Biological treatment systems and methods utilizing transfer modules

Abstract

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

Description

TECHNICAL FIELD

[0001] The present invention relates to a biological treatment system, preferably a downstream biological treatment system, utilizing a transfer module and a corresponding biological treatment method. BACKGROUND

[0002] Downstream biological treatment refers to the recovery and purification of biosynthetic products from natural sources such as animal tissue, plant tissue or fermentation broth, thereby recycling the recoverable components from these resources.

[0003] Downstream biological treatment 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 for diagnostic use, industrial enzymes, natural fragrances and flavor compounds.

[0004] It is generally accepted to divide downstream biological treatment into four stages, which apply to the conversion of a product as a component of tissue, cells or fermentation broth from its natural or post-synthetic state into a product in pure form, thereby due to high purity standards, which depend on the further intended use of the product, e.g. medical or analytical. These four stages are generally considered to be removal of insolubles (sometimes also considered as midstream biological treatment), product isolation, product purification and product formulation.

[0005] Removal of insolubles (midstream biological treatment) includes the capture of the product as a solute in a particle-free liquid. Thus, for example, cells, cell fragments or other particulate matter must be separated from the liquid containing the product. Typically, removal of insolubles is achieved by filtration, centrifugation, sedimentation, precipitation, flocculation, electroprecipitation and / or gravity settling. Additional operations required for the recovery of products from solid sources such as plant and animal tissue, such as grinding, homogenization or leaching, are typically included in this group.

[0006] Product isolation includes the removal of components having physical and chemical properties that are significantly different from those of the product. In downstream biological treatment, this mainly includes the removal of water. Product isolation thus reduces the volume of material to be processed and further concentrates the product. Typically, product isolation is achieved by solvent extraction, adsorption, ultrafiltration and / or precipitation.

[0007] Product purification aims at separating the product from components having very close physical and chemical properties. Product purification thus includes high-cost steps that require sensitive and complex equipment. This stage constitutes the main part of the overall downstream biological treatment process. Typical steps for product purification are chromatographic steps (e.g. affinity, size exclusion, hydrophobic interaction, reverse phase, ion exchange) as well as crystallization and fractional precipitation.

[0008] Product formulation describes the final processing steps, typically resulting in a product package that is stable and easy to form. Crystallization, dewatering, lyophilization and spray drying are typical unit operations. Depending on the product and its intended use, product formulation can also include operations to render the product sterile.

[0009] Certain operations combine two or more of the described stages. For example, expanded bed adsorption achieves both removal of insolubles and product separation in a single step. As another example, affinity chromatography can separate and refine in a single step.

[0010] In industrial applications, it is desirable to implement downstream bioprocessing in an efficient and cost-reduced manner. Therefore, processes have been developed that link the above described operational steps, which transfer the product in liquid phase to facilitate the transfer from one step to another. Furthermore, the output of several preceding operational steps can be pooled to a combined input for a subsequent step. This is due to the concentration effect typically achieved by each step. At the beginning of a downstream bioprocessing, the volume of liquid per product is very high, wherein the concentration of the product is significantly increased during the purification process. Therefore, at least a part of the downstream bioprocessing can typically be arranged in a tree-like structure, wherein at the beginning of the downstream bioprocessing many operational units exist in the first step, whereas the number of operational units of the steps downstream of the process typically decreases more and more.

[0011] However, it is also conceivable to design in reverse, wherein the output of an operational step is split, or at least connected to more than one subsequent operational step. This can be used, for example, to provide alternative operational steps in the subsequent operations, i.e. parallel operational steps. Another use case is to speed up typically time-intensive operational steps. Furthermore, it can also be provided to implement a flexible design and to link idle subsequent operational steps with preceding steps that are ready to provide a processed bioprocessing liquid batch.

[0012] It is generally desirable to develop semi-continuous downstream bioprocesses that are able to overcome the disadvantages of batch-driven downstream bioprocessing. Such a design allows for continuous operation within a certain parameter window and thereby enables more efficient and cost-sensitive production.

[0013] The control and automation of bioprocesses is known in the prior art. However, it is mainly directed at upstream processes, as in US 2023 / 077294 A1, US 2022 / 259532 A1, US 2022 / 010261 A1 or EP 3 839 036 A1. Other attempts have been made to automate the parameter optimization process already used in bioprocessing, i.e. also downstream bioprocessing, as seen in US 2021 / 269888 A1, US 2021 / 263482 A1 and US 2019 / 154713 A1. Even the visualization of flow paths in downstream bioprocessing has been implemented, cf. US 2021 / 109490 A1. To the maximum extent possible, the aforementioned documents are hereby further incorporated by reference. SUMMARY

[0014] However, in order to realize a semi-continuous downstream bioprocess that can be remotely or automatically controlled, it is of particular importance to consider certain configurations as set out above, to control the interaction between the operational steps. Such a controlled semi-continuous downstream bioprocess is desirable as it takes downstream bioprocessing to another level of efficiency. None of the prior art cited above addresses this problem.

[0015] It is therefore an object of the present invention to provide a downstream bioprocessing system and / or method that can be run in a semi-continuous manner without relying on the complexity of the method itself and that realizes an improved safety, efficiency and reliability.

[0016] It has now surprisingly been found that this object is achieved by a bioprocessing system comprising a central control unit; at least two bioprocessing units, wherein each 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 an outlet of an upstream bioprocessing unit of the two selected bioprocessing units and an inlet of a downstream bioprocessing unit of the two selected bioprocessing units, thereby forming a line of at least two bioprocessing units connected in series; a client control module for each 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 the client control module; and a transfer module associated with each fluid connection between each of the at least two selected bioprocessing units of the line of at least two bioprocessing units connected in series, wherein each of the transfer modules comprises an upstream parameter set characterizing the upstream bioprocessing unit of each fluid connection and a downstream parameter set characterizing the downstream bioprocessing unit of each fluid connection, wherein the upstream parameter set comprises at least an upstream state parameter characterizing a state of the upstream bioprocessing unit, and the downstream parameter set comprises at least a downstream state parameter characterizing a state of the downstream bioprocessing unit; and wherein each of the transfer modules comprises at least one algorithm to calculate a decision statement from the upstream parameter set and / or the downstream parameter set, wherein the decision statement comprises adjusting a flow rate of a fluid in the fluid connection associated with the transfer module.

[0017] It has further been found that the above object is 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 parameter set characterizing the bioprocessing unit.

[0018] It has further been found that the above objects can be achieved by a bioprocessing method for isolating a target species from a feed fluid mixture, the method comprising the steps of: (A) providing a feed fluid mixture comprising the target species; (B) purifying the feed fluid mixture resulting in 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 step sets, the sets 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 fluidic 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 at least two bioprocessing units connected in series; introducing an input fluid mixture comprising the target species into an upstream bioprocessing unit; monitoring an upstream set of parameters characterizing the upstream bioprocessing unit, monitoring a downstream set of parameters characterizing the downstream bioprocessing unit, and computing therefrom a decision statement, wherein the decision statement comprises adjusting the flow rate of fluid in the fluidic connection between the upstream bioprocessing unit and the downstream bioprocessing unit, adjusting the flow rate of fluid in the fluidic connection between the upstream bioprocessing unit and the downstream bioprocessing unit according to the computed decision statement, generating an output fluid volume at the outlet of the downstream bioprocessing unit upon initiation of the fluidic connection, transferring the output fluid volume as an input fluid volume to a subsequent step set of the series of step sets following the step set, or transferring the output fluid volume as a fluid volume to step (C) if the step set is the last step set of the series of step sets, wherein the input fluid mixture is the feed fluid mixture if the step set is the first step set of the series of step sets.

[0019] It has even further been found that the above objects can be achieved by a method for setting up a bioprocessing system, the method comprising the steps of: providing an upstream bioprocessing unit comprising an inlet, an outlet and a set of upstream parameters characterizing the 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 set of downstream parameters characterizing the downstream bioprocessing unit and its state; 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 with 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 set of upstream parameters from the upstream bioprocessing unit to the upstream client control module; transferring the set of upstream parameters from the upstream client control module to the central unit; transferring the set of downstream parameters from the downstream bioprocessing unit to the downstream client control module; transferring the set of downstream parameters from the downstream client control module to the central unit; providing a transfer module associated with the fluid connection; and configuring the transfer module to comprise at least one algorithm to calculate a decision statement from the set of upstream parameters and the set of downstream parameters, wherein the decision statement comprises adjusting a flow rate in the fluid connection associated with the transfer module.

[0020] An advantage of the present invention is that complex bioprocessing systems and methods can be run with high efficiency and without the need for manual intervention. Furthermore, a bioprocessing system is provided which is able to set itself up in a quasi-independent manner autonomously. BRIEF DESCRIPTION OF DRAWINGS

[0021] Figure 1 Schematic diagram of a bioprocessing system showing one preferred embodiment of the present invention comprising a synchronous fluid connection (6).

[0022] Figure 2 Schematic diagram of a bioprocessing system showing one preferred embodiment of the present invention comprising an asynchronous fluid connection (6) with a balance as a measurement unit (14).

[0023] Figure 3 Schematic diagram of an asynchronous fluid connection (6) wherein the critical maximum volume (16) of the buffer container (15) is smaller than the sum of the critical delivery volume (17) and the reverse critical receiving volume (18).

[0024] Figure 4 Schematic diagram of an asynchronous fluid connection (6) wherein the critical maximum volume (16) of the buffer container (15) is larger than the sum of the critical delivery volume (17) and the reverse critical receiving volume (18).

[0025] Figure 5A schematic diagram of a biological treatment system according to a preferred embodiment of the present invention is shown, which includes a confluence branch (9).

[0026] Figure 6 A schematic diagram of a biological treatment system according to a preferred embodiment of the present invention is shown, which includes a branch line (9).

[0027] Figure 7 A schematic diagram of a biological treatment system according to a preferred embodiment of the present invention is shown, including a branch (9) and a confluence branch (9'), thereby resulting in parallel biological treatment steps.

[0028] Figure 8 A schematic diagram of a biological treatment system according to an embodiment of the present invention is shown.

[0029] definition As the term "as used in this article" Fluid volume This indicates the volume containing the fluid and, preferably, the target class. Preferably, the fluid is a liquid. More preferably, the fluid is a liquid containing a solvent, preferably composed of a solvent. Even more preferably, the solvent is selected from water-based buffer solutions, such as phosphates, acetates, citrates, or tris(hydroxymethyl)aminomethane and mixtures thereof with other solvents such as ethanol. The solvent may contain additives, such as polymers, such as PEG and / or dextran; salts, such as ammonium sulfate, sodium chloride, etc.; detergents; and / or stabilizers. Some affinity stationary phases (membranes or beads) may require more complex mixtures. For example, immobilized metal chelate affinity chromatography (IMAC) requires the addition of organic compounds, such as imidazole.

[0030] As the term "as used in this article" Target species "" indicates the product to be separated. Typically, the target class is a substance that is naturally occurring in animal or plant tissues, produced by naturally occurring microorganisms or enzymes, and / or produced by modified, preferably genetically modified, microorganisms or enzymes. Therefore, the target class can be, but is not limited to, antibodies, proteins, viruses, organic matter, DNA molecules, RNA molecules, shorter nucleotide molecules, exosomes, cells (e.g., cells used in cell therapy), or specific target molecules.

[0031] As the term "as used in this article" Feedstock mixture "" indicates a mixture of various contaminants, solvents, and at least one target class. The mixture may be a natural product, such as animal or plant tissue, which has been contacted with at least one solvent, or a mixture from a bioreactor. Preferably, the feedstock mixture is a mixture from a bioreactor containing microorganisms (e.g., yeast, bacteria, and / or fungi), cells, viruses, tissues, target classes, and / or solvents.

[0032] As the term "as used in this article" Flow pattern"" indicates a chromatographic method in which impurities in a mixture of raw materials bind to a chromatographic matrix while the target class does not bind, thereby separating the target class in a diluent.

[0033] As the term "as used in this article" Binding / elution pattern "This describes a chromatographic method in which target compounds in a feed mixture bind to a chromatographic matrix, while impurities do not bind. Impurities are washed away from the column with a diluent, and the column is subsequently rinsed with an eluent, which removes the target compounds from the column, thereby separating the target compounds in the diluent."

[0034] As the term "as used in this article" Bioprocessing unit "" indicates a unit that receives a fluid volume containing a target class and common contaminants, and outputs a fluid volume containing the target class and a smaller amount of common contaminants. Preferably, the biological processing unit is selected from chromatographic apparatus (including columns and membranes), filters, centrifuges, extraction devices, and two-phase separation devices. In this invention, "" Synchronous bioprocessing unit and" Asynchronous bioprocessing unit The distinction between synchronous and asynchronous biological processing units lies in the time dependence of the input (receiving) and output (delivery) processes. Therefore, a synchronous biological processing unit is one in which the input (receiving) and output (delivery) processes occur substantially simultaneously. Thus, a synchronous biological processing unit is one in which the input process necessarily leads to the output process. Therefore, the target class is continuously delivered through the synchronous biological processing unit during operation. Conversely, in an asynchronous biological processing unit, the input (receiving) and output (delivery) processes occur at different times. Therefore, an asynchronous biological processing unit is one in which the input process does not necessarily lead to the output process. Therefore, the target class is not continuously delivered through the asynchronous biological processing unit during operation. Instead, the asynchronous biological processing unit provides a state in which at least a portion of the target class can be stored for a certain period of time. Examples of synchronous biological processing units are chromatographic apparatuses and filters suitable for flow-through modes. Examples of asynchronous biological processing units are chromatographic apparatuses suitable for binding / elution modes.

[0035] As the term "as used in this article" Fluid connection This indicates a connection between the output of an upstream biological treatment unit and the input of a downstream biological treatment unit. It may also indicate a connection to another fluid connection, thus forming a branch fluid connection. A fluid connection between two or more biological treatment units can be a "..." Synchronous fluid connection "or" Asynchronous fluid connectionThe difference lies in the time dependence of the input process (delivered by the upstream biological processing unit) and the output process (received by the downstream biological processing unit). Therefore, a synchronous fluid connection is a fluid connection in which the input process necessarily leads to the output process. Thus, the target class is continuously transferred via the fluid connection during transfer. Conversely, in an asynchronous fluid connection, the input process (delivered by the upstream biological processing unit) and the output process (received by the downstream biological processing unit) occur at different times. Therefore, an asynchronous fluid connection is a fluid connection in which the input process does not necessarily lead to the output process. Thus, the target class is not continuously transferred via the fluid connection unit during transfer. Instead, an asynchronous fluid connection provides a way to store at least a portion of the state of the target class for a certain period of time. An example of a synchronous fluid connection is a direct connection. An example of an asynchronous fluid connection is a buffered connection, i.e., a buffer container is included in the fluid connection.

[0036] As the term "as used in this article" Offline analysis Offline measurements represent an analytical step in which a sample is taken out of a bioprocessing unit or transfer line under aseptic conditions and analyzed in the laboratory after physical pretreatment (e.g., filtration and dilution). Preferably, preparation and manipulation require well-defined standard operating procedures (SOPs) and skilled personnel. Along with the complexities involved in manual manipulation, a major disadvantage of offline measurements is the time delay, which results in a lower measurement frequency. Due to these issues, offline measurements are generally not considered true PATs (process analytical techniques) unless no other measurement possibilities exist (e.g., HPLC for product titers or mass spectrometry for product quality). Offline laboratory measurements are typically used to monitor and validate the accuracy of in-line / online process analyzers.

[0037] As the term "as used in this article" Nearline analysis "Nearline" indicates an analytical step in which a sample is removed from a biological processing unit or transfer line and analyzed manually or using an automated sampling device near the production process. Similar to offline measurements, aseptic conditions must be maintained for accurate results. Nearline measurements are most commonly used for parameters that cannot be accurately measured in-line or online. Advantages of nearline measurements include reduced time delays (compared to offline) and the possibility of automated control.

[0038] As the terminology used in this article Online analysis This indicates an analytical step in which the sample is diverted from the bioprocessing unit or transfer line via a branch and can be returned to the bioprocessing method after analysis. The sample is measured automatically via process sensors in the bypass. The advantages of this method are evident in its ease of sterilization and direct sample acquisition under fixed conditions. Implementation of such a scheme requires a specifically designed or modified bioprocessing method, particularly the bioprocessing unit and / or transfer line.

[0039] As the term "as used in this article" In-line analysis "" indicates an analytical step in which measurements are performed directly using process sensors within a biological processing unit or transport line. Preferably, the resulting measurements are transmitted to the control system in real time. Process parameters, such as pH, ORP (oxidation-reduction potential), dissolved oxygen, dissolved CO2, temperature, and / or conductivity, are typically measured via in-line analysis. Furthermore, measurements that allow the detection of specific molecules can also be performed via in-line analysis, such as UV / VIS absorbance / transmittance, fluorescence emission, and refractive index.

[0040] As the term "as used in this article" Unique identification This indicates a unique identifier within the address space used to identify the object. Therefore, it ensures that the identifier is never used for two objects within the same address space.

[0041] As used in this specification and the appended claims, the singular form " a "and" an "Also includes the corresponding plural, unless the context clearly indicates otherwise. In the context of this invention, the term " about "and" about "" indicates a range of accuracy that, as will be understood by those skilled in the art, still ensures the technical effect of the features involved. This term typically represents a deviation from a specified value of ±10%, preferably ±8%, more preferably ±5%, and even more preferably ±2%. It should be understood that the term "" comprise "and" include "This is not restrictive. For the purposes of this invention, the term 'composed of' is considered to be the term 'consistent with'." comprise The preferred embodiments of “”. If a set is defined below as comprising at least a certain number of embodiments, this means that it also includes a set preferably consisting only of these embodiments. Furthermore, the term “” in the specification and claims… first "", second "", third "or" (a) "", (b) "", (c) "", (d) "etc." and so on, are used to distinguish similar elements and are not necessarily used to describe order or chronological sequence. It should be understood that such terms are interchangeable where appropriate, and embodiments of the invention described herein can operate in orders other than those described or illustrated herein. The term "..." first "", second "", third "or" (a) "", (b) "", (c) " 、 “(d) "", i In cases involving steps such as “K”, “K”, etc., relating to methods, uses, or assays, there is no temporal continuity or consistent time interval between the steps; that is, the steps may be performed simultaneously or there may be time intervals of several seconds, minutes, hours, days, weeks, months, or even years between the steps, unless otherwise specified in this application as set forth above or below. It should be understood that the invention is not limited to the specific methods, schemes, reagents, etc., described herein, as these are subject to change. It should also be understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to limit the scope of the invention, which is defined only by the appended claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0042] As the term "as used in this article" do not comprise "", do not contain "or" do not contain "In this context, it means that the composition of the invention does not contain a specific compound or a group of compounds that can be combined under a unified term, and that the composition does not contain more than 0.8% by weight of the compound or group of compounds based on the total weight of the composition. Furthermore, it is preferred that the composition according to the invention does not contain more than 0.5% by weight of the compound or group of compounds, and preferably the composition does not contain the compound or group of compounds at all."

[0043] When referring to compositions and the weight percentages of the components contained therein, it should be understood that, according to the invention, the total amount of the components does not exceed 100% (±1% due to rounding). Detailed Implementation

[0044] This invention relates to a downstream biological treatment system and method capable of making autonomous decisions regarding the transfer of fluid volumes between connected biological treatment steps or units. Typically, downstream biological treatment methods are not continuous processes. This is due to the process characteristics defined by the connection of several at least two biological treatment units or steps, which themselves are usually designed to deliver products in batches. Therefore, downstream biological treatment methods are typically arranged in a semi-continuous manner. Thus, products are delivered in fluid volumes from one operating step of the biological treatment method to subsequent operating steps. Consequently, the steps can be directly connected in a 1:1 ratio or in a tree structure, thereby receiving fluid volumes from or delivering fluid volumes to more than one preceding operating step. Furthermore, the connection itself can be synchronous (i.e., direct) or asynchronous, typically including storage containers. Finally, the at least two biological treatment units or steps can also be quasi-synchronous, i.e., in a flow-through mode, or asynchronous, i.e., in a binding / elution mode. Therefore, these requirements lead to complex problems to be solved, the complexity of which increases with the complexity of the system or method used.

[0045] The biological treatment system and biological treatment unit of the present invention are described below, followed by the biological treatment method of the present invention and the method for setting up the biological treatment system of the present invention.

[0046] Bioprocessing system This invention relates to a method in Figure 1 Or, as illustrated in example 2, a downstream biological treatment system, preferably comprising: - Central control unit (1), - At least two biological treatment units (2a, 2b), each of which includes at least one flow path (3a, 3b) including an inlet (4a, 4b) and an outlet (5a, 5b), and wherein at least two selected biological treatment units are connected in series via a fluid connection (6) between the outlet (5a) of the upstream biological treatment unit (2a) and the inlet (4b) of the downstream biological treatment unit (2b), thereby forming a line of biological treatment units connected in series. - A client control module (7a, 7b) for each of the at least two biological processing 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 biological processing units (2a, 2b) connected to the client control module (7a, 7b), and - A transfer module (8) associated with each fluid connection (6) between each of at least two selected biological treatment units in a line of at least two biological treatment units connected in series. Each of the transfer modules (8) includes an upstream parameter set characterizing the upstream bioprocessing unit (2b) of each fluid connection (6) and a downstream parameter set characterizing the downstream bioprocessing unit (2b) of each fluid connection (6), wherein the upstream parameter set includes at least upstream state parameters characterizing the state of the upstream bioprocessing unit (2a), and the downstream parameter set includes at least downstream state parameters characterizing the state of the downstream bioprocessing unit (2b); and Each of the transfer modules (8) contains at least one algorithm to calculate a decision statement from the upstream parameter set and / or downstream parameter set, wherein the decision statement includes adjusting the flow rate of the fluid in the fluid connection (6) associated with the transfer module.

[0047] The central control unit (1) can be any device for receiving, sending, and storing data, and for performing calculations using said data. Therefore, preferably, the central control unit (1) is a computer, preferably a computer connected to a network. However, the central control unit (1) can also be any other electronic device capable of performing the operations described herein. Thus, the operation of the central control unit (1) can be implemented in hardware, such as in electronic circuitry, or implemented in software and configured to run on a computer. In a preferred embodiment of the invention, the central control unit (1) is a dedicated computer, i.e., a server, which is connected via a network to all client control modules (7a, 7b) and / or all bioprocessing units (2a, 2b). In an alternative preferred embodiment of the invention, the central control unit (1) can 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 require a dedicated computer. Alternatively, the central control unit (1) may be provided by at least two connected bioprocessing units (2a, 2b), thus providing a distributed central control unit (1). This embodiment also has the further advantage of not requiring a dedicated computer, but with improved computing power.

[0048] Similarly, the transfer module (8) may be provided in hardware or 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) includes an upstream parameter set characterizing the upstream biological processing unit (2b) of each fluid connection (6) and a downstream parameter set characterizing the downstream biological processing unit (2b) of each fluid connection (6). Thus, the transfer module (8) is associated with the upstream biological processing unit (2a) and the downstream biological processing unit (2b).

[0049] In parallel, the client control modules (7a, 7b) may also be provided in hardware or software. Therefore, preferably, each client control module (7a, 7b) is provided by an associated biological processing unit (2a, 2b). Thus, preferably, the client control modules (7a, 7b) are implemented in software and configured to operate on at least two biological processing units (2a, 2b). However, most preferably, the client control modules (7a, 7b) are implemented in software and configured to operate on a central control unit (1).

[0050] In a particularly preferred embodiment of the invention, the transfer module (8) and each client control module (7a, 7b) are implemented in software and configured to run on a central control unit (1). This has the advantage of using only one computer and centralizing the computing unit. Furthermore, such a unit can run in the cloud, further improving flexibility and stability. In such an embodiment, preferably, each of the at least two biological processing units (2a, 2b) is connected to the central control unit (1), preferably via a network.

[0051] In another particularly preferred embodiment of the invention, each client control module (7a, 7b) operates on a dedicated computer connected to the corresponding biological processing unit (2a, 2b) and to a local network. Thus, one of these dedicated computers also serves as the central control unit (1). This embodiment achieves optimal reliability in the event of a failure of one of the computers.

[0052] Therefore, preferably, at least one of the at least two bioprocessing units (2a, 2b) is suitable for configuration by a user before setting the bioprocessing system by setting at least a portion of a parameter set characterizing the at least two bioprocessing units (2a, 2b). This information can be entered via an input area in the form of a small screen or LCD device combined with buttons, pointing devices, or even a keyboard. Therefore, preferably, the at least two bioprocessing units (2a, 2b) further include an input device suitable for setting at least a portion of the parameter set characterizing the at least two bioprocessing units (2a, 2b) before setting the bioprocessing system, wherein the input device is selected from a touchscreen or touch LCD device, a screen or LCD device combined with buttons, a screen or LCD device combined with pointing devices, or a screen or LCD device combined with a keyboard. Alternatively, the information can be provided by a prepared script, preferably an AI-generated script.

[0053] Preferably, the parameter set characterizing at least two biological processing units (2a, 2b) includes information about the type of the biological processing unit, i.e., whether it is a synchronous or asynchronous biological processing unit. The same applies to the type of the fluid connection (6), which can be synchronous or asynchronous. Specifically, the information about the type of the fluid connection (6) is preferably provided by the user, as defined above.

[0054] Preferably, in the biological processing system according to the invention, each of the transfer modules (8) is configured to retrieve data from a connected client control module (7a, 7b). Furthermore, preferably, in the biological processing system according to the invention, each of the transfer modules (8) is configured to send data to a connected client control module (7a, 7b). Thus, at least one parameter of either the upstream or downstream parameter group is sent or received, i.e., updated. Therefore, preferably, the transfer module (8) is configured to update at least one parameter on the upstream client control module (7a) representing the upstream parameter group of the upstream biological processing unit (2a) connected to the fluid connection (6) associated with the transfer module (8), and / or to update at least one parameter on the downstream client control module (7b) representing the downstream parameter group of the downstream biological processing unit (2b) connected to the fluid connection (6) associated with the transfer module (8). This ensures that the transfer module (8) is suitable for controlling the associated client control modules (7a, 7b). The parameters that can be updated via the transfer module (8) are preferably the status parameters of at least two biological processing units (2a, 2b) of the associated client control modules (7a, 7b). Such status parameters can be… Run Wait "", Fail "or" Wait ",in" Ready to receive "This may include information such as " Ready to deliver "or" RunAlternatively or additionally, it can be the flow rate within at least two biological processing units (2a, 2b) associated with the client control modules (7a, 7b). By updating this state parameter, the transfer module (8) is adapted to start or stop at least two biological processing units (2a, 2b) via its associated client control modules (7a, 7b), or otherwise change their flow rates. Also preferably, the upstream client control module (7a) is configured to update at least one parameter on the transfer module (8) representing the upstream parameter set of the upstream biological processing unit (2a) connected to the fluid connection (6) associated with the transfer module (8), and / or the downstream client control module (7b) is configured to update at least one parameter on the transfer module (8) representing the downstream parameter set of the downstream biological processing unit (2b) connected to the fluid connection (6) associated with the transfer module (8). This ensures that the transfer module (8) is adapted to know the current state of the biological processing units (2a, 2b) of the respective client control modules (7a, 7b).

[0055] Preferably, in the biological processing system according to the invention, each of at least two biological processing units (2a, 2b) is configured to send data to a connected client control module (7a, 7b). Furthermore, preferably, in the biological processing system according to the invention, each of at least two biological processing units (2a, 2b) is configured to send data to a connected client control module (7a, 7b). Preferably, the client control module (7a, 7b) is configured to read at least one parameter from the at least two connected biological processing units (2a, 2b). Furthermore, preferably, the client control module (7a, 7b) is configured to write at least one parameter from the at least two connected biological processing units (2a, 2b).

[0056] Typically, the status parameters of at least two biological processing units (2a, 2b) depend on other measurements available from the at least two biological processing units (2a, 2b), such as flow rate, valve position, column loading / elution status, column breakthrough status, target mass, etc. These parameters are typically measured at the at least two biological processing units (2a, 2b) and transmitted to the client control module (7a, 7b). Therefore, preferably, the at least two biological processing units (2a, 2b) are configured to measure and transmit these measurement parameters to the connected client control module (7a, 7b). Preferably, the measurement parameters are selected from flow rate, valve position, column loading / elution status, column breakthrough, target mass, and mixtures thereof. The status of the biological processing unit can be obtained based on these measurement parameters. For example, if the binding / elution chromatography apparatus reaches full column loading, it will stop processing and reach " Run"Status, with additional information" Wait If at least one algorithm of the transfer module (8) computes such a decision statement (which is further explained below), the transfer module (8) may then set the state to "". Fail "Or otherwise notify the client control modules (7a, 7b) to resume processing. The client control modules (7a, 7b) will then set appropriate parameters for at least two biological processing units (2a, 2b) to allow them to continue processing. However, in another embodiment of the invention, the corresponding calculation of the state parameters from the measured values ​​does not occur within the client control modules (7a, 7b), but has already occurred in at least two biological processing units (2a, 2b) or even in the transfer module (8). However, it is preferred that at least one upstream state parameter characterizing the state of the upstream biological processing unit (2a) and at least one downstream state parameter characterizing the state of the downstream biological processing unit (2b) are in the client control modules (7a, 7b)." The upstream biological treatment unit (2a) is configured to measure upstream state parameters and the downstream biological treatment unit (2b) is configured to measure downstream state parameters, the upstream client control module (7a) is configured to measure upstream state parameters and the client control module (7b) is configured to measure downstream state parameters, or the transfer module (8) is configured to measure both upstream and downstream state parameters. However, it is more preferable that the upstream client control module (7a) is configured to measure upstream state parameters and the client control module (7b) is configured to measure downstream state parameters.

[0057] Preferably, the upstream parameter set includes at least one parameter selected from the volumetric flow rate of the upstream biological treatment unit (2a), the critical volume of the upstream biological treatment unit (2a), and the product quality of the upstream biological treatment unit (2a), and / or the downstream parameter set includes at least one parameter selected from the volumetric flow rate of the downstream biological treatment unit (2b), the critical volume of the downstream biological treatment unit (2b), and the product quality of the downstream biological treatment unit (2b). Generally, it is sufficient for each parameter set to include the corresponding state parameters of the associated at least two biological treatment units (2a, 2b) if the transfer module should only be able to decide whether to start or stop at least two biological treatment units (2a, 2b) through the client control module (7a, 7b). In such a case, the transfer module (8) only needs to know the current state of at least two biological treatment units (2a, 2b). As mentioned above, the state parameter can be " Wait "", Ready to receive "or" Ready to deliver ",in" Figure 3 "This may include information such as " Figure 3 Figure 3 "or" Figure 3However, in the case that the transfer module (8) should be able to regulate the flow rate of at least two biological processing units (2a, 2b), the current flow rate within at least two biological processing units (2a, 2b) needs to be available to the transfer module (8).

[0058] If one of the at least two biological treatment units (2a, 2b) is an asynchronous biological treatment unit, it may be advantageous to know the critical volume of the asynchronous biological treatment unit. If the fluid connection (6) of the biological treatment system according to the invention is an asynchronous fluid connection, it preferably includes a buffer container (15). Preferably, the buffer container (15) has at least one measuring unit (14).

[0059] The filling state of the buffer container (15) should not exceed the critical maximum volume (16), otherwise target loss is foreseeable. Furthermore, if the filling state of the buffer container (15) is below the critical delivery volume (17), the downstream bioprocessing unit (2b) cannot be started, as the buffer container (15) may operate dry during the operation of the downstream bioprocessing unit (2b). If the filling state of the buffer container (15) is above the critical delivery volume (17), the downstream bioprocessing unit (2b) can be started (see reference). Figure 3 (I) Furthermore, if the filling state of the buffer container (15) is higher than the critical receiving volume (18), the upstream biological processing unit (2a) cannot be started, because otherwise the critical maximum volume (16) of the buffer container (15) may be exceeded during the operation of the upstream biological processing unit (2a). Finally, if the filling state of the buffer container (15) is lower than the critical receiving volume (18), the upstream biological processing unit (2a) can be started (see reference). Figure 3 (III)). Therefore, according to Figure 4 In the preferred embodiment of the invention (where the critical delivery volume (17) is greater than the critical receiving volume (18)), the buffer container (15) includes a volume in which the upstream biological processing unit (2a) can be started but the downstream biological processing unit (2b) cannot be started (see reference). Figure 4 (III)), where the volume in which the downstream biological treatment unit (2b) can be started but the upstream biological treatment unit (2a) cannot be started (refer to) Figure 4 (I)), where these two volumes do not overlap, and the volumes in which neither the upstream nor downstream biological treatment units (2a, 2b) can be activated (see reference). Figure 4 Similarly, according to (II)). Wait In another preferred embodiment of the invention (where the critical delivery volume (17) is less than the critical receiving volume (18)), the buffer container (15) includes a volume in which the upstream biological processing unit (2a) can be activated but the downstream biological processing unit (2b) cannot be activated (see reference).Ready to deliver (VI)), where the volume in which the downstream biological treatment unit (2b) can be started but the upstream biological treatment unit (2a) cannot be started (see reference). Wait (IV)), wherein the two volumes do not overlap, and the volumes in which both upstream and downstream biological treatment units (2a, 2b) can be activated (see reference). Ready to receive ,(V)).

[0060] In another preferred embodiment of the invention, the critical delivery volume (17) and critical receiving volume (18) of the buffer container can be dynamically adjusted according to the flow rate from the upstream biological processing unit (2a) or the flow rate to the downstream biological processing unit (2b). Therefore, when the flow rate from the upstream biological processing unit (2a) is higher than the flow rate to the downstream biological processing unit (2b), the critical receiving volume (18) can be reduced. Similarly, when the flow rate from the upstream biological processing unit (2a) is lower than the flow rate to the downstream biological processing unit (2b), the critical delivery volume (17) can be reduced.

[0061] The measuring unit (14) of the fluidly connected buffer container (15) is preferably configured to communicate with at least one of the at least two biological processing units (2a, 2b), the client control module (7a, 7b), or the transfer module (8). Preferably, the measuring unit (14) of the fluidly connected buffer container (15) is configured to communicate with the 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 measuring unit (14) of the fluidly connected buffer container (15) to the corresponding parameter group, and most preferably, the upstream client control module (7a) is configured to add the value provided by the measuring unit (14) of the fluidly connected buffer container (15) to the upstream parameter group.

[0062] Preferably, the measuring unit (14) of the buffer container (15) is selected from a balance, a float, an input batch counter, a light barrier, and a level sensor. Preferably, the level sensor is selected from a vibration point sensor, a rotating blade sensor, an admittance sensor, a magnetic float sensor, a mechanical float sensor, a pneumatic sensor, a conductivity sensor, a state-dependent frequency sensor, an ultrasonic sensor, a capacitive sensor, an optical sensor, and a microwave sensor.

[0063] The transfer module (8) includes at least one algorithm to calculate a decision statement from the upstream parameter set and / or downstream parameter set, wherein the decision statement includes adjusting the flow rate of fluid in the fluid connection (6) associated with the transfer module. Preferably, the upstream parameter set includes upstream state parameters of the biological treatment unit (2a), and / or the downstream parameter set includes downstream state parameters of the biological treatment unit (2b), and the transfer module (8) is configured to calculate the decision statement from the upstream parameter set and / or downstream parameter set using at least one algorithm, wherein the decision statement includes starting or stopping the fluid connection (6) associated with the transfer module (8).

[0064] Preferably, the upstream parameter set includes upstream state parameters of the biological treatment unit (2a) and / or upstream flow rate of the biological treatment unit (2a), and / or the downstream parameter set includes downstream state parameters of the biological treatment unit (2b) and / or downstream flow rate of the biological treatment unit (2b), and the transfer module (8) is configured to calculate a decision statement from the upstream parameter set and / or downstream parameter set by at least one algorithm, wherein the decision statement includes adjusting the flow rate of the fluid in the fluid connection (6) associated with the transfer module (8).

[0065] The initiation or termination of the fluid connection (6) depends on the type of fluid connection (6), i.e., whether it is a synchronous or asynchronous connection. Preferably, the fluid connection (6) is an asynchronous connection, and initiating or terminating the fluid connection (6) involves initiating an upstream biological treatment unit (2a), initiating a downstream biological treatment unit (2b), or initiating at least two upstream and downstream biological treatment units (2a, 2b). Furthermore, preferably, the fluid connection (6) is a synchronous connection, and initiating or terminating the fluid connection (6) involves initiating at least two upstream and downstream biological treatment units (2a, 2b), preferably simultaneously initiating at least two upstream and downstream biological treatment units (2a, 2b).

[0066] In the biological processing system according to the invention, the transfer module (8) preferably includes at least one condition used by at least one algorithm to calculate a decision statement from the parameter set. Preferably, the at least one condition includes at least one input condition for a parameter of the upstream parameter set and / or at least one output condition for a parameter of the downstream parameter set. Even more preferably, at least one input condition includes a condition for an upstream state parameter and / or at least one output condition includes a condition for a downstream state parameter.

[0067] Preferably, at least one condition is provided to the transfer module at creation time. Therefore, the transfer module (8) is preferably configured to receive at least one condition at creation time. In an alternative embodiment of the invention, the transfer module (8) is selected from a pre-selected list of transfer modules, each having several predefined conditions. Alternatively and preferably, the conditions are provided by client control modules (7a, 7b) connected to the transfer module (8). Therefore, most preferably, the upstream client control module (7a) is configured to send at least one input condition to the transfer module (8) and / or the downstream control module (7b) is configured to send at least one output condition to the transfer module (8). Thus, preferably, the input condition is part of an upstream parameter set and / or the output condition is part of a downstream parameter set.

[0068] Preferably, the input conditions include the upstream state parameter of the upstream biological treatment unit (2a) being " Wait "and" Ready to deliver Wait The condition is "". Furthermore, preferably, the output condition includes the downstream state parameter of the downstream biological treatment unit (2b) being "". Ready to receive Wait "and" Ready to deliver The condition is as follows: Most preferably, the fluid connection (6) is a synchronous connection, and the input condition includes the upstream state parameter of the upstream biological treatment unit (2a). Wait "and" Ready to receive The condition is "" and the output condition includes the downstream state parameter of the downstream biological treatment unit (2b) is "". Wait "and" Ready to deliver "Conditions.

[0069] In an alternative preferred embodiment, the input conditions include the upstream state parameter of the upstream biological treatment unit (2a) being " Wait "and" Ready to receive The conditions include the condition that the buffer container (15) is filled to a level below the critical receiving volume (18). In another alternative preferred embodiment, the output conditions include the downstream state parameter of the downstream biological processing unit (2b) being " Wait "and" Ready to deliver " Wait Conditions, and the condition that the filling state of the buffer container (15) is higher than the critical delivery volume (17). More preferably, in an alternative preferred embodiment, the fluid connection (6) is an asynchronous fluid connection, and the input condition includes the upstream state parameter of the upstream biological processing unit (2a) being " Ready to receive "and" Figure 5The conditions include the condition that the buffer container (15) is filled below the critical receiving volume (18). More preferably, in an alternative preferred embodiment, the fluid connection (6) is an asynchronous fluid connection, and the output condition includes the downstream state parameter of the downstream biological processing unit (2b) being " Figure 6 Figure 7 "and" Bioprocessing unit The conditions for “” and the conditions for the filling state of the buffer container (15) to be higher than the critical delivery volume (17).

[0070] As previously mentioned, biological treatment methods, particularly downstream biological treatment methods, are typically not linear processes but rather involve branching. Branching can be applied in a tree-like structure, where there are more preceding biological treatment steps than subsequent ones. This can be implemented to achieve faster concentration of target classes. Furthermore, branching can be used to implement parallel steps of the same type. This can be advantageous for accelerating time-intensive steps or providing redundancy in the production system. Another advantage of parallel steps of the same type is the ability to dynamically adjust capacity. For example, if a volume happens to have a high product content, it can be redirected to a larger column (if it exists as a parallel step). Similarly, if a volume has a low product content, it can be redirected to a smaller column (if it exists as a parallel step). Branching can also be implemented as an interconnection of multiple production lines. In such a case, if a biological treatment unit in one of the multiple production lines fails, the volume produced before the failed biological treatment unit can be redirected to one or more parallel production lines.

[0071] Therefore, preferably, in the biological treatment system according to the invention, the fluid connection (6) includes at least one branch (9). The branch can be selected from a valve (i.e., a two-way valve) having at least two outlets, a connector (i.e., a Y-type connector) having at least two outlets, and a buffer container. Most preferably, the branch is a vent with at least two outlets, preferably a Y-type vent. The advantage of the vent is that it can open or close the branch. Therefore, most preferably, the branch is an electrically driven vent. Most preferably, the electrically driven vent is connected to at least two biological treatment units (2a, 2b), a client control module (7a, 7b), and / or a transfer module (8). The branch (9) can be configured as an outlet or an inlet, or both.

[0072] In a preferred embodiment of the invention, branch (9) leads to analysis unit (10), preferably an offline analysis unit. This embodiment has the advantage that the system can control the quality of intermediate products without interfering with production.

[0073] According to Bioprocessing methodIn another preferred embodiment of the invention, at least two biological processing units (2a, 2b) comprise at least three biological processing units (2a, 2b, 2c), and the inlet (4b) of the downstream biological processing unit (2b) is connected via a second fluid connection (6'), preferably via a branch (9) of the fluid connection (6) to the outlet (5c) of the second upstream biological processing unit (2c). This embodiment allows the flow paths of target classes to be merged into a single downstream biological processing unit.

[0074] According to Wait In another preferred embodiment of the invention, at least two biological processing units (2a, 2b) comprise at least three biological processing units (2a, 2b, 2c), and wherein the outlet (5a) of the upstream biological processing unit (2a) is connected via a second fluid connection (6''), preferably via a branch (9) of the fluid connection (6) to the inlet (4c) of the second downstream biological processing unit (2c). This embodiment allows for the splitting of the flow path of the target class to enter at least one more downstream biological processing unit.

[0075] Similarly, according to Ready to deliver In another preferred embodiment of the invention, at least two biological treatment units (2a, 2b) comprise at least four biological treatment units (2a, 2b, 2c, 2d), wherein at least three selected of the at least four biological treatment units (2a, 2b, 2c, 2d) are connected in series via first and second fluid connections (6, 6''') at inlets (4a, 4b) and outlets (5b, 5c), thereby forming a line of biological treatment units (2a, 2b, 2c) connected in series, wherein each of the first and second connections (6, 6''') comprises a branch (9, 9'), wherein the branch (9) of the first fluid connection (6) is connected via a fluid connection (6') to the at least four biological treatment units (2a, 2b, 2c, 2d). The inlet (4d) of the selected fourth biological processing unit (2d) in 2d) is fluidly connected, and a branch (9') of the second fluid connection (6''') is fluidly connected via the fluid connection (6'') to the outlet (5d) of the selected fourth biological processing unit (2d) among the at least four biological processing units (2a, 2b, 2c, 2d). This implementation enables the parallelization of the biological processing steps (i.e., 2b and 2c). Therefore, time-intensive operations can be accelerated, and / or redundancy can be improved.

[0076] At least two biological processing units (2a, 2b) are devices that receive a fluid volume containing a target class and general contaminants and output a fluid volume containing the target class and a smaller amount of general contaminants. Each of the at least two biological processing units (2a, 2b) includes an inlet (4a, 4b) and an outlet (5a, 5b) and a flow path (3a, 3b) connecting the inlet (4a, 4b) and the outlet (5a, 5b). Preferably, the at least two biological processing units (2a, 2b) are selected from chromatographic devices (including columns and membranes), filters, centrifuges, extraction devices, and two-phase separation devices. Preferably, each of the at least two biological processing units (2a, 2b) includes at least one pump (11a, 11b) and at least one separation device (12a, 12b) connected to at least one flow path (3a, 3b) of the biological processing unit.

[0077] In a preferred embodiment of the invention, the at least one separation device (12a, 12b) is selected from liquid chromatography separation devices, filters, centrifuges, extractors, electrophoresis apparatus, and acoustic separation devices, preferably selected from chromatographic separation devices and filters. Preferably, at least one of the at least two biological processing units (2a, 2b) includes more than one separation device (12a, 12b), preferably at least three separation devices. Compared to a biological processing unit with only one separation device, such an embodiment achieves higher efficiency and loading capacity.

[0078] Preferably, the at least one separation device (12a, 12b) is a liquid chromatography device. More preferably, the liquid chromatography device is selected from liquid-liquid, liquid-solid, and ion-exchange chromatography devices, and more preferably from ion-exchange chromatography devices, size exclusion chromatography devices, hydrophobic interaction chromatography devices, and affinity chromatography devices. Preferably, the liquid chromatography device is selected from liquid chromatography columns and liquid chromatography membranes. Generally, ideally, at least one of the at least two biological treatment units (2a, 2b) includes at least two liquid chromatography devices (12, 12'), preferably liquid chromatography columns.

[0079] Preferably, in the biological processing system according to the invention, at least one of the at least two biological processing units (2a, 2b) includes at least one analytical unit (13a, 13b). Such a unit has the advantage of not requiring an external analytical unit and easily maintaining the state parameters of the associated biological processing units (2a, 2b). Preferably, the analytical unit (13a, 13b) includes at least one detector selected from ultraviolet absorption (UV) detectors, visible light absorption (VIS) detectors, photodiode array (PDA) detectors, refractive index detectors, evaporative light scattering detectors, multi-angle light scattering detectors, mass spectrometers, conductivity detectors, fluorescence detectors, chemiluminescence detectors, optical rotation detectors, and electrochemical detectors. More preferably, the analytical unit (13a, 13b) is an in-line analytical unit, an online analytical unit, or a near-line analytical unit. Further preferably, the analytical unit (13) is configured to send measured values ​​to a client control module (7a, 7b) of the biological processing unit (2a, 2b). This allows for real-time control of the state of the biological processing unit and the target class.

[0080] In a particularly preferred embodiment of the biological processing system according to the invention, the central control unit (1) is configured to automatically create and configure the transfer module (8) when at least two selected biological processing units (2a, 2b) are connected via fluid connections (6) and each client control (7a, 7b) unit connecting each of the at least two selected biological processing units (2a, 2b) is connected to the central control unit (1). Therefore, based on information received by the central control unit (1) regarding the at least two biological processing units (2a, 2b), particularly parameters characterizing the upstream biological processing unit (2b) and parameters characterizing the downstream biological processing unit (2a), the central control unit (1) is able to negotiate conditions and / or algorithms for the transfer module (8). Thus, the central control unit (1) typically operates the main module (1a), which controls the transfer module (8) and the client control modules (7a, 7b). This implementation has the advantage that setting up the biological processing system does not require sophisticated knowledge of setting up the transfer module. Therefore, the setup process of setting up the biological processing system of the invention is significantly facilitated.

[0081] Preferably, each client control module (7a, 7b) is configured to provide a set of parameters characterizing at least two biological processing units (2a, 2b) associated with the client control module (7a, 7b), identification information associated with the at least two biological processing units (2a, 2b), and connection information associated with the fluid connection (6), wherein the central control unit (1) is configured to create and configure a transfer module (8) associated with the fluid connection (6) after receiving the set of parameters, the identification information, and the connection information. Preferably, the identification information includes a unique identifier. More preferably, the connection information includes a unique identifier.

[0082] The following lists biological processing units for certain operations, which are preferably used in the biological processing system of the present invention.

[0083] Preferred biological treatment units include those suitable for performing common steps in biological treatment (preferably downstream biological treatment), such as dilution, pH adjustment, conductivity adjustment, addition, concentration, bioload degradation, and their mixing.

[0084] Furthermore, the preferred biological processing unit of the biological processing system according to the present invention is a biological processing unit suitable for cell harvesting (preferably by depth filtration, forward flow filtration, tangential flow filtration, continuous centrifugation, extraction, and mixing thereof).

[0085] Biological processing devices suitable for cell destruction (chemical or physical methods) are also preferred.

[0086] A further preferred biological treatment unit of the biological treatment system according to the invention is a biological treatment unit suitable for clarification (preferably by depth filtration, forward flow filtration, tangential flow filtration, continuous centrifugation, aseptic filtration, such as 0.2 µm filtration with a sterile filter, extraction, and the mixing thereof).

[0087] Other preferred biological processing units of the biological processing system according to the invention are biological processing units suitable for capture (preferably by gel chromatography, membrane chromatography, extraction, adsorption, and mixing thereof).

[0088] A further preferred biological processing unit of the biological processing system according to the invention is a biological processing unit suitable for intermediate purification / refining (preferably by gel chromatography, membrane chromatography, adsorption, and mixing thereof).

[0089] Furthermore, the preferred biological treatment unit of the biological treatment system according to the present invention is a biological treatment unit suitable for purification (preferably by gel chromatography, membrane chromatography, charged filtration, tangential flow filtration, and the mixing thereof).

[0090] Other preferred biological processing units of the biological processing system according to the invention are biological processing units suitable for formulations (preferably by gel chromatography, tangential flow filtration, ultrafiltration, and mixtures thereof).

[0091] A further preferred biological treatment unit of the biological treatment system according to the invention is a biological treatment unit suitable for virus filtration (preferably by nanofiltration).

[0092] Finally, a further preferred biological treatment unit of the biological treatment system according to the invention is a biological treatment unit suitable for virus inactivation (preferably by chemical treatment or heating).

[0093] Particularly preferred embodiments of the biological treatment system are described in detail below. Although the following description is intended to depict certain biological treatment units and combinations thereof used, it should be understood that each embodiment described below contains all the features of the most general embodiment described above, even if these features are not explicitly described below.

[0094] In a first particularly preferred embodiment, at least two biological processing units (2a, 2b) comprise at least six biological processing units, which are described below and preferably connected in series in the order provided below. It should be further understood that this embodiment is not limited to the actual number of biological processing units. Therefore, some of the biological processing units provided herein may exist more than once in the biological processing system, thus forming a tree structure and / or parallel biological processing units.

[0095] Generally, a first particularly preferred embodiment of the biological processing system of the present invention relates to monoclonal antibody (mAb) purification, and therefore to a system suitable for removing host cell proteins (HCP), DNA, and other contaminants while maintaining product integrity. It is important to effectively remove aggregates that may be highly toxic and reduce the therapeutic efficacy of the mAb.

[0096] Therefore, the first biological treatment unit of the biological treatment system according to the first particularly preferred embodiment of the present invention is a biological treatment unit suitable for clarification, such as a depth filtration biological treatment unit, a forward flow filtration biological treatment unit, or a continuous centrifugal biological treatment unit.

[0097] Furthermore, the second biological processing unit of the biological processing system according to the first particularly preferred embodiment of the present invention is a biological processing unit suitable for affinity capture, such as an affinity chromatography biological processing unit (e.g., Cytiva MabSelectSure or MabSelect PrismA resin or any other protein A-based resin) or an affinity membrane biological processing unit (e.g., Sartorius Sartobind Rapid A affinity membrane or any other protein A-based membrane).

[0098] Furthermore, the third biological treatment unit of the biological treatment system according to the first particularly preferred embodiment of the present invention is a biological treatment unit suitable for regulation, such as a virus inactivation biological treatment unit or a pH / conductivity regulation biological treatment unit.

[0099] The fourth biological processing unit of the biological processing system according to the first particularly preferred embodiment of the invention is a biological processing unit suitable for purification, such as a multi-mode chromatography biological processing unit (e.g., Cytiva Capto adhere or Capto adhere ImpRes), anion exchange chromatography (AIEX) biological processing unit (e.g., Cytiva Capto Q resin), or anion exchange membrane biological processing unit (e.g., Pall Mustang Q).

[0100] Furthermore, the fifth biological treatment unit of the biological treatment system according to the first particularly preferred embodiment of the present invention is a biological treatment unit suitable for tangential flow filtration.

[0101] Finally, the sixth biological treatment unit of the biological treatment system according to the first particularly preferred embodiment of the present invention is a biological treatment unit suitable for sterile filtration, such as a 0.2 µm filtration biological treatment unit with a sterile-grade filter.

[0102] In biological processing systems and therefore the biological processing methods defined by such systems, the affinity capture biological processing unit / process step and the purification biological processing unit / process step are the two most important steps. The first step provides concentration of mAb molecules, while the second step operates in flow-through mode (mAbs pass through the column without binding; only impurities, such as aggregates, HCPs, or DNA, bind).

[0103] In a second particularly preferred embodiment, at least two biological processing units (2a, 2b) comprise at least eight biological processing units, which are described below and preferably connected in series in the order provided below. It should be further understood that this embodiment is not limited to the actual number of biological processing units. Therefore, some of the biological processing units provided herein may exist more than once in the biological processing system, thus forming a tree structure and / or parallel biological processing units.

[0104] Generally, a second particularly preferred embodiment of the biological processing system of the present invention relates to adeno-associated virus (AAV) purification.

[0105] The first biological processing unit of the biological processing system according to a second particularly preferred embodiment of the present invention is a biological processing unit suitable for cell lysis nucleases.

[0106] Therefore, the second biological treatment unit of the biological treatment system according to the second particularly preferred embodiment of the present invention is a biological treatment unit suitable for clarification, such as a depth filtration biological treatment unit, a forward flow filtration biological treatment unit, or a continuous centrifugal biological treatment unit.

[0107] Furthermore, the third biological treatment unit of the biological treatment system according to the second particularly preferred embodiment of the present invention is a biological treatment unit suitable for tangential flow filtration.

[0108] Furthermore, the fourth biological processing unit of the biological processing system according to the second particularly preferred embodiment of the present invention is a biological processing unit suitable for affinity capture, such as an affinity chromatography biological processing unit (e.g., Cytiva Capto AVB resin, Thermofisher Poros Capture Select AAVX resin) or a cation exchange chromatography (CIEX) biological processing unit.

[0109] The fifth biological treatment unit of the biological treatment system according to the second particularly preferred embodiment of the present invention is a biological treatment unit suitable for dilution.

[0110] The sixth biological treatment unit of the biological treatment system according to the second particularly preferred embodiment of the invention is a biological treatment unit suitable for AIEX purification, such as an anion exchange chromatography (AIEX) biological treatment unit (e.g., CytivaCapto Q resin).

[0111] Furthermore, the seventh biological treatment unit of the biological treatment system according to the second particularly preferred embodiment of the present invention is a biological treatment unit suitable for tangential flow filtration.

[0112] Finally, the eighth biological treatment unit of the biological treatment system according to the second particularly preferred embodiment of the present invention is a biological treatment unit suitable for sterile filtration, such as a 0.2 µm filtration biological treatment unit with a sterile-grade filter.

[0113] In the biological processing system and thus the biological processing method defined by it, the affinity capture biological processing unit / process step and the AIEX purification biological processing unit / process step are the two most important steps. The first step provides the concentration of AAV, while the second step provides the efficient separation of intact and empty adeno-associated virus capsids (viral particles without the viral genome).

[0114] In a third particularly preferred embodiment, at least two biological processing units (2a, 2b) comprise at least seven biological processing units, which are described below and preferably connected in series in the order provided below. It should be further understood that this embodiment is not limited to the actual number of biological processing units. Therefore, some of the biological processing units provided herein may exist more than once in the biological processing system, thus forming a tree structure and / or parallel biological processing units.

[0115] Generally, a third particularly preferred embodiment of the biological processing system of the present invention relates to adenovirus (AdV) purification. Adenoviruses are used as viral vectors for gene therapy or vaccines, as well as as oncolytic viruses. Due to this wide range of applications, the volume of adenovirus production can vary significantly. Therefore, there is a growing interest in scalable platforms for industrial adenovirus production.

[0116] The first biological processing unit of the biological processing system according to a third particularly preferred embodiment of the invention is a biological processing unit suitable for cell lysis nucleases. This biological processing unit is preferably suitable for a process in which adenovirus is released from infected cells (upstream culture) and the cellular DNA is cleaved into smaller fragments using benzonase.

[0117] Therefore, the second biological treatment unit of the biological treatment system according to the third particularly preferred embodiment of the present invention is a biological treatment unit suitable for clarification, such as a depth filtration biological treatment unit, a forward flow filtration biological treatment unit, or a continuous centrifugal biological treatment unit.

[0118] Furthermore, the third biological treatment unit of the biological treatment system according to the third particularly preferred embodiment of the present invention is a biological treatment unit suitable for tangential flow filtration.

[0119] The fourth biological processing unit of the biological processing system according to the third particularly preferred embodiment of the invention is a biological processing unit suitable for capture, such as an anion exchange chromatography (AIEX) biological processing unit in binding / elution mode (e.g., Cytiva Q Sepharose XL or Cytiva Capto Q ImpRes).

[0120] Furthermore, the fifth biological processing unit of the biological processing system according to the third particularly preferred embodiment of the invention is a biological processing unit suitable for purification, such as a size exclusion chromatography biological processing unit (e.g., Cytiva Sepharose4 Fast Flow) or a multi-mode chromatography biological processing unit (e.g., Cytiva Capto Core 700).

[0121] Furthermore, the sixth biological treatment unit of the biological treatment system according to the third particularly preferred embodiment of the present invention is a biological treatment unit suitable for tangential flow filtration.

[0122] Finally, the seventh biological treatment unit of the biological treatment system according to the third particularly preferred embodiment of the present invention is a biological treatment unit suitable for sterile filtration, such as a 0.2 µm filtration biological treatment unit with a sterile-grade filter.

[0123] In a biological treatment system and thus a biological treatment method defined by such a system, the capture biological treatment unit / process step and the purification biological treatment unit / process step are the two most important steps. In the first step, negatively charged adenoviruses bind to AIEX resin, while in the second step they flow through chromatographic resin.

[0124] In a fourth particularly preferred embodiment, at least two biological processing units (2a, 2b) comprise at least seven biological processing units, which are described below and preferably connected in series in the order provided below. It should be further understood that this embodiment is not limited to the actual number of biological processing units. Therefore, some of the biological processing units provided herein may exist more than once in the biological processing system, thus forming a tree structure and / or parallel biological processing units.

[0125] Generally, a fourth particularly preferred embodiment of the biological processing system of the present invention relates to lentiviral (LV) purification. Lentiviral viruses (LVs) are enveloped RNA viruses belonging to the Retroviridae family, with a particle size of ~80-100 nm. LVs are among the most efficient gene transfer vectors and integrate RNA into the host cell's DNA. LVs are commonly used in chimeric antigen receptor (CAR) T-cell therapy for the successful treatment of cancer. Purification of lentiviral vectors is very challenging due to the low stability of these enveloped viruses (sensitive to, for example, low pH, high salt, temperature, and shear forces).

[0126] The first biological processing unit of the biological processing system according to the fourth particularly preferred embodiment of the present invention is a biological processing unit suitable for harvesting nucleases.

[0127] Therefore, the second biological treatment unit of the biological treatment system according to the fourth particularly preferred embodiment of the present invention is a biological treatment unit suitable for clarification, such as a depth filtration biological treatment unit, a forward flow filtration biological treatment unit, or a continuous centrifugal biological treatment unit.

[0128] Furthermore, the third biological treatment unit of the biological treatment system according to the fourth particularly preferred embodiment of the present invention is a biological treatment unit suitable for tangential flow filtration.

[0129] The fourth biological processing unit of the biological processing system according to the fourth particularly preferred embodiment of the invention is a biological processing unit suitable for + / - capture, such as an anion exchange chromatography (AIEX) biological processing unit in binding / elution mode (e.g., Cytiva Capto DEAE resin, Pall Mustang Q membrane).

[0130] Furthermore, the fifth biological processing unit of the biological processing system according to the fourth particularly preferred embodiment of the invention is a biological processing unit suitable for purification, such as a multi-mode chromatography biological processing unit (e.g., Cytiva Capto Core700 resin).

[0131] Furthermore, the sixth biological treatment unit of the biological treatment system according to the fourth particularly preferred embodiment of the present invention is a biological treatment unit suitable for tangential flow filtration.

[0132] Finally, the seventh biological treatment unit of the biological treatment system according to the fourth particularly preferred embodiment of the present invention is a biological treatment unit suitable for sterile filtration, such as a 0.2 µm filtration biological treatment unit with a sterile-grade filter.

[0133] In a biological processing system and thus the biological processing method defined by such a system, the capture biological processing unit / process step and the purification biological processing unit / process step are the two most important steps. In the first step, LV concentration and efficient purification of viral particles are achieved, while in the second step, which operates in flow-through mode, the virus does not bind to the chromatographic resin, only impurities bind.

[0134] In a fifth particularly preferred embodiment, at least two biological processing units (2a, 2b) comprise at least five biological processing units, which are described below and preferably connected in series in the order provided below. It should be further understood that this embodiment is not limited to the actual number of biological processing units. Therefore, some of the biological processing units provided herein may exist more than once in the biological processing system, thus forming a tree structure and / or parallel biological processing units.

[0135] Generally, a fifth particularly preferred embodiment of the bioprocessing system of the present invention relates to exosome purification. Exosomes are a class of cell-derived integrities originating from extracellular vesicles and typically have a diameter of 30-150 nm. Encased in a lipid bilayer, exosomes are released into an extracellular environment containing complex cargoes of contents derived from the original cell, including proteins, lipids, mRNA, miRNA, and DNA. These naturally assembled nanovesicles can be therapeutically targeted or modified into drug delivery systems.

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

[0137] The second biological processing unit of the biological processing system according to the fifth particularly preferred embodiment of the invention is a biological processing unit suitable for chromatographic purification, such as a multi-mode chromatographic biological processing unit (e.g., Cytiva Capto Core700 resin) or a size exclusion chromatographic biological processing unit (e.g., Cytiva Sephacryl S-400 HR).

[0138] Furthermore, the third biological processing unit of the biological processing system according to the fifth particularly preferred embodiment of the present invention is a biological processing unit suitable for chromatographic purification, such as an ion exchange chromatography biological processing unit (e.g., Cytiva CaptoQ, Cytiva FibroQ, or Pall MustangQ).

[0139] Furthermore, the fourth biological treatment unit of the biological treatment system according to the fifth particularly preferred embodiment of the present invention is a biological treatment unit suitable for tangential flow filtration.

[0140] Finally, the fifth biological treatment unit of the biological treatment system according to the fifth particularly preferred embodiment of the present invention is a biological treatment unit suitable for sterile filtration, such as a 0.2 µm filtration biological treatment unit with a sterile-grade filter.

[0141] In the biological processing system and thus the biological processing method defined by such system, two chromatographic purification biological processing units / process steps are the two most important steps. In the first step, exosomes flow through beads, while smaller particles / impurities enter the pores within the beads. Furthermore, preferably, the ion-exchange chromatographic biological processing unit uses an anion exchanger operating in a binding / elution mode.

[0142] In a sixth particularly preferred embodiment, at least two biological processing units (2a, 2b) comprise at least nine biological processing units, which are described below and preferably connected in series in the order provided below. It should be further understood that this embodiment is not limited to the actual number of biological processing units. Therefore, some of the biological processing units provided herein may exist more than once in the biological processing system, thus forming a tree structure and / or parallel biological processing units.

[0143] Generally, a sixth particularly preferred embodiment of the biological processing system of the present invention relates to plasmid DNA (pDNA) purification. Plasmids are small extrachromosomal DNA molecules within cells that are physically separate from chromosomal DNA and can replicate independently. They most commonly exist in bacteria as small circular double-stranded DNA molecules. While chromosomes are large and contain all the essential genetic information for survival under normal conditions, plasmids are typically small and contain only additional genes that can be used in certain situations or conditions. Artificial plasmids are widely used as vectors in molecular cloning and, in principle, in the cell and gene therapy industry. For example, they are used to generate mRNA or AAV used in gene therapy.

[0144] The first biological treatment unit of the biological treatment system according to a sixth particularly preferred embodiment of the invention is a biological treatment unit suitable for cell lysis and flocculation. In this biological treatment unit / step, bacteria (Escherichia coli) are destroyed to extract plasmids and flocculate cell debris.

[0145] Therefore, the second biological treatment unit of the biological treatment system according to the sixth particularly preferred embodiment of the present invention is a biological treatment unit suitable for clarification, such as a depth filtration biological treatment unit, a forward flow filtration biological treatment unit, or a continuous centrifugal biological treatment unit.

[0146] Furthermore, the third biological treatment unit of the biological treatment system according to the sixth particularly preferred embodiment of the present invention is a biological treatment unit suitable for tangential flow filtration.

[0147] The fourth biological treatment unit of the biological treatment system according to the sixth particularly preferred embodiment of the present invention is a biological treatment unit suitable for forward flow filtration.

[0148] Furthermore, the fifth biological processing unit of the biological processing system according to the sixth particularly preferred embodiment of the present invention is a biological processing unit suitable for chromatographic purification, such as a size exclusion chromatography biological processing unit (e.g., CytivaSepharose 6 FF).

[0149] The sixth biological processing unit of the biological processing system according to the sixth particularly preferred embodiment of the invention is a biological processing unit suitable for chromatographic purification (e.g., Cytiva Plasmid Select Xtra or Capto Plasmid Select).

[0150] The seventh biological processing unit of the biological processing system according to the sixth particularly preferred embodiment of the invention is a biological processing unit suitable for AIEX purification, such as an anion exchange chromatography (AIEX) biological processing unit (e.g., CytivaSource 30 Q).

[0151] Furthermore, the eighth biological treatment unit of the biological treatment system according to the sixth particularly preferred embodiment of the present invention is a biological treatment unit suitable for tangential flow filtration.

[0152] Finally, the ninth biological treatment unit of the biological treatment system according to the sixth particularly preferred embodiment of the present invention is a biological treatment unit suitable for sterile filtration, such as a 0.2 µm filtration biological treatment unit with a sterile-grade filter.

[0153] The biological processing system and the biological processing method defined therethrough comprise three chromatographic steps: size exclusion chromatography, removal of open-ring (OC) pDNA, and anion exchange chromatography. In size exclusion chromatography, large pDNA flows through beads, while smaller RNA enters the pores within the beads. In the OC pDNA removal step, OC and SC (supercoiled) pDNA conformations are selectively eluted, while AIEX purification is used to finely purify SC pDNA in a binding-elution mode.

[0154] In a seventh particularly preferred embodiment, at least two biological processing units (2a, 2b) comprise at least eight biological processing units, which are described below and preferably connected in series in the order provided below. It should be further understood that this embodiment is not limited to the actual number of biological processing units. Therefore, some of the biological processing units provided herein may exist more than once in the biological processing system, thus forming a tree structure and / or parallel biological processing units.

[0155] Generally speaking, a seventh particularly preferred embodiment of the biological processing system of the present invention is an alternative method involving plasmid DNA (pDNA) purification.

[0156] The first biological treatment unit of the biological treatment system according to a seventh particularly preferred embodiment of the invention is a biological treatment unit suitable for cell lysis and flocculation. In this biological treatment unit / step, bacteria (Escherichia coli) are destroyed to extract plasmids and flocculate cell debris.

[0157] Therefore, the second biological treatment unit of the biological treatment system according to the seventh particularly preferred embodiment of the present invention is a biological treatment unit suitable for clarification, such as a depth filtration biological treatment unit, a forward flow filtration biological treatment unit, or a continuous centrifugal biological treatment unit.

[0158] Furthermore, the third biological treatment unit of the biological treatment system according to the seventh particularly preferred embodiment of the present invention is a biological treatment unit suitable for tangential flow filtration.

[0159] The fourth biological treatment unit of the biological treatment system according to the seventh particularly preferred embodiment of the present invention is a biological treatment unit suitable for forward flow filtration.

[0160] Furthermore, the fifth biological processing unit of the biological processing system according to the seventh particularly preferred embodiment of the present invention is a biological processing unit suitable for chromatographic purification, such as an anion exchange membrane biological processing unit in a binding / elution mode (e.g., Pall Mustang Q XT140).

[0161] The sixth biological processing unit of the biological processing system according to the seventh particularly preferred embodiment of the invention is a biological processing unit suitable for chromatographic purification (e.g., Cytiva Plasmid Select Xtra or Capto Plasmid Select).

[0162] Furthermore, the seventh biological treatment unit of the biological treatment system according to the seventh particularly preferred embodiment of the present invention is a biological treatment unit suitable for tangential flow filtration.

[0163] Finally, the eighth biological treatment unit of the biological treatment system according to the seventh particularly preferred embodiment of the present invention is a biological treatment unit suitable for sterile filtration, such as a 0.2 µm filtration biological treatment unit with a sterile-grade filter.

[0164] The biological treatment system and the biological treatment method defined by it consist of only two chromatographic steps: AIEX chromatography and removal of OC pDNA. Anion exchange chromatography uses a charged membrane instead of chromatographic resin and normally follows the classic OC pDNA removal step as in the preceding process.

[0165] In an eighth particularly preferred embodiment, at least two biological processing units (2a, 2b) comprise at least six biological processing units, which are described below and preferably connected in series in the order provided below. It should be further understood that this embodiment is not limited to the actual number of biological processing units. Therefore, some of the biological processing units provided herein may exist more than once in the biological processing system, thus forming a tree structure and / or parallel biological processing units.

[0166] Generally, an eighth particularly preferred embodiment of the bioprocessing system of the present invention relates to messenger RNA (mRNA) purification. Messenger RNA is a single-stranded nucleic acid transcribed from DNA. When used as a preventative vaccine or therapeutic agent, mRNA is typically delivered to the cytoplasm of a cell, where it directs the production of protein-based antigens. By mimicking the behavior of natural mRNA, therapeutic mRNA utilizes the cell as a natural “bioreactor” to produce clinically relevant proteins, thereby avoiding some of the challenges associated with protein-based therapeutics.

[0167] The upstream bioprocessing unit is a bioprocessing unit suitable for in vitro transcription, namely a stirred tank bioreactor. Here, mRNA is produced by incubating a DNA template with RNA polymerase (typically T7-RNA polymerase) and nucleotides (NTPs) during cell-free in vitro transcription (IVT).

[0168] The first biological treatment unit of the biological treatment system according to the eighth particularly preferred embodiment of the present invention is a biological treatment unit suitable for tangential flow filtration.

[0169] Furthermore, the second biological processing unit of the biological processing system according to the eighth particularly preferred embodiment of the present invention is a biological processing unit suitable for affinity capture, such as an affinity chromatography biological processing unit (e.g., a highly specific chromatography resin or membrane based on oligo-DT ligands).

[0170] The third biological treatment unit of the biological treatment system according to the eighth particularly preferred embodiment of the present invention is a biological treatment unit suitable for tangential flow filtration.

[0171] The fourth biological processing unit of the biological processing system according to the eighth particularly preferred embodiment of the invention is a biological processing unit suitable for purification, such as a multi-mode chromatography biological processing unit (e.g., Cytiva Capto Core 700 resin) or a hydrophobic interaction chromatography (HIC) biological processing unit (e.g., Cytiva Butyl Sepharose 4 FastFlow).

[0172] Furthermore, the fifth biological treatment unit of the biological treatment system according to the eighth particularly preferred embodiment of the present invention is a biological treatment unit suitable for tangential flow filtration.

[0173] Finally, the sixth biological processing unit of the biological processing system according to the eighth particularly preferred embodiment of the present invention is a biological processing unit suitable for encapsulating purified mRNA in liquid nanoparticles.

[0174] In a ninth particularly preferred embodiment, at least two biological processing units (2a, 2b) comprise at least five biological processing units, which are described below and preferably connected in series in the order provided below. It should be further understood that this embodiment is not limited to the actual number of biological processing units. Therefore, some of the biological processing units provided herein may exist more than once in the biological processing system, thus forming a tree structure and / or parallel biological processing units.

[0175] Generally, a ninth particularly preferred embodiment of the biological processing system of the present invention relates to oligonucleotide synthesis. DNA oligonucleotides can be prepared chemically using a fully automated oligonucleotide synthesizer such as the Cytiva ÄKTA oligosynt. However, the resulting oligonucleotide molecules require purification procedures to achieve the product quality required for pharmaceutical / therapeutic uses.

[0176] Therefore, the upstream bioprocessing unit is a suitable bioprocessing unit for oligonucleotide synthesis.

[0177] The first biological treatment unit of the biological treatment system according to the ninth particularly preferred embodiment of the invention is a biological treatment unit suitable for pyrolysis and protection. Preferably, the first biological treatment unit of the biological treatment system according to the ninth particularly preferred embodiment of the invention is suitable for ester hydrolysis of the connector and simultaneous removal of product from the solid carrier, both of which are performed by treatment with concentrated ammonia.

[0178] Furthermore, the second biological treatment unit of the biological treatment system according to the ninth particularly preferred embodiment of the present invention is a biological treatment unit suitable for both normal flow filtration (NFF) and tangential flow filtration (TFF) to remove solids and to concentrate and buffer substances.

[0179] The third biological treatment unit of the biological treatment system according to the ninth particularly preferred embodiment of the invention is a biological treatment unit suitable for purification, such as an anion exchange chromatography (AIEX) biological treatment unit (e.g., Cytiva CaptoQ resin).

[0180] The fourth biological treatment unit of the biological treatment system according to the ninth particularly preferred embodiment of the invention is a biological treatment unit suitable for desalination and concentration, namely size exclusion chromatography (for small scale) (e.g., Sephacryl S-300HR) or tangential flow filtration (for large scale).

[0181] The fourth biological processing unit of the biological processing system according to the ninth particularly preferred embodiment of the invention is a biological processing unit suitable for purification, such as a multi-mode chromatography biological processing unit (e.g., Cytiva Capto Core 700 resin) or a hydrophobic interaction chromatography (HIC) biological processing unit (e.g., Cytiva Butyl Sepharose 4 FastFlow).

[0182] Finally, the fifth biological treatment unit of the biological treatment system according to the ninth particularly preferred embodiment of the present invention is a biological treatment unit suitable for sterile filtration, such as a 0.2 µm filter with a sterile-grade filter.

[0183] In an alternative embodiment of the ninth particularly preferred embodiment of the invention, there are two more biological processing units preceding the third biological processing unit, wherein the first of the two biological processing units is suitable for chromatographic purification (i.e., HIC or RPC), and the second of the two biological processing units is suitable for detrimethylation (acidic pH).

[0184] A key element of this alternative embodiment of the ninth particularly preferred embodiment of the invention is that the hydrophobic triphenylmethyl protecting group (DMTr) is retained after the upstream biological treatment unit and used as a handle for purification by hydrophobic interaction chromatography (HIC) (e.g., Cytiva Phenil Sepharose 6 FF) or reversed-phase chromatography (RPC) (e.g., Cytiva Source30 RPC). The triphenylmethyl group is then readily removed by lowering the pH using a strong acid solution. The purification step is then performed using conventional anion exchange chromatography resins.

[0185] Wait The present invention further relates to a biological treatment unit (2), comprising - Entrance (4), - Exports (5), - A client control module (7), configured to connect to the central control unit (1) and configured to interact with the biological processing unit (2), and - A set of parameters characterizing the biological treatment unit (2).

[0186] Preferably, the parameter set includes at least one parameter selected from the volumetric flow rate of the biological treatment unit (2), the critical volume of the biological treatment unit (2), and the product quality of the biological treatment unit (2). This embodiment allows the biological treatment system according to the invention to adjust the flow rate of the fluid connection (6) via the transfer module (8). Furthermore, it allows asynchronous fluid connection and improves product quality.

[0187] Preferably, the biological treatment unit (2) includes at least one pump (11) and at least one separation device (12) connected to at least one flow path of the biological treatment unit (2).

[0188] The biological treatment unit (2) is a device that receives a fluid volume containing a target class and general contaminants and outputs a fluid volume containing the target class and a relatively small amount of general contaminants. The biological treatment unit (2) includes an inlet (4) and an outlet (5) and a flow path (3) connecting the inlet (4) and the outlet (5). Preferably, the biological treatment unit (2) is selected from chromatographic apparatus (including columns and membranes), filters, centrifuges, extraction devices, and two-phase separation devices. Preferably, the biological treatment unit (2) includes at least one pump (11) and at least one separation device (12) connected to the flow path (3) of the biological treatment unit.

[0189] In a preferred embodiment of the invention, at least one separation device (12) is selected from liquid chromatography separation devices, filters, centrifuges, extractors, electrophoresis apparatus, and acoustic separation devices, preferably selected from chromatographic separation devices and filters. Preferably, the biological processing unit (2) includes more than one separation device (12, 12'), preferably at least three separation devices. Such an embodiment achieves higher efficiency and loading capacity compared to a biological processing unit with only one separation device.

[0190] Preferably, at least one separation device (12, 12') is a liquid chromatography device. More preferably, the liquid chromatography device is selected from liquid-liquid, liquid-solid, and ion-exchange chromatography devices, and more preferably from ion-exchange chromatography devices, size exclusion chromatography devices, hydrophobic interaction chromatography devices, and affinity chromatography devices. Preferably, the liquid chromatography device is selected from liquid chromatography columns and liquid chromatography membranes. Generally, ideally, the biological treatment unit (2) includes at least two liquid chromatography devices (12, 12'), preferably liquid chromatography columns.

[0191] Preferably, in the biological processing system according to the invention, the biological processing unit (2) includes at least one analytical unit (13). Such a unit has the advantage of not requiring an external analytical unit and being able to easily maintain the state parameters of the biological processing unit (2). Preferably, the analytical unit (13) includes at least one detector selected from ultraviolet absorption (UV) detectors, visible light absorption (VIS) detectors, photodiode array (PDA) detectors, refractive index detectors, evaporative light scattering detectors, multi-angle light scattering detectors, mass spectrometers, conductivity detectors, fluorescence detectors, chemiluminescence detectors, optical rotation detectors, and electrochemical detectors. More preferably, the analytical unit (13) is an in-line analytical unit, an online analytical unit, or a near-line analytical unit. Further preferably, the analytical unit (13) is configured to send measured values ​​to a client control module (7) of the biological processing unit (2). This allows for real-time control of the state of the biological processing unit and the target class.

[0192] In a particularly preferred embodiment of the invention, the biological processing unit (2) is further configured to provide a set of parameters characterizing the biological processing unit (2), identification information associated with the biological processing unit (2), and connection information associated with the fluid connection (6) to the further connected biological processing unit (2). Preferably, the identification information includes a unique identifier. More preferably, the connection information includes a unique identifier.

[0193] Ready to receive The present invention further relates to a biological treatment method for separating target species from a feed fluid mixture, the method comprising the following steps: (A) Providing a raw material fluid mixture comprising the target class; (B) Purify the raw material fluid mixture to obtain a fluid volume containing the target class; (C) Collect the target class from the fluid volume; Step (B) comprises at least one series of steps, each group containing the following steps: - Provide at least two biological treatment units (2a, 2b), wherein each biological treatment unit includes at least one flow path (3a, 3b) including an inlet (4a, 4b) and an outlet (5a, 5b), and wherein at least two selected biological treatment units of the at least two biological treatment units (2a, 2b) are connected in series via a fluid connection (6) between the outlet (5a) of the upstream biological treatment unit (2a) of the two selected biological treatment units (2a, 2b) and the inlet (4b) of the downstream biological treatment unit (2b) of the two selected biological treatment units (2a, 2b), thereby forming a line (2a, 2b) of at least two biological treatment units connected in series; - Introduce the input fluid mixture containing the target class into the upstream biological treatment unit (2a); - Monitor the upstream parameter set characterizing the upstream biological treatment unit (2a), monitor the downstream parameter set characterizing the downstream biological treatment unit (2b), and calculate a decision statement from therein, wherein the decision statement includes adjusting the flow rate of the fluid in the fluid connection (6) between the upstream biological treatment unit (2a) and the downstream biological treatment unit (2b). - Based on the calculated judgment statement, adjust the flow rate of the fluid in the fluid connection (6) between the upstream biological treatment unit (2a) and the downstream biological treatment unit (2b). - An output fluid volume is generated at the outlet of the downstream biological treatment unit (2b) when the fluid connection (6) is initiated. - The output fluid volume is transferred as the input fluid volume to the next step group immediately following the step group in the series of steps, or, if the step group is the last step group in the series of steps, it is transferred as the fluid volume to step (C). If the step group is the first step group in the series of step groups, then the input fluid mixture is the raw material fluid mixture.

[0194] Preferably, the decision statement includes an upstream decision statement and a downstream decision statement. Therefore, preferably, the decision statement includes statements that cause adjustment of the flow rate of the upstream biological treatment unit (2a) and statements that cause adjustment of the flow rate of the downstream biological treatment unit (2b). Therefore, preferably, the step of adjusting the flow rate of the fluid in the fluid connection (6) includes the step of adjusting the flow rate of the upstream biological treatment unit (2a) based on the upstream decision statement and the step of adjusting the flow rate of the downstream biological treatment unit (2b) based on the downstream decision statement.

[0195] Most preferably, in the method according to the invention, the step of adjusting the flow rate of the biological treatment unit includes starting or stopping the biological treatment unit, preferably comprising thereto.

[0196] Preferably, the upstream parameter set includes at least one parameter selected from the volumetric flow rate of the upstream biological treatment unit (2a) and the product quality of the upstream biological treatment unit (2a), and / or the downstream parameter set includes at least one parameter selected from the volumetric flow rate of the downstream biological treatment unit (2b) and the product quality of the downstream biological treatment unit (2b).

[0197] Preferably, the step of calculating the decision statement includes calculating at least one condition for at least one parameter of the parameter group. More preferably, the step of calculating the upstream decision statement includes calculating at least one input condition for at least one parameter of the upstream parameter group, and / or the step of calculating the downstream decision statement includes calculating at least one output condition for at least one parameter of the downstream parameter group.

[0198] Preferably, at least one input condition includes a reference to a parameter of an upstream parameter group, and / or at least one output condition includes a reference to a parameter of a downstream parameter group. Even more preferably, at least one input condition includes a reference to an upstream state parameter, and / or at least one output condition includes a reference to a downstream state parameter. Thus, preferably, the input condition is part of an upstream parameter group, and / or the output condition is part of a downstream parameter group.

[0199] Preferably, the input conditions include the upstream state parameter of the upstream biological treatment unit (2a) being " Wait "and" Ready to deliver WaitThe condition is "". Furthermore, preferably, the output condition includes the downstream state parameter of the downstream biological treatment unit (2b) being "". Ready to receive Wait "and" Ready to deliver The condition is "". Most preferably, the fluid connection (6) is a synchronous connection, and the input condition includes the upstream state parameter of the upstream biological treatment unit (2a) being "". Wait "and" Ready to receive The condition is "" and the output condition includes the downstream state parameter of the downstream biological treatment unit (2b) is "". Wait "and" Ready to deliver "Conditions.

[0200] In an alternative preferred embodiment, the input conditions include the upstream state parameter of the upstream biological treatment unit (2a) being " Wait "and" Ready to receive The conditions are "" and the filling state of the buffer container (15) is below the critical receiving volume (18). In another alternative preferred embodiment, the output conditions include the downstream state parameter of the downstream biological processing unit (2b) being "". Method for setting up a bioprocessing system "and" Figure 8 The conditions are "" and the filling state of the buffer container (15) is higher than the critical delivery volume (17). More preferably, in an alternative preferred embodiment, the fluid connection (6) is an asynchronous fluid connection, and the input conditions include the upstream state parameter of the upstream biological processing unit (2a) being "". ​ "and" ​ The conditions are "" and the filling state of the buffer container (15) is below the critical receiving volume (18). More preferably, in an alternative preferred embodiment, the fluid connection (6) is an asynchronous fluid connection, and the output conditions include the downstream state parameter of the downstream biological processing unit (2b) being "". ​ "and" ​ ​ The conditions are: "the filling state of the buffer container (15) is higher than the critical delivery volume (17)".

[0201] ​ The present invention further relates to a method for setting up a biological treatment system, the method comprising the following steps: - Provide an upstream biological processing unit (2a) comprising an inlet (4a), an outlet (5a), and an upstream parameter set characterizing the upstream biological processing unit (2a); - An upstream client control module (7a) is provided, which is configured to interact with the upstream biological processing unit (2a); - Provide a downstream biological treatment unit (2b) comprising an inlet (4b), an outlet (5b), and a set of downstream parameters characterizing the downstream biological treatment unit (2b) and its state; - A downstream client control module (7b) is provided, which is configured to interact with the downstream biological processing unit (2b); - Provides a central control unit (1); - Use a fluid connection (6) to connect the outlet (5a) of the upstream biological treatment unit (2a) to the inlet (4b) of the downstream biological treatment unit (2b); - Connect the upstream client control module (2a) and the downstream client control module (2b) to the central control unit (1); - Transfer the upstream parameter set from the upstream biological treatment unit (2a) to the upstream client control module (7a); - Transfer the upstream parameter group from the upstream client control module (7a) to the central unit (1); - Transfer the downstream parameter set from the downstream biological treatment unit (2b) to the downstream client control module (7b); - Transfer the downstream parameter group from the downstream client control module (7b) to the central unit (1); - Provide a transfer module associated with the fluid connection; and - Configure the transfer module to include at least one algorithm to calculate a decision statement from the upstream parameter set and the downstream parameter set, wherein the decision statement includes adjusting the flow rate in the fluid connection (6) associated with the transfer module, preferably starting or stopping the fluid connection (6) associated with the transfer module. Preferably, the central control unit (1) is configured to automatically set the transfer module (8) according to the upstream parameter set and the downstream parameter set. Example

[0202] The invention is further illustrated below with examples. References ​In this embodiment, the biological processing system comprises five different biological processing units connected in series. Biological processing unit C1 is a forward flow filtration unit operating on an ÄKTA Go with a non-standard flow path, connected to biological processing unit C2 via an asynchronous fluid connection containing a buffer container with a balance from Mettler Toledo as the measuring unit. Biological processing unit C2 is a capture chromatography step and operates on an ÄKTA PCC 75 using asynchronous column valve position options, where the column valve positions on the two column valves are not set using positions 1, 2, or 3, but are set individually for each column valve. Therefore, biological processing unit C2 is an asynchronous biological processing unit. C2 is connected to biological processing unit C3 via a synchronous transfer, which is a conditioning biological processing unit and operates on an ÄKTA pure using a non-standard flow path. C3 is connected to C4 via an asynchronous fluid connection. The asynchronous fluid connection contains a batch counter as the measuring unit, where a 1:1 batch ratio should be achieved. C4 is a purification step, i.e., a chromatography step, which achieves final purity and operates on an ÄKTA pure using a non-standard flow path. The biological treatment unit is connected to biological treatment unit C5 via a final asynchronous fluid connection. This asynchronous fluid connection includes a batch counter as the measurement unit, where an 8:1 ratio should be achieved. C5 is a tangential flow filtration biological treatment unit and operates on the ÄKTA Avant using a non-standard flow path.

[0203] Each ÄKTA bioprocessing unit connects to the computer via its Unicorn API (indicated by a rectangular "virtual" label), where the client control modules (clients 1-5) and the main layer containing the transfer modules run as a Python program (ORBIT) on Microsoft Windows. One client control module is associated with each bioprocessing unit. Additionally, one transfer module is associated with each fluid connection. The balance is connected to the computer using a serial port (RS232).

[0204] C1 is a continuous positive flow filtration step, which regulates the flow to the subsequent buffer container based on the liquid level in the beaker, according to a PI regulator implemented in the software on client 1. The PI regulator is designed to maintain a constant volume in the buffer container. C2 is a binding-elution capture step, which extracts material from the beaker in batches. Transfer module 1 manages the transfer between C1 and C2. The input conditions for transfer module 1 are: C1 is in the "Ready to Deliver" status. The output condition of transfer module 1 is: The critical delivery volume in the buffer container has been reached. C2 is in the "Ready to Receive" state. Even as C1 is continuously delivered to the beaker, it still has the same checkpoint as other clients, where it sets its status to "Ready to Deliver" and pauses while waiting for permission to continue. However, as can be seen in the input conditions of transfer module 1, C1 will be immediately allowed to continue when its status is "Ready to Deliver". The flow of C1 will be regulated using a PI regulator based on the level of the buffer container. The PI regulator keeps the buffer container from overflowing, which is why C1 is allowed to continue delivering.

[0205] Because the second fluid connection is synchronous, the conditions of transfer module 2 are less complex. The upstream biological processing unit is C2, which is the binding-elution capture step and delivers its output in batches. The downstream biological processing unit is C3, which is the conditioning step and receives its input in batches.

[0206] The input conditions for transfer module 2 are: C3 is in the "Ready to Receive" status. C2 is in the "Ready to Deliver" status. The output conditions of transfer module 2 are: C3 is in the "Ready to Receive" status. C2 is in the "Ready to Deliver" status. Since this is a synchronous (direct) transfer, the input and output conditions must be the same to ensure that both C2 and C3 are allowed to continue simultaneously.

[0207] The upstream biological processing unit of transfer module 3 is C3, which is the conditioning step and delivers its output in batches. The downstream biological processing unit of transfer module 3 is C4, which is the flow purification step and receives its input in batches.

[0208] The input conditions for transfer module 3 are: The critical maximum volume of the buffer container has not yet been reached. C3 is in the "Ready for Delivery" status. The output conditions of transfer module 3 are: At least one batch delivered by C3 is currently present in the buffer container. C4 is in the "Ready to Receive" status. Because C4 is a flow step, specific settings are required for the "Ready to Receive" / "Ready to Deliver" status parameters. Immediately after setting the status to "Ready to Receive" and waiting for permission to continue, the client will not load directly like other clients, but will instead set its status to "Ready to Deliver" to ensure that it can also deliver to subsequent fluid connections before continuing.

[0209] The upstream biological processing unit of transfer module 4 is C4, which is a flow purification step that delivers its output in batches. The downstream biological processing unit of transfer module 4 is C5, which is a tangential flow filtration step that receives its input in batches.

[0210] The input conditions for transfer module 5 are: The critical maximum volume of the buffer container has not yet been reached. C4 is in the "Ready to Deliver" status. The output condition is: At least eight batches delivered by C4 are currently present in buffer containers. C5 is in the "Ready to Deliver" status. Because C5 requires more fluid for TFF than C4 delivers in a single batch, it must wait for eight batches to be delivered from C4 before C5 can be loaded.

[0211] Generally, the bioprocessing unit operates according to a cyclic instruction route, which is a routine instruction program programmed by the client control unit via the Unicorn API. Therefore, the bioprocessing unit, which is asynchronous, for example suitable for binding / elution capture chromatography, is programmed to pre-condition the column, load the sample, run the capture program until column loading is complete, and finally wash the loaded column. The bioprocessing module then reports to the client control module and waits for a start command. The client control module, on the other hand, receives the start command in advance from the transfer module. The bioprocessing module then executes the remaining instructions of the cyclic instruction route, which prepare the elution column and pre-condition the column for loading. Then again, it reports to the client control module and waits for a start command to load the next sample.

[0212] In various implementations, the process is controlled by allowing transfers between unit operations (e.g., devices) when predefined criteria are met and delaying fluid transfers when criteria are not met. In the process step chain, this means that only process steps permitted by the transfer module / object are executed. The transfer module algorithm is therefore independent of the configuration of any upstream and downstream biological processing units and considers only general parameters related to fluid transfer in the transfer / non-transfer decision.

[0213] Such an implementation thus provides a modular way to manipulate process progress, where a limited number of transfer objects can handle liquid flow in almost any process, regardless of equipment and product-specific operating conditions.

[0214] Advantageously, this provides self-regulation capabilities for biological treatment operations. Furthermore, the various embodiments can be used both during the connection process and in a single-use configuration to avoid errors and extend the setup time for operable connections.

[0215] Therefore, a set of standard, universal modules can be provided, which can be used anywhere in the process. Such transfer objects / modules can drive, regulate, and control process flow based on certain parameters typically (but not always) generated by the hardware used in the process setup. The final process can thus automatically self-control and operate only when appropriate operating criteria are met.

[0216] Various embodiments of the present invention can also be applied to biological processing units that perform processes in both cyclic and / or steady-state modes. Therefore, this is advantageous because it is applicable to more versatile setups than various conventional systems.

Claims

1. A biological treatment system comprising: - Central control unit (1), - At least two biological treatment units (2a, 2b), wherein each of the at least two biological treatment units (2a, 2b) includes at least one flow path (3a, 3b), the flow path including an inlet (4a, 4b) and an outlet (5a, 5b), and wherein the at least two selected biological treatment units are connected in series via a fluid connection (6) between the outlet (5a) of the upstream biological treatment unit (2a) and the inlet (4b) of the downstream biological treatment unit (2b), thereby forming a line of at least two biological treatment units connected in series. - Each of the at least two biological processing units (2a, 2b) has a client control module (7a, 7b), 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 biological processing units (2a, 2b) connected to the client control module (7a, 7b), and - A transfer module (8) associated with each of the at least two selected biological treatment units in a line of at least two biological treatment units connected in series, via a fluid connection (6). Each of the transfer modules (8) includes an upstream parameter set characterizing the upstream biological processing unit (2b) of each fluid connection (6) and a downstream parameter set characterizing the downstream biological processing unit (2b) of each fluid connection (6), wherein the upstream parameter set includes at least an upstream state parameter characterizing the state of the upstream biological processing unit (2a), and the downstream parameter set includes at least a downstream state parameter characterizing the state of the downstream biological processing unit (2b); and Each of the transfer modules (8) includes at least one algorithm to calculate a decision statement from the upstream parameter set and / or downstream parameter set, wherein the decision statement includes adjusting the flow rate of the fluid in the fluid connection (6) associated with the transfer module.

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

3. The biological processing system according to claim 1 or 2, wherein the transfer module (8) includes at least one condition used by the at least one algorithm to calculate a decision statement from the parameter set.

4. The biological treatment system according to any one of the preceding claims, wherein the fluid connection (6) comprises a branch (9).

5. The biological treatment system according to claim 4, wherein the at least two biological treatment units (2a, 2b) comprise at least three biological treatment units (2a, 2b, 2c), and wherein the inlet (4b) of the downstream biological treatment unit (2b) and the outlet (5c) of the second upstream biological treatment unit (2c) are connected via a branch (9) through a second fluid connection (6').

6. The biological treatment system according to any one of claims 4 or 5, wherein the at least two biological treatment units (2a, 2b) comprise at least three biological treatment units (2a, 2b, 2c), wherein at least three selected biological treatment units of the at least three biological treatment units (2a, 2b, 2c) are connected in series via first and second fluid connections (6, 6'') of inlet (4a, 4b) and outlet (5b, 5c) to form a line of at least two biological treatment units connected in series, wherein the at least two biological treatment units (2a, 2b) comprise at least four biological treatment units (2a, 2b, 2c, 2d), wherein each of the first and second connections (6, 6'') comprises a branch (9, 9'), preferably a vent, wherein the branch (9) of the first fluid connection (6) is connected to the at least four biological treatment units (2a, 2b, 2c, 2d). The inlet (4d) of the selected fourth biological treatment unit (2d) in 2d) is fluidly connected, and the branch (9) of the second fluid connection (6'') is fluidly connected to the outlet (5d) of the selected fourth biological treatment unit (2d) in the at least four biological treatment units (2a, 2b, 2c, 2d).

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

8. The biological treatment system according to claim 7, wherein the at least one separation device (12a, 12b) is selected from liquid chromatography separation devices, filters, centrifuges, extractors, electrophoresis apparatus and acoustic separation devices, preferably selected from chromatographic separation devices and filters.

9. The biological treatment system according to claim 8, wherein the liquid chromatography apparatus is selected from liquid-liquid, liquid-solid and ion exchange chromatography apparatuses, preferably selected from ion exchange chromatography apparatuses, size exclusion chromatography apparatuses, hydrophobic interaction chromatography apparatuses and affinity chromatography apparatuses.

10. The biological treatment system according to claim 7 or 8, wherein the liquid chromatography device is selected from liquid chromatography columns and liquid chromatography membranes.

11. The biological treatment system according to any one of the preceding claims, wherein the central control unit (1) is configured to automatically create and configure the transfer module (8) when the at least two selected biological treatment units (2a, 2b) are connected via a fluid connection (6) and each client control (7a, 7b) unit connecting each of the at least two selected biological treatment units (2a, 2b) to the central control unit (1).

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

13. A biological treatment unit (2), comprising: - Entrance (4), - Exports (5), - A client control module (7), configured to connect to the central control unit (1) and to interact with the biological processing unit (2), and - A set of parameters characterizing the biological treatment unit (2).

14. A biological treatment method for separating target species from a feed fluid mixture, the method comprising the following steps: (A) Providing a raw material fluid mixture comprising the target class; (B) Purify the raw material fluid mixture to obtain a fluid volume containing the target class; (C) Collect the target class from the fluid volume; Step (B) comprises at least one series of steps, each group containing the following steps: - Provide at least two biological treatment units (2a, 2b), wherein each biological treatment unit includes at least one flow path (3a, 3b) including an inlet (4a, 4b) and an outlet (5a, 5b), and wherein at least two selected biological treatment units of the at least two biological treatment units (2a, 2b) are connected in series via a fluid connection (6) between the outlet (5a) of the upstream biological treatment unit (2a) of the two selected biological treatment units (2a, 2b) and the inlet (4b) of the downstream biological treatment unit (2b) of the two selected biological treatment units (2a, 2b), thereby forming a line of at least two biological treatment units connected in series; - The input fluid mixture is introduced into the upstream biological treatment unit (2a); - Monitor the upstream parameter set characterizing the upstream biological treatment unit (2a), monitor the downstream parameter set characterizing the downstream biological treatment unit (2b), and calculate a decision statement therefrom, wherein the decision statement includes adjusting the flow rate of the fluid in the fluid connection (6) between the upstream biological treatment unit (2a) and the downstream biological treatment unit (2b). - Based on the calculated judgment statement, adjust the flow rate of the fluid in the fluid connection (6) between the upstream biological treatment unit (2a) and the downstream biological treatment unit (2b). - An output fluid volume is generated at the outlet of the downstream biological treatment unit (2b) when the fluid connection (6) is initiated. - The output fluid volume is transferred as an input fluid volume to the next step group immediately following the step group in the series of step groups, or, if the step group is the last step group in the series of step groups, it is transferred as a fluid volume to step (C). If the step group is the first step group in the series of step groups, then the input fluid mixture is the raw material fluid mixture.

15. A method for setting up a biological treatment system, comprising the following steps: - Provide an upstream biological processing unit (2a) comprising an inlet (4a), an outlet (5a), and an upstream parameter set characterizing the upstream biological processing unit (2a); - An upstream client control module (7a) is provided, which is configured to interact with the upstream biological processing unit (2a); - Provide a downstream biological treatment unit (2b) comprising an inlet (4b), an outlet (5b), and a set of downstream parameters characterizing the downstream biological treatment unit (2b) and its state; - A downstream client control module (7b) is provided, which is configured to interact with the downstream biological processing unit (2b); - Provides a central control unit (1); - Use a fluid connection (6) to connect the outlet (5a) of the upstream biological treatment unit (2a) to the inlet (4b) of the downstream biological treatment unit (2b); - Connect the upstream client control module (2a) and the downstream client control module (2b) to the central control unit (1); - Transfer the upstream parameter set from the upstream biological treatment unit (2a) to the upstream client control module (7a); - Transfer the upstream parameter group from the upstream client control module (7a) to the central unit (1); - Transfer the downstream parameter set from the downstream biological treatment unit (2b) to the downstream client control module (7b); - Transfer the downstream parameter group from the downstream client control module (7b) to the central unit (1); - Provide a transfer module associated with the fluid connection; and - Configure the transfer module to include at least one algorithm to calculate a decision statement from the upstream parameter set and the downstream parameter set, wherein the decision statement includes adjusting the flow rate in the fluid connection (6) associated with the transfer module, preferably starting or stopping the fluid connection (6).

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