A Method for Predicting the Aeration Rate of a Large-Scale Production Reactor and a Production Process

Abstract

The present invention relates to the technical field of cell culture, and particularly to a method for predicting the aeration rate of a large-scale production reactor and a production process. It includes the following steps: setting variable parameters; constructing a mathematical relationship model between the mass transfer coefficient Kla in the reactor and the variable parameters; collecting the operation data of the corresponding reactor to obtain the constant values of K, α, and β for the corresponding reactor; predicting the daily aeration rate during the culture period of the enlarged reactor based on the historical data of the basic reactor. The advantages of the present invention are as follows: Based on the premise of keeping the dissolved oxygen value in the culture system constant, by measuring the mass transfer-related coefficients of the reactor, and on the premise that the tank structure remains unchanged, it is possible to predict the aeration value at any rotational speed, thereby balancing the shear force damage caused by stirring and aeration, and improving the success rate of scale-up production.

Description

Technical Field

[0001] The present invention relates to the technical field of cell culture, and particularly to a method for predicting the ventilation volume of a large-scale production reactor and a production process. Background Art

[0002] The scale-up of bioreactors is an important part of the development of cell culture processes. There are many factors that need to be focused on during the research on the scale-up of mammalian cell culture processes, such as: mixing time, oxygen transfer, and carbon dioxide removal. Currently, the process development of cell culture is usually carried out in small-scale bioreactors first. After locking the process, it is gradually scaled up until it is used in larger bioreactors for commercial production. Compared with small-scale reactors, the reduction in mixing and mass transfer effects in large-scale reactors will cause problems such as worse carbon dioxide escape effects and longer mixing times. As a result, when the culture process established in small-scale reactors is scaled up to large-scale production reactors, cell growth may not meet expectations, manifested as a series of problems such as a decrease in cell density, a shortening of the culture cycle, a significant drop in yield, or difficulty in controlling the product quality. Therefore, establishing a suitable strategy and model for the scale-up of cell culture processes is of great significance for stable large-scale production.

[0003] The parameters in the cell culture process can be divided into two categories: parameters that do not change with the size of the reactor, such as pH, DO, temperature, feeding time, etc. These parameters only need to be kept consistent between the previous and next stages during the scale-up process. Parameters that change with the size of the reactor, such as ventilation rate, stirring speed, etc.

[0004] For the stirring speed, too low a stirring speed will, on the one hand, lead to too long a mixing time, resulting in poor mass transfer and thus affecting cell growth. On the other hand, in order to maintain a constant DO value, too low a stirring speed will lead to an increase in the oxygen ventilation volume, thereby causing damage to the cells; while too high a stirring speed, although the mixing situation is better, the shear force brought by stirring may also cause irreversible damage to the cells.

[0005] The magnitude of the gas ventilation rate will change according to the size and method of the reactor ventilation aperture, as well as the size and form of the stirring paddle. Too high a gas ventilation rate will cause the flow rate of the gas instantaneously displacing the liquid at the air outlet to be too large, thereby causing damage to the cells. On the other hand, too large a gas ventilation rate will lead to an increase in the number of bubbles in the liquid. When the bubbles reach the top of the liquid and burst, the shear force brought will cause damage to the cells adsorbed around them.

[0006] In summary, the shear forces in the reactor mainly come from the following three sources: 1. The rupture of bubbles at the liquid surface; 2. The shear caused by the rotation of the agitator paddle; 3. The excessive gas flow rate at the gas outlet of the gas distributor, which causes shear to the liquid. Therefore, in the process of bioreactor scale-up, the impacts of all three should be comprehensively considered. It is necessary to consider providing sufficient mixing capacity for the reactor while avoiding unnecessary cell damage caused by shear forces under high rotation speed and high aeration conditions. These problems are the main reasons for the lower-than-expected scale-up effect or scale-up failure during the scale-up process.

[0007] In the prior art, application number: CN202411130287X, a prediction model and method for the growth rate of microorganisms in a general photobioreactor, in which the aeration / stirring power is an important part of the prediction. And this prediction is limited to the growth rate within the same reactor. If the aeration rate and stirring power in reactors of different specifications are different, then if it is necessary to predict the cultivation in a larger reactor, it is necessary to know the corresponding aeration rate and stirring power and adjust them in real time according to the needs of cell culture. Otherwise, it may damage the cells and cause the failure of the entire experiment.

[0008] Therefore, it is necessary to design a method for predicting the aeration rate of a large-scale production reactor and a production process to solve the above problems. Summary of the Invention

[0009] The purpose of the present invention is to provide a method for predicting the aeration rate of a large-scale production reactor and a production process to overcome the above-mentioned deficiencies in the current prior art.

[0010] To achieve the above purpose, the present invention adopts the following technical solutions:

[0011] A method for predicting the aeration rate of a large-scale production reactor, characterized in that it includes the following steps:

[0012] S1. Setting of variable parameters: The variable parameters include the volume V of the cell culture medium, the input power P of the agitator paddle of the reactor, and the apparent aeration rate Vs;

[0013] S2. Constructing a mathematical relationship model between the mass transfer coefficient Kla in the reactor and the variable parameters:

[0014] Kla = K(P / V) α (Vs) β

[0015] Where K, α, and β are characteristic constants of the reactor;

[0016] S3. Collecting the operation data of the basic reactor and the scaled-up reactor, and respectively solving the characteristic constants in the relationship models of the basic reactor and the scaled-up reactor (K0 , α 0 , β 0 ), (K 1 , α 1 , β 1 );

[0017] The method for solving the characteristic constant includes:

[0018] S31. Add a fixed volume of cell culture medium to the reactor and calibrate the DO according to the set process, where DO is the dissolved oxygen concentration;

[0019] S32. Close the air inlet, open the nitrogen inlet, blow the DO below 5%, and then close the nitrogen inlet;

[0020] S33. Arbitrarily set n groups of stirring speeds N and ventilation rates Q to obtain the first data set (Ni, Qi), where i = 1, 2,..., n;

[0021] S34. Set the stirring speed and ventilation rate of the reactor in sequence according to the first data set; after each set of data is set, start parameter monitoring, record the change value of DO over time, and when DO is greater than 95%, end the experiment, then balance the volume of the cell culture medium and calibrate the DO, and then set the data set of the next stirring speed and ventilation rate, and so on, until the change values of DO over time under n groups of different stirring speeds N and ventilation rates Q are obtained;

[0022] S35. Perform n linear fittings respectively according to the n groups of change values of DO over time to obtain n slope parameters, and this slope parameter is the mass transfer coefficient Kla, and then obtain n groups of mass transfer coefficients Kla;

[0023] S36. Convert the n groups of the first data set (Ni, Qi) into the input power P of the stirrer and the apparent ventilation rate Vs through formula (1) and formula (2) to obtain n groups of the second data set (Pi, Vsi), where i = 1, 2,..., n;

[0024] The formula (1) is:

[0025] ;

[0026] where Np is the stirrer power number, N is the stirring speed, is the stirrer diameter, and ρ is the liquid density;

[0027] The formula (2) is:

[0028] Vs = Q / (Π × );

[0029] where Q is the ventilation rate and D is the radius of the tank body;

[0030] S37. Substitute the n sets of second data groups (Pi, Vsi) and the cell culture medium volume V into the mathematical relationship model Kla = K(P / V) α (Vs) β , and solve to obtain K, α, and β for the corresponding reactor, thereby obtaining the relationship model between the mass transfer coefficient Kla and the stirring paddle input power P and the apparent aeration rate Vs;

[0031] S4. Predict the daily aeration volume Qgas of the enlarged reactor during the culture period based on the historical data of the basic reactor.

[0032] Preferably,

[0033] the prediction method in the S4 step includes:

[0034] S41. Based on the equality of the mass transfer coefficient Kla of the basic reactor and the mass transfer coefficient Kla* of the enlarged reactor,

[0035] the formula (3) is obtained as: K 0 (P 0 / V 0 ) α0 (Vs 0 ) β0 =K 1 (P 1 / V 1 ) α1 (Vs 1 ) β1 , where P 0 , V 0 , Vs 0 are respectively the stirring paddle input power, the cell culture medium volume, and the apparent aeration rate of the basic reactor, and P 1 , V 1 , Vs 1 are respectively the stirring paddle input power, the cell culture medium volume, and the apparent aeration rate of the enlarged reactor;

[0036] S42. Set the stirring speed N of the enlarged reactor;

[0037] S43. Obtain the historical data of the normal production of the basic reactor, and obtain the parameter data P 0 , V 0 , Vs 0 for each day during the culture period. When the cell culture medium volume V 1 , the stirring speed N, and the stirring paddle input power P 1 of the enlarged reactor are known, calculate the apparent aeration rate Vs of the enlarged reactor for each day during the culture period according to formula (3) 1, and then calculate the daily ventilation volume Qgas through formula (4);

[0038] The formula (4) is:

[0039] Vs 1 = Qgas / Ar;

[0040] Where Qgas is the ventilation volume and Ar is the surface area of the culture medium in the reactor.

[0041] Preferably, in step S42, the stirring speed N of the enlarged reactor is set according to the culture period of historical data. Specifically, the stirring speed of the enlarged reactor is set according to the maximum ventilation volume of the prediction model, so that it does not exceed the maximum ventilation volume value, or the ventilation volume is controlled within the optimal range of cell culture, or the corresponding stirring speed N is adjusted and calculated according to the set ventilation rate Q.

[0042] Preferably, in step S4, the Kla corresponding to different days is calculated for the basic reactor according to the culture period, that is, on the 1st day, the 2nd day,..., the Nth day, and the corresponding Kla1, Kla2,..., KlaN are obtained. According to the Kla value of the basic reactor corresponding to the daily ventilation volume to be calculated and the set stirring speed N of the enlarged reactor, the apparent ventilation rate Vs of the enlarged reactor corresponding to the number of days is calculated 1 .

[0043] A production process of a large-scale production reactor includes the following steps: Predict the ventilation volume Qgas of each day in the culture period after enlargement according to the large-scale production reactor ventilation volume prediction method described in steps S41 - S43, and judge whether the ventilation volume Qgas meets the process requirements. If it meets, it means that under the current set input power P of the stirring paddle 1 and apparent ventilation rate Vs 1 conditions, the enlarged reactor has the conditions for cells to grow normally; if the ventilation volume Qgas does not meet the process requirements, then according to formula (3): K 0 (P 0 / V 0 ) α0 (Vs 0 ) β0 = K 1 (P 1 / V 1 ) α1 (Vs 1 ) β1 Adjust the parameter, the input power P of the stirring paddle 1 Recalculate the apparent ventilation rate Vs 1 , and then recalculate the ventilation volume Qgas, so that the recalculated ventilation volume Qgas is within the process requirement range.

[0044] The beneficial effects of the present invention are as follows: Based on the premise of keeping the dissolved oxygen value constant in the culture system, by measuring the mass transfer correlation coefficient of the reactor, without changing the tank structure, the ventilation value at any rotation speed can be predicted, so as to balance the shear force damage caused by stirring and ventilation. It can predict the ventilation level after amplification based on the oxygen consumption of the small-scale reactor, and comprehensively consider the shear forces brought by stirring and ventilation at the same time, improving the success rate of large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 It is a line graph of Kla fitting of a 10L reactor for a method for predicting the ventilation volume of a large-scale production reactor and a production process according to the present invention;

[0046] Figure 2 It is a line comparison graph of the predicted ventilation volume and the actual ventilation volume according to the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0047] The mathematical letter symbols and definitions involved in this solution and the content in the specification can be referred to Table (1):

[0048] Definition description of the meanings of all mathematical letter symbols in Table (1):

[0049]

[0050] A method for predicting the ventilation volume of a large-scale production reactor, by analyzing the oxygen consumption rate and based on the common points between reactors of different sizes, it is obtained that the mass transfer coefficient Kla is the same;

[0051] The specific analysis process includes the following steps:

[0052] It can be known that the oxygen consumption rate OUR = the oxygen consumption rate of a single cell q(O 2 ) * X cell density. When large-scale production is carried out, the cells and the culture process are the same, so the oxygen consumption of a single cell and the cell density are also the same. Therefore, the oxygen consumption rate OUR in reactors of different sizes is equal;

[0053] Since the oxygen consumption rate OUR = the oxygen transfer rate OTR, and the value of the dissolved oxygen amount remains basically constant during the culture process, the supply and demand of oxygen by cells are in a balanced relationship during the whole culture process, that is, the consumption of oxygen and the transmission of oxygen are the same;

[0054] Under the above specified conditions, it can be obtained that the oxygen transfer rate OTR in reactors of different sizes is equal;

[0055] According to the formula for culturing cells, the oxygen transfer rate OTR = mass transfer coefficient Kla * (saturated oxygen concentration C* in air - actual oxygen concentration C in the culture system). According to actual operations, in the same environmental space and for the same type of cell culture, C* is the saturated oxygen concentration (a constant value), and C is the actual dissolved oxygen value (a constant value). Therefore, when the oxygen transfer rate OTR is equal, the mass transfer coefficient Kla is equal, and it can be concluded that the mass transfer coefficient Kla is equal in reactors of different sizes.

[0056] The data parameters that change with the reactor scale are the aeration rate and the stirring speed. The aeration rate mainly depends on the size and method of the reactor aeration aperture, as well as the size and form of the stirrer paddle. The stirring speed is controlled according to the input power of the stirrer paddle of different specifications of the reactor. Therefore, to measure the Kla mass transfer coefficient at different rotation speeds and aeration rates, it is necessary to calculate the value of the mass transfer coefficient Kla under different conditions based on the change of dissolved oxygen over time at different rotation speeds, different volumes of cell culture medium, and different air bottom aeration rates during the cultivation process in reactors of different sizes.

[0057] Establish a mathematical relationship based on Kla, apparent aeration rate Vs, and volume power ratio P / V.

[0058] Further establish a mathematical model, select different stirring speeds and air bottom aeration rates to measure several groups of data, and establish a mathematical relationship between Kla and apparent aeration rate Vs, volume power ratio P / V.

[0059] Specifically, it includes the following steps:

[0060] 1. Add a fixed volume of cell culture medium to the corresponding basic reactor or scaled-up reactor, and calibrate DO according to the set process. Here, DO is the dissolved oxygen concentration (the dissolved oxygen concentration in the fermentation broth (abbreviated as DO) is a crucial parameter in aerobic microbial fermentation and cell culture processes).

[0061] 2. Close the air inlet, open the nitrogen inlet, blow DO below 5%, and then close the nitrogen inlet.

[0062] 3. Arbitrarily set n groups of stirring speeds N and aeration rates Q to obtain the first data set (Ni, Qi), where i = 1, 2, ……, n.

[0063] 4. Set the stirring speed and aeration rate of the reactor sequentially according to the first data set; after setting each set of data, turn on parameter monitoring, record the change value of DO over time, and when DO is greater than 95%, end the experiment, then balance the volume of the cell culture medium and calibrate DO, and then set the data set of the next stirring speed and aeration rate, and so on, until the change values of DO over time under different stirring speeds N and aeration rates Q are obtained for n groups;

[0064] 5. Perform n linear fittings respectively according to the change values of DO over time for n groups to obtain n slope parameters, and this slope parameter is the mass transfer coefficient Kla, and then obtain n groups of mass transfer coefficients Kla;

[0065] 6. Convert the n groups of the first data set (Ni, Qi) into the input power P of the agitator and the apparent aeration rate Vs through formulas (1) and (2) to obtain n groups of the second data set (Pi, Vsi), where i = 1, 2,..., n;

[0066] The formula (1) is:

[0067] ;

[0068] where Np is the agitator power number, N is the stirring speed, is the agitator diameter, and ρ is the liquid density;

[0069] The formula (2) is:

[0070] Vs = Q / (Π × );

[0071] where Vs is the apparent aeration rate, Q is the aeration rate, and D is the radius of the tank body;

[0072] 7. Substitute the n groups of the second data set (Pi, Vsi) and the volume V of the cell culture medium into the mathematical relationship model Kla = K(P / V) α (Vs) β , and solve to obtain K, α, and β corresponding to the reactor, and obtain the relationship model between the mass transfer coefficient Kla and the input power P of the agitator and the apparent aeration rate Vs;

[0073] The specific operation principle is as follows. It can be known that the DO inside the reactor is related to the aeration rate inside and the input power of the stirring paddle. After adding the volume V of the cell culture medium to be cultured through the above steps, the initial state is detected, that is, the dissolved oxygen reference values of water and air in the culture medium without any external force. Then, the air inlet is closed, and the dissolved oxygen reference value inside is continuously reduced by inputting nitrogen until it is below 5%. By setting different stirring speeds and aeration rates, oxygen input is provided again, and the change of the dissolved oxygen reference over time is detected in real time until the dissolved oxygen reference value is greater than 95%, at which point the aeration and stirring are ended. This process is used to obtain the dissolved oxygen rate brought by different stirring speeds and aeration rates over time.

[0074] According to the above steps, the corresponding K, α, and β values of the basic reactor and the enlarged reactor are calculated respectively. Specifically, the constant values K, α, and β of the corresponding reactor are calculated according to different specifications of the reactor.

[0075] Finally, prediction is carried out. According to the historical data of the basic reactor, the daily aeration volume Qgas of the enlarged reactor during the culture period is predicted. The specific prediction methods include:

[0076] Based on the equality of the mass transfer coefficients Kla of the basic reactor and Kla* of the enlarged reactor, the formula (3) is obtained as: K 0 (P 0 / V 0 ) α0 (Vs 0 ) β0 =K 1 (P 1 / V 1 ) α1 (Vs 1 ) β1 , where P 0 、V 0 、Vs 0 are the input power of the stirring paddle, the volume of the cell culture medium, and the apparent aeration rate of the basic reactor respectively. Among them, P 1 、V 1 、Vs 1 are the input power of the stirring paddle, the volume of the cell culture medium, and the apparent aeration rate of the enlarged reactor respectively.

[0077] Set the stirring speed N of the enlarged reactor according to the historical data. Specifically, the stirring speed of the enlarged reactor is set according to the maximum aeration volume of the prediction model, so that it does not exceed the maximum aeration volume value of the cultured cells, or the aeration volume is controlled within the optimal range of cell culture, or the corresponding stirring speed N is adjusted and calculated according to the set aeration rate Q.

[0078] In the case where it is known that the expanded reactor needs to culture cells with a cell culture medium volume V 1 and the Kla of the expanded-scale reactor is equal to the Kla of the basic reactor, the apparent aeration rate Vs of the expanded reactor can be calculated according to formula (3) 1 , so that the daily aeration volume Qgas can be calculated;

[0079] Judge whether the corresponding daily aeration volume Qgas meets the process requirements. If it meets, it means that under the input power P of the stirrer 1 and the apparent aeration rate Vs 1 , the expanded reactor has the conditions for the cells to grow normally; if the aeration volume Qgas does not meet the process requirements, then adjust the parameter stirrer input power P according to the formula (3) 1 Recalculate the apparent aeration rate Vs 1 so that the recalculated aeration volume Qgas is within the process requirement range. Specifically, the daily aeration volume Qgas can be calculated through formula (4);

[0080] The formula (4) is:

[0081] Vs 1 =Qgas / Ar;

[0082] where Qgas is the aeration volume and Ar is the surface area of the culture solution in the reactor.

[0083] For a specific implementation case, taking a 10L basic reactor and a 200L expanded reactor as an example:

[0084] According to the cells to be cultured, a process cycle of 16 days is formulated, and the operation is carried out according to the steps described in the above 1-7, and different set stirring speeds N and aeration rates Q are brought into the formula: Kla=K(P / V) α (Vs) β

[0085] Calculate to obtain the constant term K 0 , α 0 and β 0 values of 10L;

[0086] The specific calculation results of the 10L constant term values are shown in Table (2):

[0087] Table (2) is the constant term values of K 0 , α 0 and β 0 of the 10L reactor:

[0088]

[0089] At the same time, the variation values of DO over time for each day were respectively fitted according to different stirring speeds and aeration rates each day, that is, the Kla values for each day, as shown in Table (3) below, which can be referred to in the appendix. Figure 1 , which is the linear graph of the variation values of DO over time for one of the groups;

[0090] Table (3) The Kla values corresponding to each day:

[0091]

[0092] Calculate the constant term K 1 , α 1 and β 1 values for the 200L scaled-up reactor;

[0093] The specific calculation results of the 200L constant term values are shown in Table (4);

[0094] Table (4) shows the constant term values of K 1 , α 1 and β 1 for the 200L reactor:

[0095]

[0096] For the 10L basic reactor, Kla = K 0 (P 0 / V 0 ) α0 (Vs 0 ) β0 ,

[0097] For the 200L scaled-up reactor, Kla* = K 1 (P 1 / V 1 ) α1 (Vs 1 ) β1 ,

[0098] Since the mass transfer coefficients of Kla for the 10L basic reactor and Kla* for the 200L scaled-up reactor are equal, that is, Kla = Kla*,

[0099] That is, it can be obtained that K 0 (P 0 / V 0 ) α0 (Vs 0 ) β0 = K 1 (P 1 / V 1 ) α1 (Vs 1 ) β1 ;

[0100] Set the stirring speed N corresponding to the 200L enlarged reactor according to historical data (i.e., the input power P of the stirring paddle can be obtained according to Formula 1), substitute the Kla corresponding to all days into it, and with the known K 1 , α 1 , β 1 , V 1 , the apparent aeration rate Vs corresponding to the corresponding day can be calculated. 1 , and then the aeration volume Qgas per day is calculated through the obtained apparent aeration rate Vs 1 , that is, the prediction result of the 200L enlarged reactor is completed. Finally, the prediction result is judged to determine whether the aeration volume Qgas corresponding to each day meets the process requirements. If it meets, it means that under the input power P of the stirring paddle 1 , apparent aeration rate Vs 1 , the enlarged reactor has the conditions for the cells to grow normally; if the aeration volume Qgas does not meet the process requirements, the parameter stirring paddle input power P is adjusted according to the formula (3) 1 and the apparent aeration rate Vs is recalculated 1 so that the recalculated aeration volume Qgas is within the process requirement range;

[0101] Specifically, the apparent aeration rate Vs of the 200L enlarged reactor corresponding to the corresponding day is calculated 1 ;

[0102] The aeration rate of the 200L reactor predicted by the 10L reactor is shown in Table (5);

[0103] Table (5) shows the aeration results of the 200L reactor predicted by the 10L reactor:

[0104]

[0105]

[0106] Among them, the stirring speed can be set in advance, and the preferred stirring speed is set according to the size of the cell volume and the size of the reactor scale. Since the volume of the cell culture medium for cultivation is known, the input power P of the stirring paddle can be calculated.

[0107] Verify the above-mentioned enlarged aeration volume:

[0108] The above-mentioned aeration volume calculated based on the 10L basic reactor process, and on the premise of the assumption that Kla is equal for bioreactors of different scales, establish the aeration volume prediction of the above 200L enlarged reactor, and compare it with the actual aeration volume during the 200L production process, so as to verify the reliability of the model. For details, please refer to the appendix Figure 2The line graphs of the predicted ventilation volume and the actual ventilation volume are compared. Among them, the blue line represents the actual ventilation volume of 200 L, and the red line represents the predicted ventilation volume of 200 L. The data obtained in this graph are the instantaneous ventilation volumes at the same time. By comparing the significant differences in the instantaneous ventilation volumes, it can be seen that the difference between the predicted ventilation volume and the actual ventilation volume is very small, showing a high degree of consistency, which proves the success of the ventilation volume prediction and that the cells can be cultured normally in the enlarged reactor.

[0109] The advantages of the present invention are as follows. Based on the premise of maintaining a constant dissolved oxygen value in the culture system, by measuring the mass transfer correlation coefficient of the reactor, and without changing the structure of the tank body, it is possible to predict the ventilation value at any rotational speed, thereby balancing the shear force damage caused by stirring and ventilation. It can predict the ventilation level after scale-up based on the oxygen consumption of the small-scale reactor, and at the same time comprehensively consider the shear force brought by stirring and ventilation, improving the success rate of scale-up production.

[0110] The above is only a preferred specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art within the technical scope disclosed by the present invention, according to the technical solution and inventive concept of the present invention, makes equivalent substitutions or changes, and all should be covered within the protection scope of the present invention.

Claims

1. A method for predicting the ventilation rate of a large-scale production reactor, characterized in that: It includes the following steps: S1. Variable parameter setting: The variable parameters include the volume of the cell culture medium V, the input power P of the stirring paddle of the reactor, and the apparent ventilation rate Vs; S2. Construct a mathematical relationship model between the mass transfer coefficient Kla in the reactor and the variable parameters: Kla=K(P / V) α (Sun) β Where K, α and β are characteristic constants of the reactor; S3, collecting the operating data of the basic reactor and the amplified reactor, and solving the characteristic constants (K0, α0, β0) and (K1, α1, β1) in the relationship model of the basic reactor and the amplified reactor respectively; The method for solving the characteristic constant includes: S31, adding a fixed volume of cell culture medium into the reactor, and calibrating DO according to the set process, wherein DO is the dissolved oxygen concentration; S32, close the air intake, open the nitrogen intake, blow the DO to below 5%, and close the nitrogen intake; S33, arbitrarily set n groups of stirring speeds N and ventilation rates Q to obtain a first data group (Ni, Qi), i=1, 2, ..., n; S34, setting the stirring speed and ventilation rate of the reactor in sequence according to the first data group; after each set of data, start parameter monitoring, record the change value of DO over time, and when DO is greater than 95%, end the experiment, then balance the volume of the cell culture medium and calibrate DO, and then set the next stirring speed and ventilation rate data group, and so on, until n groups of DO change values ​​over time under different stirring speeds N and ventilation rates Q are obtained; S35, performing n linear fittings according to the change values ​​of n groups of DO over time, respectively, to obtain n slope parameters, the slope parameter being the mass transfer coefficient Kla, and further obtaining n groups of mass transfer coefficients Kla; S36, converting n groups of the first data groups (Ni, Qi) into the impeller input power P and the apparent ventilation rate Vs by formula (1) and formula (2), to obtain n groups of second data groups (Pi, Vsi), i=1, 2, ..., n; The formula (1) is: P=Np× × ×ρ Where Np is the power of the stirring paddle, N is the stirring speed, is the diameter of the stirring paddle, ρ is the liquid density; The formula (2) is: Vs =Q / (Π× ); Where Vs is the apparent ventilation rate, Q is the ventilation rate, and D is the tank radius; S37, according to the n second data sets (Pi, Vsi) and the volume of the cell culture medium V, substitute into the mathematical relationship model Kla=K(P / V) α (Vs) β , and solve for the corresponding reactor's K, α and β, and obtain the relationship model between the mass transfer coefficient Kla and the impeller input power P and the apparent ventilation rate Vs; S4. Predict the daily ventilation volume Qgas of the expanded reactor during the culture period based on the historical data of the basic reactor.

2. The method for predicting the ventilation volume of a large-scale production reactor according to claim 1, characterized in that: The prediction method in step S4 includes: S41, according to the mass transfer coefficient Kla of the basic reactor and the mass transfer coefficient Kla* of the expanded reactor being equal, That is, formula (3) is: K0(P0 / V0) α0 (Vs0) β0 =K1(P1 / V1) α1 (Vs1) β1 , where P0, V0, and Vs0 are the impeller input power, cell culture medium volume, and apparent aeration rate of the basic reactor, respectively; and P1, V1, and Vs1 are the impeller input power, cell culture medium volume, and apparent aeration rate of the expanded reactor, respectively; S42, setting the stirring speed N of the enlarged reactor; S43, obtaining historical data of normal production of the basic reactor, obtaining parameter data P0, V0, Vs0 for each day during the culture cycle, and calculating the apparent ventilation rate Vs1 of the expanded reactor during each day during the culture cycle according to formula (3) when the cell culture medium volume V1, stirring speed N and stirring paddle input power P1 of the expanded reactor are known, and then calculating the daily ventilation volume Qgas according to formula (4); The formula (4) is: Vs1=Qgas / Ar; Wherein, Qgas is the ventilation volume, and Ar is the surface area of ​​the culture medium in the reactor.

3. A method for predicting the ventilation volume of a large-scale production reactor according to claim 2, characterized in that: In step S42, the stirring speed N of the expanded reactor is set according to the culture cycle of historical data, and is specifically set according to the maximum ventilation volume of the predicted model scale so that it does not exceed the maximum ventilation value, or the ventilation volume is controlled within the optimal range for cell culture, or adjusted according to the set ventilation rate Q and the corresponding stirring speed N is calculated.

4. The method for predicting the ventilation volume of a large-scale production reactor according to claim 1, characterized in that: In step S4, the basic reactor calculates the Kla corresponding to different days according to the culture cycle, that is, the 1st day, the 2nd day, ..., the Nth day, and obtains Kla1, Kla2, ..., KlaN accordingly. The Kla value of the basic reactor corresponding to the daily ventilation volume and the set stirring speed N of the expanded reactor are calculated as needed to obtain the apparent ventilation rate Vs1 of the expanded reactor for the corresponding days.

5. A production process for large-scale production of reactors, characterized in that: The method comprises the following steps: predicting the ventilation volume Qgas of each day in the culture period after expansion according to the ventilation volume prediction method of large-scale production reactor as claimed in claim 2, judging whether the ventilation volume Qgas meets the process requirements, and if so, it means that under the conditions of the currently set stirring blade input power P1 and the apparent ventilation rate Vs1, the expanded reactor has the conditions for normal cell growth; if the ventilation volume Qgas does not meet the process requirements, then according to formula (3): K0(P0 / V0) α0 (Vs0) β0 =K1(P1 / V1) α1 (Vs1) β1 The parameter agitator input power P1 is adjusted to recalculate the apparent ventilation rate Vs1, and then the ventilation volume Qgas is recalculated, so that the recalculated ventilation volume Qgas is within the process requirement range.

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