Food steamer type continuous adsorption separation device

Abstract

The utility model belongs to the technical field of adsorption separation of bioengineering products, and discloses a food steamer type continuous adsorption separation device. The device comprises a plurality of adsorption column units which are overlaid together like a food steamer, continuous adsorption separation of a feed liquid target product is achieved through multi-pipeline switching cooperation, and a liquid inlet pipe and a liquid outlet pipe between every two adjacent adsorption column units are connected through a quick connector. A bearing wall and a supporting wall are respectively arranged above and below the adsorption column unit and are used for supporting and connecting adjacent units. The whole adsorption column unit is of a flat structure with the diameter-height ratio larger than 2, adsorption of a saturated layer in a conventional chromatographic column can be rapidly completed, and the next procedure treatment is carried out. The column pressure of the adsorption column unit can adopt filler with smaller granularity, so that the resolution ratio during purification and the adsorption loading capacity of the unit column material are improved. A plurality of adsorption column units are switched and matched through multiple pipelines, so that the filler use efficiency can be greatly improved, the production efficiency is improved, meanwhile, the reagent use amount is reduced, and pollutant emission is reduced.

Description

Technical Field

[0001] The utility model relates to the technical field of adsorption and separation of bioengineering products, in particular to a cage-type continuous adsorption and separation device. Background Art

[0002] In the downstream purification of bioengineering, the use of resin fillers for adsorption separation purification or chromatography purification is one of the most effective methods in modern separation methods, especially in the separation and purification of biological macromolecules (including viruses, proteins, nucleic acids and polysaccharides, etc.). Due to its good purification effect, various impurities such as heat sources, viruses, miscellaneous proteins and impure nucleic acids, various aggregates, etc. can be effectively separated, so that the target product can reach a very high purity. Therefore, the use of chromatography for adsorption separation purification is almost a necessary step in the production of modern biopharmaceuticals.

[0003] Chromatographic adsorption separation methods are expensive to produce, with chromatography-related costs accounting for 60%-80% of the production cost of biomacromolecule drugs. This is primarily due to two factors: fixed investment costs, such as chromatography columns, chromatography systems, liquid preparation systems, and supporting storage tanks; and consumables, such as resin packings that require regular replacement, and the large quantities of buffers, eluents, and cleaning fluids used. Optimization and innovation in these two areas can significantly reduce costs, either by reducing procurement costs or improving production efficiency, while maintaining the same production scale.

[0004] The fixed bed chromatography columns used in production are mostly cylindrical in shape, with liquid entering from the top and exiting from the bottom, such as Figure 3 As shown in the figure, during the top-down adsorption process of the feed liquid, the top section (Zone I) reaches saturation first due to the long contact time between the stationary phase of the filler and the injection mobile phase. The middle section (Zone II) is the adsorption section where low adsorption transitions to saturated adsorption. The bottom section (Zone III) is the section to be adsorbed where no adsorption has occurred.

[0005] The continuous ion exchange process (ISEP) is a technology developed by AST Corporation in the United States in the mid-1980s. It consists of a horizontal rotating disk and dozens of fixed-bed chromatography columns. The fixed bed and the rotating disk rotate at a constant rate. For every 360° rotation, each fixed-bed chromatography column undergoes a cycle of equilibrium-adsorption-cleaning-elution-regeneration. This ensures continuous, 24-hour operation of each fixed-bed column, overcoming many of the shortcomings of intermittent fixed-bed adsorption columns. ISEP was initially used primarily in industrial and laboratory applications for deashing with potassium sulfate, potassium nitrate, amino acids, and citric acid, achieving excellent economic benefits. Practice has shown that this method can reduce resin usage by 30%-80%, reagent usage by 20%-60%, and wastewater discharge by approximately 50%, resulting in corresponding savings in production space. Subsequently, the technology has been applied to other fields, such as the molecular sieve preparation described in patents such as US4346067 and US3948760, with promising results.

[0006] Since ISEP technology gradually became known in China in the late 1990s, some of its concepts have been applied in production practices. Patent CN221235310U applies a continuous ion exchange method to treat acidic organic wastewater, achieving continuous treatment of acidic organic wastewater and reducing environmental pollution. Patents CN202516562U and CN201823538U apply this technology to the continuous decolorization and deacidification of juice and the production of organic acids, respectively, saving reagent usage and improving production efficiency. Patents CN207941534U, CN112191280A, CN216499413U, CN1108586A, CN01518749A, and CN104275215A apply this technology to the preparation of molecular sieves, improving product quality and reducing costs. Patents CN108893605A, CN110004306A, CN104355452A, CN107058753A, and CN201825993U apply continuous ion exchange technology to the extraction and recovery of rare metals such as lithium, gallium, and nickel, significantly improving efficiency and enabling comprehensive resource utilization. Patents CN 214514626 U and CN1443751A respectively utilize continuous flow technology for the production of vitamin C and amino acids, saving production space and costs while reducing emissions.

[0007] The above inventions and innovations have, to a certain extent, achieved the transition from single-column fixed-bed intermittent production to multi-column simulated mobile continuous production, thereby improving production efficiency, reducing material consumption, and reducing pollution emissions. It can be seen that the connection of the above multi-columns basically continues the early "carousel"-like multi-column series connection, and the size of the single column remains basically unchanged. It only changes the simple increase in the number of chromatography columns to save materials and reduce waste emissions through series operation. In addition, the above inventions are basically only applied to the field of chemical small molecule production. The production operations in this field are relatively extensive, and the requirements for filler resins and chromatography columns are not very strict. The resin particles are large (millimeter level) and have a wide particle size distribution. Ordinary resin columns are even replaced by long reaction tanks. Some resins are even used in suspension and can be transferred with liquid between different chromatography columns. In the field of biological macromolecule purification, which has very high requirements for fillers and chromatography columns, such as the purification of biological drugs such as proteins, nucleic acids, and polysaccharides, the above methods and devices are difficult to implement, and there are few reports in the existing literature. The fillers generally used in the purification of large-molecule biological drugs are micron-sized, and most of the average particle sizes are concentrated in tens of microns. This places higher requirements on the filling of the fillers, pressure resistance and flow rate, purification effect, production cost and efficiency.

[0008] In summary, the chromatography columns in the prior art are operated intermittently. In addition to the long adsorption process, the entire chromatography process steps of equilibrium-adsorption-cleaning-elution-regeneration must be performed intermittently in sequence. The packed material cannot be fully utilized, the production time is long, the amount of reagent solution used is large, and the corresponding waste liquid is generated. In addition, due to the relatively small diameter height of the packed material, it is easy to cause stigma clogging after repeated use, and the column pressure increases. During production, no matter where in the upper, middle, or lower section of the chromatography column there is an abnormality, the basic chromatography column must be unloaded and reloaded, delaying production. Utility Model Content

[0009] The purpose of the utility model is to provide a cage-type continuous adsorption separation device to solve the problems raised in the above background technology.

[0010] To achieve the above objectives, the present invention provides the following technical solutions:

[0011] A cage-type continuous adsorption and separation device comprises a plurality of adsorption column units, each having a liquid inlet connected to the center of its bottom and a liquid outlet connected to the center of its top. A receiving wall is provided on the top of each adsorption column unit, and a supporting wall is provided on the bottom of each adsorption column unit. Adjacent adsorption column units are connected by the receiving and supporting walls, and the liquid inlet and outlet pipes between adjacent adsorption column units are connected by quick-connect connectors. The adsorption column units can be made of inorganic glass, organic glass (PMMA), PC plastic, PET, transparent nylon, AS, PVC, PP, or stainless steel with a window.

[0012] Further preferably, the adsorption column unit as a whole is a flat structure with a diameter-to-height ratio greater than 2.

[0013] Further preferably, each of the adsorption column units is connected to a fermentation liquid inlet pipe, a balance liquid inlet pipe, an eluent inlet pipe and an alkali liquid inlet pipe through a liquid inlet pipe, and the liquid inlet pipe, the fermentation liquid inlet pipe, the balance liquid inlet pipe, the eluent inlet pipe and the alkali liquid inlet pipe are all provided with solenoid valves.

[0014] Further preferably, the inlet ends of the fermentation liquid inlet pipe, the balance liquid inlet pipe, the eluent inlet pipe and the alkali liquid inlet pipe are also connected to liquid delivery pumps respectively.

[0015] Further preferably, each of the adsorption column units is connected to a balance liquid outlet pipe, a sample liquid outlet pipe, an eluent outlet pipe and a regeneration liquid outlet pipe through a liquid outlet pipe, and solenoid valves are provided on the liquid outlet pipe, the balance liquid outlet pipe, the sample liquid outlet pipe, the eluent outlet pipe and the regeneration liquid outlet pipe.

[0016] Further preferably, the top of the receiving wall and the bottom of the supporting wall are both provided with a step-shaped or concave-convex structure, and the receiving wall and the supporting wall are supported and connected to each other through the step-shaped or concave-convex structure.

[0017] Further preferably, a distribution tray is provided at one end of the adsorption column unit near the liquid inlet pipe, with a first filter screen disposed on the surface of the distribution tray. A second filter screen is provided at one end of the adsorption column unit near the liquid outlet pipe, a liquid collection tray is provided between the second filter screen and the liquid outlet pipe, and a filler is provided between the first and second filters. The filler material in the adsorption column unit can be agarose, dextran, cellulose, polystyrene, polymethacrylic acid, silica gel, hydroxyapatite, and their derivatives.

[0018] Further preferably, handles are symmetrically provided on the outside of the adsorption column unit.

[0019] Further preferably, the opening and closing of the plurality of liquid delivery pumps and the plurality of solenoid valves, as well as the liquid inlet and outlet amounts, are all controlled by a preset program.

[0020] Compared with the prior art, the beneficial effects of the present invention are:

[0021] The adsorption column unit is a flat structure with a diameter-to-height ratio greater than 2, which can quickly complete the adsorption of the saturated layer in conventional chromatography columns and proceed to the next process step. The flat structure of the adsorption column unit significantly reduces column pressure and avoids the phenomenon of increased column pressure caused by contamination of the head of conventional adsorption columns. The low column pressure allows the use of smaller particle size fillers, which can improve both purification resolution and adsorption capacity per unit column material. Adding or removing adsorption column units is extremely convenient, facilitating the scale-up or scale-down of production. If a problem occurs in an adsorption column unit, such as a column bed collapse, it can be quickly replaced in parallel with a spare adsorption column unit without the complete removal and reinstallation of fillers required in traditional fixed-bed columns, minimizing production downtime. This significantly improves production efficiency, reduces material loss and waste liquid discharge, and conserves production space. Compared to continuous adsorption separation using traditional fixed-bed columns, it offers higher efficiency. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 This is a schematic diagram of the adsorption column unit structure of the utility model;

[0023] Figure 2 It is a schematic diagram of the overall structure of the utility model;

[0024] Figure 3 Schematic diagram of the structure of a traditional fixed bed adsorption column;

[0025] In the figure: 1. Fermentation liquid inlet pipe; 2. Balance liquid inlet pipe; 3. Eluent inlet pipe; 4. Alkali liquid inlet pipe; 5. Balance liquid outlet pipe; 6. Sample liquid outlet pipe; 7. Eluent outlet pipe; 8. Regeneration liquid outlet pipe; 9. Adsorption column unit; 10. Liquid inlet pipe; 11. Liquid outlet pipe; 12. Receiving wall; 13. Support wall; 14. Distribution plate; 15. Liquid collection plate. DETAILED DESCRIPTION

[0026] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0027] See also Figure 1-2 , the utility model provides a technical solution:

[0028] A cage-type continuous adsorption and separation device includes multiple adsorption column units 9. The bottom center of the adsorption column unit 9 is connected to a liquid inlet pipe 10, the top center of the adsorption column unit 9 is connected to a liquid outlet pipe 11, the top of the adsorption column unit 9 is provided with a receiving wall 12, and the bottom of the adsorption column unit 9 is provided with a support wall 13. Two adjacent adsorption column units 9 are connected to each other through the receiving wall 12 and the support wall 13, and the liquid inlet pipe 10 and the liquid outlet pipe 11 between two adjacent adsorption column units 9 are connected by a quick-connect joint. The material of the adsorption column unit 9 can be selected from inorganic glass, organic glass (PMMA), PC plastic, PET, transparent nylon, AS, PVC, PP or stainless steel with a window.

[0029] In the present invention, the adsorption column unit 9 is a flat structure with a diameter-to-height ratio greater than 2.

[0030] In the present invention, each adsorption column unit 9 is connected to a fermentation liquid inlet pipe 1, a balance liquid inlet pipe 2, an eluent inlet pipe 3, and an alkali liquid inlet pipe 4 via a liquid inlet pipe 10, and electromagnetic valves are provided on the liquid inlet pipe 10, the fermentation liquid inlet pipe 1, the balance liquid inlet pipe 2, the eluent inlet pipe 3, and the alkali liquid inlet pipe 4. The inlet ends of the fermentation liquid inlet pipe 1, the balance liquid inlet pipe 2, the eluent inlet pipe 3, and the alkali liquid inlet pipe 4 are also connected to liquid delivery pumps, respectively. Each adsorption column unit 9 is connected to a balance liquid outlet pipe 5, a sample liquid outlet pipe 6, an eluent outlet pipe 7, and a regeneration liquid outlet pipe 8 via a liquid outlet pipe 11, and electromagnetic valves are provided on the liquid outlet pipe 11, the balance liquid outlet pipe 5, the sample liquid outlet pipe 6, the eluent outlet pipe 7, and the regeneration liquid outlet pipe 8. It is convenient to automatically switch each electromagnetic valve and the liquid delivery pump on and off according to a preset time through the control system.

[0031] In the present invention, the top of the receiving wall 12 and the bottom of the supporting wall 13 are both provided with a stepped or concave-convex structure, and the receiving wall 12 and the supporting wall 13 are supported and connected to each other through the stepped or concave-convex structure.

[0032] In the present invention, a distribution tray 14 is provided at one end of the adsorption column unit 9 near the liquid inlet pipe 10. A first filter is provided on the surface of the distribution tray 14. A second filter is provided at one end of the adsorption column unit 9 near the liquid outlet pipe 11. A liquid collection tray 15 is provided between the second filter and the liquid outlet pipe 11. A filler is provided between the first and second filters. The filler material within the adsorption column unit 9 can be agarose, dextran, cellulose, polystyrene, polymethacrylic acid, silica gel, hydroxyapatite, and their derivatives.

[0033] In the present invention, handles are symmetrically provided on the outside of the adsorption column unit 9 .

[0034] Example: Taking the purification of recombinant protein A using nickel chelate agarose as an example, when using, Figure 1As shown, an adsorption column unit 9 with a diameter of 20 cm and a height of 2 cm was used, and nickel-chelated high-flow agarose was used as the filler. Before combining multiple adsorption column units 9, detailed parameters such as the amount of each liquid, column flow time, pressure, and product concentration of the equilibrium liquid (cleaning liquid), feed liquid, eluent, and regeneration liquid passing through a single adsorption column unit 9 were pre-tested. Based on the measured parameters, six adsorption column units 9 were determined for use in combination.

[0035] like Figure 2 As shown, the six adsorption column units 9 are supported and connected to each other by step-shaped or concave-convex structures provided at the top of the receiving wall 12 and the bottom of the supporting wall 13. The liquid inlet pipe 10 and the liquid outlet pipe 11 between two adjacent adsorption column units 9 are connected by quick-connect joints. The ends of the topmost liquid outlet pipe 11 and the bottommost liquid inlet pipe 10 are provided with plugs. The six adsorption column units 9 are stacked together in a cage-like manner. Each adsorption column unit 9 is connected to the fermentation liquid inlet pipe 1, the balance liquid inlet pipe 2, the eluent inlet pipe 3 and the alkali liquid inlet pipe 4 through the liquid separation plate 14 and the liquid inlet pipe 10. Solenoid valves are provided on the liquid inlet pipe 10, the fermentation liquid inlet pipe 1, the balance liquid inlet pipe 2, the eluent inlet pipe 3 and the alkali liquid inlet pipe 4. The inlet ends of the balance liquid inlet pipe 2, the eluent inlet pipe 3 and the alkaline solution inlet pipe 4 are also connected to liquid delivery pumps respectively. Each adsorption column unit 9 is connected to the balance liquid outlet pipe 5, the sample liquid outlet pipe 6, the eluent outlet pipe 7 and the regeneration liquid outlet pipe 8 through the liquid collecting tray 15 and the liquid outlet pipe 11.

[0036] First, the balancing liquid enters the balancing liquid through the balancing liquid inlet pipe 2, that is, PBS containing 10mm imidazole to balance the adsorption column unit 9. The balancing liquid is balanced from bottom to top by the inlet pipe 10 and the outlet pipe 11 of the adsorption column unit 9. After the balance of the first adsorption column unit 9 at the bottom is completed, the fermentation liquid enters the pipe 1 to enter the protein A fermentation liquid after the initial treatment, that is, the fermentation liquid is broken, centrifuged and microfiltered, and the fermentation liquid is clarified. After the adsorption of the first adsorption column unit 9 is completed, the fermentation liquid continues to enter the balancing liquid through the balancing liquid inlet pipe 2 to wash away the weakly adsorbed excess. Then the eluent enters the PBS containing 100mm imidazole through the eluent inlet pipe 3 to elute the adsorbed target protein A. Then the balancing liquid continues to enter the balancing liquid through the balancing liquid inlet pipe 2 to re-balance the adsorption column unit 9 and enter the next cycle.

[0037] Other adsorption column units 9 repeat the above steps of the previous adsorption column unit 9 in sequence according to the conditions determined by the preliminary experiment.

[0038] The above steps can be performed based on the results of preliminary experiments. For example, after running 30 cycles, alkali solution is introduced from the alkali solution inlet pipe 4 to perform a regeneration treatment on the agarose filler.

[0039] The balance liquid outlet pipe 5, the sample liquid outlet pipe 6, the eluent outlet pipe 7 and the regeneration liquid outlet pipe 8 are respectively the recovery pipelines or discharge pipelines of the balance liquid, the sample liquid, the eluent and the regeneration liquid.

[0040] Experiments using this method have shown that, compared with conventional fixed-bed batch operation, processing the same amount of liquid, while using half the amount of nickel-chelated high-flow agarose resin, production time is reduced by approximately one-third, reagent liquid usage is halved, and product yield and purity indicators meet acceptable standards. Further expansion will further enhance these advantages.

[0041] The adsorption column unit 9 as a whole is a flat structure with a diameter-to-height ratio greater than 2, which can quickly complete the adsorption of the saturated layer in a conventional chromatography column and enter the next step of process processing. The overall column pressure of the adsorption column unit 9 with a flat structure will be greatly reduced, and the phenomenon of increased column pressure caused by contamination of the conventional adsorption column head can also be avoided. The ability to use fillers with smaller particle sizes can improve the resolution during purification and the adsorption load per unit column material. It is extremely convenient to increase or decrease the adsorption column units 9, which facilitates the expansion or reduction of production scale. If a problem occurs in a certain adsorption column unit 9, such as the collapse of the column bed, it can be quickly replaced in parallel with another adsorption column unit 9, and the filler does not need to be completely removed and reinstalled like a traditional fixed bed column, which can minimize the loss of production suspension. It greatly improves production efficiency, reduces material loss and waste liquid discharge, and saves production space. Compared with the continuous adsorption separation composed of a traditional fixed bed, it is more efficient.

[0042] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the present invention can be implemented in other specific forms without departing from the spirit or essential features of the present invention. Therefore, the embodiments should be considered in all respects as illustrative and non-restrictive, and the scope of the present invention is defined by the appended claims rather than the foregoing description. It is intended that all variations within the meaning and range of equivalents of the claims be encompassed within the present invention, and any reference numerals in the claims should not be construed as limiting the claims to which they relate.

[0043] The above is only a preferred specific implementation method of the present invention, but the protection scope of the present invention is not limited to this. Any technician familiar with the technical field within the technical scope disclosed by the present invention can make equivalent replacements or changes based on the technical solution and utility model concept of the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A cage-type continuous adsorption separation device, characterized in that: The invention comprises a plurality of adsorption column units (9), wherein the bottom center of each adsorption column unit (9) is connected to a liquid inlet pipe (10), the top center of each adsorption column unit (9) is connected to a liquid outlet pipe (11), the top of each adsorption column unit (9) is provided with a receiving wall (12), the bottom of each adsorption column unit (9) is provided with a supporting wall (13), two adjacent adsorption column units (9) are connected to each other through the receiving wall (12) and the supporting wall (13), and the liquid inlet pipe (10) and the liquid outlet pipe (11) between the two adjacent adsorption column units (9) are connected through a quick-connect joint.

2. The cage-type continuous adsorption separation device according to claim 1, characterized in that: The adsorption column unit (9) is a flat structure with a diameter-to-height ratio greater than 2.

3. The cage-type continuous adsorption separation device according to claim 1, characterized in that: Each of the adsorption column units (9) is connected to a fermentation liquid inlet pipe (1), a balance liquid inlet pipe (2), an eluent inlet pipe (3) and an alkali liquid inlet pipe (4) via a liquid inlet pipe (10), and electromagnetic valves are provided on the liquid inlet pipe (10), the fermentation liquid inlet pipe (1), the balance liquid inlet pipe (2), the eluent inlet pipe (3) and the alkali liquid inlet pipe (4).

4. The cage-type continuous adsorption separation device according to claim 3, characterized in that: The inlet ends of the fermentation liquid inlet pipe (1), the balance liquid inlet pipe (2), the eluent inlet pipe (3) and the alkali liquid inlet pipe (4) are also connected to liquid delivery pumps respectively.

5. The cage-type continuous adsorption separation device according to claim 1, characterized in that: Each of the adsorption column units (9) is connected to a balance liquid outlet pipe (5), a sample liquid outlet pipe (6), an eluent outlet pipe (7) and a regeneration liquid outlet pipe (8) via a liquid outlet pipe (11), and solenoid valves are provided on the liquid outlet pipe (11), the balance liquid outlet pipe (5), the sample liquid outlet pipe (6), the eluent outlet pipe (7) and the regeneration liquid outlet pipe (8).

6. The cage-type continuous adsorption separation device according to claim 1, characterized in that: The top of the receiving wall (12) and the bottom of the supporting wall (13) are both provided with a step-shaped or concave-convex structure, and the receiving wall (12) and the supporting wall (13) are mutually supported and connected via the step-shaped or concave-convex structure.

7. The cage-type continuous adsorption separation device according to claim 1, characterized in that: A distribution plate (14) is provided at one end of the adsorption column unit (9) near the liquid inlet pipe (10), and a first filter is provided on the surface of the distribution plate (14). A second filter is provided at one end of the adsorption column unit (9) near the liquid outlet pipe (11), and a liquid collection plate (15) is provided between the second filter and the liquid outlet pipe (11), and a filler is filled between the first filter and the second filter.

8. The cage-type continuous adsorption separation device according to claim 1, characterized in that: A handle is symmetrically provided on the outside of the adsorption column unit (9).

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