CN115920639A

CN115920639A - Production equipment for biological macromolecular substance product

Info

Publication number: CN115920639A
Application number: CN202211729337.7A
Authority: CN
Inventors: 宋开益; 袁如月; 王晓祥
Original assignee: Shanghai Funuojian Biotechnology Co ltd
Current assignee: Shanghai Funuojian Biotechnology Co ltd
Priority date: 2022-12-30
Filing date: 2022-12-30
Publication date: 2023-04-07

Abstract

The present disclosure discloses a production apparatus for a biomacromolecule product, comprising: an ultrafiltration treatment device, an upstream three-way connector and a downstream three-way connector, the upstream three-way connector and the downstream three-way connector being configured to remain physically connected to the feed liquid container and the cleaning liquid container simultaneously during production of the production facility, and the feed liquid container and the cleaning liquid container being in fluid communication with the production facility at different time periods during the production process by switching between the respective internal feed liquid channel and internal cleaning liquid channel by the upstream three-way connector and the downstream three-way connector. The pipeline of the production equipment can be connected in advance through the aseptic three-way connector, and the reserved interface is flexibly suitable for whole-course closed production of cleaning, disinfecting, sampling, harvesting, transferring and other procedures in various production processes.

Description

Production equipment for biological macromolecular substance product

Technical Field

The present disclosure relates generally to the field of production of biomacromolecule products. More particularly, the present disclosure relates to a production apparatus for biomacromolecule products.

Background

For the ultrafiltration process of biological macromolecular substance (such as virus) products, the cleaning and disinfection of equipment and the concentration of feed liquid are main procedures. Cleaning and disinfection of equipment refers to that cleaning solution (such as lye) is introduced into the whole equipment for production before use, water is used for washing to be neutral after circular disinfection, and finally buffer solution is introduced to replace the production environment. The concentration of the feed liquid refers to that the feed liquid containing the biomacromolecule substance product is concentrated to a final concentrated liquid by utilizing a hollow fiber column.

Current production equipment has only one liquid inlet. In the whole process of the ultrafiltration process, cleaning before production is needed firstly; cleaning and sterilizing an ultrafiltration container, and adding a cleaning solution into the ultrafiltration container; the ultrafiltration vessel is connected to the production facility to cycle clean the entire production facility. Thereafter, the ultrafiltration vessel is removed from the production equipment, cleaned again, sterilized, and product feed is added. Loading the ultrafiltration container filled with product liquid on production equipment, and circularly concentrating. And collecting the final concentrated solution after the completion, and subpackaging the concentrated solution into centrifuge tubes for centrifugation. Then, the ultrafiltration container is detached from the production equipment, and cleaning solution is added into the ultrafiltration container; the ultrafiltration vessel is connected to the production facility to cycle clean the entire production facility. And (5) storing the production equipment after the circular cleaning is finished.

Due to the particularity of the biomacromolecule product, the contact of personnel to feed liquid in the production process needs to be reduced so as to ensure the sterility of the product. However, the number of times of disassembling and assembling the pipe joint is frequent when cleaning and sterilizing the production equipment. When the interface needs to be disassembled once for each kind of liquid (such as cleaning liquid, buffer liquid, feed liquid and the like), the risk of bacteria contamination is increased sharply.

Disclosure of Invention

It is an object of the present disclosure to provide a production apparatus that overcomes at least one of the deficiencies of the prior art.

One aspect of the present disclosure relates to a production apparatus for a bio-macromolecular substance product, wherein the production apparatus includes:

an ultrafiltration treatment device configured to perform ultrafiltration treatment on a feed liquid containing a product to be treated, the ultrafiltration treatment device comprising an inlet end, an outlet end, and a discharge end;

an upstream three-way connector comprising a first inlet, a second inlet and an outlet, the upstream three-way connector forming an internal feed liquid channel and an internal cleaning liquid channel between the first inlet and the outlet and between the second inlet and the outlet, respectively, and the internal feed liquid channel and the internal cleaning liquid channel being isolated from each other, the first inlet and the second inlet being removably connected to a sample inlet end of the feed liquid container and a sample inlet end of the cleaning liquid container, respectively, and the outlet being connected to an inlet end of the ultrafiltration treatment device by an inlet line; and

a downstream three-way connector comprising an inlet, a first outlet and a second outlet, the downstream three-way connector forming an internal feed liquid channel and an internal cleaning liquid channel between the inlet and the first outlet and between the inlet and the second outlet, respectively, and being isolated from each other, the inlet being connected to the outlet end of the ultrafiltration treatment device by an outlet line, and the first outlet and the second outlet removably connecting the return end of the feed liquid container and the return end of the cleaning liquid container, respectively;

wherein the upstream and downstream three-way connectors are configured to remain physically connected to the feed liquid and cleaning liquid containers simultaneously during production of the production facility, and the feed liquid and cleaning liquid containers are in fluid communication with the production facility at different time periods during the production process by switching between the respective internal feed liquid and cleaning liquid passages by the upstream and downstream three-way connectors.

In some embodiments, the upstream and downstream three-way connectors are configured to remain physically connected to both the feed liquid container and the cleaning liquid container during cleaning of the production process, wherein the internal cleaning liquid channel of the upstream three-way connector and the internal cleaning liquid channel of the downstream three-way connector are open to fluidly connect the cleaning liquid container to the production equipment, and the internal feed liquid channel of the upstream three-way connector and the internal feed liquid channel of the downstream three-way connector are closed to fluidly disconnect the feed liquid container from the production equipment.

In some embodiments, the upstream three-way connector and the downstream three-way connector are configured to remain physically connected to the feed liquid container and the cleaning liquid container simultaneously during ultrafiltration of the production process, wherein the internal feed liquid channel of the upstream three-way connector and the internal feed liquid channel of the downstream three-way connector are open to fluidly connect the feed liquid container to the production equipment, and the internal cleaning liquid channel of the upstream three-way connector and the internal cleaning liquid channel of the downstream three-way connector are closed to fluidly disconnect the cleaning liquid container from the production equipment.

In some embodiments, the inner feed liquid channel and the inner cleaning liquid channel of the upstream three-way connector are separated by a membrane, and the inner feed liquid channel and the inner cleaning liquid channel of the downstream three-way connector are separated by a membrane.

In some embodiments, the upstream and downstream tee connectors are made using a bio-affinity material.

In some embodiments, a pumping mechanism is disposed on the inlet line and is configured to pump the liquid in the inlet line through the ultrafiltration treatment device.

In some embodiments, a flow monitor is disposed on the inlet line and is configured to monitor the flow of liquid through the inlet line.

In some embodiments, a pneumatic valve is disposed on the outlet line and is configured to control the magnitude of the flow rate of the liquid through the outlet line.

In some embodiments, the discharge line of the ultrafiltration treatment device is configured to discharge the liquid separated after the treatment of the feed liquid by the ultrafiltration treatment device out of the production facility, and one end of the discharge line of the ultrafiltration treatment device is connected to the discharge port of the production facility and the opposite end is connected to the discharge end of the ultrafiltration treatment device.

In some embodiments, one end of the discharge line for the cleaning liquid is connected to the outlet line and the opposite end is connected to a discharge of the production device.

In some embodiments, the ultrafiltration treatment device comprises a hollow fiber column.

In some embodiments, the production plant further comprises 2 nd to nth ultrafiltration treatment devices connected in parallel with the ultrafiltration treatment device, and a minimum treatment volume of the feed liquid by an mth of the 2 nd to nth ultrafiltration treatment devices is less than a minimum treatment volume of the feed liquid by an (m-1) th ultrafiltration treatment device, wherein: n is an integer greater than or equal to 2, m is any integer greater than 2 and less than or equal to n, and the 1 st ultrafiltration treatment device is the ultrafiltration treatment device.

In some embodiments, the inlet line of the m-th ultrafiltration treatment device is provided with a valve thereon, and has one end connected to the inlet end of the m-th ultrafiltration treatment device and the opposite end connected to the inlet line of the (m-1) -th ultrafiltration treatment device; the outlet pipeline of the mth ultrafiltration treatment device is provided with a valve, one end of the outlet pipeline is connected to the outlet end of the mth ultrafiltration treatment device, and the other opposite end of the outlet pipeline is connected to the outlet pipeline of the (m-1) th ultrafiltration treatment device; one end of the discharge line of the m-th ultrafiltration treatment device is connected to the discharge port of the production apparatus, and the opposite end is connected to the discharge end of the m-th ultrafiltration treatment device.

In some embodiments, during ultrafiltration of the production process, the ultrafiltration treatment devices and the 2 nd to nth ultrafiltration treatment devices sequentially treat the feed liquid according to the order of the smallest treatment volumes from large to small, and only one ultrafiltration treatment device treats the feed liquid during a period of time.

In some embodiments, the replacement fluid line is configured to replenish the feed fluid container with feed fluid and has one end connected to the replacement fluid end of the feed fluid container and an opposite end having a connector for connection to a feed fluid storage device.

Additional features and advantages of the disclosed subject matter will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the disclosed subject matter. The advantages of the subject technology of the present disclosure will be realized and attained by the structure particularly pointed out in the written description and claims hereof as well as the appended drawings.

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory and are intended to provide further explanation of the subject technology of the present disclosure as claimed.

Drawings

Various aspects of the disclosure will be better understood upon reading the following detailed description in conjunction with the drawings in which:

fig. 1 shows a schematic view of a production apparatus according to a first embodiment of the present disclosure;

FIG. 2 is an exemplary perspective view of a feed liquid container of the production facility of FIG. 1;

fig. 3 shows a schematic view of a production device according to a second embodiment of the present disclosure.

Additional features and advantages of the disclosed subject technology will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the disclosed subject technology. The advantages of the subject technology of the present disclosure will be realized and attained by the structure particularly pointed out in the written description and claims hereof as well as the appended drawings.

Detailed Description

The present disclosure will now be described with reference to the accompanying drawings, which illustrate several embodiments of the disclosure. It should be understood, however, that the present disclosure may be presented in many different ways and is not limited to the embodiments described below; rather, the embodiments described below are intended to provide a more complete disclosure of the present disclosure, and to fully convey the scope of the disclosure to those skilled in the art. It is also to be understood that the embodiments disclosed herein can be combined in various ways to provide further additional embodiments.

It should be understood that like reference numerals refer to like elements throughout the several views. In the drawings, the size of some of the features may be varied for clarity.

It is to be understood that the terminology used in the description is for the purpose of describing particular embodiments only, and is not intended to be limiting of the disclosure. All terms (including technical and scientific terms) used in the specification have the meaning commonly understood by one of ordinary skill in the art unless otherwise defined. Well-known functions or constructions may not be described in detail for brevity and/or clarity.

As used in this specification, the singular forms "a", "an" and "the" include plural referents unless the content clearly dictates otherwise. The terms "comprising," "including," and "containing" when used in this specification specify the presence of stated features, but do not preclude the presence or addition of one or more other features. The term "and/or" as used in this specification includes any and all combinations of one or more of the associated listed items. The terms "between X and Y" and "between about X and Y" as used in the specification should be construed to include X and Y. The term "between about X and Y" as used herein means "between about X and about Y" and the term "from about X to Y" as used herein means "from about X to about Y".

In the description, when an element is referred to as being "on," "attached" to, "connected" to, "coupled" to, or "contacting" another element, etc., another element may be directly on, attached to, connected to, coupled to, or contacting the other element, or intervening elements may be present. In contrast, when an element is referred to as being "directly on," "directly attached to," directly connected to, "directly coupled to," or "directly contacting" another element, there are no intervening elements present. In the description, one feature may be "adjacent" to another feature, and may mean that one feature has a portion overlapping with or is located above or below the adjacent feature.

In the description, spatial terms such as "upper", "lower", "left", "right", "front", "rear", "high", "low", and the like may describe a relationship of one feature to another feature in the drawings. It will be understood that the spatial relationship terms are intended to encompass different orientations of the device in use or operation in addition to the orientation depicted in the figures. For example, features originally described as "below" other features may be described as "above" other features when the device in the figures is inverted. The device may also be otherwise oriented (rotated 90 degrees or at other orientations) and the relative spatial relationships may be interpreted accordingly.

The utility model relates to a production facility that handles is carried out feed liquid to containing biological macromolecular substance product, it can reduce the frequent dismantlement of pipeline in the flows such as cleaning, disinfection, sample among the existing equipment production process, avoids the product microbiological contamination problem that uncovered increase brought in the production process. Fig. 1 shows a schematic view of a production device 1 according to a first embodiment of the present disclosure. As shown, production apparatus 1 includes fluid lines to connect feed liquid container 10, cleaning liquid container 20, and ultrafiltration treatment devices (two are shown in the figure, ultrafiltration treatment devices 30 and 30', respectively) to one another. The feed solution container 10 is used to store a feed solution containing products to be treated, which are biomacromolecules, such as viruses, mRNA, and the like. The cleaning liquid container 20 is used to store a cleaning liquid to clean all or part of the apparatus. The ultrafiltration treatment device is used to treat (e.g., ultrafilter/concentrate) the feed liquid from the feed liquid container 10 and discharge the separated liquid after treatment.

The feed liquid container 10 has a sample introduction end, a return end, and a fluid replacement end to be connected to the sample introduction line 11, the return line 12, and the fluid replacement line 13, respectively. The sample inlet line 11 is used for conveying the feed liquid in the feed liquid container 10 to the ultrafiltration processing device 30, and has one end connected to the sample inlet end of the feed liquid container 10 and the other opposite end connected to the first inlet of the three-way connector 14. A return line 12 is used to convey the treated feed liquid back to feed liquid vessel 10 and is connected at one end to the return end of feed liquid vessel 10 and at the opposite end to a first outlet of three-way connector 15. The fluid replenishment line 13 is used to replenish the fluid vessel 10 with fluid and has one end connected to the fluid replenishment end of the fluid vessel 10 and the other end having a connector 13C for connection to a fluid storage device (not shown). A pumping mechanism 13P may be provided on the fluid replacement line 13 for pumping the feed fluid from the feed fluid storage device into the feed fluid container 10. The pumping mechanism 13P may be, for example, a peristaltic pump, or any other suitable pump. The feed liquid container 10 may be placed on a weighing platform 16 to detect the weight of the feed liquid container 10. A controller (not shown) can activate or deactivate the pumping mechanism 13P to replenish the feed liquid container 10 according to the weight change of the feed liquid container 10 fed back from the weighing platform 16. In some embodiments, the feed liquid container 10 can be, for example, a three-dimensional reservoir bag provided with two three-way connectors, as shown in FIG. 2. The liquid storage bag can be used for storing sterile bags of liquid such as buffer solution, culture medium, biological stock solution and the like, and has extremely low gas permeability, good physical strength and excellent biological and chemical compatibility.

The cleaning liquid container 20 has a sample introduction end and a return end to be connected to the sample introduction line 21 and the return line 22, respectively. The sample inlet line 21 is used for delivering the cleaning solution in the cleaning solution container 20 to the ultrafiltration treatment device 30 and the connected fluid line, and has one end connected to the sample inlet end of the cleaning solution container 20 and the opposite end connected to the second inlet of the three-way connector 14. The return line 22 is used to deliver cleaning liquid back to the cleaning liquid container 20 and has one end connected to the return end of the cleaning liquid container 20 and the opposite end connected to the second outlet of the three-way connector 15.

The introduction of the three-

way connectors

14 and 15 enables the connection or disconnection of the flow paths between the feed liquid container 10, the cleaning liquid container 20 and the production apparatus 1 to be accomplished without the need to disassemble the interfaces. In some embodiments, each of the three-

way connectors

14 and 15 includes three ports and an internal passage connecting the three ports. An internal feed liquid passage is provided between the first inlet and the outlet of the three-way connector 14, and an internal cleaning liquid passage is provided between the second inlet and the outlet. An internal feed liquid channel is provided between the inlet and the first outlet of the three-way connector 15, and an internal cleaning liquid channel is provided between the inlet and the second outlet. The inside feed liquid passageway of three way connection ware and inside cleaning solution passageway are kept apart through the membrane, have realized the dual-channel cleanliness nature in cleaning and disinfecting and the production process. In some embodiments, the three-

way connectors

14 and 15 may be made using a biocompatible material. The three-

way connectors

14 and 15 may be the available stem-Thru II three-way connectors from le pure, or may be assembled by valve block structures to perform three-way functions, such as two-position three-way solenoid valves, three-way ball valves, Y-type three-way connectors, etc.

The ultrafiltration treatment device 30 has an inlet end, an outlet end and a discharge end to be connected to an inlet line 31, an outlet line 32 and a discharge line 33, respectively. The inlet line 31 is used to introduce various liquids (e.g., feed liquid from feed liquid tank 10, cleaning liquid from cleaning liquid tank 20, etc.) into all of the ultrafiltration treatment apparatuses located downstream of the inlet line 31, and has one end connected to the inlet end of the ultrafiltration treatment apparatus 30 and the opposite end connected to the outlet of the three-way connector 14. A pumping mechanism 31P and/or a flow monitor 31M may be provided on the inlet line 31. Pumping mechanism 31P is used to pump various liquids (e.g., feed liquid from feed liquid container 10, cleaning liquid from cleaning liquid container 20, etc.) through the ultrafiltration treatment device, and may be, for example, a peristaltic pump, or any other suitable pump. The flow monitor 31M is used to monitor the flow of liquid through the inlet line 31.

The outlet line 32 is used to return liquid passing through all of the ultrafiltration treatment units upstream of the outlet line 32 to the respective tank (e.g., feed liquid tank 10, cleaning liquid tank 20, etc.), and is connected at one end to the outlet end of the ultrafiltration treatment unit 30 and at the opposite end to the inlet of the three-way connector 15. A pneumatic valve 32V may be provided on the outlet line 32 for controlling the amount of flow rate of the liquid through the outlet line 32. A controller (not shown) may control the pneumatic valve 32V according to a change in the liquid flow rate through the inlet line 31 fed back by the flow monitor 31M.

The discharge line 33 is used for discharging the liquid separated after the feed liquid is treated by the ultrafiltration treatment device 30, and has one end connected to the discharge port 40 and the opposite end having two branches, one branch connected to the discharge end of the ultrafiltration treatment device 30 and the other branch connected to the discharge end of the second ultrafiltration treatment device 30' (to be described in detail later). A valve 33V may be provided on the discharge line 33 for controlling the opening and closing of the discharge line 33.

The second ultrafiltration treatment device 30 'and the ultrafiltration treatment device 30 are connected in parallel with each other, and the minimum treatment volume of the second ultrafiltration treatment device 30' for the feed liquid is smaller than the minimum treatment volume of the ultrafiltration treatment device 30. Thus, the apparatus can first treat the feed solution using the ultrafiltration treatment device 30, and after the volume of the feed solution is less than the minimum treatment volume of the ultrafiltration treatment device 30, the apparatus can then process the feed solution using the second ultrafiltration treatment device 30'. For example, the ultrafiltration treatment device 30 and the second ultrafiltration treatment device 30' may be of a dual-column design, and may be a large-column hollow fiber column and a small-column hollow fiber column, respectively. The hollow fiber column membrane area of the large column position column body is large, and the production efficiency is high; however, large membrane area leads to large column volume, with a large minimum process volume (filling the entire column); therefore, the final concentration of the large column does not reach the product requirement, and multiple centrifugations and concentrations are needed. The hollow fiber column membrane area of the small column position column body is small, and the production efficiency is low; but its minimum treatment volume is small and the final concentration achievable thereby is large. The two columns are combined into the same equipment, so that the minimum processing volume of the equipment can be reduced, and the production efficiency can be improved.

Similar to the ultrafiltration treatment device 30, the second ultrafiltration treatment device 30' has an inlet end, an outlet end and a discharge end for connection to an inlet line 31', an outlet line 32' and a discharge line 33, respectively. Inlet line 31' is used to introduce various liquids (e.g., feed liquid from feed liquid container 10, cleaning liquid from cleaning liquid container 20, etc.) into all of the ultrafiltration treatment devices (or all other ultrafiltration treatment devices except ultrafiltration treatment device 30) downstream of inlet line 31', and has one end connected to the inlet end of ultrafiltration treatment device 30' and an opposite end connected to inlet line 31 of ultrafiltration treatment device 30, e.g., connected to inlet line 31 between the inlet end of ultrafiltration treatment device 30 and flow monitor 31M. A valve 31V may be provided on the inlet line 31 'for controlling the opening and closing of the inlet line 31'.

Outlet line 32' is used to return liquid that has passed through all of the ultrafiltration treatment units upstream of outlet line 32' to the respective tank (e.g., feed liquid tank 10, cleaning liquid tank 20, etc.), and is connected at one end to the outlet end of ultrafiltration treatment unit 30' and at the opposite end to outlet line 32 of ultrafiltration treatment unit 30, e.g., between the outlet end of ultrafiltration treatment unit 30 and pneumatic valve 32V, of outlet line 32. A valve 32V ' may be provided on the outlet line 32' for controlling the opening and closing of the outlet line 32 '.

As described above, the discharge line 33 is used to discharge the liquid separated after the treatment of the feed liquid, and has one end connected to the discharge port 40 and the opposite end having two branches, one branch connected to the discharge end of the second ultrafiltration treatment device 30' and the other branch connected to the discharge end of the ultrafiltration treatment device 30.

In some embodiments, the at least two ultrafiltration treatment devices may include not only the ultrafiltration treatment device 30 and the second ultrafiltration treatment device 30', but also more ultrafiltration treatment devices in parallel with the ultrafiltration treatment device 30 and the second ultrafiltration treatment device 30'. In other words, the production apparatus includes 2 nd to nth ultrafiltration treatment devices connected in parallel to the ultrafiltration treatment device 30, and a minimum treatment volume of the mth of the 2 nd to nth ultrafiltration treatment devices for the feed liquid is smaller than a minimum treatment volume of the (m-1) th ultrafiltration treatment device for the feed liquid, wherein: n is an integer greater than or equal to 2, m is any integer greater than 2 and less than or equal to n, and the 1 st ultrafiltration treatment device is the ultrafiltration treatment device. The inlet pipeline of the mth ultrafiltration treatment device is provided with a valve, one end of the inlet pipeline is connected to the inlet end of the mth ultrafiltration treatment device, and the other opposite end of the inlet pipeline is connected to the inlet pipeline of the (m-1) th ultrafiltration treatment device; the outlet pipeline of the mth ultrafiltration treatment device is provided with a valve, one end of the outlet pipeline is connected to the outlet end of the mth ultrafiltration treatment device, and the other opposite end of the outlet pipeline is connected to the outlet pipeline of the (m-1) th ultrafiltration treatment device; one end of the discharge line of the m-th ultrafiltration treatment device is connected to the discharge port of the production apparatus, and the opposite end is connected to the discharge end of the m-th ultrafiltration treatment device. During ultrafiltration in the production process, the ultrafiltration treatment device 30 and the 2 nd to nth ultrafiltration treatment devices sequentially treat the feed liquid in descending order of the minimum treatment volume, and only one ultrafiltration treatment device treats the feed liquid during one period.

A drain line 23 is connected between the outlet line 32 and the drain 40 for the discharge of the cleaning liquid. For example, one end of the discharge line 23 is connected between the three-way connector 15 of the outlet line 32 and the pneumatic valve 32V, and the opposite end is connected to the discharge port 40. A valve 23V may be provided on the discharge line 23 for controlling the opening and closing of the discharge line 23.

The operation of the production apparatus 1 according to the first embodiment of the present disclosure is described below. The ultrafiltration treatment device 30 and the second ultrafiltration treatment device 30 'are loaded (e.g., by means of a clamp) into the production apparatus 1 in parallel, so that the inlet, outlet and discharge ends of the ultrafiltration treatment device 30 are connected to the inlet line 31, the outlet line 32 and the discharge line 33, respectively, and the inlet, outlet and discharge ends of the second ultrafiltration treatment device 30' are connected to the inlet line 31', the outlet line 32' and the discharge line 33, respectively.

A feed liquid containing a product to be treated is filled in the feed liquid container 10, and the feed liquid container 10 is loaded into the production apparatus 1, so that the sample introduction end, the return flow end, and the fluid replacement end of the feed liquid container 10 are connected to the sample introduction line 11, the return flow line 12, and the fluid replacement line 13, respectively. A cleaning liquid is filled into the cleaning liquid container 20, and the cleaning liquid container 20 is loaded into the production apparatus 1, so that the introduction end and the return end of the cleaning liquid container 20 are connected to the introduction line 21 and the return line 22, respectively.

Opening an internal cleaning liquid channel between the second inlet and the outlet of the three-way connector 14 and opening an internal cleaning liquid channel between the inlet and the second outlet of the three-way connector 15; the valve 31V 'on the inlet line 31' and the valve 32V 'on the outlet line 32' are opened, while the

valves

33V and 23V on the discharge lines 33 and 23 are closed. Thus, the cleaning liquid flows out of the sample inlet line 21 from the sample inlet end of the cleaning liquid container 20, and flows into the inlet line 31 through the internal cleaning liquid channel of the three-way connector 14. The cleaning solution flows from the inlet line 31 into the ultrafiltration treatment unit 30 and the second ultrafiltration treatment unit 30' connected in parallel and out into the outlet line 32. The cleaning liquid flows through the internal cleaning liquid channel of the three-way connector 15 into the return line 22 and returns to the cleaning liquid container 20 through the return end of the cleaning liquid container 20. And circulating once or more times, thereby completing the cleaning operation of the equipment. In some embodiments, it is also possible to close the internal cleaning liquid channel of the three-way connection 15 and to open the valve 23V on the discharge line 23, so that the cleaning liquid entering the outlet line 32 is discharged out of the apparatus through the discharge line 23 without flowing back into the cleaning liquid container 20.

After the cleaning of the equipment is finished, an internal cleaning liquid channel between the second inlet and the outlet of the three-way connector 14 is closed, and an internal feed liquid channel between the first inlet and the outlet is opened; the internal cleaning liquid channel between the inlet and the second outlet of the three-way connector 15 is closed and the internal feed liquid channel between the inlet and the first outlet is opened, thereby disconnecting the cleaning liquid container 20 from the flow path of the apparatus and connecting the feed liquid container 10 to the flow path of the apparatus. The introduction of the two containers and the arrangement of the three-way connector reduce the frequent disassembly of pipelines in the processes of cleaning, disinfecting, sampling and the like, and avoid the problem of bacterial contamination of products caused by the increase of openings in the production process. Cleaning liquid flows in from an inlet of the three-way connector through the cleaning liquid container, and flows out from an outlet to the production equipment for cleaning and disinfection; after cleaning and disinfection are finished, the cleaning solution container is closed without disassembly and assembly, and production feed liquid is injected from a second inlet in the three-way connector to participate in production.

The valve 31V 'on the inlet line 31' and the valve 32V 'on the outlet line 32' are closed, the valve 33V on the discharge line 33 is opened, and the valve 23V on the discharge line 23 is kept closed. Thus, feed liquid containing the product to be treated flows out of the sample introduction line 11 from the sample introduction end of the feed liquid container 10, through the internal feed liquid channel of the three-way connector 14 and into the inlet line 31. Feed flows from inlet line 31 into ultrafiltration treatment device 30. The feed liquid is treated (e.g., ultrafiltered/concentrated) in ultrafiltration treatment apparatus 30, and the separated liquid after treatment is discharged through discharge line 33. Treated feed liquid (e.g., concentrated feed liquid) enters outlet line 32, flows through the internal feed liquid channel of three-way connector 15 into return line 12, and returns to feed liquid container 10 through the return end of feed liquid container 10. Thereby, the primary treatment process of the feed liquid is completed.

The treatment process of the feed liquid is circulated until the treated feed liquid volume is less than the minimum treatment volume of the ultrafiltration treatment device 30. At this point, the ultrafiltration treatment device 30 is no longer capable of treating the current feed solution. The valve 31V 'on the inlet line 31' and the valve 32V 'on the outlet line 32' are opened. Thus, feed liquid containing the product to be treated flows out of the sample introduction line 11 from the sample introduction end of the feed liquid container 10, through the internal feed liquid channel of the three-way connector 14 and into the inlet line 31. The feed liquid flows from the inlet line 31 into the second ultrafiltration treatment unit 30'. The feed liquid is treated (e.g., ultrafiltered/concentrated) in the second ultrafiltration treatment device 30', and the separated liquid after treatment is discharged through the discharge line 33. Treated feed liquid (e.g., concentrated feed liquid) enters outlet line 32, flows through the internal feed liquid channel of three-way connector 15 into return line 12, and returns to feed liquid container 10 through the return end of feed liquid container 10. Thereby, one further treatment process of the feed liquid is completed. Continues to circulate to the final treatment liquor (e.g., the final concentrate product) and is collected in the liquor container 10. The ultrafiltration treatment device with the two-column design improves the production efficiency of the production equipment 1 and improves the concentration multiple of the product.

Thereafter, the valve 33V of the drain passage 33 is closed, the internal feed liquid passage between the first inlet and the outlet of the three-way connector 14 is closed, the internal cleaning liquid passage between the second inlet and the outlet is opened, and the internal feed liquid passage between the inlet and the first outlet of the three-way connector 15 is closed, and the internal cleaning liquid passage between the inlet and the second outlet is opened. The cleaning process of the apparatus is repeated. The equipment was stored after cleaning.

It can thus be seen that during production in the production plant 1, the three-way connector 14 and the three-way connector 15 are configured to remain physically connected to both the feed liquid container 10 and the cleaning liquid container 20, and that the feed liquid container 10 and the cleaning liquid container 20 are in fluid communication with the production plant 1 at different periods of the production process by switching between the respective internal feed liquid channel and internal cleaning liquid channel by means of the three-way connector 14 and the three-way connector 15. Specifically, during cleaning of the production process, the three-way connector 14 and the three-way connector 15 are configured to remain physically connected to both the feed liquid container 10 and the cleaning liquid container 20 simultaneously, wherein the internal cleaning liquid channel of the three-way connector 14 and the internal cleaning liquid channel of the three-way connector 15 are open to fluidly connect the cleaning liquid container 20 to the production apparatus 1, and the internal feed liquid channel of the three-way connector 14 and the internal feed liquid channel of the three-way connector 15 are closed to fluidly disconnect the feed liquid container 10 from the production apparatus 1. During ultrafiltration of the production process, the three-way connector 14 and the three-way connector 15 are configured to simultaneously remain physically connected to the feed liquid container 10 and the cleaning liquid container 20, wherein the internal feed liquid channel of the three-way connector 14 and the internal feed liquid channel of the three-way connector 15 are open to fluidly connect the feed liquid container 10 with the production apparatus 1, and the internal cleaning liquid channel of the three-way connector 14 and the internal cleaning liquid channel of the three-way connector 15 are closed to fluidly disconnect the cleaning liquid container 20 from the production apparatus 1.

A schematic diagram of a production facility 101 for a feed liquid according to a second embodiment of the present disclosure is described below with reference to fig. 3. The production apparatus 101 will refer to the same or similar structures with reference numerals increased by 100 in the production apparatus 1. As shown in FIG. 3, production facility 101 includes fluid lines to connect feed solution tank 110, cleaning solution tank 120, and an ultrafiltration treatment device 130 to one another. The production apparatus 101 differs from the production apparatus 1 in structure in that only one ultrafiltration treatment device 130 is provided, and there is no other ultrafiltration treatment device connected in parallel to the ultrafiltration treatment device 130. Thus, the production facility 101 differs from the production facility 1 in operation in that different ultrafiltration treatment apparatuses are not switched to be used. Will not be described in detail.

The production apparatus 1 according to the embodiment of the present disclosure splits a conventional ultrafiltration vessel into two vessels (i.e., a feed liquid vessel and a cleaning liquid vessel), which are physically connected by two three-way connectors. The solution in the two containers is prevented from contacting by additionally adding a membrane in the three-way connector, so that the solutions in the two containers are isolated. The separation into two containers realizes that all required feed liquid can be pre-installed before production and the whole process of the production process of the biomacromolecule substance is closed. The production equipment 1 according to the embodiment of the disclosure does not frequently detach joints due to production procedures, thereby realizing automatic procedure operation without human intervention.

The connection of the pipelines of the production equipment 1 according to the embodiment of the present disclosure can be set in advance through the aseptic three-way connector, and the reservation of the interface is flexibly adapted to the whole-course closed production of all procedures such as cleaning, disinfection, sample loading, sampling, harvesting, transferring and the like in various production processes.

According to the ultrafiltration treatment device double-column design of the production equipment 1 disclosed by the embodiment of the disclosure, the production efficiency can be improved, and the production time is shortened by 3-5 times. The double-column design can also improve the concentration multiple of the product, and the product of the biological macromolecular substance can reach higher titer.

According to this production facility 1 who discloses the embodiment designs a series of pipelines and interface on three-dimensional stock solution bag's basis, makes it can replace traditional stainless steel ultrafiltration container to carry out the ultrafiltration flow under the condition that need not to carry out the cleanness to stock solution bag inside, has aseptic sample and the function of aseptic transfer feed liquid simultaneously concurrently, keeps the production mode of inside sterile condition throughout at the ultrafiltration process.

Although exemplary embodiments of the present disclosure have been described, it will be understood by those skilled in the art that various changes and modifications can be made to the exemplary embodiments of the present disclosure without substantially departing from the spirit and scope of the present disclosure. Accordingly, all changes and modifications are intended to be included within the scope of the present disclosure as defined in the appended claims. The disclosure is defined by the following claims, with equivalents of the claims to be included therein.

Claims

1. A production apparatus for a biomacromolecule product, characterized in that the production apparatus comprises:

an ultrafiltration treatment device configured to ultrafiltration treat a feed solution containing a product to be treated, the ultrafiltration treatment device comprising an inlet end, an outlet end, and a discharge end;

2. The production facility of claim 1, wherein the upstream tee connector and the downstream tee connector are configured to remain physically connected to the feed liquid container and the cleaning liquid container simultaneously during cleaning of the production process, wherein the internal cleaning liquid channel of the upstream tee connector and the internal cleaning liquid channel of the downstream tee connector are open to fluidly connect the cleaning liquid container to the production facility, and the internal feed liquid channel of the upstream tee connector and the internal feed liquid channel of the downstream tee connector are closed to fluidly disconnect the feed liquid container from the production facility.

3. The production facility of claim 1, wherein the upstream tee connector and the downstream tee connector are configured to remain physically connected to the feed liquid container and the cleaning liquid container simultaneously during ultrafiltration of the production process, wherein the internal feed liquid channel of the upstream tee connector and the internal feed liquid channel of the downstream tee connector are open to fluidly connect the feed liquid container to the production facility, and the internal cleaning liquid channel of the upstream tee connector and the internal cleaning liquid channel of the downstream tee connector are closed to fluidly disconnect the cleaning liquid container from the production facility.

4. The production facility according to any one of claims 1 to 3, wherein the internal feed liquid channel and the internal cleaning liquid channel of the upstream three-way connector are separated by a membrane, and the internal feed liquid channel and the internal cleaning liquid channel of the downstream three-way connector are separated by a membrane.

5. The production apparatus according to any one of claims 1 to 3, wherein the upstream and downstream three-way connectors are made of a biocompatible material.

6. A production plant according to any of claims 1-3, characterized in that a pumping mechanism is provided in the inlet line, said pumping mechanism being configured to pump the liquid in the inlet line through the ultrafiltration treatment unit.

7. The production apparatus of any one of claims 1-3, wherein a flow monitor is provided on the inlet line, the flow monitor being configured to monitor a flow of liquid through the inlet line.

8. The production apparatus according to any one of claims 1 to 3, wherein a pneumatically actuated valve is provided on the outlet line, the pneumatically actuated valve being configured to control the magnitude of the flow rate of the liquid through the outlet line.

9. The production facility according to any one of claims 1 to 3, wherein the discharge line of the ultrafiltration treatment device is configured to discharge the liquid separated after the feed liquid is treated by the ultrafiltration treatment device out of the production facility, and one end of the discharge line of the ultrafiltration treatment device is connected to a discharge port of the production facility and the opposite end is connected to a discharge end of the ultrafiltration treatment device.

10. A production device according to any one of claims 1-3, characterized in that one end of the discharge line for cleaning liquid is connected to the outlet line and the opposite end is connected to a discharge opening of the production device.

11. A production plant according to any one of claims 1-3, characterized in that the ultrafiltration treatment unit comprises a hollow fiber column.

12. The production plant according to any of claims 1 to 3, further comprising 2 nd to nth ultrafiltration treatment devices connected in parallel to the ultrafiltration treatment device, and wherein a minimum treatment volume of an mth of the 2 nd to nth ultrafiltration treatment devices for the feed liquid is smaller than a minimum treatment volume of an (m-1) th ultrafiltration treatment device for the feed liquid, wherein: n is an integer more than or equal to 2, m is any integer more than 2 and less than or equal to n, and the 1 st ultrafiltration treatment device is the ultrafiltration treatment device.

13. The production apparatus according to claim 12, wherein the inlet line of the mth ultrafiltration treatment device is provided with a valve thereon, and has one end connected to the inlet end of the mth ultrafiltration treatment device and the opposite end connected to the inlet line of the (m-1) th ultrafiltration treatment device; the outlet pipeline of the mth ultrafiltration treatment device is provided with a valve, one end of the outlet pipeline is connected to the outlet end of the mth ultrafiltration treatment device, and the other opposite end of the outlet pipeline is connected to the outlet pipeline of the (m-1) th ultrafiltration treatment device; one end of the discharge line of the mth ultrafiltration treatment device is connected to the discharge port of the production apparatus, and the opposite end is connected to the discharge end of the mth ultrafiltration treatment device.

14. The production facility according to claim 12, wherein the ultrafiltration treatment devices and the 2 nd to nth ultrafiltration treatment devices sequentially treat the feed liquid in order of the smallest treatment volume from large to small during the ultrafiltration of the production process, and only one ultrafiltration treatment device treats the feed liquid during a period of time.

15. A production plant according to any one of claims 1-3, characterized in that the replenishment line is configured to replenish the feed liquid container with feed liquid and has one end connected to the replenishment end of the feed liquid container and the opposite end provided with a connector for connection to a feed liquid storage means.