Production unit of the biopharmaceutical workshop

Abstract

The present invention relates to a production unit in a biological products workshop. By independently equipping each reactor with a dedicated culture medium preparation tank in the culture medium preparation module and providing multiple in-line cleaning systems in the present invention, the cleaning of the reactor and the culture medium preparation tank can be carried out simultaneously, so as to improve the production efficiency on the premise of reducing the reactor cost through a scientific and reasonable operation plan, and effectively reduce the pollution risk.

Description

Technical Field

[0001] The present invention relates to a production unit in a biological products workshop, and particularly to a biological products workshop, the layout of a production line, and a production method. Background Art

[0002] As more and more people benefit from biological products, the competition in the biological products field has become increasingly fierce. A biological products workshop is not only related to the production scale, production efficiency, and production cost of biopharmaceutical companies, but also related to the ability to respond to the market. Therefore, a rational layout of the production line and production method in a biopharmaceutical workshop will effectively help biopharmaceutical companies improve product competitiveness.

[0003] The production of biological products mainly includes two stages: cell culture and separation and purification. That is, cell culture is completed in the final reactor line (hereinafter referred to as the reactor line), and then separation and purification are completed in the separation and purification production line. Its production capacity is mainly determined by the final reactor and separation and purification equipment. In actual production, multiple reactor lines and one separation and purification line can be used to complete the above production process. Among them, multiple reactor lines are arranged in the same culture room and are equipped with a set of common culture medium preparation systems and an in-line cleaning system (CIP). After each reactor line spends a certain culture cycle to complete the cell culture of one batch, it must spend a certain cleaning and preparation cycle to perform cleaning and preparation (including the CIP step) on the reactor line and the culture medium preparation tank in sequence before it can carry out the cell culture of the next batch. Therefore, in reality, multiple reactor lines are used to switch production, so that each reactor line can perform cleaning and preparation during the time from the completion of a certain batch of culture to the arrival of the next batch, which can play the role of efficient switching between batches and reduce the impact of the cleaning and preparation cycle on production capacity.

[0004] In cell culture, the culture cycle of the final reactor is usually about 14 days, and the cleaning and preparation cycle between batches is usually about 6 days. The sum of each cycle is about 20 days. The purification cycle in separation and purification is usually about 7 days.

[0005] In view of the characteristics of the above cycles in the prior art, 3 reactor lines are often used to play the role of the most efficient switching between batches, with an interval of 7 days. For example, reactor lines 1-3 usually operate in the following manner:

[0006] (1) Reactor 1 starts culturing the first batch of cells;

[0007] (2) After a specific batch interval (such as 7 days), reactor 2 starts culturing the second batch of cells;

[0008] (3) After two specific batch intervals (such as 14 days), reactor 3 starts culturing the third batch of cells;

[0009] (4) After three specific batch interval times (e.g., 21 days), reactor 1 starts culturing the fourth batch of cells. At this time, reactor 1 has completed the culturing of the first batch of cells (e.g., on the 14th day) within the time period of step (2) or (3), and the reactor and the formulation system have completed the cleaning and preparation (e.g., on the 20th day). Therefore, a new batch of cell culturing can be started.

[0010] ......The cycle proceeds as described above.

[0011] Although with the innovation of technology and the optimization of processes, the relevant cycles may change, the technical problems existing in the prior art include: after the production of a certain batch of products is completed, not only the reactor line needs to be cleaned and prepared, but also the general culture medium preparation tank needs to be further cleaned and prepared before the next batch of production can be carried out on this reactor line. The cleaning and preparation time of the reactor and the culture medium preparation system makes the operation of any reactor line unable to achieve seamless connection.

[0012] In addition, using too many reactor lines will also cause the following technical problems:

[0013] (1) The equipment in the reactor line is costly, and using multiple reactor lines will significantly increase the equipment cost;

[0014] (2) Each reactor line needs to be equipped with personnel for operation and maintenance, and the labor employment cost is also relatively high;

[0015] (3) When producing different types of products, from the perspective of GMP, it is not conducive to pollution control and production process control; Summary of the Invention

[0016] The object of the present invention includes providing a production system for biological products with reduced costs, controllable processes, and improved market response capabilities to solve the above problems in the prior art. The specific technical solutions are as follows.

[0017] On the one hand, the present invention provides a production system for a biological products workshop. The production system includes one or more biological products workshop production units.

[0018] In some solutions, the production unit includes a production line, a culture medium preparation module, and an in-line cleaning system / device. The production line sequentially includes a cell culture module and a separation and purification module from upstream to downstream. The culture medium preparation module provides culture medium for the cell culture module. At least two reactor lines are provided in the cell culture module, and at least one separation and purification line is provided in the separation and purification module. The processing capacity of the separation and purification line is greater than or equal to the production capacity of a single reactor line. Among them, the culture medium preparation module independently equips each reactor with a dedicated culture medium preparation tank, and at least two sets of the in-line cleaning system are provided.

[0019] In some specific embodiments, one separation and purification line is provided in the separation and purification module.

[0020] In some specific embodiments, three sets of the in-line cleaning system or in-line cleaning device are provided.

[0021] In some specific embodiments, one cell culture room is provided in the cell culture module.

[0022] In some specific embodiments, one cell culture room and one reserved cell culture room are provided in the cell culture module.

[0023] In some specific embodiments, two cell culture rooms are provided in the cell culture module.

[0024] In some specific embodiments, two reactor lines are provided in the cell culture room in the cell culture module.

[0025] In some specific embodiments, the separation and purification processing capacity of the separation and purification line is equal to the production capacity of a single reactor line.

[0026] In some specific embodiments, the separation and purification processing capacity of the separation and purification line is the sum of the production capacities of all reactor lines in a single cell culture room.

[0027] In some specific embodiments, the biological product workshop is a monoclonal antibody workshop.

[0028] In some specific embodiments, the present invention provides a production unit of a monoclonal antibody workshop, which includes a production line, a culture medium preparation module, and an in-line cleaning system. The production line sequentially includes a cell culture module and a separation and purification module from upstream to downstream. The culture medium preparation module provides culture medium for the cell culture module. Two reactor lines are provided in the cell culture module, and one separation and purification line is provided in the separation and purification module. The separation and purification processing capacity of the separation and purification line is equal to the production capacity of a single reactor line. Among them, the culture medium preparation module independently equips each reactor with a dedicated culture medium preparation tank, and three sets of the in-line cleaning system are provided.

[0029] In some specific embodiments, the production unit operates according to the following scheme: each reactor line is enabled in turn at specific intervals. After each reactor line completes a batch of cell culture cycles, multiple in-line cleaning systems are used to clean the reactor and its preparation tank simultaneously, and preparations for the next batch are carried out to complete a cleaning preparation cycle. Then, the reactor is enabled again to complete a new batch of cell culture cycles, and this process is repeated cyclically. The interval is: (cell culture cycle + cleaning preparation cycle) / number of reactors, and the minimum value is taken on the premise that the interval is greater than or equal to the purification cycle.

[0030] In some specific embodiments, the production unit operates according to the following scheme: two reactor lines are enabled in turn at specific intervals. After each reactor line completes a batch of cell culture cycles, multiple in-line cleaning systems are used to clean the reactor and its preparation tank simultaneously, and preparations for the next batch production are carried out to complete a cleaning preparation cycle. Then, the reactor is enabled again to complete a new batch of cell culture cycles, and this process is repeated cyclically. The interval is: (cell culture cycle + cleaning preparation cycle) / number of reactors, and the number of reactors is 2.

[0031] On the other hand, the present invention provides a structure of a biological product workshop or its production area, including a preparation room, a cell culture room, a chromatography room, an ultrafiltration room, and an in-line cleaning system. A culture medium preparation tank is provided in the preparation room. At least two reactor lines are provided in the cell culture room. A chromatography system with a processing capacity greater than or equal to the production capacity of a single reactor line is provided in the chromatography room. An ultrafiltration system with a processing capacity greater than or equal to the production capacity of a single reactor line is provided in the ultrafiltration room. The products in the at least two reactor lines are uniformly separated and purified by the chromatography system and the ultrafiltration system. Among them, dedicated culture medium preparation tanks are independently equipped for each reactor line in the preparation room, and at least two sets of the in-line cleaning system are provided.

[0032] In some specific embodiments, there are three sets of the in-line cleaning system.

[0033] In some specific embodiments, the number of cell culture rooms is one.

[0034] In some specific embodiments, the number of cell culture rooms is two.

[0035] In some specific embodiments, two reactor lines are provided in a single cell culture room.

[0036] In some specific embodiments, a chromatography system with a processing capacity equal to the production capacity of a single reactor line is provided in the chromatography room, and an ultrafiltration system with a processing capacity equal to the production capacity of a single reactor line is provided in the ultrafiltration room.

[0037] In some specific embodiments, the processing capacity of the chromatography system and / or ultrafiltration system is the sum of the production capacities of all reactor lines in a single cell culture room.

[0038] In yet another aspect, the present invention provides a method for producing a biologic using the biologic production unit or biologic production area.

[0039] In some embodiments, the biologics of the present invention include, but are not limited to, proteins, polypeptides, and their derivatives prepared using engineered cells of different expression systems, such as bacteria, yeast, insects, plants, and mammalian cells, including cytokines, fibrinolytic enzyme activators, recombinant plasma factors, growth factors, fusion proteins, enzymes, receptors, hormones, and monoclonal antibodies, etc.; also include single-component endogenous proteins extracted from human or animal tissues; as well as gene therapy products, allergens, multi-component products with biological activity extracted from human or animal tissues or body fluids or prepared by fermentation, probiotic products, and other biologics. In some specific embodiments, the biologic is a monoclonal antibody.

[0040] The production system of the biologic workshop of the present invention has at least the following advantages:

[0041] (1) Improves the utilization rate of reactor lines, achieving higher production efficiency with fewer reactors, and thus reducing the expensive cost of reactors.

[0042] (2) By setting aside reserved cell culture rooms, it is easier to expand production capacity according to market conditions; and when two cell culture rooms are used, two sets of reactor lines can produce different types of products, with strong compatibility.

[0043] (3) Effectively reduces the risk of contamination.

[0044] Glossary

[0045] Cell culture cycle: The time for a single final reactor to complete one batch of cell culture.

[0046] Cleaning preparation cycle: The sum of the cleaning time of the reactor and its corresponding medium preparation tank after a single final reactor completes one batch of cell culture and the pre-production preparation time for the reactor and its corresponding medium preparation tank to be put into the next batch of cell culture.

[0047] Separation and purification cycle: For one batch of cell culture in a single final reactor, the time for the separation and purification line to perform chromatography, ultrafiltration, and other treatments.

[0048] Interval time: When multiple final reactors are enabled in turn, the time difference between the enabling times of two reactors with adjacent enabling times. Description of the Drawings

[0049] Figure 1 It shows the layout of the production system in the production area structure of Example 1.

[0050] Figure 2 It shows the layout of the production system in the production area structure of Example 2.

[0051] Figure 3 It shows the layout of the production system in the production area structure of Example 3. Detailed implementation manners

[0052] Example 1

[0053] The production area structure of the monoclonal antibody workshop includes a culture medium preparation module, a cell culture module, a separation and purification module, and an in-line cleaning system. The cell culture module includes a cell culture room, and there are three reactor lines in each cell culture room. The separation and purification module has a separation and purification line. The culture medium preparation module is uniformly provided with a set of culture medium preparation system corresponding to all reactor lines, and the number of in-line cleaning systems is one set.

[0054] Specifically, as Figure 1 shown, the culture medium preparation module is located in the culture medium preparation room and provides culture medium for the upstream cell culture. The separation and purification module includes a chromatography room and an ultrafiltration room. The chromatography room includes Chromatography Room 1 and Chromatography Room 2. The separation and purification line of this example is composed of a chromatography system arranged in the chromatography room and an ultrafiltration system arranged in the ultrafiltration room. The chromatography system includes two groups, which are respectively located in Chromatography Room 1 and Chromatography Room 2. In addition, a centrifuge is also provided between the cell culture module and the separation and purification module. The number of in-line cleaning systems is one set, which can sequentially clean a single reactor line and the culture medium preparation tank.

[0055] The production system in the production area structure of this example operates according to the following scheme: The 3 reactor lines are alternately enabled at specific intervals. After each reactor line completes a batch of cell culture cycles, the single in-line cleaning system is used to sequentially perform cleaning preparation on the reactor and its preparation tank to complete a cleaning preparation cycle, and then the reactor is enabled again to complete a new batch of cell culture cycles, and the cycle repeats.

[0056] In cell culture, the culture cycle of the reactor is 14 days, the cleaning and preparation time of the reactor and the medium preparation system is 6 days, and the sum of each cycle is 20 days. The purification cycle in separation and purification is 7 days. When using 3 reactor lines, the batch interval time can be shortened to the minimum. This interval time is subject to the purification cycle, so the interval time is calculated according to 7 days (Calculation process: Assume the batch interval time is N days. Both batch 1 and batch 4 use the 1st reactor production line. Therefore, the start time of batch 4 needs to be later than the end time of the cleaning and preparation of batch 1. That is, 3N + 1 ≥ 20, N ≥ 6. At this time, the batch interval time is subject to the purification cycle, and the purification cycle is 7 days, that is, the batch interval time N = 7). For example, reactor lines 1-3 usually operate in the following manner:

[0057] (1) Reactor 1 starts culturing the first batch of cells;

[0058] (2) After a specific batch interval time (7 days), reactor 2 starts culturing the second batch of cells;

[0059] (3) After two specific batch interval times (14 days), reactor 3 starts culturing the third batch of cells;

[0060] (4) After three specific batch interval times (21 days), reactor 1 starts culturing the fourth batch of cells. At this time, reactor 1 has completed the culturing of the first batch of cells within the time period of step (2) or (3) (for example, on the 14th day), and reactor 1 and the medium preparation system have completed cleaning and preparation (on the 20th day). Therefore, reactor 1 can start culturing a new batch of cells after the 21st day.

[0061] Reactor 2, reactor 3, reactor 1... are enabled again in a manner similar to step (4), and the cycle is carried out as described above.

[0062] The relevant parameters of this embodiment are as follows:

[0063] Cell culture: 3 × 2000L reactor lines

[0064] Separation and purification: 1 × 2000L separation and purification production line

[0065] The production scale of each batch is 2000L, and the dosage is 25,000 vials per batch. The reactor culture cycle is 14 days. Theoretically, the interval time must be greater than 5 days (3 × interval time ≥ 14 days). Considering that the sum of the cleaning and preparation time is 6 days, this interval time is limited by the purification cycle. According to the optimal plan of 7 days per batch, when the actual production is 300 days, the output value is shown in Table 1.

[0066] Table 1 Output data table of Example 1

[0067]

[0068] Example 2

[0069] The production area structure of the monoclonal antibody workshop includes a culture medium preparation module, a cell culture module, a separation and purification module, and an in-line cleaning system. The cell culture module includes a cell culture room, and each cell culture room is equipped with two reactor lines. The separation and purification module is equipped with one separation and purification line. The culture medium preparation module is respectively equipped with a set of culture medium preparation system corresponding to each reactor line. The number of in-line cleaning systems is three, including one set for the culture medium preparation system, one set for the reactor, and one set for the separation and purification module (including the centrifuge).

[0070] Specifically, as Figure 2 shown, the culture medium preparation module is located in the culture medium preparation room and includes two sets of culture medium preparation systems, which respectively provide culture medium for the upstream cell culture (two reactor lines). The separation and purification module includes a chromatography room and an ultrafiltration room. The chromatography room includes Chromatography Room 1 and Chromatography Room 2. The separation and purification line of the present invention is composed of a chromatography system arranged in the chromatography room and an ultrafiltration system arranged in the ultrafiltration room. The chromatography system includes two groups, which are respectively located in Chromatography Room 1 and Chromatography Room 2. In addition, a centrifuge is also provided between the cell culture module and the separation and purification module. The number of in-line cleaning systems is three, which can clean a single reactor line and its culture medium preparation tank simultaneously.

[0071] The production system in the production area structure of this embodiment operates according to the following scheme: The two reactor lines are alternately enabled at specific intervals. After each reactor line completes a batch of cell culture cycles, multiple in-line cleaning systems are used to simultaneously perform the site clearance preparation for the reactor and its preparation tank to complete a site clearance preparation cycle, and then the reactor is enabled again to complete a new batch of cell culture cycles, and so on in a cycle.

[0072] In cell culture, the culture cycle of the reactor is 14 days. Since the reactor and the preparation tank can perform the site clearance preparation simultaneously, the site clearance and preparation cycle of the reactor and the culture medium preparation system is about 3 days. The sum of each cycle is 17 - 18 days, and the purification cycle in separation and purification is about 7 days. Although theoretically when using 3 reactor lines, the batch interval time can be shortened to the minimum, due to the high cost of reactor lines, in order to save costs, only 2 reactor lines are used in this embodiment, and the interval time is calculated according to a relatively generous 10 days (the optimal scheme can be compressed to 8 - 9 days). For example, reactor lines 1 - 2 usually operate in the following way:

[0073] (1) Reactor 1 starts culturing the first batch of cells;

[0074] (2) After a specific batch interval (10 days), reactor 2 begins to culture the second batch of cells;

[0075] (3) After two specific batch intervals (20 days), reactor 1 starts to culture the third batch of cells. At this time, reactor 1 has completed the first batch of cell culture within the time period of step (2) (14th day), and the reactor and culture medium preparation tank have completed the cleaning preparation (18th day), so reactor 1 is sufficient to start a new batch of cell culture after the 20th day.

[0076] In a similar manner to step (3), reactor 2, reactor 1, reactor 2, ... are activated again and the cycle is repeated as described above.

[0077] The relevant parameters of this embodiment are as follows:

[0078] Cell culture: 2×3000L reactor lines

[0079] Separation and purification: 1×3000L separation and purification production line

[0080] The production scale of each batch is 3000L, and the dosage is 37,500 pieces / batch. The reactor culture cycle is 14 days. Theoretically, the interval time must be greater than 7 days (2×interval time ≥ 14 days). Considering the cleaning and preparation time, the optimal plan of 10 days per batch is followed.

[0081] Table 2 Capacity data table of Example 2

[0082]

[0083] It can be seen that even according to the generous time interval scheme, the production capacity of this embodiment is greater than that of embodiment 1.

[0084] Example 3

[0085] The production area structure of the monoclonal antibody workshop includes a culture medium preparation module, a cell culture module, a separation and purification module and an online cleaning system. The cell culture module includes two cell culture rooms, each of which is provided with two reactor lines. The separation and purification module is provided with a separation and purification line. The culture medium preparation module is provided with a culture medium preparation tank corresponding to each reactor line. There are three sets of online cleaning systems.

[0086] like Figure 3 As shown, the specific layout of the production area structure of this embodiment is similar to that of Embodiment 2. Compared with Embodiment 2, a cell culture room is newly added, and the separation and purification processing capacity is correspondingly doubled.

[0087] The specific configuration is as follows:

[0088] Cell culture: 2 lines of 2×3000L reactors (located in two different cell culture rooms)

[0089] Separation and purification: 1 line of 6000L production line

[0090] The production scale per batch is 6000L, the dosage form is 75,000 doses per batch, and cross-batch operation is carried out. The reactor culture cycle is 14 days. Theoretically, the interval time must be greater than 7 days (2×interval time ≥ 14 days). Considering the cleaning and preparation time, the optimization plan of one batch every 10 days is adopted.

[0091] Table 3 Production capacity data table of Example 3

[0092]

Claims

1. A production unit of a biological product workshop, which comprises a production line, a culture medium preparation module and an on-line cleaning system. The production line successively includes a cell culture module and a separation and purification module from upstream to downstream. The culture medium preparation module provides culture medium for the cell culture module. At least two reactor lines are arranged in the cell culture module, and at least one separation and purification line is arranged in the separation and purification module. The processing capacity of the separation and purification line is greater than or equal to the production capacity of a single reactor line, and it is characterized in that, The culture medium preparation module independently equips each reactor line with a dedicated culture medium preparation tank, and the on-line cleaning system is set to three sets or more. The culture medium preparation module, the cell culture module, and the separation and purification module are respectively equipped with an on-line cleaning system.

2. The production unit according to claim 1, characterized in that The separation and purification module is provided with one separation and purification line.

3. The production unit according to claim 1, characterized in that The cell culture module is provided with a cell culture room and a reserved cell culture room.

4. The production unit according to claim 1, characterized in that The cell culture module is provided with two cell culture rooms.

5. The production unit according to any one of claims 1 to 4, characterized in that Each cell culture room in the cell culture module is provided with two reactor lines.

6. The production unit according to any one of claims 1 to 4, characterized in that The separation and purification processing capacity of the separation and purification line is equal to the production capacity of a single reactor line or equal to the sum of the production capacities of all reactor lines in a single cell culture room.

7. The production unit according to any one of claims 1-4 operates according to the following scheme: Each reactor line is alternately enabled at specific intervals. After each reactor line completes a batch of cell culture cycles, multiple on-line cleaning systems are used to simultaneously clean the reactor and its preparation tank, and preparations for the next batch are made to complete a cleaning preparation cycle. Then, the reactor is enabled again to complete a new batch of cell culture cycles, and so on in a cycle. The interval is: (cell culture cycle + cleaning preparation cycle) / number of reactor lines, provided that the interval is greater than or equal to the purification cycle.

8. The production unit according to claim 7, wherein the number of reactor lines is 2.

9. The production area structure of a biological product workshop includes a preparation room, a cell culture room, a chromatography room, an ultrafiltration room, and an in-line cleaning system. A culture medium preparation tank is provided in the preparation room. At least two reactor lines are provided in the cell culture room. A chromatography system with a processing capacity greater than or equal to the production capacity of a single reactor line is provided in the chromatography room. An ultrafiltration system with a processing capacity greater than or equal to the production capacity of a single reactor line is provided in the ultrafiltration room. The products from the at least two reactor lines are uniformly separated and purified by the chromatography system and the ultrafiltration system. It is characterized in that In the preparation room, each reactor line is independently equipped with a dedicated culture medium preparation tank, and the on-line cleaning system is set to three sets or more. The culture medium preparation module is located in the preparation room, the cell culture module includes the cell culture room, the separation and purification module includes the chromatography room and the ultrafiltration room, and the culture medium preparation module, the cell culture module, and the separation and purification module are respectively equipped with an on-line cleaning system.

10. The production area structure according to claim 9, characterized in that The number of cell culture rooms is one or two.

11. The production area structure according to any one of claims 9-10, characterized in that A single cell culture room is provided with two reactor lines.

12. The production area structure according to any one of claims 9-10, characterized in that The chromatography room is provided with a chromatography system with a processing capacity equal to the production capacity of a single reactor line, and the ultrafiltration room is provided with an ultrafiltration system with a processing capacity equal to the production capacity of a single reactor line.

13. The production area structure according to any one of claims 9-10, characterized in that The processing capacity of the chromatography system and / or the ultrafiltration system is the sum of the production capacities of all reactor lines in a single cell culture room.

14. The production unit according to any one of claims 1-4 or the production area structure according to any one of claims 9-10, characterized in that The biological products include cytokines, fibrinolytic enzyme activators, recombinant plasma factors, growth factors, fusion proteins, enzymes, receptors, hormones, and / or monoclonal antibodies.

Images