters characterizing the upstream bioprocessing unit (2b) of each fluid connections (6) and a downstream set of parameters characterizing the downstream bioprocessing unit (2b) of each fluid connection (6), wherein the upstream set of parameters comprises at least an upstream status parameter characterizing the status of the upstream bioprocessing unit (2a) and the downstream set of parameters comprises at least a downstream status parameter characterizing the status of the downstream bioprocessing unit (2b); and wherein each of the transfer modules (8) comprises at least one algorithm to compute a decision statement from said upstream set of parameters and / or the downstream set of parameters, wherein the decision statement comprises adjusting the flow rate of the fluid in the fluid connection (6) associated with said transfer module.

2. The bioprocessing system according to claim 2, wherein each of the transfer modules (8) is configured to retrieve data from the connected client control modules (7a, 7b) and to update at least one parameter of the upstream set of parameters characterizing the upstream bioprocessing unit (2a) , which is connected to the fluid connection (6) associated with said transfer module (8), and / or to update at least one parameter of the downstream set of parameters characterizing the downstream bioprocessing unit (2b), which is connected to the fluid connection (6) associated with said transfer module (8).

3. The bioprocessing system according to claims 1 or 2, wherein the transfer module (8) comprises at least one condition used by the at least one algorithm to compute a decision statement from said set of parameters.

4. The bioprocessing system according to any of the preceding claims, wherein the fluid connection (6) comprises a branching (9).

5. The bioprocessing system according to claim 4, wherein the at least two bioprocessing units (2a, 2b) comprise at least three bioprocessing units (2a, 2b, 2c), and wherein the inlet (4b) of the downstream bioprocessing unit (2b) is connected to the outlet (5c) of a second upstream bioprocessing unit (2c) by a second fluid connection (6’) via the branching (9).

6. The bioprocessing system according to any of the preceding claims 4 or 5, wherein the at least two bioprocessing units (2a, 2b) comprise at least three bioprocessing units (2a, 2b, 2c), wherein at least three selected bioprocessing units of the at least three at least two bioprocessing units (2a, 2b, 2c) are connected in series by a first and a second fluid connection (6, 6”) of the inlet (4a, 4b) and the outlet (5b, 5c), thereby forming a line of serially connected at least two bioprocessing units, wherein the at least two bioprocessing units (2a, 2b) comprise at least four at least two bioprocessing units (2a, 2b, 2c, 2d), wherein each of the first and the second connections (6, 6”) comprises a branching (9, 9’), preferably a vent, wherein the branching (9) of the first fluid connection (6) is fluidly connected to the inlet (4d) of a selected fourth bioprocessing unit (2d) of the at least four at least two bioprocessing units (2a, 2b, 2c, 2d) and wherein the branching (9) of the second fluid connection (6”) is fluidly connected to the outlet (5d) of the selected fourth bioprocessing unit (2d) of the at least four at least two bioprocessing units (2a, 2b, 2c, 2d).

7. The bioprocessing system according to preceding claims, wherein each of the at least two bioprocessing units (2a, 2b) comprises at least one pump (11 a, 11 b) andat least one separation device (12a, 12b) connected to the at least one flow path (3a, 3b) of the bioprocessing unit.

8. The bioprocessing system according to claim 7, wherein the at least one separation device (12a, 12b) is selected from the list consisting of a liquid chromatography separation device, a filter, a centrifugal, an extractor, an electrophoresis apparatus, and an acoustic wave separation device, preferably selected from the list consisting of a chromatography separation device and a filter.

9. The bioprocessing system according to claim 8, wherein the liquid chromatography device is selected from the list consisting of liquid-liquid, liquidsolid, and ion exchange chromatography devices, preferably selected from the list consisting of an ion exchange chromatography device, a size exclusion chromatography device, a hydrophobic interaction chromatography device, and an affinity chromatography device.

10. The bioprocessing system according to claims 7 or 8, wherein the liquid chromatography device is selected from the list consisting of a liquid chromatography column and a liquid chromatography membrane.

11. The bioprocessing system according to any of the preceding claims, wherein the central control unit (1) is configured to automatically create and configure the transfer module (8) upon connection of the at least two selected bioprocessing units (2a, 2b) by a fluid connection (6) and connection of each client control (7a, 7b) unit per each of the at least two selected bioprocessing units (2a, 2b) with the central control unit (1).

12. The bioprocessing system according to claim 11 , wherein each client control module (7a, 7b) is configured to provide said set of parameters characterizing the at least two bioprocessing units (2a, 2b) associated with said client control module (7a, 7b), an identification information associated with said at least two bioprocessing units (2a, 2b), and a connection information associated with said fluid connection (6), and wherein the central control unit (1) is configured to create and configure after reception of said set of parameters, said identification information and said connection information the transfer module (8) associated with said fluid connection (6).

13. A bioprocessing unit (2), comprising: an inlet (4),an outlet (5), a client control module (7), configured to be connected to a central control unit (1) and configured to interact with the bioprocessing unit (2), and a set of parameters characterizing the bioprocessing unit (2).

14. A bioprocessing process for separating a target species from a raw fluid mixture, the process comprising the steps of:(A) providing a raw fluid mixture comprising the target species;(B) purifying the raw fluid mixture yielding a fluid volume comprising the target species;(C) collecting the target species from the fluid volume; wherein step (B) comprises at least one series of sets of steps, said set comprising the steps of, providing at least two bioprocessing units (2a, 2b), wherein each bioprocessing unit comprises at least one flow path (3a, 3b) comprising an inlet (4a, 4b) and an outlet (5a, 5b) and wherein at least two selected bioprocessing units of the at least two bioprocessing units (2a, 2b) are connected in series by a fluid connection (6) of the outlet (5a) of an upstream bioprocessing unit (2a) of the two selected bioprocessing units (2a, 2b) and the inlet (4b) of a downstream bioprocessing unit (2b) of the two selected bioprocessing units (2a, 2b), thereby forming a line of serially connected at least two bioprocessing units; introducing an input fluid mixture into the upstream bioprocessing unit (2a); monitoring an upstream set of parameters characterizing said upstream bioprocessing unit (2a), monitoring a downstream set of parameters characterizing said downstream bioprocessing unit (2b), and calculating a decision statement therefrom, wherein the decision statement comprises adjusting the flow rate of the fluid in a fluid connection (6) between said upstream bioprocessing unit (2a) and the downstream bioprocessing unit (2b), depending on the calculated decision statement, adjusting the flow rate of the fluid in the fluid connection (6) between said upstream bioprocessing unit (2a) and said downstream bioprocessing unit (2b), producing upon starting the fluid connection (6) an output fluid volume at the outlet of the downstream bioprocessing unit (2b),transferring the output fluid volume as input fluid volume to a subsequent set of steps of the series of sets of steps directly following the set of steps or, if the set of steps is the last set of steps in the series of sets of steps, as fluid volume to step (C) wherein the input fluid mixture is the raw fluid mixture, if the set of steps is the first set of steps in the series of set of steps.

15. A process for setting up a bioprocessing system, comprising the steps of: providing an upstream bioprocessing unit (2a) comprising an inlet (4a), an outlet (5a), and an upstream set of parameters characterizing said upstream bioprocessing unit (2a); providing an upstream client control module (7a) configured to interact with the upstream bioprocessing unit (2a); providing a downstream bioprocessing unit (2b) comprising an inlet (4b), an outlet (5b), and a downstream set of parameters characterizing said downstream bioprocessing unit (2b) and the status thereof; providing a downstream client control module (7b) configured to interact with the downstream bioprocessing unit (2b); providing a central control unit (1); connecting the outlet (5a) of the upstream bioprocessing unit (2a) to the inlet (4b) of the downstream bioprocessing unit (2b) using a fluid connection (6); connecting the upstream client control module (2a) and the downstream client control module (2b) with the central control unit (1); transferring the upstream set of parameters from the upstream bioprocessing unit (2a) to the upstream client control module (7a); transferring the upstream set of parameters from the upstream client control module (7a) to the central unit (1); transferring the downstream set of parameters from the downstream bioprocessing unit (2b) to the downstream client control module (7b); transferring the downstream set of parameters from the downstream client control module (7b) to the central unit (1); providing a transfer module associated with said fluid connection; andconfiguring the transfer module to comprise at least one algorithm to compute a decision statement from said upstream set of parameters and downstream set of parameters, wherein the decision statement comprises adjusting the flow rate in the, preferably starting or stopping the, fluid connection (6) associated with said transfer module.

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