A zero dead leg and in-line sterilization transfer line system for a fermenter

Abstract

The utility model discloses a kind of seed transfer pipeline systems of zero dead angle and on-line sterilization for fermentation tank, belong to the field of microbial fermentation equipment, including seed tank and fermentation tank, seed tank is connected with fermentation tank by seed main pipeline, and the outlet end of seed tank is connected with seed tank discharge valve group, and the inlet end of fermentation tank is connected with fermentation tank seed valve group, seed tank discharge valve group and fermentation tank seed valve group are all using zero dead angle diaphragm valve, and one end of seed main pipeline close to seed tank discharge valve group is equipped with steam introduction branch, and the both ends of steam introduction branch are respectively connected with pure steam source and seed tank discharge valve group, and first pressure sensor is set on steam introduction branch, for real-time monitoring and recording steam pressure in sterilization process, by unique pipeline layout and valve configuration, ensure that whole pipeline has no liquid stagnation and steam sterilization dead angle, and can be verified by instrument on-line sterilization, to greatly reduce the probability of contamination, guarantee the purebred of fermentation production.

Description

Technical Field

[0001] This utility model belongs to the field of microbial fermentation equipment, and more specifically, relates to a transfer pipeline system for fermenters with zero dead angles and online sterilization. Background Technology

[0002] In the fermentation production of active pharmaceutical ingredients (APIs) with extremely high aseptic requirements, the transfer piping is a crucial piece of equipment connecting the seed tank and the fermentation tank. Traditional transfer piping systems have the following inherent drawbacks:

[0003] Dead corners in pipelines: Traditional valve installations, pipe connections, and tees can easily create "dead corners" that cannot be fully covered and circulated by saturated steam. These dead corners can easily become hiding places for miscellaneous bacteria, which is the main risk of contamination during transplantation.

[0004] Incomplete sterilization: Existing pipeline sterilization often uses fixed steam inlets and outlets, which can easily create "cold spots" due to poor condensate drainage. This results in the temperature in these areas not reaching the sterilization requirements, thus affecting the sterilization effect.

[0005] The process is cumbersome and risky: Traditional sterilization methods often require disassembling some pipes for separate treatment or relying on multiple steam venting and pressurization operations, which not only increases the labor intensity but also introduces the risk of bacterial contamination during manual intervention.

[0006] Lack of process validation: Traditional systems make it difficult to intuitively and effectively prove that the entire pipeline has reached the set sterilization temperature and maintained it for a sufficient time during the sterilization process.

[0007] Therefore, providing an online sterilization and transfer pipeline system that fundamentally eliminates dead zones and achieves high efficiency, reliability, and verifiability is a problem that urgently needs to be solved by those skilled in the art. Utility Model Content

[0008] The main purpose of this invention is to provide a transfer pipeline system for fermenters with zero dead zones and online sterilization. Through a unique pipeline layout and valve configuration, it ensures that there is no liquid stagnation or steam sterilization dead zones in the entire pipeline, and can be verified for online sterilization by pressure gauges, thereby greatly reducing the probability of contamination and ensuring the purity of the fermentation production.

[0009] According to a first aspect of this utility model, a transfer pipeline system for zero-dead-angle and online sterilization of a fermenter is provided, including a seed tank and a fermenter. The seed tank and the fermenter are connected by a main transfer pipeline. The outlet end of the seed tank is connected to a seed tank discharge valve group, and the inlet end of the fermenter is connected to a fermenter transfer valve group. Both the seed tank discharge valve group and the fermenter transfer valve group are zero-dead-angle diaphragm valves. A steam inlet branch is provided at one end of the main transfer pipeline near the seed tank discharge valve group. One end of the steam inlet branch is connected to a pure steam source, and the other end of the steam inlet branch is connected to the seed tank discharge valve group. A first pressure sensor is provided on the steam inlet branch for real-time monitoring and recording of the steam pressure during the sterilization process.

[0010] According to the first aspect of the present invention, the seed transfer pipeline system for zero dead angle and online sterilization of fermentation tank includes a seed tank discharge valve group comprising a first discharge valve and a second discharge valve. The first discharge valve is provided with a first small exhaust valve. Both the first discharge valve and the second discharge valve are provided on the main seed transfer pipeline. The first discharge valve is located at one end near the seed tank.

[0011] According to the first aspect embodiment of the present invention, the transfer pipeline system for zero dead angle and online sterilization of fermenters includes a first transfer valve and a second transfer valve. The first transfer valve is provided with a second small exhaust valve. Both the first transfer valve and the second transfer valve are provided on the main transfer pipeline. The first transfer valve is located at one end near the fermenter. The first discharge valve, the second discharge valve, the second transfer valve and the first transfer valve are sequentially arranged on the main transfer pipeline.

[0012] According to the first aspect of the present invention, the transfer pipeline system for zero dead zone and online sterilization of fermenters includes a steam inlet branch comprising a first steam valve and a second steam valve connected in series, a first pressure sensor being disposed between the first steam valve and the second steam valve, and the first steam valve being connected to the pure steam source.

[0013] According to the first aspect of the present invention, a transfer pipeline system for zero dead angle and online sterilization of a fermenter is provided, wherein the fermenter is connected to a first pipeline and the first pipeline is provided with a fermenter air valve.

[0014] According to the first aspect of the present invention, a seed transfer pipeline system for zero dead angle and online sterilization in a fermenter is provided, wherein the seed tank is connected to a second pipeline, and the second pipeline is provided with a seed tank air valve.

[0015] According to the first aspect of the present invention, a seed transfer pipeline system for zero dead angle and online sterilization of a fermenter is provided, wherein a third pipeline is connected to the seed tank and a seed tank exhaust valve is provided on the third pipeline, a fourth pipeline is connected to the fermenter and a fermenter exhaust valve is provided on the fourth pipeline, and a second pressure sensor is provided on both the third pipeline and the fourth pipeline.

[0016] According to the first aspect of the present invention, a transfer pipeline system for zero dead angle and online sterilization of a fermenter is provided on the fermenter, wherein the fermenter is connected to a discharge pipeline and the discharge pipeline is provided with a fermenter discharge valve.

[0017] One of the above-described technical solutions of this utility model has at least one of the following advantages or beneficial effects:

[0018] This invention, through the design of the seed tank discharge valve assembly and the fermentation tank transfer valve assembly, fundamentally eliminates all possible spaces for liquid accumulation and bacterial hiding at valve connections and within pipelines, completely eliminating dead zones. Utilizing the property that steam is lighter than air, the rational steam flow design ensures complete air removal and timely drainage of condensate, avoiding areas where temperatures do not meet standards due to water accumulation, resulting in extremely reliable sterilization. By installing a first pressure sensor at the steam inlet branch, real-time monitoring and data recording of the sterilization process are achieved, meeting the verification requirements of Good Manufacturing Practices (GMP) for key process parameters and ensuring the effectiveness of sterilization for each batch. This design is not only suitable for the fermentation production of raw materials such as acarbose, moxifloxacin, and tobramycin, but can also be widely applied in other pharmaceutical, food, and chemical fermentation fields with extremely high aseptic requirements. Attached Figure Description

[0019] The present invention will be further described below with reference to the accompanying drawings and embodiments;

[0020] Figure 1 This is a structural diagram of the seed transfer pipeline system in the first embodiment of this utility model. Detailed Implementation

[0021] The embodiments of this utility model are described in detail below. Examples of the embodiments are shown in the accompanying drawings, wherein the same or similar reference numerals denote the same or similar elements or elements having the same or similar functions throughout. The embodiments described below with reference to the accompanying drawings are exemplary and are only used to explain this utility model, and should not be construed as limiting this utility model.

[0022] In the description of this utility model, it should be understood that the directional descriptions, such as up, down, front, back, left, right, etc., indicate the directional or positional relationship based on the directional or positional relationship shown in the accompanying drawings. They are only for the convenience of describing this utility model and simplifying the description, and do not indicate or imply that the device or element referred to must have a specific orientation, or be constructed and operated in a specific orientation. Therefore, they should not be construed as limitations on this utility model.

[0023] In the description of this utility model, "several" means one or more, "multiple" means two or more, "greater than," "less than," and "exceeding" are understood to exclude the stated number, while "above," "below," and "within" are understood to include the stated number. If "first" or "second" is used in the description, it is only for the purpose of distinguishing technical features and should not be construed as indicating or implying relative importance, or implicitly indicating the number of indicated technical features, or implicitly indicating the order of the indicated technical features.

[0024] Furthermore, the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of technical features indicated. Therefore, a feature defined as "first" and "second" may explicitly or implicitly include one or more features.

[0025] In the description of this utility model, it should be noted that, unless otherwise explicitly specified and limited, the term "connection" should be interpreted broadly. For example, it can be a fixed connection or a movable connection, a detachable connection or a non-detachable connection, or an integral connection; it can be a mechanical connection or an electrical connection or a connection that can communicate with each other; it can be a direct connection or an indirect connection through an intermediate medium; it can be a connection within two elements, an indirect connection, or an interaction between two elements.

[0026] The following disclosure provides many different implementation methods or examples for different solutions to implement this utility model.

[0027] Reference Figure 1 As shown, a transfer pipeline system for zero-dead-angle and online sterilization of fermenters is provided, including a seed tank 100 and a fermenter 200. The seed tank 100 and the fermenter 200 are connected by a transfer main pipeline 300. The outlet end of the seed tank 100 is connected to a seed tank discharge valve group, and the inlet end of the fermenter 200 is connected to a fermenter transfer valve group. Both the seed tank discharge valve group and the fermenter transfer valve group adopt zero-dead-angle diaphragm valves. A steam inlet branch is provided at one end of the transfer main pipeline 300 near the seed tank discharge valve group. One end of the steam inlet branch is connected to a pure steam source, and the other end of the steam inlet branch is connected to the seed tank discharge valve group. A first pressure sensor 14 is provided on the steam inlet branch for real-time monitoring and recording of steam pressure during the sterilization process.

[0028] Application of zero-dead-angle diaphragm valves: The seed tank discharge valve group and the fermentation tank transfer valve group both adopt zero-dead-angle diaphragm valves. The flow channel of this type of valve is smooth and perfectly matches the inner diameter of the pipe. Moreover, its opening and closing parts can completely block the flow channel when closed and are flush with the inner wall of the pipe when open, thus fundamentally eliminating dead angles inside the valve.

[0029] This system, through the design of the seed tank discharge valve assembly and the fermentation tank transfer valve assembly, fundamentally eliminates all possible spaces for liquid accumulation and bacterial hiding at valve connections and within pipelines, completely eliminating dead zones. Utilizing the property that steam is lighter than air, the rational steam flow design ensures complete air removal and timely drainage of condensate, avoiding areas where temperatures do not meet standards due to water accumulation, resulting in extremely reliable sterilization. By installing a first pressure sensor at the steam inlet branch, real-time monitoring and data recording of the sterilization process are achieved, meeting the verification requirements of Good Manufacturing Practice (GMP) for key process parameters and ensuring the effectiveness of sterilization for each batch. This design is not only suitable for the fermentation production of raw materials such as acarbose, moxifloxacin, and tobramycin, but can also be widely applied in other pharmaceutical, food, and chemical fermentation fields with extremely high aseptic requirements.

[0030] In some embodiments of this utility model, the seed tank discharge valve group includes a first discharge valve 2 and a second discharge valve 6. A first small exhaust valve 3 is provided on the first discharge valve 2. Both the first discharge valve 2 and the second discharge valve 6 are provided on the seed transfer main pipeline 300. The first discharge valve 2 is located at one end near the seed tank 100.

[0031] In some embodiments of this utility model, the fermenter transfer valve group includes a first transfer valve 9 and a second transfer valve 8. A second small exhaust valve 10 is provided on the first transfer valve 9. Both the first transfer valve 9 and the second transfer valve 8 are provided on the main transfer pipeline 300. The first transfer valve 9 is located at one end near the fermenter 200. The first discharge valve 2, the second discharge valve 6, the second transfer valve 8 and the first transfer valve 9 are sequentially provided on the main transfer pipeline 300.

[0032] In some embodiments of this utility model, the steam introduction branch includes a first steam valve 5 and a second steam valve 4 connected in series, a first pressure sensor 14 is disposed between the first steam valve 5 and the second steam valve 4, and the first steam valve 5 is connected to a pure steam source.

[0033] In some embodiments of this utility model, the fermenter 200 is connected to a first pipeline 15, and the first pipeline 15 is provided with a fermenter air valve 11.

[0034] In some embodiments of this utility model, the seed tank 100 is connected to a second pipeline 16, and the second pipeline 16 is provided with a seed tank air valve 1.

[0035] In some embodiments of this utility model, a third pipe 17 is connected to the seed tank 100, and a seed tank exhaust valve 7 is provided on the third pipe 17. A fourth pipe 18 is connected to the fermentation tank 200, and a fermentation tank exhaust valve 12 is provided on the fourth pipe 18. A second pressure sensor 19 is provided on both the third pipe 17 and the fourth pipe 18.

[0036] In some embodiments of this utility model, a discharge pipe 20 is connected to the fermentation tank 200, and a fermentation tank discharge valve 13 is provided on the discharge pipe 20.

[0037] Intelligent introduction and export of online sterilization steam: At both ends of the main transfer pipeline 300, i.e., downstream of the seed tank discharge valve group, a steam introduction branch is set up and connected to a pure steam source through a first discharge valve 2; at the other end, i.e., upstream of the fermenter transfer valve group, the small exhaust valve attached to the first transfer valve 9 serves as the outlet point for steam and condensate.

[0038] Sterilization process monitoring system: A first steam pressure sensor 14 is installed at the sterilization steam inlet end of the transfer main pipeline 300, i.e., between the first steam valve 5 and the second steam valve 4, to monitor and record the pressure of the steam introduced into the transfer main pipeline 300 in real time during the online sterilization process, ensuring that the pipeline pressure is within the preset sterilization steam pressure of 0.15-0.25 MPa and maintained for the specified sterilization time of 60±10 min.

[0039] Preferably, after the sterilization process is completed, the system can also introduce sterile air into the first pipeline 15 to use the pressure of the fermenter 200 to dry the residual condensate in the transfer pipeline 300 and maintain the pressure of the pipeline.

[0040] Connection relationships of core components:

[0041] The seed tank 100's discharge port is connected to the seed transfer main pipeline 300 via the first discharge valve 2 and the second discharge valve 6. Both valves are zero-dead-angle diaphragm valves.

[0042] The end of the main transfer pipeline 300 is connected to the transfer port of the fermenter 200 via the second transfer valve 8 and the first transfer valve 9 in sequence. These two valves are also zero-dead-angle diaphragm valves.

[0043] The steam inlet branch is connected downstream of the second discharge valve 6, at the beginning of the main transfer branch 300. A first steam valve 5 and a second steam valve 4 are connected in series on this branch, and a first pressure sensor 14 is installed between the two valves to monitor the sterilization steam pressure.

[0044] The first transfer valve 9 is accompanied by a second small exhaust valve 10.

[0045] The first discharge valve 2 is equipped with a first small exhaust valve 3.

[0046] The sterile air purging branch (which can be achieved through the fermenter air valve 11 and corresponding pipelines in the figure) can introduce sterile air into the system after sterilization for purging and pressure maintenance.

[0047] Online sterilization workflow:

[0048] 1. Preparation and Isolation: Close the first transfer valve 9 and slightly open its attached second small vent valve 10; fully open the second discharge valve 6, close the first discharge valve 2, and slightly open its attached first small vent valve 3. This effectively isolates the main transfer pipeline 300 to be sterilized from the seed tank 100 and fermentation tank 200.

[0049] 2. Steam Introduction and Venting: Open the second steam valve 4 of the steam introductory branch, and then slowly open the first steam valve 5 to introduce pure steam. The steam enters from the pipe near the seed tank outlet and flows along the main seed transfer pipe 300 to the fermentation tank seed transfer port pipe, completely "forcing out" the air in the pipe through the second small exhaust valve 10 of the first seed transfer valve 9.

[0050] 3. Pressure Holding Sterilization: Once a continuous, dry, and full stream of steam is observed exiting from the outlet of the second small exhaust valve 10 (indicating that all air has been expelled), adjust the opening of the first steam valve 5 to put the system into a pressure holding and heat preservation state. At this time, the first pressure sensor 14 monitors the pipeline pressure in real time, ensuring that it is maintained within the sterilization pressure range of 0.15-0.25 MPa, and starts timing, maintaining this pressure for 60±10 minutes. During this period, the steam flow path covers the entire pipeline without any dead zones; the generated condensate flows with the steam and is continuously discharged from the second small exhaust valve 10, ensuring that there are no "cold spots".

[0051] 4. Purging and Pressure Holding: After the sterilization time is reached, first close the second small exhaust valve 10 and the first small exhaust valve 3, then close the first steam valve 5 and the second steam valve 4. Next, open the fermenter air valve 11 and fully open the first transfer valve 9. Through the fermenter sterile air purging branch, sterile air is introduced into the pipeline to purge and cool it, and finally, pressure is maintained in the pipeline to keep it at a positive pressure, ready for transfer.

[0052] Transplantation process:

[0053] During transplantation, reduce the air valve 11 of the fermenter, open the exhaust valve 12 of the fermenter, close the exhaust valve 7 of the seed tank, and fully open the air valve 1 of the seed tank and the first discharge valve 2. At this time, the seed tank is under positive pressure, and the fermenter is under negative pressure or low pressure. Driven by the pressure difference, the bacterial solution flows through the sterilized and pressurized main transplantation pipeline and enters the fermenter aseptically and smoothly.

[0054] The above is a further detailed description of this utility model and should not be considered as a limitation on the specific implementation of this utility model. For those skilled in the art, simple deductions or substitutions without departing from the concept of this utility model are all within the protection scope of this utility model.

Claims

1. A seed transfer pipeline system for zero-dead-angle and online sterilization in a fermenter, comprising a seed tank (100) and a fermenter (200), characterized in that, The seed tank (100) and the fermentation tank (200) are connected by a main transfer pipeline (300). The seed tank (100) is connected to a seed tank discharge valve group at its outlet end, and the fermentation tank (200) is connected to a fermentation tank transfer valve group at its inlet end. Both the seed tank discharge valve group and the fermentation tank transfer valve group are zero-dead-angle diaphragm valves. A steam inlet branch is provided at one end of the main transfer pipeline (300) near the seed tank discharge valve group. One end of the steam inlet branch is connected to a pure steam source, and the other end of the steam inlet branch is connected to the seed tank discharge valve group. A first pressure sensor (14) is provided on the steam inlet branch for real-time monitoring and recording of the steam pressure during the sterilization process.

2. The transfer pipeline system for zero dead zones and online sterilization in fermenters according to claim 1, characterized in that, The seed tank discharge valve group includes a first discharge valve (2) and a second discharge valve (6). The first discharge valve (2) is provided with a first small exhaust valve (3). The first discharge valve (2) and the second discharge valve (6) are both provided on the main transfer pipeline (300). The first discharge valve (2) is provided at one end near the seed tank (100).

3. The transfer pipeline system for zero dead zones and online sterilization in fermenters according to claim 2, characterized in that, The fermenter transfer valve group includes a first transfer valve (9) and a second transfer valve (8). The first transfer valve (9) is provided with a second small exhaust valve (10). The first transfer valve (9) and the second transfer valve (8) are both provided on the main transfer pipeline (300). The first transfer valve (9) is provided at one end close to the fermenter (200). The first discharge valve (2), the second discharge valve (6), the second transfer valve (8) and the first transfer valve (9) are sequentially provided on the main transfer pipeline (300).

4. The transfer pipeline system for zero dead zones and online sterilization in fermenters according to claim 1, characterized in that, The steam inlet branch includes a first steam valve (5) and a second steam valve (4) connected in series. The first pressure sensor (14) is located between the first steam valve (5) and the second steam valve (4). The first steam valve (5) is connected to the pure steam source.

5. The transfer pipeline system for zero dead zones and online sterilization in fermenters according to claim 1, characterized in that, The fermenter (200) is connected to a first pipeline (15), and the first pipeline (15) is equipped with a fermenter air valve (11).

6. The transfer pipeline system for zero dead zones and online sterilization in fermenters according to claim 1, characterized in that, The seed container (100) is connected to a second pipeline (16), and the second pipeline (16) is equipped with a seed container air valve (1).

7. The transfer pipeline system for zero dead zones and online sterilization in fermenters according to claim 1, characterized in that, The seed tank (100) is connected to a third pipeline (17), and the third pipeline (17) is equipped with a seed tank exhaust valve (7). The fermentation tank (200) is connected to a fourth pipeline (18), and the fourth pipeline (18) is equipped with a fermentation tank exhaust valve (12). Both the third pipeline (17) and the fourth pipeline (18) are equipped with a second pressure sensor (19).

8. The transfer pipeline system for zero dead zones and online sterilization in fermenters according to claim 1, characterized in that, The fermentation tank (200) is connected to a discharge pipe (20), and the discharge pipe (20) is equipped with a fermentation tank discharge valve (13).

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