WO2020258705A1 - 模块化层析装置 - Google Patents

模块化层析装置 Download PDF

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Publication number
WO2020258705A1
WO2020258705A1 PCT/CN2019/120926 CN2019120926W WO2020258705A1 WO 2020258705 A1 WO2020258705 A1 WO 2020258705A1 CN 2019120926 W CN2019120926 W CN 2019120926W WO 2020258705 A1 WO2020258705 A1 WO 2020258705A1
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Prior art keywords
chromatography
module
basic
valve
modules
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PCT/CN2019/120926
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English (en)
French (fr)
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杨忠华
蔺智勇
王亚东
周凯松
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信达生物制药(苏州)有限公司
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Priority to CN201980097855.1A priority Critical patent/CN114072216B/zh
Publication of WO2020258705A1 publication Critical patent/WO2020258705A1/zh

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
    • B01D15/08—Selective adsorption, e.g. chromatography
    • B01D15/10—Selective adsorption, e.g. chromatography characterised by constructional or operational features
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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  • the invention relates to the technical field of separation and purification, in particular to the purification of biological preparations, and in particular to a modular chromatography device.
  • the continuous flow chromatography device in the prior art has a low utilization rate when used for single-column chromatography; when used for multi-column chromatography, an intermediate storage tube/tank is required between the chromatography columns to store intermediate products , The process time is long, the solution storage tank is large, and the equipment cost is high.
  • existing chromatographic devices often cannot process samples online, and cannot prepare or dilute solutions online.
  • Patent CN103562145B discloses a continuous processing method for biological products. Although this solution can selectively use one or more chromatography columns, however, each part of the device is not easy to disassemble and has low adaptability to various production environments.
  • the purpose of the present invention is to overcome or at least alleviate the above-mentioned shortcomings of the prior art, and to provide a multi-module combination modular chromatography device.
  • the present invention provides a modular chromatography device.
  • the modular chromatography device includes a plurality of basic chromatography modules, and each of the basic chromatography modules includes a chromatography column, an injection selection valve, and an outlet valve,
  • the injection selection valve is connected to the upstream of the chromatography column, and the outlet valve is connected to the downstream of the chromatography column,
  • Each of the injection selection valve and the outlet valve includes at least three ports, and the injection selection valve of any one of the plurality of basic chromatography modules is connected to another basic chromatography module.
  • the outlet valve of the chromatography module is connected to another basic chromatography module.
  • the modular chromatography device further includes at least one expanded basic chromatography module, and the expanded basic chromatography module further includes a multi-channel selection valve and at least two pumps,
  • the multi-channel selection valve is connected to the upstream of the injection selection valve of the extended basic chromatography module,
  • the pump is connected to the inlet of the multi-channel selection valve, and each pump is connected to at least one solution.
  • the pump is connected to the multi-channel solution through an inlet selector valve.
  • the modular chromatography device includes a plurality of expanded basic chromatography modules, and the multi-channel selection valves of at least two of the expanded basic chromatography modules are connected together.
  • the modular chromatography device includes a plurality of expanded basic chromatography modules
  • the outlet valve of the expanded basic chromatography module located upstream is connected to the multi-channel selection valve of the expanded basic chromatography module located downstream, or
  • the outlet valve of the expanded basic chromatography module located upstream is connected to the injection selection valve of the expanded basic chromatography module located downstream.
  • the extended basic chromatography module is connected downstream of the basic chromatography module.
  • the elution times of the chromatography columns of the multiple basic chromatography modules are different, and there is no intermediate storage container between the extended basic chromatography module and the basic chromatography module.
  • an online mixer for assisting solution mixing is connected upstream of the injection selection valve of each module.
  • the injection selection valve and the outlet valve of each module include a port for draining waste liquid.
  • the circulation path of the modular chromatography device is manually controlled or automatically controlled by software.
  • each module can be operated independently, or any several modules can be connected to realize continuous flow chromatography, seamless connection chromatography or seamless continuous flow chromatography .
  • Fig. 1 is a schematic diagram of a continuous flow chromatography apparatus including a basic chromatography module according to an embodiment of the present invention.
  • Fig. 2 is a schematic diagram of a seamlessly connected chromatography device including an expanded basic chromatography module according to an embodiment of the present invention.
  • 3 to 5 are chromatograms of the three chromatography columns of the seamlessly connected chromatography device shown in FIG. 2.
  • Fig. 6 is a schematic diagram of a seamless continuous flow chromatography apparatus according to an embodiment of the present invention.
  • V inlet selection valve Vm multi-channel connection valve; Vs sampling selection valve; Vp column position valve; Vx outlet valve;
  • P pump P1 first pump; P2 second pump;
  • the invention combines a single chromatography column with valves, pumps and other accessories to form a chromatography module.
  • Chromatography modules can be used singly or in multiple combinations to achieve continuous flow chromatography, seamless connection chromatography or seamless continuous flow chromatography.
  • the chromatography device shown in Fig. 1 includes three basic chromatography modules, namely module one M1, module two M2 and module three M3.
  • the structure of the above three basic chromatography modules is the same.
  • the basic chromatography module includes: chromatography column C1, pump P, online mixer Mx, pressure sensor N, conductivity detector D, ultraviolet (UV) detector U, pH detector H, inlet Liquid selection valve Ve, multi-channel connection valve Vm, injection selection valve Vs, column position valve Vp and outlet valve Vx.
  • Each basic chromatography module can load sample S independently, collect product Pr independently, and drain waste liquid W independently.
  • each basic chromatography module connects the sample S and a plurality of (four in this embodiment) different solutions L through an inlet selection valve Ve.
  • the outlet of the inlet selection valve Ve is connected to the inlet of the pump P.
  • the outlet of the pump P is connected to an inlet of the multi-channel connection valve Vm.
  • the outlet of the multi-channel connecting valve Vm is connected to the online mixer Mx to realize the mixing of multiple solutions.
  • the solution after being mixed by the online mixer Mx further flows to an inlet of the injection selection valve Vs.
  • the other inlets of the injection selection valve Vs are used to connect to other modules and obtain samples S from other modules to realize continuous flow chromatography or seamless connection chromatography between the modules.
  • One outlet of the injection selection valve Vs is used to discharge the waste liquid W.
  • the solution flowing out from the other outlet of the injection selection valve Vs further flows to the column valve Vp.
  • the column position valve Vp is connected to the chromatography column C1. By adjusting the opening and closing state of the column position valve Vp, it is possible to selectively make the solution flow in from the upper port of the chromatography column C1, flow out from the lower port of the chromatography column C1, or make the solution flow in from the lower port of the chromatography column C1 , Flow out from the upper port of the chromatography column C1, or prevent the solution from flowing through the chromatography column C1.
  • the solution flowing out through the outlet of the column position valve Vp flows through the ultraviolet detector U, the conductivity detector D, and the pH detector H in sequence, and then flows to the outlet valve Vx.
  • the outlet valve Vx has more than three ports (more than two outlets).
  • the outlet of the outlet valve Vx can be used to harvest the product Pr, or be connected to the injection selection valve Vs, or used to discharge the waste liquid W.
  • each basic chromatography module can realize the connection and switching of the flow path between the multiple modules through the multi-channel connection valve Vm, the injection selection valve Vs and the outlet valve Vx.
  • the conductivity detector D, the ultraviolet (UV) detector U, and the pH detector H in the above-mentioned embodiments can be selectively set as required, and the present invention does not limit the connection sequence of these three detectors.
  • the number and position of the pressure sensor N can also be adjusted as needed.
  • the pressure sensor N can also be arranged downstream of the chromatography column.
  • valve path can be manually controlled, or the valve path can be automatically controlled in combination with the control software.
  • software for automatic control for example, one control interface can be used to control multiple modules at the same time; the control commands can be real-time or pre-programmed.
  • the chromatography device shown in Figure 2 includes three extended basic chromatography modules, namely module one M10, module two M20 and module three M30.
  • the expanded basic chromatography module is a variant of the basic chromatography module, and the expansion lies in that at least two ports of the multi-channel connection valve Vm are respectively connected to a pump. That is, compared with the basic chromatography module, the extended basic chromatography module includes at least two pumps (P1, P2) for extracting solutions. Each pump can be directly connected to one solution or multiple solutions through the inlet selection valve Ve.
  • the multi-channel connection valve Vm includes a port connected to the first pump P1 and a port connected to the second pump P2.
  • Each pump is connected to an inlet selection valve Ve, and the inlet selection valve Ve is connected to one or more solutions according to the needs of solution selection.
  • the online mixer Mx can receive four-way solution through two pumps of module one M10 and two pumps of module two M20.
  • the salt solution, the aqueous solution, the acid solution, and the alkali solution are fed all the way, and the required solution can be obtained in real time by controlling the flow rates of the four pumps without mixing the four solutions in the container in advance.
  • each module includes a port for connecting the sample S
  • each injection selection valve Vs includes a port for draining the waste liquid W
  • each outlet valve Vx includes a harvested product. Pr port and a port for draining waste liquid W.
  • the samples S of the three modules are the same, and the fillers of the three chromatography columns (C1, C2, C3) are also the same.
  • the outlet valve Vx of module one M1 is connected to the injection selection valve Vs of module two M2, the outlet valve Vx of module two M2 is connected to the injection selection valve Vs of module three M3, and the outlet valve Vx of module three M3 is connected The injection selection valve Vs of module one M1. Therefore, the sample S can flow in the three modules in the order of "module one M1-module two M2-module three M3-module one M1-" according to the needs of the production arrangement.
  • Steps can be performed on different chromatography columns asynchronously, without waiting for a large-capacity chromatography column to complete a certain step before proceeding to the next step.
  • any two of the three chromatography columns can be controlled by the same pump while loading samples at the same time, while the other chromatography column is equilibrated or re-equilibrated.
  • the sample injection selection valve Vs of the module one M1 selects the sample S of the module one M1 to be injected, and the sample S flows into the chromatography column C1 to load the chromatography column C1. Before the capacity of the chromatography column C1 is saturated, the outlet valve Vx of the first module M1 selects to flow the outflowing liquid to the second module M2.
  • Module two M2 elutes and post-processes the chromatography column C2 through the solution L of M2. After the chromatography column C2 is equilibrated, the sample selection valve Vs of the module two M2 selects the sample S from the module one M1 and the sample flows into the layer. Column C2 loads the sample on column C2. The outlet valve Vx of the second module M2 is connected to the waste liquid W.
  • the injection selection valve Vs of the module three M3 selects the solution L of the module three M3 to balance the chromatography column C3.
  • the outlet valve Vx of module three M3 is connected to the waste liquid W.
  • the utilization rate of the filler of the chromatography column C1 can reach 100% (in traditional single-column chromatography, the utilization rate of the filler can generally only reach about 70%), and the utilization rate of the filler passing through the chromatography column C1 exceeds
  • the sample S with the purification ability of the chromatography column C1 is further loaded onto the chromatography column C2.
  • the injection selection valve Vs of module one M1 selects the solution L of module one M1 to rebalance the chromatography column C1.
  • the outlet valve Vx of module one M1 chooses to flow the outflowing liquid to module two M2. This is because part of the sample may fall off during the rebalance of the chromatography column C1. By making the liquid flow to module two M2, the loss of the sample can be reduced. It should be understood that since the injection selection valve Vs of each module is connected to the outlet valve Vx of any other module, in other possible implementations, it is also possible to choose to flow the partially dropped sample from the chromatography column C1 to the module Three M3, and at the same time, module two M2 are loaded independently.
  • the sample injection selection valve Vs of the second module M2 selects the sample S of the second module M2 to be injected, and the sample flows into the chromatography column C2 to load the chromatography column C2.
  • the outlet valve Vx of the second module M2 selects to flow the outflowing liquid to the third module M3.
  • Module two M3 eluted and post-processed the chromatography column C3 through the solution L of M3.
  • the sample selection valve Vs of the module three M3 was used to select the sample S of the module two M2 for injection, and the sample S flowed in The chromatography column C3 loads the chromatography column C3.
  • the outlet valve Vx of module three M3 is connected to the waste liquid W.
  • the injection selection valve Vs of module one M1 selects the solution L of module one M1 to perform elution, cleaning in place (CIP) and equilibration on the chromatography column C1.
  • the outlet valve Vx of the module one M1 is connected to the collected product Pr.
  • the outlet valve Vx of module one M1 is connected to the waste liquid W.
  • the injection selection valve Vs of the second module M2 selects the solution L of the second module M2 to rebalance the chromatography column C2.
  • the outlet valve Vx of the second module M2 selects to flow the outflowing liquid to the third module M3.
  • the sample injection selection valve Vs of the module three M3 selects the sample S of the module three M3 to be injected, and the sample flows into the chromatography column C3 to load the chromatography column C3.
  • the outlet valve Vx of module three M3 selects to flow the outflowing liquid to module one M1.
  • three extended basic chromatography modules (M10, M20, M30) are connected together to form a chromatography device that can realize seamless connection chromatography.
  • the fillers of the three chromatography columns (C1, C2, C3) are different, and the sample S is only set in one of the modules (module one M10 in this embodiment), and the sample S passes through
  • one module (module two M20 in this embodiment) collects the product Pr.
  • the outlet valve Vx of the first module M10 is connected to the multi-channel connection valve Vm of the third module M30, and the outlet valve Vx of the third module M30 is connected to the injection selection valve Vs of the second module M20.
  • the multi-channel connecting valve Vm of module one M10 is connected to the multi-channel connecting valve Vm of module two M20. Therefore, the sample S can be purified by the chromatography column of the corresponding module in the order of "module one M10-module three M30-module two M20" according to the needs of the production arrangement.
  • the injection selection valve Vs of the module one M10 selects the sample S of the module one M10 to be injected, and the sample S flows into the chromatography column C1 to load the chromatography column C1.
  • the outlet valve Vx of module one M10 selects waste liquid W.
  • the injection selection valve Vs of the second module M20 selects the solution from the online mixer Mx of the second module M20 to equilibrate the chromatography column C2.
  • the outlet valve Vx of module 2 M20 selects waste liquid W.
  • the injection selection valve Vs of the module three M30 selects the solution from the online mixer Mx of the module three M30 to equilibrate the chromatography column C3.
  • the outlet valve Vx of module three M30 selects waste liquid W.
  • the injection selection valve Vs of module one M10 selects the solution from the online mixer Mx of module one M10 to elute the chromatography column C1.
  • the outlet valve Vx of module one M10 is selected to make the eluent flow to module three M30, which is used to load the chromatography column C3.
  • the multi-channel connecting valve Vm of module three M30 first selects and leads to the outlet valve Vx of module one M10, and the eluate from module one M10 is used to load the chromatography column C3. After that, the multi-channel connecting valve Vm of the third module M30 is connected to the solution L of the third module M30 to rebalance the chromatography column C3, and the outlet valve Vx of the third module M30 selects the waste liquid W.
  • the injection selection valve Vs of the second module M20 selects the solution from the online mixer Mx of the second module M20 to equilibrate the chromatography column C2.
  • the outlet valve Vx of module 2 M20 selects waste liquid W.
  • the injection selection valve Vs of the module one M10 selects the solution from the online mixer Mx of the module one M10 to clean and balance the chromatography column C1 in place.
  • the outlet valve Vx of module one M10 selects waste liquid W.
  • the multi-channel connection valve Vm of the third module M30 selects the solution L from the third module M30 to elute the chromatography column C3.
  • the outlet valve Vx of the third module M30 is selected so that the eluent flows to the second module M20 for loading the sample on the chromatography column C2.
  • the injection selection valve Vs of the second module M20 first selects the outlet valve Vx connected to the third module M30, and the eluate from the third module M30 loads the sample on the chromatography column C2. After that, the injection selection valve Vs of the second module M20 is connected to the solution L of the second delivery module M20 to rebalance the chromatography column C2, and the outlet valve Vx of the second module M20 selects the waste liquid W.
  • the injection selection valve Vs of the module one M10 selects the sample S of the module one M10 to be injected, and the sample S flows into the chromatography column C1 to load the chromatography column C1.
  • the outlet valve Vx of module one M10 selects waste liquid W.
  • the multi-channel connecting valve Vm of module three M30 selects the solution L from module three M30 to clean and balance the chromatography column C3 in place.
  • the outlet valve Vx of module three M30 selects waste liquid W.
  • the injection selection valve Vs of the second module M20 is connected to the solution L of the second delivery module M20 to elute the chromatography column C2.
  • the outlet valve Vx of module 2 M20 selects waste liquid W.
  • affinity chromatography module one M10
  • cation chromatography module three M30
  • hydrophobic chromatography module two M20
  • Figures 3 to 5 are chromatograms obtained from experiments.
  • Figure 3 is the chromatogram of chromatographic column C1
  • Figure 4 is the chromatogram of chromatographic column C3
  • Figure 5 is the chromatogram of chromatographic column C2.
  • the solid line UV represents the ultraviolet absorption curve
  • the double-dotted line Cond represents the conductivity value curve
  • the long dashed line Injection represents the node where the sample is started
  • the short dashed line represents the node where a certain component is obtained.
  • Table 1 is a comparison between the quality inspection results of the chromatography product according to this embodiment and the quality inspection results of the chromatography product in the traditional single-column chromatography.
  • the chromatography device According to the chromatogram and the quality inspection result, it can be known that the chromatography device according to this embodiment can achieve the chromatographic quality of a traditional single-column chromatography device.
  • a seamless continuous flow chromatography device is formed.
  • a plurality of basic chromatography modules can be connected to an extended basic chromatography module through a multi-way valve, for example.
  • the outlet valve Vx of each module is connected to the injection selection valve Vs of another module; in multiple basic chromatography modules, each module outlet valve Vx is connected to the injection selection valve of another module Vs.
  • three basic chromatography modules (M1, M2, M3) are connected in series with two extended basic chromatography modules (M10, M20) to form a 5-column seamless continuous flow chromatography device.
  • the three basic chromatography modules and the extended basic chromatography module M10 are connected through a four-way valve Vt.
  • the product captured by the chromatography column of any basic chromatography module constitutes the sample S of the extended basic chromatography module M10, and the product Pr is finally harvested by the extended basic chromatography module M20.
  • the chromatography device of the present invention adopts a modular design.
  • Each module includes a chromatography column and multiple multi-channel valves.
  • a single module can operate independently to achieve single column chromatography, and multiple modules can be connected through valves. It can realize continuous flow chromatography, seamless connection chromatography or seamless continuous flow chromatography together, and can also realize online solution preparation, online dilution of solution, and online sample processing (such as pH adjustment, dilution, salt addition, etc.).
  • the present invention is suitable for but not limited to the purification of biological agents.
  • the biological agents mentioned above especially include antibodies, fusion proteins, and cytokines.
  • antibody includes references to sugars of any isotype or subclass. Glycosylated and non-glycosylated immunoglobulins or their antigen-binding regions that compete with intact antibodies for specific binding, including human antibodies, humanized antibodies, chimeric antibodies, multispecific antibodies, monoclonal antibodies, polyclonal antibodies, and Its oligomers or antigen-binding fragments.
  • the embodiment of the present invention shows a scheme in which three chromatography modules constitute one chromatography device, the present invention does not limit the number of chromatography modules used in the chromatography device. Preferably, one chromatography The number of chromatography modules of the device does not exceed 10.

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Abstract

一种模块化层析装置，包括多个基础层析模块(M1，M2，M3)，每个基础层析模块(M1，M2，M3)包括层析柱(C1，C2，C3)、进样选择阀(Vs)和出口阀(Vx)，进样选择阀(Vs)连接于层析柱(C1，C2，C3)的上游，出口阀(Vx)连接于层析柱(C1，C2，C3)的下游，进样选择阀(Vs)和出口阀(Vx)均包括至少三个口，多个基础层析模块(M1，M2，M3)中的任一个基础层析模块(M1，M2，M3)的进样选择阀(Vs)连接到另一个基础层析模块(M1，M2，M3)的出口阀(Vx)。模块化层析装置中的每个模块可单独运行，也可以将任意几个模块连接，实现连续流层析、无缝连接层析或是无缝连续流层析。

Description

模块化层析装置
相关申请的引用
本发明要求2019年6月28日在中国提交的，名称为“模块化层析装置”、申请号为201910574105.0的发明专利申请的优先权，该申请的全部内容通过引用并入本文。
技术领域
本发明涉及分离纯化技术领域，尤其是生物制剂的纯化，特别涉及一种模块化层析装置。
背景技术
现有技术中存在的连续流层析装置在用于单柱层析时，其利用率低；在用于多柱层析时，在层析柱之间需要中间储管/罐以存放中间产物，工艺时间长，溶液储罐体积大，设备成本高。此外，现有的层析装置往往不能在线处理样品、不能在线配溶液或稀释溶液。
专利CN103562145B公开了一种生物制品的连续加工方法，该方案虽然能够选择性地使用一个或多个层析柱，然而，装置的各部分不容易拆分，对于各种生产环境的适应性低。
发明内容
本发明的目的在于克服或至少减轻上述现有技术存在的不足，提供一种多模块组合的模块化层析装置。
本发明提供一种模块化层析装置，所述模块化层析装置包括多个基础层析模块，每个所述基础层析模块包括层析柱、进样选择阀和出口阀，
所述进样选择阀连接于所述层析柱的上游，所述出口阀连接于所述层析柱的下游，
所述进样选择阀和所述出口阀均包括至少三个口，所述多个基础层析模块中的任一个所述基础层析模块的所述进样选择阀连接到另一个所述基础层析模块的所述出口阀。
在至少一个实施方式中，所述模块化层析装置还包括至少一个扩展的基础层析模块，所述扩展的基础层析模块还包括多通道选择阀和至少两个泵，
所述多通道选择阀连接于所述扩展的基础层析模块的进样选择阀的上游，
所述泵连接于所述多通道选择阀的入口，每一个所述泵与至少一路溶液相连。
在至少一个实施方式中，所述泵通过进液选择阀与多路溶液相连。
在至少一个实施方式中，所述模块化层析装置包括多个扩展的基础层析模块，至少两个所述扩展的基础层析模块的所述多通道选择阀连接在一起。
在至少一个实施方式中，所述模块化层析装置包括多个扩展的基础层析模块，
位于上游的扩展的基础层析模块的出口阀连接到位于下游的扩展的基础层析模块的所述多通道选择阀，或者
位于上游的扩展的基础层析模块的出口阀连接到位于下游的扩展的基础层析模块的进样选择阀。
在至少一个实施方式中，所述扩展的基础层析模块连接于所述基础层析模块的下游。
在至少一个实施方式中，所述多个基础层析模块的所述层析柱的洗脱时间不相同，所述扩展的基础层析模块和所述基础层析模块之间没有中间存储容器。
在至少一个实施方式中，每一个所述模块的所述进样选择阀的上游连接有用于帮助溶液混合的在线混合器。
在至少一个实施方式中，每一个所述模块的所述进样选择阀和所述出口阀均包括一个用于排废液的口。
在至少一个实施方式中，所述模块化层析装置的流通路径由手动控制或者由软件自动控制。
根据本发明的模块化层析装置采用模块化的设计，每个模块可单独运行，也可以将任意几个模块连接，实现连续流层析、无缝连接层析或是无缝连续流层析。
附图说明
图1是根据本发明的一个实施方式的包括基础层析模块的连续流层析装置的示意图。
图2是根据本发明的一个实施方式的包括扩展的基础层析模块的无缝连接层析装置的示意图。
图3至图5是图2所示的无缝连接层析装置的三个层析柱的层析图谱。
图6是根据本发明的一个实施方式的无缝连续流层析装置的示意图。
附图标记说明
M1、M10 模块一；M2、M20 模块二；M3、M30 模块三；
Pr 产品；S 样品；
C1、C2、C3 层析柱；
Ve 进液选择阀；Vm 多通道连接阀；Vs 进样选择阀；Vp 柱位阀；Vx 出口阀；
H pH检测器；D 电导检测器；U 紫外线检测器；
P 泵；P1 第一泵；P2 第二泵；
Mx 在线混合器；N 压力感应器。
具体实施方式
下面参照附图描述本发明的示例性实施方式。应当理解，这些具体的说明仅用于示教本领域技术人员如何实施本发明，而不用于穷举本发明的所有可行的方式，也不用于限制本发明的范围。
本发明将单个层析柱与阀、泵等配件组合，构成层析模块。层析模块可以单个使用，也可以多个组合以实现连续流层析、无缝连接层析或是无缝连续流层析。
首先结合图1介绍根据本发明的基础层析模块和使用基础层析模块构建的层析装置。
(基础层析模块)
图1所示的层析装置包括三个基础层析模块，分别为模块一M1、模块二M2和模块三M3。上述三个基础层析模块的构造是相同的。
以模块一M1为例，基础层析模块包括：层析柱C1、泵P、在线混合器Mx、压力感应器N、电导检测器D、紫外线(UV)检测器U、pH检测器H、进液选择阀Ve、多通道连接阀Vm、进样选择阀Vs、柱位阀Vp和出口阀Vx。
每个基础层析模块均能够独立负载样品S、独立收集产品Pr、独立排废液W。
优选地，每个基础层析模块通过进液选择阀Ve连接样品S和多个(本实施方式中为四个)不同的溶液L。
进液选择阀Ve的出口连接泵P的入口。
泵P的出口连接多通道连接阀Vm的一个入口。
多通道连接阀Vm的出口连接在线混合器Mx以实现对多种溶液的混合。
经在线混合器Mx完成混合后的溶液进一步流至进样选择阀Vs的一个入 口。进样选择阀Vs的其它入口用于连接到其它模块，从其它模块获取样品S，以在模块之间实现连续流层析或无缝连接层析。进样选择阀Vs的一个出口用于排废液W。
由进样选择阀Vs的另一个出口流出的溶液进一步流至柱位阀Vp。柱位阀Vp与层析柱C1相连。通过调整柱位阀Vp的开闭状态，可以选择性地使溶液从层析柱C1上部的口流入、从层析柱C1下部的口流出，或是使溶液从层析柱C1下部的口流入、从层析柱C1上部的口流出，或是使溶液不流过层析柱C1。
经柱位阀Vp的出口流出的溶液依次流过紫外线检测器U、电导检测器D和pH检测器H，之后流至出口阀Vx。
出口阀Vx具有三个以上的口(两个以上出口)。出口阀Vx的出口可以用于收获产品Pr、或是连接到进样选择阀Vs，或是用于排废液W。
以上，各个基础层析模块通过多通道连接阀Vm、进样选择阀Vs和出口阀Vx，可以实现多模块之间的流路的连接和切换。
应当理解，上述实施方式中的电导检测器D、紫外线(UV)检测器U和pH检测器H可以根据需要选择性地设置，本发明对这三个检测器的连接顺序不作限制。压力感应器N的设置数量和设置位置也可以根据需要调整，例如，压力感应器N也可以设置在层析柱的下游。
对于基础层析模块的液体流路控制，可以手动控制阀的通路，也可以结合控制软件自动地控制阀的通路。当使用软件自动控制时，例如可以通过一个控制界面，同时控制多个模块；控制命令可以是实时的，也可以是预编程的。
(扩展的基础层析模块)
参照图2介绍根据本发明的扩展的基础层析模块。图2示出的层析装置包括三个扩展的基础层析模块，分别为模块一M10、模块二M20和模块三M30。
扩展的基础层析模块是基础层析模块的变型，扩展之处在于多通道连接阀Vm的至少两个口分别连接了一个泵。即相比于基础层析模块，扩展的基础层析模块包括至少两个用于抽取溶液的泵(P1、P2)。每一个泵可以直接连接一路溶液、或是通过进液选择阀Ve连接多路溶液。
例如在模块一M10中，多通道连接阀Vm包括一个连接了第一泵P1的口，还包括一个连接了第二泵P2的口。每一个泵连接一个进液选择阀Ve，进液选择阀Ve根据溶液选配的需要而连接一路或多路溶液。
通过多个泵向多通道连接阀Vm供应溶液，可以实现配溶液时的例如双泵走梯度，或者在线处理样品，例如在线稀释和在线调pH等。
且当两个扩展的基础层析模块的多通道连接阀Vm连接在一起的时候，可以实现在线配溶液。例如参考图2中模块一M10和模块二M20的多通道连接阀Vm相连的方案，此时在线混合器Mx能够通过模块一M10的两个泵和模块二M20的两个泵接收四路溶液，例如一路进盐溶液、一路进水溶液、一路进酸溶液、一路进碱溶液，通过控制四个泵的流速即可实时地获得需要的溶液，而无需提前在容器中将四路溶液混合。
(连续流层析装置)
参照图1，将三个基础层析模块连接在一起，形成了一个能实现连续流层析的层析装置。在连续流层析装置中，每一个模块的进液选择阀Ve包括一个连接样品S的口，每一个进样选择阀Vs包括一个排废液W的口，每一个出口阀Vx包括一个收获产品Pr的口和一个排废液W的口。三个模块的样品S相同，三个层析柱(C1、C2、C3)的填料也相同。
在本实施方式中，模块一M1的出口阀Vx连接模块二M2的进样选择阀Vs，模块二M2的出口阀Vx连接模块三M3的进样选择阀Vs，模块三M3的出口阀Vx连接模块一M1的进样选择阀Vs。从而样品S可以根据生产安排需要，按“模块一M1-模块二M2-模块三M3-模块一M1-…”的顺序在三个模块中流 动。
假设将三个层析柱(C1、C2、C3)的填料放在一起形成一个大(容量)层析柱，则有，上述三个层析柱构成的连续流层析能够在更短的时间内完成一个大层析柱的纯化作业，并且可以相应减小溶液存放容器的体积。这是因为，通过将多个基础层析模块连接的方式，一个大批量的制剂的层析被分配到不同的层析柱小批量地分散地进行，平衡、上样、再平衡、洗脱等步骤可以不同步地在不同的层析柱进行，而不必等待一个大容量的层析柱完成某一步骤后再进行下一步骤。例如，在该连续流层析中，三个层析柱中的任两个可以由同一个泵控制而同时上样，与此同时另一个层析柱进行平衡或再平衡。
接下来介绍使用该连续流层析装置进行连续流层析的方法。
(i)层析柱C1上样，C2洗脱、后处理、上样，层析柱C3再平衡
模块一M1的进样选择阀Vs选择由模块一M1的样品S进样，样品S流入层析柱C1使层析柱C1上样。在层析柱C1载量饱和前，模块一M1的出口阀Vx选择将流出的液体流向模块二M2。
模块二M2通过M2的溶液L对层析柱C2洗脱、后处理，层析柱C2完成平衡后通过模块二M2的进样选择阀Vs选择由模块一M1的样品S进样，样品流入层析柱C2使层析柱C2上样。模块二M2的出口阀Vx接通至排废液W。
保持上述流路直至层析柱C1过载(填料的利用率达到100％)、而层析柱C2未过载(填料的利用率低于100％)。
模块三M3的进样选择阀Vs选择由模块三M3的溶液L平衡层析柱C3。模块三M3的出口阀Vx接通至排废液W。
该步骤中，层析柱C1的填料的利用率可以达到100％(在传统的单柱层析中，填料的利用率一般仅能达到约70％)，流过层析柱C1的、且超过层析柱C1的纯化能力的样品S进一步上样到层析柱C2。
(ii)层析柱C1再平衡，层析柱C2上样，C3洗脱、后处理、上样
模块一M1的进样选择阀Vs选择由模块一M1的溶液L对层析柱C1进行再 平衡。模块一M1的出口阀Vx选择将流出的液体流向模块二M2，这是因为在层析柱C1再平衡过程中，可能有部分样品脱落，通过使液体流向模块二M2，可以减少样品的损失。应当理解，由于每个模块的进样选择阀Vs均与任何另外一个模块的出口阀Vx相连，因此在其它可能的实施方式中，也可以选择将来自层析柱C1的部分脱落的样品流向模块三M3，与此同时模块二M2独立上样。
一段时间后(可以根据生产工艺的安排控制该段时间的长度，模块一M1的出口阀Vx导通至将流出的液体流向模块二M2的时间越长，可能从层析柱C1损失的样品越少)，模块二M2的进样选择阀Vs选择由模块二M2的样品S进样，样品流入层析柱C2使层析柱C2上样。模块二M2的出口阀Vx选择将流出的液体流向模块三M3。
模块二M3通过M3的溶液L对层析柱C3洗脱、后处理，层析柱C3完成平衡后通过模块三M3的进样选择阀Vs选择由模块二M2的样品S进样，样品S流入层析柱C3使层析柱C3上样。模块三M3的出口阀Vx接通至排废液W。
保持上述流路直至层析柱C2过载、而层析柱C3未过载。
(iii)层析柱C1洗脱、后处理、上样，层析柱C2再平衡，层析柱C3上样
模块一M1的进样选择阀Vs选择由模块一M1的溶液L对层析柱C1进行洗脱、在位清洗(CIP)和平衡。洗脱时，模块一M1的出口阀Vx导通至收集产品Pr。在位清洗和平衡时，模块一M1的出口阀Vx导通至排废液W。
模块二M2的进样选择阀Vs选择由模块二M2的溶液L对层析柱C2进行再平衡。模块二M2的出口阀Vx选择将流出的液体流向模块三M3。
一段时间后，模块三M3的进样选择阀Vs选择由模块三M3的样品S进样，样品流入层析柱C3使层析柱C3上样。模块三M3的出口阀Vx选择将流出的液体流向模块一M1。
(iv)依次重复上述三个步骤(i)、(ii)和(iii)。
(无缝连接层析装置)
参照图2，将三个扩展的基础层析模块(M10、M20、M30)连接在一起，形成了一个能实现无缝连接层析的层析装置。在无缝连接层析装置中，三个层析柱(C1、C2、C3)的填料不相同，样品S只设置在其中一个模块(在本实施方式中为模块一M10)中，样品S经由三个层析柱进行三次不同的纯化后，由一个模块(在本实施方式中为模块二M20)收集产品Pr。
在本实施方式中，模块一M10的出口阀Vx连接模块三M30的多通道连接阀Vm，模块三M30的出口阀Vx连接模块二M20的进样选择阀Vs。模块一M10的多通道连接阀Vm和模块二M20的多通道连接阀Vm相连。从而样品S可以根据生产安排需要，按“模块一M10-模块三M30-模块二M20”的顺序被相应模块的层析柱纯化。
接下来介绍使用该无缝连接层析装置进行无缝连接层析的方法。
(i)层析柱C1上样，层析柱C2、C3平衡
模块一M10的进样选择阀Vs选择由模块一M10的样品S进样，样品S流入层析柱C1使层析柱C1上样。模块一M10的出口阀Vx选择排废液W。
模块二M20的进样选择阀Vs选择由来自模块二M20的在线混合器Mx的溶液使层析柱C2平衡。模块二M20的出口阀Vx选择排废液W。
模块三M30的进样选择阀Vs选择由来自模块三M30的在线混合器Mx的溶液使层析柱C3平衡。模块三M30的出口阀Vx选择排废液W。
(ii)层析柱C1洗脱，层析柱C3上样后再平衡，层析柱C2平衡
模块一M10的进样选择阀Vs选择由来自模块一M10的在线混合器Mx的溶液对层析柱C1进行洗脱。模块一M10的出口阀Vx选择使洗脱液流至模块三M30，用于对层析柱C3上样。
模块三M30的多通道连接阀Vm先选择导通至模块一M10的出口阀Vx，由来自模块一M10的洗脱液对层析柱C3上样。之后，模块三M30的多通道连接阀Vm导通至输送模块三M30的溶液L使层析柱C3再平衡，模块三M30的出口阀Vx选择排废液W。
模块二M20的进样选择阀Vs选择由来自模块二M20的在线混合器Mx的 溶液对层析柱C2进行平衡。模块二M20的出口阀Vx选择排废液W。
(iii)层析柱C1在位清洗后平衡，层析柱C3洗脱，层析柱C2上样后再平衡
模块一M10的进样选择阀Vs选择由来自模块一M10的在线混合器Mx的溶液对层析柱C1进行在位清洗和平衡。模块一M10的出口阀Vx选择排废液W。
模块三M30的多通道连接阀Vm选择由来自模块三M30的溶液L对层析柱C3进行洗脱。模块三M30的出口阀Vx选择使洗脱液流至模块二M20，用于对层析柱C2上样。
模块二M20的进样选择阀Vs先选择导通至模块三M30的出口阀Vx，由来自模块三M30的洗脱液对层析柱C2上样。之后，模块二M20的进样选择阀Vs导通至输送模块二M20的溶液L使层析柱C2再平衡，模块二M20的出口阀Vx选择排废液W。
(iv)层析柱C1上样，层析柱C3在位清洗后平衡，层析柱C2洗脱
模块一M10的进样选择阀Vs选择由模块一M10的样品S进样，样品S流入层析柱C1使层析柱C1上样。模块一M10的出口阀Vx选择排废液W。
模块三M30的多通道连接阀Vm选择由来自模块三M30的溶液L对层析柱C3进行在位清洗和平衡。模块三M30的出口阀Vx选择排废液W。
模块二M20的进样选择阀Vs导通至输送模块二M20的溶液L使层析柱C2洗脱。模块二M20的出口阀Vx选择排废液W。
(v)依次重复上述三个步骤(ii)、(iii)和(iv)。
使用根据本实施方式的无缝连接层析装置依次进行亲和层析(模块一M10)、阳离子层析(模块三M30)和疏水层析(模块二M20)。
图3至5为实验得到的层析图谱，其中，图3是层析柱C1的层析图谱，图4是层析柱C3的层析图谱，图5是层析柱C2的层析图谱。图中，实线UV表示紫外吸收曲线，双点画线Cond表示电导率值曲线，长虚线Injection表示开始上样的节点，短虚线表示获取某一组分的节点。
表1是根据本实施方式的层析产品的质量检测结果与传统的单柱层析方式的层析产品的质量检测结果的对比。
表1 无缝连接层析产品质量检测结果
Figure PCTCN2019120926-appb-000001
根据层析图谱和质量检测结果可知，根据本实施方式的层析装置能达到传统单柱层析装置的层析质量。
(无缝连续流层析装置)
参照图6，当把连续流层析装置(多个基础层析模块)和扩展的基础层析模块串联在一起后，便形成了无缝连续流层析装置。其中多个基础层析模块例如可以通过多通阀与扩展的基础层析模块相连。多个基础层析模块中，每一个模块出口阀Vx连接另一个模块的进样选择阀Vs；多个扩展的基础层析模块中，每一个模块出口阀Vx连接另一个模块的进样选择阀Vs。
在本实施方式中，3个基础层析模块(M1、M2、M3)串联2个扩展的基础层析模块(M10、M20)，构成一个5柱无缝连续流层析装置。3个基础层析模块和扩展的基础层析模块M10之间通过一个四通阀Vt相连。
由任一个基础层析模块的层析柱捕获的产品构成扩展的基础层析模块M10的样品S，由扩展的基础层析模块M20最终收获产品Pr。
本发明至少具有以下优点中的一个优点：
(i)本发明的层析装置采用模块化的设计，每个模块包括一个层析柱和多个多通路的阀，单个模块可以单独运行实现单柱层析，多个模块可以通过阀连接在一起实现连续流层析、无缝连接层析或是无缝连续流层析，还可 以实现在线配溶液、在线稀释溶液、在线处理样品(例如pH调节、稀释、加盐等)。
(ii)当把多个模块连接在一起后，模块间不需要中间储罐存储中间样品，节约了设备成本和占地空间。
(iii)模块之间组合的灵活性强，能够适应多种生产规模和不同的生产工艺。
当然，本发明不限于上述实施方式，本领域技术人员在本发明的教导下可以对本发明的上述实施方式做出各种变型，而不脱离本发明的范围。例如：
(i)本发明适用于但不限于对生物制剂的纯化，上述生物制剂尤其包括抗体、融合蛋白以及细胞因子，除非另外说明，否则术语“抗体”包括提及任何同种型或子类的糖基化和非糖基化免疫球蛋白或其与完整抗体竞争特异性结合的抗原结合区，包括人类抗体、人源化抗体、嵌合抗体、多特异性抗体、单克隆抗体、多克隆抗体以及其低聚物或抗原结合片段。
(ii)虽然本发明实施方式中示出了由三个层析模块构成一个层析装置的方案，但是本发明对层析装置中使用的层析模块的数量不作限制，优选地，一个层析装置的层析模块的数量不超过10个。

Claims (10)

  1. 一种模块化层析装置，其特征在于，所述模块化层析装置包括多个基础层析模块(M1/M2/M3……)，每个所述基础层析模块包括层析柱、进样选择阀(Vs)和出口阀(Vx)，
    所述进样选择阀(Vs)连接于所述层析柱的上游，所述出口阀(Vx)连接于所述层析柱的下游，
    所述进样选择阀(Vs)和所述出口阀(Vx)均包括至少三个口，所述多个基础层析模块中的任一个所述基础层析模块的所述进样选择阀(Vs)连接到另一个所述基础层析模块的所述出口阀(Vx)。
  2. 根据权利要求1所述的模块化层析装置，其特征在于，所述模块化层析装置还包括至少一个扩展的基础层析模块(M10/M20/M30)，所述扩展的基础层析模块还包括多通道选择阀(Vm)和至少两个泵(P1、P2)，
    所述多通道选择阀(Vm)连接于所述扩展的基础层析模块的进样选择阀(Vs)的上游，
    所述泵(P1/P2)连接于所述多通道选择阀(Vm)的入口，每一个所述泵(P1/P2)与至少一路溶液(L)相连。
  3. 根据权利要求2所述的模块化层析装置，其特征在于，所述泵通过进液选择阀(Ve)与多路溶液相连。
  4. 根据权利要求2所述的模块化层析装置，其特征在于，所述模块化层析装置包括多个扩展的基础层析模块，至少两个所述扩展的基础层析模块的所述多通道选择阀(Vm)连接在一起。
  5. 根据权利要求2所述的模块化层析装置，其特征在于，所述模块化层析装置包括多个扩展的基础层析模块，
    位于上游的扩展的基础层析模块的出口阀(Vx)连接到位于下游的扩展的基础层析模块的所述多通道选择阀(Vm)，或者
    位于上游的扩展的基础层析模块的出口阀(Vx)连接到位于下游的扩展 的基础层析模块的进样选择阀(Vs)。
  6. 根据权利要求2所述的模块化层析装置，其特征在于，所述扩展的基础层析模块连接于所述基础层析模块的下游。
  7. 根据权利要求6所述的模块化层析装置，其特征在于，所述多个基础层析模块的所述层析柱的洗脱时间不相同，所述扩展的基础层析模块和所述基础层析模块之间没有中间存储容器。
  8. 根据权利要求1至7中任一项所述的模块化层析装置，其特征在于，每一个所述模块(M1/M2/M3/M10/M20/M30……)的所述进样选择阀(Vs)的上游连接有用于帮助溶液混合的在线混合器(Mx)。
  9. 根据权利要求1至7中任一项所述的模块化层析装置，其特征在于，每一个所述模块(M1/M2/M3/M10/M20/M30……)的所述进样选择阀(Vs)和所述出口阀(Vx)均包括一个用于排废液(W)的口。
  10. 根据权利要求1至7中任一项所述的模块化层析装置，其特征在于，所述模块化层析装置的流通路径由手动控制或者由软件自动控制。
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