Disposable devices for separating or purifying large mixtures of substances

Abstract

A disposable device (10) for separating or purifying a large number of substance mixtures, comprising a plurality of membrane chromatography modules (12) which are fixedly arranged in a predetermined grid. The disposable device (10) also comprises a pipeline system for connecting the membrane chromatography modules (12) and for connecting the membrane chromatography modules (12) to one another. The membrane chromatography modules (12), in particular with respect to the membrane adsorber type, the structural type and / or the structural dimensions, and / or the pipelines of the pipeline system, are preconfigured or preconfigurable for the desired process. A cover device (56) and / or a bottom device (58) can be arranged on the upper side or the lower side of the plurality of membrane chromatography modules (12), which holds the membrane chromatography modules (12) in place in the predetermined grid. At least a part of the pipeline system of the disposable device (10) is formed in the cover device (56) and / or the bottom device (58), wherein connecting pipelines are provided between the membrane chromatography modules (12). In a method for separating or purifying a large amount of a substance mixture using a disposable device (10), the disposable device (10) has a plurality of automatic valves (44) and sensors (48, 50, 52, 56) which are connected to a control unit for controlling the automatic valves (44) based on an evaluation of parameters measured by the sensors (48, 50, 52, 56).

Description

Technical Field

[0001] The invention relates to a disposable device for separating or purifying a large mixture of substances. Background Art

[0002] In general, in the production of pharmaceuticals with high-quality active ingredients, single-use systems are becoming increasingly popular due to the high flexibility they enable and the savings in time, investment, and operational costs, such as cleaning and its validation and inspection. Single-use systems are increasingly desirable for larger scales (mass production processes), but the costs for such systems should not rise to unrealistic levels.

[0003] WO 2017 / 032560 A1 describes a fully pre-sterilizable, fully wired, and fully testable disposable filter device designed for use in a wide range of filtration processes. The device comprises a plurality of disposable filter capsules of standard sizes arranged in a pre-set grid and interconnected by tubing. The filter capsules are supported by a rigid holder. A common air filter can be provided to vent the entire filter capsule unit.

[0004] A preconfigured disposable filter device is known from DE 10 2017 111 133 A1. The filter device comprises a plurality of disposable filter capsules connected to one another by rigid pipes and fixedly mounted in a universally predetermined grid by rigid retaining members. In this filter device, a pressure-stabilized observation window is integrated into the exhaust line between the exhaust port and the sterile air filter, which is provided for exhausting all filter capsules. The observation window allows the operator to see the medium that has risen to the air filter. If the operator detects that water or other medium has risen to the air filter, he or she closes the relevant exhaust valve in the line and, if necessary, takes further measures.

[0005] Known filter devices can be integrated into the filter line of a process arrangement by means of sterile connectors or hose welding or in a non-sterile manner, for example by means of a tri-clamp connection, and are thus "ready to use" after delivery to the user. It is possible to sterilize the filter device before delivery. Summary of the Invention

[0006] The object of the present invention is to simplify the separation or purification of large substance mixtures on the user's side by means of an optimized and flexible disposable device and to design it more safely.

[0007] This object is achieved by a disposable device according to the features of the present invention. Advantageous and expedient embodiments of the disposable device according to the present invention are given in this document.

[0008] The disposable device according to the present invention for separating or purifying a large number of substance mixtures comprises a plurality of membrane chromatography modules fixedly arranged in a predefined grid. The disposable device also comprises a pipeline system for connecting the membrane chromatography modules and for interconnecting the membrane chromatography modules. The membrane chromatography modules, in particular with respect to the membrane adsorber type, the structural type and / or the structural dimensions, and / or the pipelines of the pipeline system, are preconfigured or preconfigurable for the desired process.

[0009] With regard to the areas of application of the disposable device according to the invention, a distinction must be made between small media volumes, as are used, for example, in the laboratory when developing new processes (laboratory scale), and large media volumes, which are used in production processes (production scale). Although it is difficult to draw a clear line between small and large medium volumes, the publication by Stefan Fischer-Frühholz “Membranadsorber-Chromatographische Aufreinigung in neutral dimensions”, GIT Labor-Fachzeitschrift 06 / 2004, pages 603 to 605, GIT Verlag GmbH & Co. KG, Darmstadt, which can be accessed on the Internet at the following address: http: / / microsite.sartorius.com / en / biotechnology / laboratory / products_applications / membrane_adsorbers / literature / pdfs / Fischer-F_2004_MA_Aufreinigung_in_neuen_Dimensionen.pdf, provides some insights into which substance mixture quantities or flow rate ranges are more likely to be relevant for analysis and which quantity or flow rate ranges are more likely to be relevant for production. In principle, however, quantities below one liter generally belong to the laboratory scale, regardless of the respective concrete field of application (vaccines, antibodies, etc.).

[0010] The present invention is based on the following cognition: with the help of suitable measures, a large number of membrane chromatography processes can be simply and still variably performed. Membrane chromatography is used for polishing applications (especially removing viruses, DNA and host cell proteins). Other typical applications are the concentration, purification and desalination of peptides, waste streams and analyte collection, protein purification and sample preparation. A relatively new application area is the purification of viruses in vaccine production. In the membrane chromatography module of the disposable device according to the present invention, a thin, synthetic, porous membrane that can be a single layer or multiple layers is used. The surface of the membrane can be modified in a known manner, for example, with the help of a ligand, so that it can bind to a specific molecule. The membrane can also be formed by a nonwoven material (fiber layer), which is also modified.

[0011] Since a plurality of membrane chromatography modules are fixedly arranged in a preset grid, but the type of membrane chromatography modules and the connection of the lines are preconfigured or preconfigurable, a process that is specific and individually designed with respect to the production scale can be realized with the disposable device according to the invention, with a relatively small space requirement for the disposable device. Due to the preset grid for the modules, the preferably rigid lines of the line system can be very short, minimizing the material and installation costs. The lines can be configured so that only a relatively small dead volume remains. In particular, in the case of a line arrangement with parallel flow into the membrane chromatography modules (parallelization), a uniform inflow can be ensured (this will be discussed in more detail later). When changing the buffer, relatively little backmixing is expected to occur, so that, for example, after cleaning, a smaller amount of flushing medium is sufficient.

[0012] The modularly constructed disposable device can be sealed and packaged as a whole after being equipped with the membrane chromatography module and its connections, and then pre-sterilized (especially by gamma or hot steam sterilization) so that it can be put into operation immediately after delivery to the user without having to add or repair components.

[0013] Preferably, at least some of the membrane chromatography modules are designed as wound modules due to their high packing density and the wide variety of possible combinations. In particular, these wound modules offer the possibility of easily scaling up the process by parallelization.

[0014] It is particularly important in an advantageous embodiment of the disposable device according to the present invention that the disposable device has at least two inlets separated from each other and preferably also has a plurality of outlets assigned to different media. Therefore, it is feasible to provide different media to the module effortlessly, which is particularly advantageous in terms of the process steps of balancing / washing, feeding and eluting. Due to the multiple separate inlets and outlets, it is no longer necessary to flush the pipeline connected to the module. Buffer can enter the module directly. It is not necessary to connect a hose and / or a plastic flange to the valve block upstream. The inlet or outlet can be provided with a connector, which can be directly connected to the buffer tank. It is no longer necessary to connect or disconnect alternately. All of these advantages result in minimal risk, especially with regard to incorrect feeding and undesirable medium mixing or contamination.

[0015] In principle, the membrane chromatography module itself can also have at least two inlets separated from one another and preferably also a plurality of outlets. This configuration of the module can be advantageous, in particular, when the modules are connected in series.

[0016] According to a preferred embodiment of the disposable device according to the present invention, a prefilter is connected upstream of at least one membrane chromatography module, in particular a spiral wound module. The prefilter preferably comprises a pleated filter element. This prefilter is used to remove aggregates or clumps. A pore size of approximately 0.45 μm is recommended.

[0017] At least some of the pipelines of the pipeline system are preferably designed as rigid pipelines. Rigid pipelines, in particular rigid common inlet pipelines and / or rigid common outlet pipelines for a plurality of membrane chromatography modules of a disposable device, can be designed as pressure-stable tubes with a defined diameter. This means that the diameter is not selected arbitrarily and does not change during operation due to material stretching, etc. As a result, a uniform pressure distribution and a uniform flow rate of the medium are generated when flowing into the membrane chromatography module, which is advantageous in particular when using chromatography gel. This is not easy to achieve when connecting the membrane chromatography module to a (thin) hose, because there are usually different hose lengths and different hose diameters, so that their consistency cannot be ensured during operation, especially in the case of high pressure and pressure fluctuations.

[0018] The specific diameter of the rigid tubing for the disposable device according to the invention is selected based on the knowledge and consideration of the typical flow rate of the adsorber and a maximum flow rate of 2.5 m / s (recommended in order to keep pressure losses and shear forces low). If the free cross-sectional area of ​​the supply line is related to the adsorber volume, the free cross-sectional area should be at least 1.5 cm 2 / L of membrane volume, preferably at least 2cm 2 / L. To avoid unnecessary dead volume, this value should not be greater than 5cm 2 / L. The appropriate diameter of the pipe can then be determined based on these specified values.

[0019] Rigid pipes are generally stronger, more pressure-resistant and safer than flexible tubing, meaning they are more fail-safe. Processes can be executed faster because higher operating pressures are possible.

[0020] Furthermore, the use of rigid distribution pipes has the advantage that, due to the common inflow, a smoothing of the flow occurs and pressure surges are reduced.

[0021] Depending on the type and requirements of the process to be performed using the disposable device according to the invention, the membrane chromatography modules can be arranged (connected) in different ways. In principle, the following operating modes are possible: (i) some, preferably all, membrane chromatography modules are fed in parallel (hereinafter referred to as parallelization), (ii) at least one group of modules is fed in parallel with another group of modules, while the modules within this group are fed in sequentially, or (iii) all membrane chromatography modules are fed in sequentially.

[0022] For the evaluation of the measurement results, in the case of parallelization (operating mode (i)), it is important that the sum of the flow paths through the individual membrane chromatography modules is of equal length (path from the inflow port through module 1 to the outflow port = path from the inflow port through module 2 to the outflow port, etc.). If, for example, the path from the inflow port to the module inlet is short in the first module and long in the second, then the path from the outlet to the outflow port must accordingly be long in the first module and short in the second. Only in this way can clearly defined elution peaks with narrow widths be achieved. In this way, premature overloading of the modules is avoided during the feed step.

[0023] Operating modes (ii) and (iii) have the advantage that, in the event of a membrane rupture in one of the membrane chromatography modules, the protein can be collected by the downstream membrane chromatography module. This advantage applies, in principle, to all operating modes in which at least some modules are connected in series. Consequently, the total capacity of the disposable system is better utilized.

[0024] According to a particular aspect of the invention, automatic valve arrangements controlled by a control unit are provided at multiple locations in the pipelines of the pipeline system. At these locations, the flow of the medium flowing through can be specifically released or interrupted in order to achieve different flow paths during the process.

[0025] Additional inlets and outlets are preferably present in the line system at the locations where the valves are provided, thereby making it possible in a simple manner to individually supply a membrane chromatography module or a group of modules with a correspondingly suitable buffer medium.

[0026] For the bind / elute (B / E) operation of the disposable device according to the present invention, it is useful to arrange at least one disposable conductivity sensor and / or pH sensor and / or disposable UV sensor upstream of the inlet and / or downstream of the outlet of a membrane chromatography module or a group of connected membrane chromatography modules. The arrangement of the sensor device upstream and downstream of a membrane chromatography module or a group of modules allows the input and output values ​​of the measured parameters to be compared, thereby, for example, detecting membrane ruptures. Using more complex sensor devices or spectrometers (Raman, FT-IR, UV, fluorescence), the composition of the substance mixture can be analyzed upstream of the inlet and / or downstream of the outlet of a membrane chromatography module or a group of membrane chromatography modules.

[0027] Furthermore, with regard to parameter-dependent control of the operation of the disposable device according to the present invention, at least one disposable pressure sensor and / or disposable flow sensor can be arranged in one of the lines of the pipeline system. For example, the optimal flow rate can be determined in small-scale pilot tests. During actual operation of the disposable device, open-loop or closed-loop control can then be performed using the measured values ​​of the sensors, with the optimal flow rate as the desired value. Furthermore, the pressure sensor can be used to detect overpressure in the system, enabling an emergency shutdown to be initiated immediately. If the disposable device according to the present invention is used in a continuously executed method in which further process steps are performed after or before chromatography, it is important to be able to know the flow rate and, if necessary, set it to an appropriate value. Thus, for example, the volume flow rate can be adapted to upstream and downstream steps.

[0028] A particularly advantageous embodiment of the disposable device according to the present invention is achieved by connecting one or more sensors to a control unit that also controls the automatic valves. This arrangement enables automatic control of the disposable device based on measured operating parameters without manual intervention. Automatic valve control also enables the simultaneous execution of multiple processes or partial processes by connecting the valves so that the pipelines form separate, mutually independent pipeline branches with the associated membrane chromatography modules.

[0029] As already pointed out, the disposable device according to the present invention can form a closed and pre-sterilized unit in the assembled state, which can be stored and transported as a whole. It is therefore possible to deliver a disposable device with a membrane chromatography module that has already been equilibrated in a buffer medium. This saves the user from having to perform additional process steps and prevents possible errors on the user's part. The module can also contain a storage medium, in particular ethanol. This reduces the level of extractables and leachables because it has already been pre-extracted in ethanol. It is also possible to rinse the module before storing it in ethanol, thereby reducing the level of extractables and leachables. Flushing before delivery also makes it possible to perform an integrity test at the manufacturer. When the disposable device is delivered, the medium for stabilizing the membrane, in particular glycerol, contained in the module, if necessary, has already been rinsed out. Therefore, filling is carried out before the rinsing step.

[0030] With regard to the emptying and venting of the membrane chromatography modules used in the disposable device according to the present invention, it is desirable that the membrane chromatography modules be upright in their position of use. This can be achieved, for example, by rigid holders of the disposable device. When all membrane chromatography modules of the device are in the upright position, a central air filter can optionally be provided for venting the entire unit of membrane chromatography modules. This means that all membrane chromatography modules can be vented at a single location. Furthermore, when all membrane chromatography modules are in the upright position, they can all be emptied at the lowest point. A central collection device for venting can be provided at this location.

[0031] A special aspect of the present invention, which is essentially independent of the type of module used (here, membrane chromatography modules), is the provision of a cover and / or base device that is attached to the upper or lower side of a plurality of membrane chromatography modules. The cover and / or base device has a dual function. On the one hand, it holds the membrane chromatography modules in place in a pre-set grid. On the other hand, at least part of the conduit system of the disposable device, with connecting lines between the membrane chromatography modules, is formed in the cover device. This further reduces the space requirement of the disposable device, since separate hoses or pipes can be omitted.

[0032] According to a special embodiment of the cover device and / or the bottom device, the cover device and / or the bottom device have individual sections that are fixedly connected to one another and are each assigned to a membrane chromatography module.

[0033] In addition, the cover device and / or the bottom device, in particular its sections, have interfaces and pipeline sections that can be preconfigured or preconfigured individually. Thus, it is possible to create an individually configured pipeline system from the individual sections, depending on the type of module, wherein each membrane chromatography module is integrated into one or more flow paths in a desired manner. After the corresponding configuration, no additional / external fluid distribution devices or valves are required. More precisely, all required media can be directly connected and directly controlled by the control unit via automatic valves. Thus, additional hoses, valves, etc. that would otherwise be required can be omitted. By predetermining the associated ports for each process medium, the risk of confusion can be significantly reduced.

[0034] One or more sensors or spectroscopic devices can be placed directly on one or more otherwise unused interfaces of the cover device or the base device. No additional lines are required for this, resulting in a very compact structure.

[0035] According to a basic alternative of the present invention, the chromatography module of the disposable device of the present invention can also be filled with chromatography gel or integral chromatography material, and is not filled with chromatography membrane. In particular, all or some modules can comprise highly cross-linked, porous polymethyl methacrylate material, and described material has well-defined channel size distribution. The high surface accessibility of binding site can realize the ability that exceeds resin-based column and can realize rapid mass transfer based on convection. The characteristics of this module are its performance, low back pressure and its diversity that are independent of flow, and this can contribute to faster separation, concentration, purification, removal and analysis of biological material. The integral chromatography material is particularly suitable for the demanding requirements when purifying very large biomolecules, such as viral particles, vesicles, proteins, RNA, plasmids and other forms of DNA.

[0036] As already indicated, the provision of the above-mentioned cover means and / or bottom means is essentially irrelevant whether the disposable device has a membrane chromatography module, a chromatography module filled with gel or monolithic material, or in general a disposable filtration unit, in particular a filter capsule.

[0037] The present invention also provides a method for separating or purifying a large number of substance mixtures using a disposable device according to the present invention, wherein the disposable device comprises a plurality of automated valves and sensors, in particular at least one disposable conductivity sensor, a disposable UV sensor, a disposable pressure sensor, or a disposable flow sensor, which are connected to a control unit. The method according to the present invention provides for controlling the automated valves based on an evaluation of operating parameters measured by the sensors. Automatic valve control is particularly advantageous in bind / elute mode due to the varying process steps.

[0038] Signal threshold values ​​can be predefined for the operating parameters measured by the sensors, so that depending on whether the signal threshold value is exceeded or fallen below, predetermined process steps are executed, for example automatically executing a switching sequence of valves for collecting selected and separated fractions. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Further features and advantages of the present invention will be apparent from the following description and the accompanying drawings to which reference is made. In the accompanying drawings:

[0040] Figure 1 shows a perspective view of a disposable device according to the invention according to a first embodiment;

[0041] Figure 2 A schematic diagram showing a disposable device according to the invention according to a second embodiment without a holder;

[0042] Figure 3 shows a schematic arrangement of components of a disposable device according to the present invention;

[0043] Figure 4 A perspective view showing another disposable device according to the invention according to a third embodiment with a cover device and a bottom device;

[0044] Figure 5 Shown in the first operating mode Figure 4 Disposable devices in

[0045] Figure 6 Shown in the second operating mode Figure 4 Disposable devices in

[0046] Figure 7 In the third operating mode Figure 4 Disposable devices in

[0047] Figure 8 In the fourth operating mode Figure 4 Disposable devices in

[0048] Figure 8a Shows the fourth operating mode Figure 4 flow paths in disposable devices;

[0049] Figure 9 Shown in the fifth operating mode Figure 4 Disposable devices in

[0050] Figure 9a Shows the fifth operating mode Figure 4 A flow path in a cover device of a disposable device. DETAILED DESCRIPTION

[0051] exist Figure 1 A disposable device 10 for separating or purifying a large number of substance mixtures is shown and is described in more detail below. Possible modifications of the device are then explained, in particular with regard to a preferred embodiment as a membrane chromatography device.

[0052] The disposable device 10 comprises a plurality of membrane chromatography modules 12. The membrane chromatography modules 12 are held in an upright position in a pre-set arrangement (grid) by a rigid holder 14 (rack). Figure 1 In the embodiment shown in FIG, six membrane chromatography modules 12 are arranged in a 3×2 grid. Other grids with more or fewer membrane chromatography modules 12 are obviously also possible, with preference being given to an arrangement that is as compact as possible. The holder 14 comprises at least two opposing side walls 16, which are connected to one another by a crossbeam 18. A holding mechanism 20 for each membrane chromatography module 12 is arranged on the crossbeam 18. The holding mechanism 20 is provided with an elastic material. Thus, shock and vibration damping is provided for the membrane chromatography modules 12 during transport and operation of the disposable device 10.

[0053] The membrane chromatography modules 12 are completely or at least largely connected to one another via rigid, pressure-stable pipes 22. The rigid pipes 22 ensure a uniform flow behavior without pressure fluctuations. The direction of the pipes 22 is determined by the operation of the disposable device 10 provided. Figure 1 , a complete parallel connection of six membrane chromatography modules 12 is shown. However, a partial parallel connection or a complete or partial series connection of the membrane chromatography modules 12 can also be provided. The pipeline 22 has the necessary branches 24 leading to the individual membrane chromatography modules 12. In this regard, it is necessary to fasten the pipeline 22 to the holder 14.

[0054] exist Figure 2 , another embodiment of a disposable device 10 according to the invention is schematically shown, but without the associated holder 14. A particular feature of this embodiment is the piping of the membrane chromatography modules 12. Instead of the pipes 22 and branches 24, a rigid, standardized inlet and outlet unit 26 made of plastic is provided. Each membrane chromatography module 12 is provided with its own inlet and outlet unit 26, which has an inlet device 28 and an outlet device 30, which are coordinated with the end-side inlet and outlet connections of the respective membrane chromatography module 12. The inlet device 28 and the outlet device 30 are designed to be identical or at least largely identical.

[0055] A connecting strut or housing wall 32 extends between the inflow device 28 and the outflow device 30 in order to be able to connect these two devices to one another. In the latter case, the membrane chromatography module 12 is surrounded by the completely surrounding housing wall 32 and is thus protected from external influences.

[0056] The inflow device 28 and the outflow device 30 each have two opposite external interfaces 34. A plurality of inflow and outflow units 26 can be connected to each other by suitable connecting components 36, such as a three-clamp connection. Here, the external interface 34 on the inflow side of a membrane chromatography module 12 is connected to the external interface 34 on the inflow side of an adjacent membrane chromatography module 12. Similarly, the external interface 34 on the outflow side of one membrane chromatography module 12 is connected to the external interface 34 on the outflow side of an adjacent membrane chromatography module 12. In any case, a seal is provided between the connections. In this way, any number of membrane chromatography modules 12 can be joined together for parallel inflow. Unnecessary external interfaces 34 are sealed by suitable closures 38. This closure 38 or blind cover is also arranged by means of suitable connecting components 36.

[0057] The inflow and outflow unit 26 can be formed in one piece as a kit or as a prefabricated unit. In particular, a plurality of inflow devices 28 and / or outflow devices 30 can be formed in one piece or preassembled before being mounted on the membrane chromatography module 12 .

[0058] The membrane chromatography module 12 is oriented so that the flow passes through it from bottom to top, which ensures uniform hydrostatic conditions. However, reverse operation is also possible, that is, the flow passes through from top to bottom.

[0059] Shutoff valves can be provided between the membrane chromatography modules 12 to enable targeted blocking of the connection between specific membrane chromatography modules 12. This allows targeted, sterile venting of individual membrane chromatography modules 12 or a group of connected membrane chromatography modules.

[0060] The shutoff valve can also be used for an integrity test, where the adsorption membrane is moistened before any undesired bypass is detected with a test gas. The integrity test is performed on the membrane chromatography module 12 in essentially the same manner as in the filter capsule. The shutoff valve and a common exhaust line with a sterile air filter also make it possible to test a group of modules 12 together. The integrity test can be performed even before the disposable device 10 is delivered, saving the user this effort.

[0061] Most importantly, all valves required for operating the disposable device 10 are preferably located on the same side of the disposable device 10 , which allows for an improved overview and simplified operability.

[0062] The valves or at least parts thereof as well as other devices of the disposable device 10 can be automated, meaning that a programmable control unit (not shown) takes over the control of these components during a process or process step.

[0063] The following describes measures for optimizing the disposable device 10. The membrane chromatography module 12 is preferably a wound module with multiple layers, the bed height of which is preferably 1 mm to 30 mm. For uniform flow through, it is expedient to use membranes from the same batch in the module.

[0064] The connections of the membrane chromatography modules 12 are preconfigured for the desired separation or purification process. Thus, different operating modes can be implemented by correspondingly preconfigured pipeline routes. In particular, the membrane chromatography modules 12 can be fed in serially (sequentially) or in parallel. It is also possible for one or more groups (strips, blocks) of membrane chromatography modules 12 to be fed in parallel, while the modules 12 within a group are fed in sequentially. Due to the pre-set grid, flexible hose or rigid pipe connections can be made very short, which reduces material and installation costs, but also minimizes dead space, i.e., non-functional areas.

[0065] The membrane chromatography modules 12 of the disposable device 10 are all interconnected via common inlet and outlet lines, optionally with branching for parallel operation of the modules. These lines are dead-space-optimized by having a maximum diameter that is compatible with the maximum flow rate and a minimum length required for distribution or merging. In this regard, the line diameter is also kept as small as possible to prevent backmixing.

[0066] Furthermore, at least one common, dead-space-optimized discharge line is provided for the entire disposable device 10, through which the medium to be disposed of can be discharged. However, it is preferred that the cover device and the bottom device for the membrane chromatography module 12 have a plurality of inlets and outlets, which will be described in more detail later.

[0067] Due to the compact, dead-space-optimized design of the disposable device 10 , the volume of the required process medium is reduced to a minimum, so that firstly the costs and expenditure for subsequent treatment steps, which are required due to the use of different process media, are reduced.

[0068] The membrane chromatography modules 12 used in the disposable device 10 can be of different types. This relates in particular to the type of membrane adsorber used in the module 12.

[0069] A prefilter, for example in the form of a filter capsule, can be integrated into the inlet line to the membrane chromatography module or modules 12 . The effective filter surface of the prefilter is significantly smaller than the associated membrane chromatography module or modules 12 .

[0070] The disposable device 10 has at least one, preferably at least two, outlets and preferably at least two inlets. Thus, the module 12 can be operated with at least two, and possibly even with three or more different media, which are fed / discharged alternately or separately (equilibration / washing, loading and elution).

[0071] The inlet and outlet are each provided with a disposable valve (which can be designed as a multi-way valve), a common inlet line, a common outlet line, and, if necessary, further connecting lines. The valves are preferably automated, for example, they are connected to a control unit of the disposable device 10, which can open and close the corresponding inlet and outlet or lines. The automated valves enable different operating modes without modifying the disposable device 10, in particular with regard to selective sequential or parallel flow into the membrane chromatography modules 12 or module groups.

[0072] Thanks to the flexible interconnection, the adsorber capacity in the membrane chromatography modules can also be better utilized. In a series connection, the second membrane chromatography module 12 connected downstream can withstand a rupture of the first module 12 connected upstream in the event of an overload. If the first module 12 is full, it is eluted / cleaned. During this time, the second module 12 can optionally continue to be loaded. After regeneration, the first module 12 can then be connected downstream.

[0073] The sequential flow through the membrane chromatography module 12 makes it possible to link different process steps to one another, in particular different chromatography types.

[0074] By means of additional inlets and outlets at the interruption points in the connecting lines, i.e. at the locations where the valves are arranged, it is possible to individually supply the corresponding membrane chromatography module 12 or the corresponding module group 12 with the buffer medium required. This is particularly important when interconnecting successive membrane chromatography modules 12 having different membrane adsorber types.

[0075] exist Figure 3 An exemplary arrangement of components of a disposable device 10 according to the invention is shown in FIG. A substance mixture to be separated or purified and one or more buffers can be conveyed to one or more membrane chromatography modules 12 via a supply line 40. The membrane chromatography modules 12 can also have further inlets, for example for a separate supply of a flushing medium.

[0076] Before being supplied to the membrane chromatography module 12, the substance mixture passes through a pre-filter 42. After passing through the membrane chromatography module 12, the medium or buffer is filled into the bag.

[0077] Depending on the respective operating mode (flushing, flow-through, bind / elute, integrity test, washing, disinfection, cleaning) of the disposable device 10 , different flow paths can be set by means of valves 44 . The prefilter 42 and the membrane chromatography module 12 can be vented via vent valves 46 .

[0078] In particular, with regard to the operation of the disposable device 10 during binding / elution, at least one disposable conductivity sensor 48 and / or a disposable pH sensor 50 and / or a disposable UV sensor 52 is provided. One or more sensors 48, 50, 52 are arranged at the outlet of the membrane chromatography module 12 or downstream of the prefilter 42 of the disposable device 10. In the case of serially connected membrane chromatography modules 12, one or more sensors 48, 50, 52 are arranged after the last process step, optionally also before the first process step and / or between individual process steps.

[0079] Furthermore, pressure sensors 54 and / or flow sensors are provided at strategic locations in the pipe system, which are connected to the control unit of the disposable device 10 together with one or more disposable conductivity sensors 48 , disposable pH sensors 50 and / or disposable UV sensors 52 .

[0080] Thus, continuous measurement of operating parameters of the disposable device 10 and automatic control related to these parameters are possible.

[0081] The disposable device 10 with the membrane chromatography module 12 can be operated in flow-through mode (FT), but particularly preferably in bind / elute mode (B / E). In B / E mode, automatic valve switching processes and automatic regulation based on sensor measurements are particularly advantageous due to varying process steps.

[0082] The defined signal thresholds of the sensors 48 , 50 , 52 enable automation of the valve switching sequence for collecting selected and separated fractions in the FT or B / E mode 12 (autosampling).

[0083] A plurality of processes or parts of processes can also be carried out simultaneously with the disposable device 10. In this case, it is provided that the line with the associated membrane chromatography module 12 forms at least two separate, mutually independent line branches.

[0084] Thanks to valves integrated into the lines, such independent line branches can be created flexibly. In combination with additional inlets and outlets and the pH and / or conductivity and / or UV sensors provided therein, a largely continuous operation mode is possible by operating at least two systems or groups of systems in parallel, one in loading mode and the other in elution mode. Additional series connections allow for multiple purification steps (seamless loading after elution) in continuous operation using pre-sterilizable, pre-assembled systems that can be installed either aseptically or non-sterilely.

[0085] The entire disposable device 10 is sealed in the assembled state and can be shipped pre-sterilized. This allows the membrane chromatography module 12 to be equilibrated in a buffered medium or delivered loaded with a product solution. Integrity testing can also be performed before delivery, thus saving the user lengthy preparation steps.

[0086] exist Figures 4 to 9 , a plurality of membrane chromatography modules 12 of a disposable device 10 are shown in different operating modes. A special feature here is a rigid disposable cover device 56 and a rigid disposable bottom device 58. These devices 56, 58 replace the holder 14 and individually hold the membrane chromatography modules 12 in place in a pre-set arrangement (grid). The cover device 56 and the bottom device 58 can be formed integrally or consist of individual elements fixedly connected to each other. In any case, the cover device 56 and the bottom device 58 are divided into individual sections 60, which are each associated with a membrane chromatography module 12.

[0087] The cover device 56 and the bottom device 58, more precisely each segment 60, include individually preconfigured or pre-configurable ports 62 and pipe sections 64. The ports 62 and pipe sections 64 of a segment 60 are in fluid communication with the inlet or outlet of the associated membrane chromatography module 12 and with the ports of adjacent segments 60, or are not (depending on the configuration). The number of ports 62 per segment 60 is variable, and in principle, the ports 62 can be arbitrarily occupied or blocked. The pipe sections 64 can also be arranged across segments.

[0088] The sensors 48 , 50 , 52 , 52 , 54 and / or the spectroscopic device can be mounted, in particular plugged onto, the cover device 56 and / or the base device 58 , more precisely onto the unused interface 62 .

[0089] By means of the cover device 56 and the bottom device 58, a corresponding configuration makes it possible to ensure a uniform flow distribution with respect to the inlets for the substance mixture (product inlet) and for the elution buffer (buffer inlet) of one or a group of membrane chromatography modules 12, i.e., the respective flow paths to the respective outlets are of equal length. This results in narrow, clearly recognizable peaks in the spectrum (high resolution).

[0090] As already mentioned, the disposable device 10 can be operated in flow-through mode (FT) or bind / elute (B / E) mode. The operation of the disposable device 10 with the cover device 56 and the bottom device 58 in B / E mode is described below.

[0091] exist Figure 4 It follows that the individual interfaces 62a to 62k of segment 60 are used for operation in B / E mode:

[0092] The treated product flow (pH, conductivity, etc. pre-adjusted by buffer) is marked via the inlet connection 62a labeled "Product."

[0093] Inlet port 62b labeled "Vent / Buffer" is provided in FT mode for venting the membrane chromatography module 12. In B / E mode, it is used to supply process buffer, for example for loading adjustment for ion exchange chromatography or the like.

[0094] A sodium hydroxide solution for cleaning the adsorption membrane of the membrane chromatography module 12 is supplied via the inlet port 62 c having the label “NaOH”.

[0095] The inlet port 62d labeled "Fluid 4" is used to supply elution buffer.

[0096] The inlet port 62e labeled "Fluid 5" enables the supply of equilibration buffer and / or wash buffer.

[0097] Exhaust can be performed in B / E mode via the outlet port 62f labeled "Breakfast / Pressure Air."

[0098] The delivered product flow is discharged via the outlet connection 62g labeled “Product”.

[0099] The outlet ports 62h, 62i, 62j, 62k labeled "NaOH," "Fluid 4," "Fluid 5," and "Buffer" serve to discharge the corresponding media. At least the media NaOH, Fluid 5, and Buffer can all be routed to one of the aforementioned outlet ports 62h, 62j, 62k, allowing a common waste bag to be used for disposal.

[0100] Typically, the following process steps occur in a B / E operation:

[0101] 1. Filling and evacuation, usually with buffer, to be able to wet the membrane chromatography module 12 with liquid.

[0102] 2. Optional integrity testing.

[0103] 3. Disinfection, usually with an alkaline solution, in order to be able to reduce the bacterial load (bioburden) before first use.

[0104] 4a. (Optional) Treatment with a buffer, especially a high salt buffer, to bring all ligands and binding sites to the same level (stationary phase).

[0105] 4b. Alternative to 4a: Rinse with buffer to remove the alkali.

[0106] 5. Equilibrate with buffer (other buffer if necessary) to set the column equilibrium so that the ligand can bind.

[0107] 6. Loading target molecules.

[0108] 7. At least one washing step, preferably with an equilibration buffer, in order to remove unbound protein residues or bound contaminants.

[0109] 8. Elute with elution buffer to dissolve the protein from the column.

[0110] 9. Wash with buffer to remove residues and contaminants.

[0111] 10a. Optional cleaning with acid or base to remove residues and contaminants from the matrix. Reuse of the apparatus 10 after treatment or washing of the membrane chromatography modules 12 in the same batch (intra-batch reuse).

[0112] 10b. Alternative to 10a: Keep the membrane chromatography modules 12 in a storage solution (eg ethanol) and reuse the apparatus 10 after disinfecting or treating or washing the membrane chromatography modules 12 from the same batch (intra-batch reuse).

[0113] 10c. Alternative to 10a and 10b: Discard the membrane chromatography module 12 and do not reuse it.

[0114] Of course, this typical process can be varied according to method and requirements, particularly in terms of the order of steps and the number of intermediate steps. For example, multiple washing steps can be performed, and / or the elution step can be repeated with different elution buffers, etc.

[0115] Some details regarding the use of the lid assembly 56 and the bottom assembly 58 during specific process steps in the B / E mode are described below.

[0116] As in Figure 5 As shown in FIG, in order to disinfect the membrane chromatography module 12 (a specific cleaning and disinfection process for significantly reducing the number of bacteria), the system (the composite structure of the membrane chromatography module 12) is filled with sodium hydroxide solution via the inlet connection 62c of the cover device 56, which is marked with NaOH. In this case, the outlet connection 62h of the bottom device 58, which is marked with NaOH, is initially kept closed so that the system can be vented via the outlet connection 62f marked with "Ventilation / Pressure Air". The system is then disinfected using the flow-through method, with the NaOH outlet connection 62h opened. After a predetermined contact time has elapsed, the sodium hydroxide solution is forced out of the system via the outlet connection 62f, while the inlet connection 62c is closed. Finally, the inlet connection 62c and the outlet connection 62f are closed again, and the valve 44 is set so that the membrane chromatography modules 12 are connected in parallel.

[0117] Before disinfection, the system is usually flushed with buffer, including venting. Figure 6 The optional step shown in is used for the required loading setting in some ion exchange chromatography. For this reason, the system is filled with suitable buffer via the inlet interface 62e marked with "fluid 5". The outlet interface initially remains closed so that the system can be exhausted via the outlet interface 62f marked with "ventilation / pressurized air". Subsequently, the system can be processed optionally with a flow-through method, wherein the outlet interface 62j is opened. After the preset contact time, the inlet interface 62e and the outlet interface 62f are closed again, and the valve 44 is set to so as to connect the membrane chromatography module 12 in parallel. If a subsequent equilibrium step (especially CEX) is performed with a similar buffer having a lower salt concentration, it is usually not necessary for the buffer to be squeezed out from the system. Therefore, it is possible to abandon re-exhausting. If the buffer should still need to be squeezed out, then proceed according to the disinfection step described above.

[0118] exist Figure 7 The system is shown balanced with a buffer solution. The system is treated with a suitable buffer solution in a flow-through method via inlet port 62b labeled "Ventilation / Buffer," with outlet port 62k opened. After a predetermined contact time, inlet port 62b and outlet port 62k are closed again, and valve 44 is set to connect the membrane chromatography modules 12 in parallel. It is generally not necessary to expel the buffer solution from the system. Therefore, re-venting can be omitted. If it is still necessary to expel the buffer solution, this is done according to the previously described disinfection steps.

[0119] Figure 8The acquisition / loading step for purifying the product solution is shown. For this process, the system is operated via the inlet connection 62a marked with "Product". The system is flowed through and loaded up to a predetermined maximum amount (volume), which is sufficiently below the known breakthrough amount (typically 70% of the 10% DBC value (dynamic binding capacity)). During this time, the product outlet connection 62g remains open and the so-called flow-through is omitted (alternatively, in FT mode, the product is obtained in the flow-through). The concentration of the product can optionally be determined by sensors, in particular UV sensors 52 and / or conductivity sensors 48, directly before the inflow and directly after the group of membrane chromatography modules 12 through which the flow is passed.

[0120] Once the predetermined injection volume has been reached, the control unit of the disposable device 10 switches to the next process step (elution). This is preceded by at least one washing step in order to be able to wash nonspecifically bound material from the chromatographic bed.

[0121] When the capacity of the system is reached, ie when the adsorption membrane binds a predetermined maximum value of the target product to the ligand (eg 70% of a 10% DBC value), the inlet port 62a and the outlet port 62g are closed.

[0122] exist Figure 4 A special feature of the embodiment shown in is that during purification the loading of the individual membrane chromatography modules 12 is synchronized. This is achieved by virtue of the fact that the inflow and outflow paths are designed to be S-shaped and are arranged in mirror-inverted fashion.

[0123] Figure 8a The flow path through the cover device 56 is shown, which is referred to below as the inflow path. This inflow path extends so that in a 3×3 grid of membrane chromatography modules 12, initially the three modules 12 in the outer rows flow in, then the three modules 12 in the adjacent middle row flow in via a first connecting section 66, and finally the remaining three modules 12 in the opposite outer row flow in via a second connecting section 68. The two connecting sections 66, 68 are located on opposite sides of the grid.

[0124] In each section 60 of the cover device 56 , a branch of the inflow path is provided, which opens into the upper inlet of the associated membrane chromatography module 12 . Correspondingly, the lower outlet of the respective membrane chromatography module 12 opens into the outflow path formed in the bottom device 58 .

[0125] As already mentioned, the course of the section 60 of the outflow path through the bottom device 58 is mirror-inverted to the course of the inflow path in the cover device 56. This means that, with respect to the flow direction, the first membrane chromatography module 12 in the inflow path is also the first module 12 in the outflow path, the second membrane chromatography module 12 in the inflow path is also the second module 12 in the outflow path, and so on.

[0126] This ensures that the path from the inflow connection (here inlet connection 62a) through the first module 12 to the outflow connection (here outlet connection 62g) is as long as the path from the inflow connection through the other modules 12 to the outflow connection.

[0127] This is a prerequisite for obtaining clear narrow peaks in the chromatogram.

[0128] exist Figure 9 The elution step of the purification of the product solution is shown in FIG. For this process, the system is operated via the inlet interface 62d marked with "fluid 4". The system is flowed through and, due to the buffer, the target molecule is eluted into the mobile phase. During this period, the outlet interface 62i remains open and the eluent (the discharged mixture of solvent and dissolved substances) is collected in a product bag or another container (plastic box, stainless steel tank, etc.). The concentration of the product is determined by sensors, in particular UV sensors 52 and / or conductivity sensors 48, in the outflow path after the group of membrane chromatography modules 12 that have been flowed through. Once the chromatogram reaches the baseline, that is, when the concentration drops to approximately 0, the elution is terminated. No more buffer inflow then occurs. The buffer remaining in the system is pressed out via the outlet interface 62f marked with "ventilation / pressurized air". Here, the inlet interface 62d is closed.

[0129] If necessary, the elution process does not wait until the baseline is completely reached, so that a generally undesirable dilution of the elution ("cutting" of the elution peak) can be avoided. If a membrane chromatography module 12 is to be reused in the same batch (intra-batch reuse), it should be noted that the binding sites are still "blocked" due to incomplete elution. A further washing step is then carried out before a new cycle begins, optionally followed by cleaning. Depending on the peak crossing point, the buffer is forced into the product flow or into the flow path to a waste bag, and the outlet connection 62f is then closed.

[0130] In order to synchronize the elution peaks in the elution step, similarly to the cleanup step, the inflow and outflow paths are designed to be S-shaped and arranged mirror-inverted with respect to each other, as in Figure 9a. The order of the membrane chromatography modules 12 in the inflow path and outflow path is therefore identical compared to the purification steps. This also applies here: with respect to the flow direction, the first membrane chromatography module 12 in the inflow path is also the first module 12 in the outflow path, the second membrane chromatography module 12 in the inflow path is also the second module 12 in the outflow path, and so on. Generally, the goal here is also to ensure that the paths from the inflow connection (here, the inlet connection 62d) through the corresponding modules 12 to the outflow connection (here, the outlet connection 62i) are as exactly the same length as possible.

[0131] Since the capacity of a membrane adsorber is usually insufficient to purify a complete production batch in one pass, a so-called multi-cycle design is often used, as already explained, in which the membrane chromatography module 12 is reused (reuse within the batch). In this case, after elution, the process is restarted with a washing or disinfection step. Instead of a washing step, an equilibration step can also be started.

[0132] In the case of multi-cycle operation, all eluent in a single cycle is conducted via a defined outlet, completely separated from other media, and collected in a bag or other container (pooling).

[0133] The multiway valve 44, located in the disposable device 10 and connected to the control unit, facilitates automation, or at least partial automation, of the aforementioned process steps. Decisive for this are the sensors 48, 50, 52, and 54, which, on the one hand, signal when the medium / buffer enters or leaves the system and, on the other hand, output a signal representing the actual chromatogram. By defining signal thresholds, it is possible to define the intersection point at which the control unit automatically switches. This is briefly explained below using two examples.

[0134] 1. Example: A 1-molar sodium hydroxide solution, used as a cleaning medium, is easily distinguishable from the running buffer due to its high pH. Sufficient removal of the cleaning medium is necessary: ​​After the disinfection step, sufficient flushing with buffer is necessary until the pH (and, if necessary, the conductivity) at the system outlet reaches (or remains at) a defined value. In this case, the inlet port 62e and outlet port 62j for the flushing buffer are switched to the inlet port 62b or outlet port 62k for the equilibration buffer or other buffer.

[0135] 2. Example: Elution begins and the maximum UV value is reached. After a certain volume has passed, the signal decays to a preset signal threshold. This event is recognized and used to automatically switch from inlet port 62d and outlet port 62i to inlet port 62c and outlet port 62h for the sodium hydroxide solution (as long as there is no further rinsing step upstream) to initiate the next cycle.

[0136] The materials used in the disposable device 10 (also for any flexible hose lines etc.) can be sterilized, in particular by means of gamma radiation, heat or gas treatment, or can be autoclaved. Thus, the disposable device 10 can also be pre-cleaned (flushed) before sterilization. The disposable device 10 can thus be sterilized and packaged in a pre-assembled, i.e. ready-to-connect state, or first packaged and sterilized together with the packaging. After delivery to the customer, the entire disposable device 10 can be connected there with the aid of already pre-assembled sterile connectors (e.g. ) or aseptic welding of inlet and outlet hoses, and can be installed in existing process lines, meaning it is immediately ready for use. Preferably, the disposable device 10 is delivered with a sterile barrier at the inlet and outlet. If pre-cleaning is performed before delivery, the user also saves the expense of free rinsing, for example, to remove glycerol used to stabilize the membrane.

[0137] In order to enable professional disposal of the disposable device 10, which includes a sterilization step in an autoclave, the membrane chromatography modules 12 are connected to one another in the disposable device 10 so that they can be connected to one another without great effort. (Aseptic Tube Sealing System, sterile tube sealing system) or To avoid contamination, the separate segments are designed to be of a size and weight that can be carried by a person and moved into the autoclave. Each separate filter segment has at least one valve that can be opened during autoclaving to avoid overpressure in the filter segment during sterilization.

[0138] List of reference numerals:

[0139] 10Disposable equipment for separation or purification

[0140] 12 membrane chromatography modules

[0141] 14 retaining parts

[0142] 18 beams

[0143] 20 Holding mechanism

[0144] 22 pipelines

[0145] 24 branches

[0146] 26 inflow and outflow units

[0147] 28 Inflow device

[0148] 30 outflow device

[0149] 32 shell wall

[0150] 34 external interfaces

[0151] 36 connecting components

[0152] 38 closures

[0153] 40 supply pipeline

[0154] 42 pre-filter

[0155] 44 valve

[0156] 46 Exhaust valve

[0157] 48 conductivity sensor

[0158] 50pH sensor

[0159] 52UV sensor

[0160] 54 pressure sensor

[0161] 56 cover device

[0162] 58 bottom device

[0163] 60 sections

[0164] 62a-k interface

[0165] 64 pipeline section

[0166] 66 First connecting section

[0167] 68 Second connecting section

Claims

1. A disposable device (10) for separating or purifying a large amount of a substance mixture, the disposable device comprising: a plurality of membrane chromatography modules (12), said membrane chromatography modules being fixedly arranged in a predetermined grid, and a pipe system for connecting the membrane chromatography modules (12) and for connecting the membrane chromatography modules (12) to each other, wherein the membrane chromatography module (12) is preconfigured or can be preconfigured for a desired separation or purification process with respect to the membrane adsorber type, the structural type and / or the structural size, and / or the pipeline system, It is characterized in that A cover device (56) and a bottom device (58) are provided for the plurality of membrane chromatography modules (12), wherein the cover device and the bottom device are respectively arranged on the upper side and the lower side of the membrane chromatography module (12), and the membrane chromatography module (12) is held in place in a predetermined grid by means of the cover device (56) and / or the bottom device (58). wherein at least a part of the conduit system of the disposable device (10) is formed in the cover device (56) and the bottom device (58), wherein connecting lines are provided between the membrane chromatography modules (12), The cover device (56) and the bottom device (58) have individual sections (60) that are fixedly connected to one another and are each associated with a membrane chromatography module (12). The membrane chromatography modules (12) are arranged such that some or all of the membrane chromatography modules (12) are flowed in parallel from the inflow path, or such that at least one group of membrane chromatography modules and at least one other group of membrane chromatography modules are flowed in parallel, wherein the membrane chromatography modules within a group are flowed in sequentially, wherein the flow paths through the membrane chromatography modules (12) into which the flow flows are in parallel are of equal length and the inflow and outflow paths are arranged in mirror-inverted fashion, The disposable device (10) has at least two inlets separated from each other on the cover device (56) and / or the base device (58), each of which is provided with a disposable valve and is assigned to different media, and The cover device (56) and the section (60) of the base device (58) have individually preconfigured or individually preconfigurable interfaces (62) and line sections (64).

2. The disposable device (10) according to claim 1, It is characterized in that At least some of the membrane chromatography modules (12) are designed as wound modules.

3. The disposable device (10) according to claim 1 or 2, It is characterized in that A prefilter is connected upstream of at least one membrane chromatography module (12).

4. The disposable device (10) according to claim 3, It is characterized in that The pre-filter comprises a pleated filter element.

5. The disposable device (10) according to claim 4, It is characterized in that The pre-filter had a pore size of 0.45 μm.

6. The disposable device (10) according to claim 1 or 2, It is characterized in that At least some of the lines of the line system are designed as rigid lines.

7. The disposable device (10) according to claim 1 or 2, It is characterized in that Automatic valves (44) are provided at multiple locations in the pipelines of the pipeline system and are controlled by a control unit.

8. The disposable device (10) according to claim 7, It is characterized in that Additional inlets and outlets are provided in the pipe system at locations where automatic valves (44) are provided.

9. The disposable device (10) according to claim 7, It is characterized in that The disposable device comprises at least one disposable conductivity sensor (48) and / or a disposable pH sensor (50) and / or a disposable UV sensor (52), which is arranged upstream of the inlet and / or downstream of the outlet of a membrane chromatography module (12) or a group of membrane chromatography modules (12) connected together.

10. The disposable device (10) according to claim 7, It is characterized in that The disposable device has at least one disposable pressure sensor (54) and / or disposable flow sensor, which is arranged in one of the lines of the line system.

11. The disposable device (10) according to claim 9, It is characterized in that The disposable conductivity sensor (48) and / or the disposable pH sensor (50) and / or the disposable UV sensor (52) are connected to the control unit.

12. The disposable device (10) according to claim 1 or 2, It is characterized in that In the assembled state, the disposable device (10) forms a closed and pre-sterilized unit, in which the membrane chromatography module (12) is equilibrated in a buffer medium.

13. The disposable device (10) according to claim 1 or 2, It is characterized in that The membrane chromatography module (12) stands upright in its use position.

14. The disposable device (10) according to claim 1 or 2, It is characterized in that At least one sensor or spectroscopic device is mounted on an unused interface (62) of the cover device (56) or the base device (58).

15. The disposable device (10) according to claim 1 or 2, It is characterized in that A chromatography module filled with chromatography gel or integral chromatography material is provided instead of the membrane chromatography module (12).

16. A method for separating or purifying a large amount of a substance mixture using a disposable device (10) according to any one of claims 1 to 15, The disposable device (10) comprises a plurality of automatic valves (44) and sensors connected to a control unit, wherein the automatic valves (44) are controlled based on an evaluation of parameters measured by the sensors.

17. The method according to claim 16, It is characterized in that The sensor comprises at least one disposable conductivity sensor (48) or a disposable pH sensor (50) or a disposable UV sensor (52) or a disposable pressure sensor (54) or a disposable flow sensor.

18. The method according to claim 16 or 17, It is characterized in that predefined signal thresholds for said parameters, and Depending on whether the signal threshold is exceeded or fallen below, a predetermined process step of separation or purification is automatically carried out.

19. The method according to claim 18, It is characterized in that Depending on whether the signal threshold is exceeded or fallen below, a valve switching sequence for collecting the selected and separated fractions is automatically executed.

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