Valve switching system for selectively interconnecting components of a bioprocessing facility - Patents.com

Abstract

The present invention is directed to a valve switching system for selectively interconnecting components of a bioprocessing facility (2), comprising a valve switching cassette (15) and an actuator block (16). It is proposed that the valve switching cassette (15) comprises a perforated sandwich plate (22) having perforated holes (23), the sandwich plate (22) being disposed between a cassette manifold (17) and an actuator block body (21).

Description

[Technical field]

[0001] This application is filed as a PCT international patent application dated March 21, 2023, in the name of Sartorius Stedim North America, Inc., a U.S. corporation, applicant in all countries designation, and in the name of Dinesh Shukla, a U.S. citizen, inventor in all countries designation, claiming priority to U.S. Application No. 17 / 699,622, filed March 21, 2022, the entire contents of which are incorporated herein by reference.

[0002] The present invention relates to the design of a valve switching system for selectively interconnecting components of a bioprocessing installation according to the general part of claim 1, to a bioprocessing installation having such a valve switching system according to claim 12 and to the use of such a valve switching system according to claim 13. [Background technology]

[0003] The term "bioprocess" currently refers to any kind of biotechnological process, especially biopharmaceutical processes. The operation of a chromatography apparatus having multiple chromatography columns connected to a valve switching system for performing simulated moving bed (SMB) chromatography can be part of such a bioprocess.

[0004] The proposed valve switching system can be applied in various fields of biotechnology and for different kinds of bioprocesses. In biopharmaceutical processes, cost efficiency and process reliability are particularly important. Cost efficiency is not only related to material costs but also to production costs. Furthermore, cost efficiency is important considering, for example, the labor time and maintenance costs required for the installation of the equipment as well as the operation of the bioprocess itself. Process reliability is important in terms of the materials utilized, the installation procedures as well as the correct operation of the bioprocess. Especially in environments that are heavily regulated by authorities (e.g., the Food and Drug Administration (FDA)), process reliability is crucial to ensure the safety of the product.

[0005] In a valve switching system as part of an SMB process related to biopharmaceutical manufacturing, it is also key to ensure easy installation of the valve switching system. Therefore, a disposable and compact design of the individual valves and connectors is essential. A valve switching cassette as part of a valve switching system, designed as a disposable item and having a compact design of the valve switching cassette, is disclosed in EP 1775001. In the above known valve switching system, which is the starting point of the present invention, the ports and fluid lines of the valve switching cassette are grouped together in a compact cassette manifold. The fluid lines in the cassette manifold are selectively connected by an array of switchable valve units designed as a membrane valve unit for controlling the fluid flow in the cassette manifold. The valve units each comprise a valve seat, and the respective valve membranes selectively engage or disengage with the valve seat to switch the valve unit. The valve membranes can be actuated by actuators. The actuators act on the valve membranes to switch the valve units. The actuators are part of an actuator block, which is part of the valve switching system. Several actuators may be arranged in the actuator block body.

[0006] A liquid or a gas may be used to actuate the valve membranes. To achieve this, the actuator comprises an actuation outlet that leads into an actuator block pocket. An actuator block pocket refers to a portion of the actuator block body that leads into the actuation outlet and has contact points with the valve membranes. These contact points need to be sealed air-tight or liquid-tight when the gas or liquid is guided towards the valve membranes through the actuation outlet. To ensure reliable actuation of the valve membranes and thus correct functioning of the valve unit, the contact points between the actuator block and the valve membranes need to be sealed air-tight or liquid-tight.

[0007] On the other hand, the valve membranes must be as thin as possible to reduce material costs, yet flexible enough to ensure reliable operation of the valve unit: if the valve membranes are not flexible enough, the membrane valve may not open and close properly.

[0008] Thus, the valve membrane of known configurations performs not only a valve function but also a sealing function to the cassette manifold and actuator block, which makes it difficult to design an optimized valve membrane for reliability and cost.

[0009] In addition to reliable operation of the valve unit, as mentioned above, proper positioning and fixation of the valve leaflets relative to the cassette manifold and actuator block must also be ensured to allow leak-free operation of the valve switching system. Proper positioning must be ensured not only during manufacture, installation, but also during operation of the valve switching system. Depending on the type of process (e.g., biopharmaceutical process) in which the valve switching system is used, the materials used must meet certain requirements. For example, the materials, and in particular the adhesives used, may need to be certified to a certain class (e.g., Class VI) according to the United States Pharmacopeia (USP). Furthermore, the type of connection (e.g., removable or non-removable) may be specified by regulatory authorities such as the Food and Drug Administration (FDA). Despite the different requirements that the connections between the different parts and the materials themselves may need to meet, it is desirable to allow proper positioning of the valve leaflets before fixation to ensure a reproducible and leak-free connection independent of the fixation mode. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] European Patent No. 1775001 Summary of the Invention [Problem to be solved by the invention]

[0011] It is therefore an object of the present invention to provide a means to enable reliable switching of the valve unit during operation, allowing reproducible and reliable fastening of the valve membranes during manufacture, installation and operation of the valve switching system. [Means for solving the problem]

[0012] The above problem is solved by a valve switching system according to the general part of claim 1 having the features of the characterizing part of claim 1.

[0013] It is the basic idea of ​​the present invention to arrange a perforated sandwich plate between the cassette manifold and the actuator block, whose interface with the cassette manifold is provided by a valve membrane and whose interface with the actuator block is provided by another membrane, namely a gasket membrane. In this way, the structural design of both sides of the sandwich plate can be adapted to their individual requirements. For example, the valve membrane can be optimized in terms of valve function while being enclosed between the cassette manifold and the sandwich plate. It is noted here that the resulting valve switching cassette is preferably a single-use component, so that the connection between the cassette manifold and the sandwich plate can also be non-detachable.

[0014] The gasket membrane can be designed to provide an optimal seal between the sandwich plate and the actuator block body, and preferably to be usable multiple times for different valve switching cassettes. In particular, the air-tight or liquid-tight seal between the sandwich plate and the actuator block can be realized by selecting the material of the gasket membrane that is most suitable for air-tight sealing, without compromising the function of the valve membrane structure to switch the valve unit. The material of the gasket membrane structure is not in contact with the process fluid in the cassette manifold, so the material selection is wider. Furthermore, since the air-tight or liquid-tight seal is reinforced by the gasket membrane structure, the valve membrane structure can be made thinner, resulting in lower costs and more emphasis on the switching of the valve unit by the valve membrane structure. This contributes to the operational reliability of the valve switching system.

[0015] Finally, by arranging a sandwich plate between the valve membrane structure and the gasket membrane structure, the sandwich plate can be used for fixing, i.e. fastening, both membrane structures, which allows pre-assembly, especially of the gasket membrane structure, independently of the actuator block, thus simplifying the installation procedure of the valve switching system.

[0016] Claims 2 to 4 are directed to the features of the valve membrane structure and the gasket membrane structure. Claim 2 focuses in particular on the valve function of the valve membrane structure and on the sealing function of the gasket membrane structure. Claims 3 and 4 focus on the preferred materials used. All these measures contribute to the fact that both membrane structures can be individually selected to suit their respective functions in the best way.

[0017] According to claim 5, the gasket membrane structure is perforated with perforations which are at least partially aligned with the perforations of the sandwich plate, whereby actuation of the valve membrane structure by the actuator can be easily achieved through the perforations of the gasket membrane structure.

[0018] The cassette manifold and / or the sandwich plate may, according to claim 6, be provided with grooves for inserting the valve membrane structures and / or the gasket membrane structures, which makes the appropriate positioning of the respective membrane structures particularly simple.

[0019] According to claim 7 it is proposed that at least some of the perforated holes in the sandwich plate and the perforated holes in the gasket membrane structure are aligned with the valve seats of the valve units, resulting in a compact arrangement with direct access from the respective actuators to the valve membrane structure.

[0020] Claim 8 is directed to a valve membrane and / or gasket membrane comprising a membrane strip. The use of a membrane strip reduces the material required for the membrane structure. In this way, the overall cost is reduced. In this way, the overall cost is reduced. Furthermore, the proper positioning of the membrane structure is supported.

[0021] The sandwich plate may be sealingly engaged with the cassette manifold according to claim 9, thereby enclosing and / or fixing the valvular structure. As mentioned above, this can be realized independently of the interface between the sandwich plate and the actuator body, again highlighting the advantage of flexibility with the optimized design. In a preferred embodiment, no adhesive is required, for example when a compressive force between the cassette manifold and the sandwich plate is used to fix the valvular structure. Omitting the use of an adhesive to fix the valvular structure not only simplifies the manufacturing process, since proper application and selection of the adhesive is not required, but also increases the safety of the process by eliminating the risk that the adhesive may come into contact with the process fluid.

[0022] The above-mentioned pre-assembly can be easily realised by fastening at least one of the membrane structures to a sandwich plate according to claim 10. By fastening e.g. a gasket membrane structure to a sandwich plate, an easy pre-assembly of the gasket membrane structure is possible.

[0023] According to claim 11, each actuator comprises an actuation outlet, preferably a gas pressure outlet or a hydraulic pressure outlet. At least some of the actuation outlets are aligned with the perforations of the sandwich plate. In this way, the actuation of the valve membrane structure by the actuator can also be controlled, for example, by the size of the perforations of the sandwich plate. This increases the flexibility of the operation.

[0024] The independent teaching according to claim 12 is directed to a bioprocessing facility comprising a chromatography device having a plurality of chromatography columns connected to the proposed valve switching system for performing a simulated bed chromatography (SMB) process.

[0025] In another independent teaching according to claim 13, the use of the proposed valve switching system for switching columns of a bioprocessing installation is claimed as such. All the descriptions given regarding the proposed valve switching system and the proposed bioprocessing installation are fully applicable.

[0026] In the following, embodiments of the invention will be described with reference to the drawings, in which: [Brief description of the drawings]

[0027] [Figure 1] FIG. 1 is a schematic diagram of a proposed valve switching system as part of a proposed bioprocessing facility. [Diagram 2] FIG. 2 is an exploded rear view of the valve switching system of FIG. 1. [Diagram 3] FIG. 2 is an exploded front view of the proposed valve switching system of FIG. 1. [Figure 4] 1A and 1B are diagrams illustrating the operating principle of a valve unit of a valve switching cassette as part of a valve switching system. [Diagram 5] FIG. 2 shows a portion of the bioprocessing installation according to FIG. 1 in an exemplary mode of operation. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0028] As shown in Figure 1, the proposed valve switching system 1 is preferably used here for selectively interconnecting components of a bioprocessing installation 2. The expression "interconnect" should be understood in the sense of a fluid connection.

[0029] In particular, Figure 1 shows the successive steps carried out for the recovery and purification of a desired product, such as a monoclonal antibody, as part of a downstream process in a bioprocess. In the first step of the downstream process, the product is separated in a separation unit 3. Assuming that the product is located in the supernatant of the fermentation broth, centrifugation may be performed to separate the product from the cells and cell debris. Concentration, for example by ultrafiltration, may also be performed as part of the product separation in order to increase the product concentration and reduce the volume of material to be processed in the successive downstream processing steps.

[0030] After product separation in separation unit 3, product purification takes place in purification unit 4. Product purification may be performed by different means including multi-column chromatography, as shown in FIG. 1 by chromatography apparatus 5. Chromatography apparatus 5 may comprise multiple chromatography columns 6-13, as shown in FIG. 1. In a preferred embodiment, the number of chromatography columns 6-13 connected to valve switching system 1 is between 1 and 8.

[0031] Compared with conventional single-column chromatography, multi-column chromatography significantly improves the efficiency of the purification step. However, multi-column chromatography is more complicated than single-column chromatography, especially with respect to fluid flow. Therefore, a high degree of control of the fluid flow path is required, which is currently achieved using the proposed valve switching system as shown in Figure 1.

[0032] After purification, product polishing is preferably carried out by a polishing unit 14. At the end of product polishing, the product is typically packaged for further distribution. Depending on the bioprocess, product polishing may include, for example, a viral inactivation step to comply with regulatory requirements, followed by ion exchange chromatography. Another example of product polishing is a crystallization step, which converts a fluid product into a solid, and thus easily transportable, form.

[0033] The valve switching system 1 comprises a valve switching cassette 15 and an actuator block 16. The valve switching cassette 15 comprises a cassette manifold 17 having at least one fluid flow system 18, 19 of ports and fluid lines. The first fluid flow system 18 comprises a primary fluid line L p Primary port P communicates with p and the secondary fluid line L s Secondary port P communicates with s The second fluid flow system 19 includes a primary fluid line l p Primary port p communicating with p and the secondary fluid line l s Secondary port p communicating with s Includes.

[0034] The general function of the two fluid flow systems 18, 19 of ports and fluid lines is identical such that a description given to one fluid flow system 18, 19 is equally applicable to the respective other fluid flow system 18, 19. In the following, to reduce complexity, reference will be made primarily to the second fluid flow system 19.

[0035] The valve switching cassette 15 also connects the primary fluid line L via the transfer fluid line T. p , l p The secondary fluid line L s , l s A switchable valve unit for selectively interconnecting with x,y It also has an array of.

[0036] The term "port" refers to an interface for interconnecting components of the bioprocessing equipment 2 to respective fluid lines. This may include fluid connectors to the respective fluid lines.

[0037] The term "line" refers to any longitudinal volume capable of holding and directing a fluid between two points. p , l p , L s , l s, and T are drilled or otherwise machined, preferably by deep hole drilling or the like, into cassette manifold 17.

[0038] The terms "primary" and "secondary" refer to the valve unit n x,y The terms "primary" and "secondary" are used to distinguish between two groups of fluid ports interconnected by a primary fluid port and a secondary fluid port. In the preferred embodiment as shown, these terms also indicate the direction of fluid flow F, which is then directed from the primary fluid port to the secondary fluid port. However, this can also be achieved in the opposite direction. Thus, the terms "primary" and "secondary" do not imply or exclude any structural and / or functional differences between the respective ports and fluid lines.

[0039] The term "selectively interconnect" refers to a primary fluid line p One or more of the secondary fluid lines l s This means that the 10-bit 110-bit 120-bit 130-bit 140-bit 150-bit 160-bit 170-bit 180-bit 200-bit 210-bit 220-bit 230-bit 240-bit 250-bit 260-bit 270-bit 280-bit 290-bit 300-bit 310

[0040] The term "switchable" refers to the ability to switch a valve unit n from an "open" state to a "closed" state or from a "closed" state to an "open" state. x,y The valve unit n x,y When the valve is in an “open” state, the fluid flows through the primary fluid line l, as exemplarily shown in the inset of FIG. p from the transfer fluid line T through the secondary fluid line l s Preferably, each of the transfer lines T may be connected to a primary fluid line l p or secondary fluid line l s The open valve unit n x,y is shown as a solid ellipse in Figs. 1 and 5. Valve unit n x,y When the primary fluid line l is in the "closed" state, p from the transfer fluid line T through the secondary fluid line l s Fluid flow is prevented into the valve unit 10. A closed valve unit is shown as a hollow oval in FIGS.

[0041] Primary Fluid Line p and secondary fluid line l s are preferably arranged in rows and columns in a valve switching cassette 15, and the valve units n x,y are the flow rates of each fluid line l p ,l s is each valve unit n x,y and the primary fluid lines l, which may be interconnected by respective transfer fluid lines T. p and secondary fluid line l s Therefore, the valve unit n x,y The array of valve units n is aligned to these rows and columns and numbered accordingly. 11,3 is shown in detail in the inset of Fig. 1 .

[0042] Valve unit n x,y are the valve seats s x,y As shown in FIG. 3, each valve unit n x,y Regarding the primary fluid line l p one of the transfer fluid lines T in communication with the secondary fluid line l; s and one of the transfer fluid lines T is preferably connected to the valve seat s x,y It leads to the inside.

[0043] In another preferred embodiment, the primary fluid line l p is the valve seat x,y Directly connected to the secondary fluid line s is connected to the valve seat s by the transfer fluid line T. x,y is connected to.

[0044] To control the fluid flow, the valve switching cassette 15 of the valve switching system 1 includes a valve membrane structure 20. The valve membrane structure 20 includes valve units n x,y To switch between valve units, x,y Valve seat s x,y The valvular structure 20 may be sealingly engaged with the valve seat s as described below in connection with FIG. x,y ("closed" state) or the valve seat s x,y("open" state).

[0045] The actuator block 16 is connected to each valve unit n of the valve switching cassette 15. x,y The actuator block 16 further comprises an actuator block body 21 having an actuator for the valvular structure 20, in particular the valvular membrane m. x,y As a result, the valve structure 20 is x,y and engage or disengage with.

[0046] Preferably, the proposed valve switching system 1 serves to control the fluid flow of selectively interconnected components, such as the illustrated chromatography device 5. The fluids whose flow is controlled by the valve switching system 1 are called process fluids. Process fluids addressed within the present invention can include a wide variety of liquid media, such as buffers, cleaning solutions, acids, bases, culture media, unprocessed product-containing liquids, partially processed product-containing liquids, purified product-containing liquids, sanitary solutions, etc. Fluids addressed within the present invention can also be media in the gas phase.

[0047] It is essential to the invention that the valve switching cassette 15 comprises a perforated sandwich plate 22 having perforated holes 23, the sandwich plate 22 having a flat surface being arranged between the cassette manifold 17 and the actuator block body 21. The term "perforated hole" is generally understood in a broad sense and refers to an opening in the flat surface 26 of the respective component, e.g. the sandwich plate 22, facing the cassette manifold 17.

[0048] The valve membrane structure 20 is disposed between the cassette manifold 17 and the sandwich plate 22, and the gasket membrane structure 24 is disposed between the actuator block body 21 and the sandwich plate 22. Here, preferably, one flat surface of the sandwich plate 22 faces the valve membrane structure 20, and the flat surface of one half of the sandwich plate 22 faces the gasket membrane structure 24.

[0049] Figure 4 shows the valve unit n x,yTo selectively switch between the valve seats s, an actuator in the actuator block 16 is x,y 1 shows that the valvular structure 20 can be actuated through the perforations 23 in the sandwich plate 22 when selectively engaging with the valvular structure 20.

[0050] The valvular structure 20 includes at least one valvular membrane m that is made of a first material. x,y and the gasket membrane structure 24 includes at least one gasket membrane g that is made of a second material different from the first material. x,y It is further essential to the present invention that

[0051] As described above, the valvular structure 20 includes valve units n x,y The gasket membrane structure 24 serves the purpose of switching between the actuator block 16 and the valve membrane m x,y Since the valvular structure 20 and the gasket membrane structure 24 each have different materials that are best suited to serve their respective purposes, different materials may be selected for the valvular structure 20 and the gasket membrane structure 24, respectively. Preferably, the valvular structure 20 has at least one valvular membrane m x,y and / or the gasket membrane structure 24 comprises at least one gasket membrane g x,y Equipped with.

[0052] In addition to the drilled holes 23, the sandwich plate 22 comprises a recess 25 for each drilled hole 23, as will be described below. In addition, the sandwich plate 22 comprises fastening holes for the introduction of fastening elements such as screws, as will also be described below.

[0053] Preferably, the shape of the perforated holes 23 of the sandwich plate 22 is circular. However, other shapes, such as oval or square, are also envisaged. The recesses 25 of the sandwich plate 22 are located on a flat surface 26 of the sandwich plate 22 facing the valve membrane structure 20. Each recess 25 is assigned at least one perforated hole 23, which is preferably located in the centre of the recess 25. Preferably, the shape and number of the recesses 25 are determined by the valve seat s. x,y At least a part of the recess 25 corresponds to the shape and number of the valve seat s x,y At least a portion of the above will be aligned.

[0054] Each drilled hole 23 in the sandwich plate 22 forms a channel in the sandwich plate 22. Preferably, the channels extend transversely to each planar surface of the sandwich plate 22.

[0055] The sandwich plate 22 may be made of any kind of plastic material, preferably acrylic, such as PMMA, PEEK or PVDF. In particular, the sandwich plate 22 may be manufactured from PEEK, which is a thermoplastic material with high temperature stability. Manufacturing from a plastic material makes the sandwich plate 22 lightweight. In addition, the sandwich plate 22 may be manufactured translucent, which allows visual inspection of the inner channels of the sandwich plate 22. It should be noted that these materials merely represent examples and in no way limit the choice of material for the sandwich plate 22. In general, the material of the sandwich plate 22 may be different from the material of the cassette manifold 17, which means that it can be selected to allow, for example, optimal fastening of the valve membrane structure 20 and / or the gasket membrane structure 24.

[0056] Because the sandwich plate 22 may be constructed from a variety of materials, there are a wide variety of methods used to introduce the recesses 25 and drilled holes 23 into the sandwich plate 22. As a result, the drilled holes 23 and recesses 25 may be introduced into the sandwich plate 22 by punching, drilling, injection molding, cutting, and the like.

[0057] As mentioned above, according to the present invention, the first material allocated to the valvular membrane structure 20 and the second material allocated to the gasket membrane structure 24 may be laid out separately.

[0058] Preferably, the first material comprises a higher hardness and can be thinner than the second material, and for safe switching, valve function may require the first material to withstand significant back pressure.

[0059] Additionally or alternatively, it may be preferred that the second material has a higher porosity than the first material. Since the gasket requires a high degree of elasticity, a higher porosity is reasonable. In any case, the porosity of the first material and / or the second material is a kind of closed cell porosity to ensure the required sealing performance.

[0060] Also in addition or alternatively, at least one valve m x,y At least one gasket membrane g x,y The compression of the second material of the gasket membrane structure 24 is advantageous from the standpoint of mechanical tolerance compensation and is less critical or desirable for the valve membrane structure 20. In any event, it is preferred that the first material is a first elastomer and the second material is a second elastomer different from the first elastomer.

[0061] Preferably, at least one valve m x,y is composed of a fluorocarbon-based fluoroelastomer (FKM), a rubber compound with vinylidene fluoride as a monomer. The FKM material is robust when in contact with critical fluids such as various acids and bases as mentioned above. The hardness (Shore A) is preferably between 50 and 80, more preferably 70. The valve m x,y The thickness is preferably less than 2 mm, more preferably between 0.75 mm and 1.5 mm.

[0062] Preferably, at least one gasket membrane g x,y As described above, the gasket membrane g is made of a resilient and flexible elastomer. x,y Since the gasket membrane g is not in contact with any process fluid, a wider range of materials can be selected. x,y The materials do not necessarily comply with certain requirements for biocompatibility (e.g., USP Class VI certification). Since certification is not required, material costs can be significantly reduced by selecting a non-certified material. In a preferred embodiment, the gasket membrane g x,yThe material is selected for best hermetic sealing ability. Preferably, the gasket membrane g x,y is composed of thermoplastic polyester (e.g., Hytrel®) or thermoplastic vulcanizate (e.g., Santroprene™) or polychloroprene (also known as neoprene). However, the gasket membrane g x,y The materials are not limited to those listed above, but may be composed of any other material that complies with the requirements set forth above and below.

[0063] Preferably, the gasket membrane d x,y The hardness (Shore A) of the gasket membrane g is between 50 and 80, more preferably 60. x,y The thickness is preferably less than 3 mm, more preferably between 1 and 2 mm.

[0064] It should be pointed out that even though the gasket membrane structure 24 represents an additional component, the overall cost of the valve switching system 1 may be significantly reduced because the savings in valve membrane material, specifically the FKM material, may easily exceed the cost of the gasket membrane structure 24.

[0065] Preferably, the gasket membrane structure 24 is also perforated with perforation holes 27, and at least some of the perforation holes 27 of the gasket membrane structure 24 are aligned with at least some of the perforation holes 23 of the sandwich plate 22. The shape of these perforation holes 27 of the gasket membrane structure 24 is also not limited and can be, for example, circular, elliptical or square. Preferably, the perforation holes 27 have a circular shape. It is also preferred that the number of perforation holes 27 of the gasket membrane structure 24 is the same as the number of actuation outlets 28 of the actuator block 16 and the number of perforation holes 23 of the sandwich plate 22. The perforation holes 27 can be introduced into the gasket membrane structure 24 by punching, drilling, injection molding, cutting, etc.

[0066] Here, preferably, the cassette manifold 17 and / or the sandwich plate 22 are provided with grooves 29, 30 for inserting the valve membrane structure 20 and / or the gasket membrane structure 24. Depending on the depth of the grooves 29, 30, the respective membrane structure 20, 24 is press-fitted, i.e. clamp-engaged, form-fitted or loose-fitted with the surrounding parts, which are the cassette manifold 17 and the sandwich plate 22 for the valve membrane structure 20 on the one hand and the actuator block body 21 and the sandwich plate 22 for the gasket membrane structure 24 on the other hand.

[0067] The use of grooves 29, 30 allows for easy installation and proper positioning of the membrane structures 20, 24 before fastening. Preferably, the shape and number of grooves 29, 30 correspond to the shape and respective number of membrane structures 20, 24. As shown in Figures 2 and 3, the sandwich plate 22 may or may not include grooves 29, 30 on one or both flat surfaces of the sandwich plate 22, and the cassette manifold 17 may include grooves 29, 30 on a flat surface of the cassette manifold 17 that is located opposite the flat front surface 18 of the cassette manifold 17 (Figure 2). The grooves 29, 30 may be introduced into the cassette manifold 17 and / or the sandwich plate 22 by punching, drilling, injection molding, cutting, etc.

[0068] It is particularly advantageous that proper positioning of the membrane structures 20, 24, and in particular the valve membrane structure 20, using the described grooves 29, 30, omits the use of adhesives to fix the membrane structures 20, 24 in a specific position.

[0069] As mentioned above, the valve membrane structure 20 and the gasket membrane structure 24 may differ in terms of material and / or shape, particularly thickness, which is advantageous given that each membrane structure 20, 24 serves a different function. Accordingly, the depth of the grooves 29, 30 may also differ.

[0070] As can be seen in FIG. 2 and FIG. 3, at least a portion of the recess 25 and the perforated hole 23 of the sandwich plate 22 and the perforated hole 27 of the gasket membrane structure 24 are connected to the valve unit n. x,yValve seat s x,y As will be explained in detail below, this is done by aligning the valve units n x,y This will contribute to a reliable switchover.

[0071] Valve unit n x,y The realization of the valve unit n x,y is in the open position (Fig. 4, valve unit n 11,3 ) and closed position (Fig. 4, valve unit n 10,3 ) can be moved between the valves m x,y The membrane valve unit is designed to have the following structure.

[0072] Valve unit n x,y are valve seats s x,y Each of the valves m provided by the valve structure 20 x,y is valve unit n x,y To switch the valve unit x,y ("closed" state), or valve unit s x,y As shown in FIG. 4, each valve unit n x,y For fluid line l p , l s Each of the valves is connected to a transfer fluid line T. Preferably, the transfer fluid line T is connected to a valve seat s x,y The valve seat s x,y is the valve m provided by the valve structure 20 x,y The device may sealingly interact with the

[0073] Valve seat x,y By aligning the recess 25 of the sandwich plate 22, the valve membrane m x,y is the valve seat x,y When disengaged from the valve m x,y A defined protrusion of the valve m is achieved. x,y This is because the bending of the valve membrane m is restricted by the recesses 25 of the sandwich plate 22. x,y Further, the recess 25 in the sandwich plate 22 and the perforated hole 23 in the sandwich plate 22 reduce the mechanical wear of the valve seat s. x,ySince the valve seat s is aligned with the center of the valve seat (Fig. 4), x,y Valvular m x,y A defined engagement is achieved.

[0074] For cost optimization and to enhance proper fixation, the valve membrane structure 20 and / or the gasket membrane structure 24 are preferably provided with membrane strips 31, 32. Here, preferably, the membrane m x,y , g x,y These groups are membrane strips 31, 32.

[0075] It is particularly advantageous if the valvular structure 20 comprises membrane strips 31, since if strips are used, the required membrane material is reduced. In a preferred embodiment, the number of valvular strips 31 is between 2 and 8. In a particularly preferred embodiment, the number of valvular strips 31 is determined by the number of the primary ports p of the valve switching cassette 15. p However, it is also conceivable that the valvular structure 20 is constructed in a single piece. In a particularly preferred embodiment, each valvular strip 31 is connected to a valve seat s x,y In this manner, the amount of valve leaflet material required is significantly reduced while at the same time facilitating easy fixation of the valve leaflet structure 20 to the cassette manifold 17 through the use of membrane strips, as described below.

[0076] Additionally or alternatively, the gasket membrane structure 24 also includes membrane strips 32. In a preferred embodiment, each gasket membrane strip 32 is disposed adjacent the valve seat s x,y However, each strip 32 covers one vertical row of valve seats s x,y The number of gasket membrane strips 32 may be determined by the number of primary ports p of the valve switching cassette 15. p However, it is more preferable that the number of valve seats s x,yIt is also possible to use one gasket membrane strip 32 to cover several rows and / or columns of the gasket membrane structure 24. It is particularly preferred that the number of gasket membrane strips 32 is between 2 and 8. Nevertheless, the gasket membrane structure 24 can also be manufactured as a single piece. Also, the use of strips in the gasket membrane structure 24 requires less material, thereby reducing overall material costs.

[0077] In a preferred embodiment, the number and orientation of the membrane strips 31 of the valvular structure 20 and the membrane strips 32 of the gasket membrane structure 24 are identical. However, it is also conceivable that the number of membrane strips 32 of the gasket membrane structure 24 is greater or less than the number of membrane strips 31 of the valvular structure 20, as well as that the orientation of these strips is different. Preferably, the membrane strips 31, 32 have a particular cross-sectional shape, preferably an arcuate, polygonal, in particular rectangular, shape.

[0078] The above-mentioned grooves 29, 30 in the cassette manifold 17 and / or sandwich plate 22 are particularly beneficial for proper positioning of the leaflet strip 31. By inserting the leaflet strip 31 into the grooves 29, 30 in the cassette manifold 17 and / or sandwich plate 22, the leaflet strip 31 can be completely sealed between the cassette manifold 17 and the sandwich plate 22. In this way, the leaflet strip m x,y In addition to reducing the ingress of bioburden, this containment design also reduces the risk of bioburden ingress between the cassette manifold 17 and the valve membrane. x,y A fluid-tight seal between the valve and the x,y and the sandwich plate 22, thereby contributing to strengthening the air-tight and / or fluid-tight seal between the valve unit n x,y This improves the reliable operation of the valve switching system 1 by ensuring reliable switching of the valve.

[0079] The completely sealed design of the valvular structure 20, as described above, is particularly advantageous in that the fluid lines 11 to the cassette manifold 17 p , l s and valve seat sx,y The only potential entry point for contaminants (e.g., bacteria) in this case is the perforations 23 in the sandwich plate 22. However, even if contaminants attempt to enter the valve switching cassette 15 through the perforations 23, they will not be able to enter the fluid lines 11. p , l s and valve seat s x,y The entry into the cassette manifold 17 and the valvular structure 20, particularly the valvular m x,y 20。 Additionally, the valvular structure 20 is protected from damage by the sealed and encapsulated design.

[0080] No adhesive is required to secure the leaflet strips 31 prior to assembly, as the grooves 29, 30 in the sandwich plate 22 and / or cassette manifold 17 can be used for proper positioning of the leaflet strips 31. This greatly simplifies the manufacturing process and eliminates all of the disadvantages of using adhesives discussed in this application. However, as mentioned above, adhesives may still be used to secure the leaflet structure 20.

[0081] 2 and 3, fixing elements 33, such as screws, are passed between the leaflet strips 31. This significantly simplifies the installation and manufacture of the leaflet structure 20, since the leaflet structure 20 does not need to be provided with additional holes or the like for passing the fixing elements 33. The leaflet strips 31 are indirectly fixed between the cassette manifold 17 and the sandwich plate 22 by the fixing elements 33.

[0082] To ensure leak-free operation of the valve switching system 1 and to prevent the ingress of contaminants (e.g., bacteria) into the cassette manifold 17, a fluid-tight, secure mechanical connection needs to be established between the cassette manifold 17 and the valvular membrane structure 20. In addition, to allow reliable passage of gas or liquid from the actuation outlet 28 to the valvular membrane structure 20, the mechanical connection between the actuation outlet 28 and the sandwich plate 22 needs to be gas-tight or liquid-tight. As the gasket membrane structure 24 and the sandwich plate 22 are disposed between the valvular membrane structure 20 and the actuation outlet 28, they also need to be connected in a fluid-tight or gas-tight manner.

[0083] The mechanical connection between the cassette manifold 17 and the valvular structure 20 may be achieved using an adhesive. The adhesive may be applied directly to the valvular structure 20 and / or the cassette manifold 17.

[0084] Here, it is further preferred that the cassette manifold 17 comprises an adhesive channel system (not shown) for introducing adhesive. The adhesive channel system may be machined into the cassette manifold 17 by injection molding, drilling, etc. The adhesive channel system is connected to the valve membrane structure 20, in particular the valve membrane m. x,y The cassette manifold 17 may also include a riser channel for introducing adhesive after the valvular structure 20 is already positioned on the cassette manifold 17. Furthermore, as the adhesive is applied to the channel system, the adhesive can be applied in a defined manner and the application can be controlled. The advantage here is that the adhesive is applied in a reproducible and consistent manner. Furthermore, since the riser channel allows for application of adhesive when the valvular structure 20 is already positioned, the valvular structure m can be applied before it is fixed to the cassette manifold 17. x,y This simplifies fixation of the valvular structure 20.

[0085] The mechanical connection between the cassette manifold 17 and the sandwich plate 22 may be realized in a removable or non-removable manner.

[0086] The removable connection may be realized using a suitable number of fastening elements 33 (FIGS. 2 and 3), such as screws. Preferably, the sandwich plate 22 and the cassette manifold 17 are provided with fastening holes for inserting the fastening elements 33. This allows for the reuse of certain parts (e.g., the sandwich plate 22), if required. Alternatively, such a removable connection may be realized by clamps or the like.

[0087] According to another preferred embodiment, a non-removable connection may be realized between the sandwich plate 22 and the cassette manifold 17. Preferably, such a mechanical connection may be realized by diffusion bonding, adhesives, rivets, welding, etc. Such a non-removable connection is particularly desirable to reduce the ingress of bioburden. In addition, as already mentioned above, a permanent connection may also be required by regulatory authorities.

[0088] If the cassette manifold 17 and the sandwich plate 22 are connected in a non-removable manner, the valvular structure 20 is preferably connected to both components by clamping the valvular structure 20 between the cassette manifold 17 and the sandwich plate 22, without the need for fastening elements or adhesives. In this case, the sandwich plate 22 is sealingly engaged with the cassette manifold 17, enclosing and / or fixing the valvular structure 20.

[0089] As mentioned above, the valve switching cassette 15 is preferably designed as a single use component. Additionally or alternatively, the actuator block 16 is preferably a multi-use component.

[0090] The mechanical connection between the pre-assembled valve switching cassette 15 (comprising the sandwich plate 22 and the valve membrane structure 20, and preferably also the gasket membrane structure 24) and the actuator block 16 is preferably a detachable connection, which can be realized in different ways. For example, the connection can be achieved by applying pressure to the valve switching cassette 15 and the actuator block 16 in order to bond both parts, preferably in a mold. In an alternative embodiment, the actuator block 16 may be provided with openings for the insertion of fixing elements 33, such as screws (FIG. 3).

[0091] Additionally or alternatively, the valvular membrane structure 20 and / or the gasket membrane structure 24 may be fixed to the sandwich plate 22, in particular using an adhesive. The advantage here is that the adhesive does not come into contact with the process fluid, and as a result does not have to follow the same stringent requirements as would be required if the adhesive were in contact with the cassette manifold 17 and thus potentially with the process fluid. For example, the adhesive does not have to be certified as Class VI according to General Chapter 88 of the United States Pharmacopeia and National Formulary (USP-NF). As a result, the variety of adhesives to choose from increases. In addition, the material of the sandwich plate 22 can also be optimized for an optimal bond between the valvular membrane structure 20 and the sandwich plate 22. This is particularly advantageous when the valvular membrane material is limited to FKM, since the material of the sandwich plate 22 can be selected to be compatible with the adhesive used for the bond.

[0092] The mechanical connection between the gasket membrane structure 24 and the sandwich plate 22 is achieved by the gas or hydraulic pressure of the valve membrane m x,y In order to allow reliable operation of the device, it must be air-tight or liquid-tight.

[0093] The gasket membrane structure 24 and the sandwich plate 22 are preferably connected by adhesive. The adhesive connection is particularly simple since the adhesive does not come into contact with the process fluid, reducing the adhesive requirements. In particular, the adhesive does not need to be certified as Class VI according to USP-NF General Chapter 88, as mentioned above.

[0094] The gasket membrane structure 24 may be connected to the sandwich plate 22 before or after sterilization. It is preferred that the gasket membrane structure 24 is connected to the sandwich plate 22 before sterilization. In this case, the adhesive must be compatible with the sterilization conditions, which means that it must maintain its structural integrity and maintain the connection between the sandwich plate 22 and the gasket membrane structure 24 during and after sterilization. In a preferred embodiment, the adhesive must withstand a certain level of gamma radiation without losing its bonding ability and / or structural integrity. Preferably, the dose level of gamma radiation that the adhesive must withstand is between 25 and 75 kGy, preferably 50 kGy.

[0095] The valve switching cassette 15, which includes the cassette manifold 17, the valve membrane structure 20, the sandwich plate 22, and preferably also the gasket membrane structure 24, can be pre-assembled and sterilized independently of the actuator block 16. During installation, only the pre-assembled and already sterilized valve switching cassette 15 needs to be connected to the actuator block 16. This greatly simplifies the installation procedure as the operator needs to assemble and connect fewer parts.

[0096] As described above and shown in FIG. 4, the actuator block 16 includes actuators for acting on the valvular structure 20, specifically the valve m. x,y Through the actuation outlet 28, pressure, preferably by gas or liquid, is applied to the valve membrane m x,y In a particularly preferred embodiment, compressed air pressure is used for actuation.

[0097] The valvular structure 20 is actuated by applying hydraulic or gas pressure through the actuation outlet 28. In particular, the valvular structure m x,y is actuated, so that the valvular structure 20 contacts the valve seat s x,y This is the valve unit n 10,34. When liquid or gas pressure is applied, the pressure of the process fluid distributed inside the cassette manifold 17 is applied to the valve membrane structure 20, in particular the valve membrane m x,y 2 is bent relative to the recess 25 of the sandwich plate 22. As a result of this bending, the valve m x,y is the valve seat x,y This means that the valve unit n 11,3 This is shown in Figure 4.

[0098] The term "sealingly engages" refers to the valve structure 20 and the valve seat s x,y and "disengaging from sealing engagement" refers to establishing a fluid-tight seal, typically a press-fit engagement, between the valvular structure 20 and the valve seat s. x,y It may include loose contact between the casing and the housing, but it may be noted that this is not fluid tight.

[0099] A particular advantage of actuating the valve structure 20 by gas or hydraulic pressure is that the pressure can be precisely controlled, so that the valve unit n can be moved between open and closed positions, or between closed and open positions, in a controlled and coordinated manner. x,y can be switched.

[0100] As shown in Fig. 4, a control valve 34 may be used to control the pressure in the actuation outlet 28. When the control valve 34 is open (indicated by the letter "o" in Fig. 4), the pressure introduced into the recess 25 through the actuation outlet 28 is increased by the process fluid flow F through the valve membrane m x,y If the pressure applied to the valve m is greater than the pressure applied to the valve m, as explained above, x,y When the control valve 34 is closed (indicated by the letter "c" in FIG. 4), the current pressure is maintained in the recess 25. The valve membrane m x,y The bending of the recess 25 can be precisely controlled. It is also conceivable that the control valve 34 is a blow-off valve that maintains a certain pressure within the recess 25.

[0101] The actuator block 16 may be controlled by an electronic control (not shown), preferably including a microprocessor, operated on the basis of control software, where it becomes apparent that with only corresponding modifications of the control software, the complete process fluid flow F can be flexibly and precisely controlled electronically.

[0102] According to the independent teaching, a bioprocessing installation 2 is claimed as such. The proposed bioprocessing installation 2 comprises a chromatography device 5 having a number of chromatography columns 6-13 connected to a proposed valve switching system 1 as shown in Figure 1, for carrying out, for example, a simulated moving bed (SMB) chromatography process. Reference is made to all explanations given with respect to the first teaching.

[0103] 5 shows an exemplary operation of the proposed valve switching system 1. Here, it becomes clear that many variations in the sequential and parallel use of the chromatography columns 6-13 are possible. Chromatography columns 6, 7, 8 are sequentially used, while chromatography column 10 is used in parallel therewith. In general, a fluid flow F is introduced into the primary port P of the first fluid flow system 18. p from any one of the inlets provided by the second fluid flow system 19 to the secondary fluid port p s Any number of chromatography columns 6-13 can be utilized in any desired manner, either sequentially or in parallel, directed to any one of the outlets provided by

[0104] Further independent teachings are directed to the use of the proposed valve switching system 1 for switching chromatography columns 6-13 of a chromatography apparatus 5 for carrying out a simulated bed chromatography (SMB) process. Again, reference is made to all explanations given for the previous teachings.

Claims

1. A valve switching system for selectively interconnecting components of a bioprocessing facility (2), comprising a valve switching cassette (15) and an actuator block (16), said valve switching cassette (15) connecting a primary fluid line (L ｐ ) and a primary port (P ｐ ) and the secondary fluid line (L ｓ ) and a secondary port (P ｓ ), the valve switching cassette (15) is connected to the primary fluid line (L) via a transfer fluid line (T). ｐ ) to the secondary fluid line (L ｓ ) and a switchable valve unit (n ｘ，ｙ ), wherein the valve units (n ｘ，ｙ ) are the valve seats (s ｘ，ｙ ), and the valve switching cassette (15) includes a valve unit (n ｘ，ｙ ) to selectively switch the valve seat (s ｘ，ｙ ), the actuator block (16) includes a valve structure (20) that can engage with each valve unit (n ｘ，ｙ An actuator block body (21) having an actuator for The valve switching cassette (15) includes a perforated sandwich plate (22) having perforated holes (23), the sandwich plate (22) is disposed between the cassette manifold (17) and the actuator block body (21), the valve membrane structure (20) is disposed between the cassette manifold (17) and the sandwich plate (22), a gasket membrane structure (24) is disposed between the actuator block body (21) and the sandwich plate (22), and the valve unit (n ｘ，ｙ To selectively switch the valve seat (s), an actuator of the actuator block (16) is ｘ，ｙ The valvular structure (20) can be actuated through the perforations (23) to selectively engage with at least one valve leaflet (m) made of a first material, and the valvular structure (20) can be actuated through the perforations (23) to selectively engage with at least one valve leaflet (m) made of a first material. ｘ，ｙ ), and the gasket membrane structure (24) comprises at least one gasket membrane (g) composed of a second material different from the first material. ｘ，ｙ ).

2. The first material has a higher hardness than the second material, and / or the second material has a higher porosity than the first material, and / or at least one valve membrane (m ｘ，ｙ ) is at least one gasket membrane (g ｘ，ｙ 2. The valve switching system of claim 1, wherein the valve switching system is thinner than a first connecting member.

3. 3. The valve switching system of claim 1 or 2, wherein the first material is a first elastomer and the second material is a second elastomer different from the first elastomer.

4. At least one valve (m) of the valve structure (20) ｘ，ｙ ) is made of a fluorocarbon-based fluoroelastomer material (FKM); and / or At least one gasket membrane (g) of the gasket membrane structure (24) ｘ，ｙ ) are composed of thermoplastic polyesters (e.g., Hytrel®) or thermoplastic vulcanizates (e.g., Santroprene™) or polychloroprene; A valve switching system according to any one of claims 1 to 3.

5. 5. The valve switching system according to claim 1, wherein the gasket membrane structure (24) is perforated with perforation holes (27), and at least some of the perforation holes (27) of the gasket membrane structure (24) are aligned with at least some of the perforation holes (23) of the sandwich plate (22).

6. 6. The valve switching system according to claim 1, wherein the cassette manifold (17) and / or the sandwich plate (22) are provided with grooves (29, 30) for inserting the valve membrane structure (20) and / or the gasket membrane structure (24).

7. At least a portion of the perforations (23) of the sandwich plate (22) and the perforations (27) of the gasket membrane structure (24) are connected to the valve unit (n ｘ，ｙ ) of the valve seat (s ｘ，ｙ 7. A valve switching system (1) according to any one of claims 1 to 6, characterized in that it is aligned with the

8. The valve (m ｘ，ｙ ) and / or the gasket membrane (g ｘ，ｙ 8. A valve switching system (1) according to any one of claims 1 to 7, characterized in that the valves (31, 32) are provided with membrane strips (31, 32).

9. The valve switching system (1) according to any one of claims 1 to 8, characterized in that the sandwich plate (22) is sealingly engaged with the cassette manifold (17) and encapsulates and / or fixes the valve membrane structure (20).

10. 10. A valve switching system (1) according to any one of claims 1 to 9, characterized in that the valve membrane structure (20) and / or the gasket membrane structure (24) are fixed to the sandwich plate (22), preferably by means of an adhesive.

11. 11. A valve switching system (1) according to any one of claims 1 to 10, characterized in that each actuator of the actuator block (16) is provided with an actuation outlet (28), preferably a gas pressure outlet or a hydraulic pressure outlet, which communicates with an assigned valve seat through a drilled hole (23) in the sandwich plate (22).

12. A bioprocessing installation comprising a chromatography device (5) having a plurality of chromatography columns (6 to 13) connected to a valve switching system (1) according to any one of claims 1 to 11 for carrying out a simulated bed chromatography (SMB) process.

13. Use of the valve switching system according to any one of claims 1 to 11 for switching the chromatographic columns (6-13) of a chromatographic device (5) for performing a simulated bed chromatography (SMB) process.

Images