CN115920639A - Production equipment for biomacromolecular substance products - Google Patents

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 biomacromolecular substance products

technical field

The present disclosure relates generally to the field of production of biomacromolecular substance products. More specifically, the present disclosure relates to a production facility for biomacromolecular substance products.

Background technique

For the ultrafiltration process of biological macromolecular substances (such as viruses), the cleaning and disinfection of equipment and the concentration of feed liquid are the main processes. The cleaning and disinfection of equipment means that the equipment used for production is injected with a cleaning solution (such as lye) as a whole before use, rinsed with water after circulation and disinfection to neutrality, and finally replaced with a buffer solution for the production environment. The concentration of the feed liquid refers to the use of hollow fiber columns to concentrate the feed liquid containing biomacromolecular substance products to the final concentrated liquid.

Current production equipment has only one liquid inlet. In the whole process of the ultrafiltration process, pre-production cleaning is first required; after the ultrafiltration vessel is cleaned and sterilized, a cleaning solution is added to the ultrafiltration vessel; the ultrafiltration vessel is connected to the production equipment to cycle clean the entire production equipment . After that, the ultrafiltration container is disassembled from the production equipment, the ultrafiltration container is cleaned and sterilized again, and the product feed liquid is added. Load the ultrafiltration container containing the product feed liquid on the production equipment, and circulate and concentrate. After completion, collect the final concentrate, aliquot into centrifuge tubes for centrifugation. Afterwards, the ultrafiltration container is disassembled from the production equipment, and cleaning liquid is added to the ultrafiltration container; the ultrafiltration container is connected to the production equipment to cycle clean the entire production equipment. Save production equipment after cycle cleaning is complete.

Due to the particularity of biological macromolecule products, it is necessary to reduce the contact of personnel with the material liquid during the production process to ensure the sterility of the product. However, when cleaning and disinfecting production equipment, the frequency of disassembling and assembling pipeline interfaces is frequent. Every time a type of liquid (such as cleaning solution, buffer solution, feed solution, etc.) is changed, the interface needs to be disassembled once, and the risk of bacterial contamination increases dramatically.

Contents of the invention

One of the objects of the present disclosure is to provide a production plant capable of overcoming at least one of the drawbacks of the prior art.

One aspect of the present disclosure relates to a production facility for biomacromolecular substance products, wherein the production facility comprises:

An ultrafiltration treatment device, the ultrafiltration treatment device is configured to perform ultrafiltration treatment on the feed liquid containing the product to be treated, and the ultrafiltration treatment device includes an inlet port, an outlet port and a discharge port;

an upstream three-way connector comprising a first inlet, a second inlet and an outlet, the upstream three-way connector forming an interior between the first inlet and the outlet and between the second inlet and the outlet, respectively The material liquid channel and the internal cleaning liquid channel, and the internal material liquid channel and the internal cleaning liquid channel are isolated from each other, and the first inlet and the second inlet are respectively connected to the sampling end of the material liquid container and the cleaning liquid container in a removable manner. A sampling port, and the outlet is connected to the inlet port of the ultrafiltration treatment device through 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 internal The feed liquid channel and the internal cleaning liquid channel, and the internal feed liquid channel and the internal cleaning liquid channel are isolated from each other, the inlet is connected to the outlet end of the ultrafiltration treatment device through an outlet pipeline, and the first outlet and the second outlet are respectively connected to a removable Connect the return end of the feed liquid container and the return end of the cleaning liquid container by means of removal;

Wherein, the upstream three-way connector and the downstream three-way connector are configured to keep physically connected to the feed liquid container and the cleaning liquid container at the same time during the production process of the production equipment, and the feed liquid container and the cleaning liquid container are connected through the upstream three-way The switching between the inner feed liquid channel and the inner cleaning liquid channel of the filter and the downstream three-way connector is in fluid communication with the production equipment at different time periods in the production process.

In some embodiments, 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 interior of the upstream tee connector is cleaned The liquid channel and the internal cleaning liquid channel of the downstream tee connector are open to fluidly communicate the cleaning liquid container with the production equipment, 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 disconnect the fluid container from the production equipment.

In some embodiments, 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 interior of the upstream tee connector The feed liquid channel and the internal feed liquid channel of the downstream tee connector are opened to fluidly communicate the feed liquid container with the production equipment, and the internal cleaning liquid channel of the upstream tee connector and the internal cleaning liquid channel of the downstream tee connector Close to fluidly disconnect the cleaning fluid container from the production equipment.

In some embodiments, the internal feed liquid channel and the internal cleaning liquid channel of the upstream tee connector are separated by a membrane, and the internal feed liquid channel and the internal cleaning liquid channel of the downstream tee connector are separated by a membrane.

In some embodiments, the upstream tee connector and the downstream tee connector are made of biocompatible materials.

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

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

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

In some embodiments, the discharge pipeline of the ultrafiltration treatment device is configured to discharge the liquid separated from the feed liquid after being treated by the ultrafiltration treatment device out of the production equipment, and one end of the discharge pipeline of the ultrafiltration treatment device is connected to the production equipment. The discharge port of the equipment, 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 fluid is connected to the outlet line, and the opposite end is connected to the discharge of the production facility.

In some embodiments, the ultrafiltration treatment device includes a hollow fiber cartridge.

In some embodiments, the production equipment further includes the second to nth ultrafiltration treatment devices in parallel with the ultrafiltration treatment device, and the mth of the second to nth ultrafiltration treatment devices The minimum processing volume of the ultrafiltration treatment device for the feed liquid is smaller than the 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, and m is greater than 2 and less than or equal to n Any integer of , the first ultrafiltration treatment device is the ultrafiltration treatment device.

In some embodiments, the inlet pipeline of the mth ultrafiltration treatment device is provided with a valve thereon, and one end thereof is connected to the inlet end of the mth ultrafiltration treatment device, and the opposite end is connected to the (m- 1) on the inlet pipeline of the ultrafiltration treatment device; the outlet pipeline of the m ultrafiltration treatment unit is provided with a valve thereon, and one end thereof is connected to the outlet end of the m ultrafiltration treatment unit, the opposite end Connect to the outlet pipeline of the (m-1)th ultrafiltration treatment device; one end of the discharge pipeline of the mth ultrafiltration treatment device is connected to the discharge port of the production equipment, and the opposite end is connected to the mth ultrafiltration treatment unit. The discharge end of the filter treatment device.

In some embodiments, during the ultrafiltration period of the production process, the ultrafiltration treatment device and the second to nth ultrafiltration treatment devices sequentially process the feed liquid according to the order of the smallest treatment volume from large to small, and In a period of time, only one ultrafiltration treatment device processes the feed liquid.

In some embodiments, the replenishment line is configured to replenish the feed container with feed liquid, and one end thereof is connected to the feed liquid end of the feed liquid container, and the opposite end has a connector for connecting to a feed liquid storage device .

Additional features and advantages of the subject technology of the present disclosure 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 subject technology of the present disclosure. 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.

Description of drawings

Aspects of the present disclosure will be better understood after reading the following detailed description in conjunction with the accompanying drawings, in which:

1 shows a schematic diagram of a production facility according to a first embodiment of the present disclosure;

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

Fig. 3 shows a schematic diagram of a production facility according to a second embodiment of the present disclosure.

Additional features and advantages of the subject technology of the present disclosure 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 subject technology of the present disclosure. 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.

Detailed ways

The present disclosure will be described below with reference to the accompanying drawings, which illustrate several embodiments of the disclosure. However, it should be understood that the present disclosure can be presented in many different ways, and is not limited to the embodiments described below; in fact, the embodiments described below are intended to make the disclosure of the present disclosure more complete and contribute to this Those skilled in the art fully explain the protection scope of the present disclosure. It should also be understood that the embodiments disclosed herein can be combined in various ways to provide even more additional embodiments.

It should be understood that like reference numerals refer to like elements throughout the drawings. In the drawings, the dimensions of some features may be distorted for clarity.

It should be understood that the terminology used in the specification is for the purpose of describing particular embodiments only and is not intended to be limiting of the present disclosure. Unless otherwise defined, all terms (including technical terms and scientific terms) used in the specification have the meanings commonly understood by those skilled in the art. Well-known functions or constructions may not be described in detail for brevity and/or clarity.

The singular forms "a", "the" and "the" used in the specification include plural forms unless clearly stated otherwise. The terms "comprising", "comprising" and "comprising" are used in the specification to indicate the presence of claimed features but not to exclude the presence of one or more other features. The term "and/or" used in the specification includes any and all combinations of one or more of the related listed items. The terms "between X and Y" and "between about X and Y" used in the specification should be construed to include X and Y. As used in this specification, the phrase "between about X and Y" means "between about X and about Y", and the phrase "from about X to Y" is used in this specification to mean "from about X to about Y".

In the specification, when an element is referred to as being “on,” “attached to,” “connected to,” “coupled to,” or “in contact with” another element, etc., another element, The element may be directly on, attached to, connected to, coupled to, or contact another element, or intervening elements may be present. In contrast, saying that an element is "directly on" another element, "directly attached to" another element, "directly connected to" another element, "directly coupled" to another element or, or " When "directly contacting" another element, there will be no intervening elements present. In the specification, a feature arranged "adjacent" to another feature may mean that a feature has a portion overlapping an adjacent feature or a portion above or below the adjacent feature.

In the specification, terms of spatial relation such as "upper", "lower", "left", "right", "front", "rear", "high", "low", etc. may describe the relationship between one feature and another. Relationships in the attached drawings. It will be understood that the spatially relative terms encompass different orientations of the device in use or operation in addition to the orientation depicted in the figures. For example, if the device in the figures is turned over, features described as "below" other features would then be oriented "above" the other features. The device may be otherwise oriented (rotated 90 degrees or at other orientations) and the relative spatial relationships interpreted accordingly.

The disclosure relates to a production equipment for processing feed liquid containing biological macromolecular substances, which can reduce the frequent disassembly of pipelines in the cleaning, disinfection, sampling and other processes in the production process of the existing equipment, and avoid exposure during the production process. Increase the product contamination problem brought about. Fig. 1 shows a schematic diagram of a production plant 1 according to a first embodiment of the present disclosure. As shown in the figure, the production equipment 1 includes fluid pipelines to connect the feed liquid container 10, the cleaning liquid container 20 and the ultrafiltration treatment device (two are shown in the figure, respectively ultrafiltration treatment device 30 and 30') to each other connect. The feed liquid container 10 is used for storing the feed liquid containing the product to be processed, which is a biological macromolecular substance, such as virus, mRNA, and the like. The cleaning liquid container 20 is used for storing cleaning liquid to clean all or part of the equipment. The ultrafiltration treatment device is used to process (for example, ultrafiltration/concentration) the feed liquid from the feed liquid container 10, and discharge the separated liquid after treatment.

The feed liquid container 10 has a sampling end, a return end and a replenishment end, so as to be respectively connected to the sampling line 11 , the return line 12 and the liquid replenishment line 13 . The sampling line 11 is used to transport the feed liquid in the feed liquid container 10 to the ultrafiltration treatment device 30, and one end thereof is connected to the sampling end of the feed liquid container 10, and the opposite end is connected to the three-way connector 14. Import first. The return pipeline 12 is used to transport the processed feed liquid back to the feed liquid container 10 , and one end thereof is connected to the return end of the feed liquid container 10 , and the opposite end is connected to the first outlet of the three-way connector 15 . The replenishment pipeline 13 is used to replenish the feed liquid to the feed liquid container 10, and one end thereof is connected to the feed liquid end of the feed liquid container 10, and the other end has a connector 13C for connecting to a feed liquid storage device (not shown) . A pumping mechanism 13P may be provided on the replenishment pipeline 13 for pumping the feed liquid in the feed liquid storage device to the feed liquid container 10 . The pumping mechanism 13P may be, for example, a peristaltic pump, or any other suitable pump. The feed liquid container 10 can be placed on the weighing platform 16 to detect the weight of the feed liquid container 10 . The controller (not shown) can activate or deactivate the pumping mechanism 13P according to the weight change of the feed liquid container 10 fed back by the weighing platform 16 to replenish the feed liquid container 10 . In some embodiments, the feed liquid container 10 may be, for example, a three-dimensional liquid storage bag provided with two three-way connectors, as shown in FIG. 2 . The liquid storage bag can be used as a sterile bag for storing liquids such as buffer, culture medium, and biological stock solution, and has extremely low gas permeability, good physical strength, and excellent biological and chemical compatibility.

The cleaning solution container 20 has a sampling end and a return end, so as to be connected to the sampling line 21 and the return line 22 respectively. The sampling line 21 is used to transport the cleaning solution in the cleaning solution container 20 to the ultrafiltration treatment device 30 and the connected fluid pipeline, and one end thereof is connected to the sampling end of the cleaning solution container 20, and the opposite end is connected to the The second inlet of the tee connector 14. The return line 22 is used to transport the cleaning liquid back to the cleaning liquid container 20 , and one end thereof is connected to the return end of the cleaning liquid container 20 , and the opposite end is connected to the second outlet of the three-way connector 15 .

The introduction of the three-way connectors 14 and 15 realizes the connection or disconnection between the material liquid container 10, the cleaning liquid container 20 and the flow path of the production equipment 1 without disassembling the interface. In some embodiments, each of the three-way connectors 14 and 15 includes three inlets and outlets and internal passages connecting the three outlets. Between the first inlet and the outlet of the three-way connector 14 is an internal material liquid passage, and between the second inlet and the outlet is an internal cleaning liquid passage. Between the inlet and the first outlet of the three-way connector 15 is an internal feed liquid channel, and between the inlet and the second outlet is an internal cleaning liquid channel. The inner material liquid channel and the inner cleaning liquid channel inside the three-way connector are separated by a membrane, which realizes the cleanliness of the double channel during cleaning and disinfection and production. In some embodiments, three-way connectors 14 and 15 can be made using biocompatible materials. The three-way connectors 14 and 15 can be Steam-Thru II three-way joints purchased from Lepur, or realize the three-way function through the assembly of the valve block structure, such as two-position three-way solenoid valve, three-way ball valve, Y-type Three-way interface, etc.

The ultrafiltration treatment device 30 has an inlet port, an outlet port, and a discharge port to be connected to an inlet line 31 , an outlet line 32 , and a discharge line 33 , respectively. Inlet pipeline 31 is used for introducing various liquids (such as feed liquid from feed liquid container 10, cleaning liquid from cleaning liquid container 20, etc.) The inlet end of the ultrafiltration treatment device 30 and the opposite end are 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 . The pumping mechanism 31P is used to pump various liquids (such as feed liquid from the feed liquid container 10, cleaning liquid from the cleaning liquid container 20, etc.) through the ultrafiltration treatment device, and can be, for example, a peristaltic pump, or any other suitable pump. The flow monitor 31M is used to monitor the liquid flow through the inlet line 31 .

The outlet pipeline 32 is used to return the liquid passing through all the ultrafiltration treatment devices upstream of the outlet pipeline 32 to the corresponding container (such as the feed liquid container 10, the cleaning liquid container 20, etc.), and one end thereof is connected to the ultrafiltration treatment device The outlet end of 30 and the opposite end are connected to the inlet of three-way connector 15 . A pneumatic valve 32V may be provided on the outlet pipeline 32 to control the flow rate of the liquid passing through the outlet pipeline 32 . A controller (not shown) can control the pneumatic valve 32V according to the change of the liquid flow through the inlet pipe 31 fed back by the flow monitor 31M.

The discharge pipeline 33 is used to discharge the separated liquid after the feed liquid is treated by the ultrafiltration treatment device 30, and one end thereof is connected to the discharge port 40, and the opposite end has two branches, one branch is connected to the ultrafiltration treatment The other branch of the discharge end of the device 30 is connected to the discharge end of the second ultrafiltration treatment device 30' (described in detail below). A valve 33V may be provided on the discharge pipeline 33 for controlling the opening and closing of the discharge pipeline 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 feed liquid by the second ultrafiltration treatment device 30' is smaller than the minimum treatment volume of the ultrafiltration treatment device 30. Thus, the equipment can first use the ultrafiltration treatment device 30 to process the feed liquid, and after the volume of the feed liquid is less than the minimum treatment volume of the ultrafiltration treatment device 30, turn to use the second ultrafiltration treatment device 30' to process the feed liquid to process. For example, the ultrafiltration treatment device 30 and the second ultrafiltration treatment device 30' can adopt a double-column design, and are respectively a hollow fiber column with a large column position and a hollow fiber column with a small column position. The hollow fiber column membrane area of the large-column column body is large, and the production efficiency is high; however, the large membrane area leads to a large column volume, and the minimum processing volume (filling the entire column) is large; therefore, the final concentrated concentration of the large-column column body reaches Less than the product needs, need to carry out multiple centrifugation and concentration. The hollow fiber column membrane area of the small column column is small, and the production efficiency is low; but its minimum processing volume is small, and the final concentrated concentration that can be achieved is large. Combining two columns into the same equipment can not only reduce the minimum processing volume of the equipment, but also improve production efficiency.

Similar to the ultrafiltration treatment device 30, the second ultrafiltration treatment device 30' has an inlet port, an outlet port and a discharge port to be connected to an inlet line 31', an outlet line 32' and a discharge line 33, respectively. The inlet pipeline 31' is used to introduce various liquids (such as the feed liquid from the feed liquid container 10, the cleaning liquid from the cleaning liquid container 20, etc.) All other ultrafiltration treatment devices except the filtration treatment device 30), and one end thereof is connected to the inlet end of the ultrafiltration treatment device 30', and the opposite end is connected to the inlet pipeline 31 of the ultrafiltration treatment device 30, for example, connected The inlet line 31 is located between the inlet end of the ultrafiltration treatment device 30 and the flow monitor 31M. A valve 31V' may be provided on the inlet pipeline 31' for controlling the opening and closing of the inlet pipeline 31'.

The outlet pipeline 32' is used to return the liquid passing through all the ultrafiltration treatment devices upstream of the outlet pipeline 32' to the corresponding container (such as the feed liquid container 10, the cleaning liquid container 20, etc.), and one end thereof is connected to the ultrafiltration filter. The outlet end of the processing device 30', and the opposite end is connected to the outlet pipeline 32 of the ultrafiltration treatment device 30, for example, connected to the outlet end of the outlet pipeline 32 located between the outlet end of the ultrafiltration treatment device 30 and the pneumatic valve 32V . A valve 32V' may be provided on the outlet pipeline 32' for controlling the opening and closing of the outlet pipeline 32'.

As mentioned above, the discharge pipeline 33 is used to discharge the separated liquid after the feed liquid treatment, and its one end is connected to the discharge port 40, and the opposite end has two branches, one branch is connected to the second ultrafiltration treatment device The discharge end of 30 ′ and the other branch are connected to the discharge end of the ultrafiltration treatment device 30 .

In some embodiments, the at least two ultrafiltration treatment devices may not only include the ultrafiltration treatment device 30 and the second ultrafiltration treatment device 30 ′, but also include the ultrafiltration treatment device 30 and the second ultrafiltration treatment device 30 'More ultrafiltration treatment units in parallel. In other words, the production equipment includes the 2nd to the nth ultrafiltration treatment device in parallel with the ultrafiltration treatment device 30, and the mth ultrafiltration treatment device in the 2nd to the nth ultrafiltration treatment device The minimum processing volume of the feed liquid is less than the minimum processing volume of the (m-1) ultrafiltration treatment device for the feed liquid, wherein: n is an integer greater than or equal to 2, and m is any integer greater than 2 and less than or equal to n, The first ultrafiltration treatment device is the ultrafiltration treatment device. The inlet pipeline of the mth ultrafiltration treatment device has a valve on it, and one end is connected to the inlet end of the mth ultrafiltration treatment device, and the opposite end is connected to the (m-1)th ultrafiltration treatment On the inlet pipeline of the device; the outlet pipeline of the m ultrafiltration treatment device is provided with a valve thereon, and one end thereof is connected to the outlet end of the m ultrafiltration treatment device, and the opposite end is connected to the (m- 1) On the outlet pipeline of the ultrafiltration treatment device; one end of the discharge pipeline of the mth ultrafiltration treatment unit is connected to the discharge port of the production equipment, and the opposite end is connected to the discharge end of the mth ultrafiltration treatment unit . During the ultrafiltration period of the production process, the ultrafiltration treatment device 30 and the second to nth ultrafiltration treatment devices sequentially process the feed liquid according to the order of the smallest treatment volume from large to small, and there is only one The ultrafiltration treatment device processes the feed liquid.

A discharge line 23 is connected between the outlet line 32 and the discharge port 40 for the discharge of 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 pipeline 23 for controlling the opening and closing of the discharge pipeline 23 .

The operation process of the production equipment 1 according to the first embodiment of the present disclosure will be described below. The ultrafiltration treatment device 30 and the second ultrafiltration treatment device 30' are loaded into the production equipment 1 in parallel (for example, by means of a clamp), so that the inlet end, the outlet end and the discharge end of the ultrafiltration treatment device 30 are respectively Connected to the inlet pipeline 31, outlet pipeline 32 and discharge pipeline 33, and the inlet port, outlet port and discharge end of the second ultrafiltration treatment device 30' are respectively connected to the inlet pipeline 31 ', outlet pipeline 32' and Discharge line 33 .

Fill the feed liquid container 10 with the feed liquid containing the product to be treated, and load the feed liquid container 10 into the production equipment 1, so that the sample inlet, return end and replenishment liquid end of the feed liquid container 10 are respectively connected to the sample feed pipeline 11. Return pipeline 12 and liquid replenishment pipeline 13. The cleaning liquid is filled into the cleaning liquid container 20, and the cleaning liquid container 20 is loaded into the production equipment 1, so that the sampling end and the return end of the cleaning liquid container 20 are respectively connected to the sampling line 21 and the return line 22.

Open the internal cleaning liquid passage between the second inlet and the outlet of the three-way connector 14, and open the internal cleaning liquid passage between the inlet and the second outlet of the three-way connector 15; Valve 31V' and valve 32V' on outlet line 32' are open, while valves 33V and 23V on discharge lines 33 and 23 are closed. Thus, the cleaning solution flows out of the sample injection pipeline 21 from the sample injection end of the cleaning solution container 20 , and flows into the inlet pipeline 31 through the internal cleaning solution channel of the three-way connector 14 . The cleaning liquid flows into the parallel ultrafiltration treatment device 30 and the second ultrafiltration treatment device 30' from the inlet pipeline 31, and enters the outlet pipeline 32 after flowing out. The cleaning liquid flows into the return line 22 through the internal cleaning liquid channel of the three-way connector 15 , and returns to the cleaning liquid container 20 through the return end of the cleaning liquid container 20 . Cycle one or more times, thereby completing the cleaning operation of the equipment. In some embodiments, the internal cleaning liquid channel of the three-way connector 15 can also be closed, and the valve 23V on the discharge line 23 can be opened, so that the cleaning liquid entering the outlet line 32 can be discharged out of the device through the discharge line 23 , without returning to the cleaning solution container 20.

After completing the cleaning of the equipment, the internal cleaning liquid channel between the second inlet and the outlet of the three-way connector 14 is closed, and the internal material liquid channel between the first inlet and the outlet is opened; the inlet of the three-way connector 15 is The internal cleaning liquid passage between the second outlet and the second outlet is closed, and the internal feed liquid passage between the inlet and the first outlet is opened, thereby disconnecting the cleaning liquid container 20 from the flow path of the equipment and connecting the feed liquid container 10 to the equipment on the flow path. The introduction of two types of containers and the setting of three-way connectors reduce the frequent disassembly of pipelines in cleaning, disinfection, sampling and other processes, and avoid the problem of product contamination caused by increased exposure during the production process. The cleaning liquid flows in from one inlet of the three-way connector through the cleaning liquid container, and one outlet flows out to the production equipment for cleaning and disinfection; after the cleaning and disinfection is completed, close the cleaning liquid container without disassembly, and at the same time, the production material liquid flows from the three-way connector The second inlet injection participates in production.

The valve 31V' on the inlet pipeline 31' and the valve 32V' on the outlet pipeline 32' are closed, the valve 33V on the discharge pipeline 33 is opened, and the valve 23V on the discharge pipeline 23 is kept closed. Thus, the feed liquid containing the product to be processed flows out of the sample inlet pipeline 11 from the sample injection end of the feed liquid container 10 , and flows into the inlet pipeline 31 through the internal feed liquid channel of the three-way connector 14 . The feed liquid flows into the ultrafiltration treatment device 30 from the inlet pipeline 31 . The feed liquid is processed (such as ultrafiltration/concentration) in the ultrafiltration treatment device 30 , and the separated liquid after treatment is discharged through the discharge pipeline 33 . The processed feed liquid (for example, concentrated feed liquid) enters the outlet pipeline 32, flows into the return pipeline 12 through the internal feed liquid channel of the three-way connector 15, and returns to the feed liquid container through the return end of the feed liquid container 10 10. Thus, the primary treatment process of the feed liquid is completed.

The process of circulating the feed liquid is performed until the volume of the processed feed liquid is smaller than the minimum processing volume of the ultrafiltration treatment device 30 . At this time, the ultrafiltration treatment device 30 is no longer able to process the current feed liquid. The valve 31V' on the inlet line 31' and the valve 32V' on the outlet line 32' are opened. Thus, the feed liquid containing the product to be processed flows out of the sample inlet pipeline 11 from the sample injection end of the feed liquid container 10 , and flows into the inlet pipeline 31 through the internal feed liquid channel of the three-way connector 14 . Feed liquid flows into the second ultrafiltration treatment device 30' from the inlet pipeline 31. The feed liquid is processed (such as ultrafiltration/concentration) in the second ultrafiltration treatment device 30', and the separated liquid after treatment is discharged through the discharge pipeline 33. The processed feed liquid (for example, concentrated feed liquid) enters the outlet pipeline 32, flows into the return pipeline 12 through the internal feed liquid channel of the three-way connector 15, and returns to the feed liquid container through the return end of the feed liquid container 10 10. Thus, a further treatment process of the feed liquid is completed. Continue to circulate to the final processed feed liquid (eg final concentrated liquid product), and collect into the feed liquid container 10 . The ultrafiltration treatment device with two-column design improves the production efficiency of the production equipment 1 and increases the product concentration ratio.

Afterwards, the valve 33V of the discharge channel 33 is closed, the internal 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 three-way The internal feed liquid channel between the inlet of the connector 15 and the first outlet is closed, and the internal cleaning liquid channel between the inlet and the second outlet is opened. Repeat the cleaning process for the device. Store the device after cleaning.

It can be seen that during the production process of the production equipment 1, the three-way connector 14 and the three-way connector 15 are configured to keep physically connected to the feed liquid container 10 and the cleaning liquid container 20 at the same time, and the feed liquid container 10 and the cleaning liquid container The liquid container 20 is in fluid communication with the production equipment 1 at different time periods of the production process through the switching between the three-way connector 14 and the three-way connector 15 between the respective internal feed liquid channels and internal cleaning liquid channels. Specifically, during the cleaning of the production process, the three-way connector 14 and the three-way connector 15 are configured to remain physically connected to the feed liquid container 10 and the cleaning liquid container 20 at the same time, wherein the inside of the three-way connector 14 The cleaning liquid channel and the internal cleaning liquid channel of the three-way connector 15 are opened to fluidly communicate the cleaning liquid container 20 with the production equipment 1, and the internal material liquid channel of the three-way connector 14 and the internal material of the three-way connector 15 are opened. The liquid channel is closed to disconnect the feed liquid container 10 from the production equipment 1 in fluid connection. During the ultrafiltration of the production process, the three-way connector 14 and the three-way connector 15 are configured to remain physically connected to the feed liquid container 10 and the cleaning liquid container 20 at the same time, wherein the internal feed liquid channel of the three-way connector 14 and the internal feed liquid passage of the three-way connector 15 are opened to fluidly communicate the feed liquid container 10 with the production equipment 1, and the internal cleaning liquid passage of the three-way connector 14 and the internal cleaning liquid passage of the three-way connector 15 are closed , to disconnect the cleaning fluid container 20 from the production equipment 1 in fluid connection.

A schematic diagram of a production device 101 for feed liquid according to a second embodiment of the present disclosure will be introduced below with reference to FIG. 3 . Production facility 101 will denote identical or similar structures with the reference numeral in production facility 1 plus 100 . As shown in FIG. 3 , the production equipment 101 includes fluid pipelines to connect a feed liquid container 110 , a cleaning liquid container 120 and an ultrafiltration treatment device 130 to each other. The structural difference between the production equipment 101 and the production equipment 1 is that there is only one ultrafiltration treatment device 130 , and there is no other ultrafiltration treatment device connected in parallel with the ultrafiltration treatment device 130 . Therefore, the difference between the production equipment 101 and the production equipment 1 in the operation process is that there is no need to switch between different ultrafiltration treatment devices for use. Will not repeat them.

The production equipment 1 according to the embodiment of the present disclosure divides a traditional ultrafiltration container into two containers (ie, a feed liquid container and a cleaning liquid container), and the two containers are physically connected through two three-way connectors. An additional diaphragm is added in the three-way connector to block the contact of the solutions in the two containers and isolate the solutions in the two containers. Splitting into two containers realizes the pre-installation of all required feed liquids before production and the full sealing of the production process of biological macromolecules. The production equipment 1 according to the embodiment of the present disclosure does not frequently disassemble joints due to production procedures, thereby realizing automatic program 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 a sterile three-way connector, and the interface is reserved to flexibly adapt to various processes such as cleaning, disinfection, sample loading, sampling, harvesting, and transfer in various production processes The whole process is airtight production.

The double-column design of the ultrafiltration treatment device of the production equipment 1 according to the embodiment of the present disclosure can improve production efficiency, and the production time is shortened by 3-5 times. The double-column design can also increase the concentration factor of the product, and the product of biological macromolecules can achieve a higher titer.

According to the production equipment 1 of the embodiment of the present disclosure, a series of pipelines and interfaces are designed on the basis of the three-dimensional liquid storage bag, so that it can replace the traditional stainless steel ultrafiltration container for ultrafiltration without cleaning the inside of the liquid storage bag It has the functions of aseptic sampling and aseptic transfer of feed liquid, and maintains the production mode of internal aseptic state during the ultrafiltration process.

Although the 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. Therefore, all changes and modifications are included in the protection scope of the present disclosure as defined by the claims. The disclosure is defined by the appended claims, with equivalents of those claims to be embraced therein.

Claims (15)

1. A production equipment for biological macromolecular substance products, characterized in that, the production equipment comprises: An ultrafiltration treatment device, the ultrafiltration treatment device is configured to perform ultrafiltration treatment on the feed liquid containing the product to be treated, and the ultrafiltration treatment device includes an inlet port, an outlet port and a discharge port; an upstream three-way connector comprising a first inlet, a second inlet and an outlet, the upstream three-way connector forming an interior between the first inlet and the outlet and between the second inlet and the outlet, respectively The material liquid channel and the internal cleaning liquid channel, and the internal material liquid channel and the internal cleaning liquid channel are isolated from each other, and the first inlet and the second inlet are respectively connected to the sampling end of the material liquid container and the cleaning liquid container in a removable manner. A sampling port, and the outlet is connected to the inlet port of the ultrafiltration treatment device through 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 internal The feed liquid channel and the internal cleaning liquid channel, and the internal feed liquid channel and the internal cleaning liquid channel are isolated from each other, the inlet is connected to the outlet end of the ultrafiltration treatment device through an outlet pipeline, and the first outlet and the second outlet are respectively connected to a removable Connect the return end of the feed liquid container and the return end of the cleaning liquid container by means of removal; Wherein, the upstream three-way connector and the downstream three-way connector are configured to keep physically connected to the feed liquid container and the cleaning liquid container at the same time during the production process of the production equipment, and the feed liquid container and the cleaning liquid container are connected through the upstream three-way The switching between the inner feed liquid channel and the inner cleaning liquid channel of the filter and the downstream three-way connector is in fluid communication with the production equipment at different time periods in the production process. 2. The production facility of claim 1, wherein the upstream tee connector and the downstream tee connector are configured to simultaneously remain physically connected to the feed liquid container and the cleaning liquid container during cleaning of the production process, Among them, the internal cleaning liquid channel of the upstream three-way connector and the internal cleaning liquid channel of the downstream three-way connector are opened to fluidly communicate the cleaning liquid container with the production equipment, and the internal material liquid channel of the upstream three-way connector and the downstream The internal fluid channel of the tee connector is closed to fluidly disconnect the fluid container from the production equipment. 3. The production facility of claim 1, wherein the upstream tee connector and the downstream tee connector are configured to simultaneously remain physically connected to the feed liquid container and the cleaning liquid container 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 opened to fluidly communicate the feed liquid container with the production equipment, and the internal cleaning liquid channel of the upstream three-way connector and The internal cleaning fluid channel of the downstream tee connector is closed to fluidly disconnect the cleaning fluid container from the production equipment. 4. The production equipment according to any one of claims 1-3, characterized in that, the internal feed liquid channel and the internal cleaning liquid channel of the upstream three-way connector are separated by a membrane, and the inside of the downstream three-way connector The feed liquid channel and the internal cleaning liquid channel are separated by a membrane. 5. The production equipment according to any one of claims 1-3, characterized in that the upstream three-way connector and the downstream three-way connector are made of bio-affinity materials. 6. The production equipment according to any one of claims 1-3, characterized in that a pumping mechanism is provided on the inlet pipeline, and the pumping mechanism is configured to pump the liquid in the inlet pipeline through Ultrafiltration treatment device. 7. The production plant according to any one of claims 1-3, characterized in that a flow monitor is provided on the inlet line, the flow monitor being configured to monitor the liquid flow through the inlet line. 8. The production equipment according to any one of claims 1-3, characterized in that a pneumatic valve is provided on the outlet pipeline, and the pneumatic valve is configured to control the flow rate of the liquid passing through the outlet pipeline. 9. The production equipment according to any one of claims 1-3, characterized in that, the discharge pipeline of the ultrafiltration treatment device is configured to discharge the liquid separated from the feed liquid after being treated by the ultrafiltration treatment device out of the production line. Equipment, and one end of the discharge pipeline of the ultrafiltration treatment device is connected to the discharge port of the production equipment, and the opposite end is connected to the discharge end of the ultrafiltration treatment device. 10. Production plant according to any one of claims 1-3, characterized in that one end of the discharge line for the cleaning liquid is connected to the outlet line and the opposite end is connected to the discharge port of the production plant . 11. The production facility according to any one of claims 1-3, characterized in that the ultrafiltration treatment device comprises a hollow fiber column. 12. The production equipment according to any one of claims 1-3, characterized in that, the production equipment also comprises the 2nd to the nth ultrafiltration treatment equipment connected in parallel with the ultrafiltration treatment equipment, and the The minimum treatment volume of the mth ultrafiltration treatment device for the feed liquid in the second to the nth ultrafiltration treatment device is less than the minimum treatment volume of the (m-1) 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 first ultrafiltration treatment device is the ultrafiltration treatment device. 13. production equipment according to claim 12, is characterized in that, the inlet line of m ultrafiltration treatment device is provided with valve thereon, and its one end is connected to the inlet end of m ultrafiltration treatment device, The opposite end is connected to the inlet pipeline of the (m-1) ultrafiltration treatment device; the outlet pipeline of the m ultrafiltration treatment device is provided with a valve, and one end is connected to the m ultrafiltration treatment unit. The outlet end of the treatment device, the opposite end is connected to the outlet pipeline of the (m-1) ultrafiltration treatment unit; one end of the discharge pipeline of the m ultrafiltration treatment unit is connected to the discharge port of the production equipment, and The opposite end is connected to the discharge end of the mth ultrafiltration treatment device. 14. The production equipment according to claim 12, characterized in that, during the ultrafiltration of the production process, the ultrafiltration treatment device and the second to nth ultrafiltration treatment devices are ordered from large to small according to the minimum treatment volume The feed liquid is processed in sequence, and only one ultrafiltration treatment device processes the feed liquid within a period of time. 15. The production equipment according to any one of claims 1-3, characterized in that, the replenishment pipeline is configured to replenish the feed liquid container, and one end thereof is connected to the feed liquid end of the feed liquid container, and is relatively The other end has a connector for connection to a feed liquid storage device.

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