CN114410458A - Pharmacy fermentation cylinder and fermentation control system - Google Patents
Pharmacy fermentation cylinder and fermentation control system Download PDFInfo
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- CN114410458A CN114410458A CN202210321032.6A CN202210321032A CN114410458A CN 114410458 A CN114410458 A CN 114410458A CN 202210321032 A CN202210321032 A CN 202210321032A CN 114410458 A CN114410458 A CN 114410458A
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
- C12M41/00—Means for regulation, monitoring, measurement or control, e.g. flow regulation
- C12M41/12—Means for regulation, monitoring, measurement or control, e.g. flow regulation of temperature
- C12M41/18—Heat exchange systems, e.g. heat jackets or outer envelopes
- C12M41/22—Heat exchange systems, e.g. heat jackets or outer envelopes in contact with the bioreactor walls
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
- C12M37/00—Means for sterilizing, maintaining sterile conditions or avoiding chemical or biological contamination
Abstract
The invention discloses a fermentation tank for pharmacy and a fermentation control system, the fermentation tank for pharmacy comprises a fermentation tank body, a first heating mechanism, a pressure keeping and ventilating mechanism, a second heating mechanism, a cooling mechanism and a control module, which combines a plurality of heating modes and heating positions and combines the components to realize comprehensive and balanced heating, temperature rise and sterilization of a fermentation culture medium, particularly combines improved heating and temperature control steps and theoretical sterilization time with basis deduced by a formula, abandons the existing uncertain control mode, can simultaneously realize coarse adjustment and fine adjustment of the sterilization process, not only obtains excellent sterilization effect, but also reduces the damage of the heating, temperature rise and temperature control sterilization processes to the fermentation culture medium, can correspondingly reduce the sterilization time, reduces the demand on heating energy, has high sterilization production efficiency and can be automatically controlled, the production process is safer and is suitable for use as part of a fermentation control system and for sterilization of fermentation media.
Description
Technical Field
The invention belongs to the field of microbial pharmaceutical fermentation, and particularly relates to a pharmaceutical fermentation tank and a fermentation control system.
Background
The fermentation pharmaceutical engineering is to produce final compounds (such as antibiotics, vitamins and other medicines) by using microbial cells (animal cells and plant cells) as production factories and enzyme-catalyzed substrates (such as glucose) in bacteria bodies by using certain specific functions of microorganisms by adopting modern engineering technical means. The fermentation pharmaceutical process comprises the steps of strain breeding, culture medium preparation, culture medium sterilization, expanded culture and inoculation, seed tank expanded culture, fermentation production, medicine separation, purification, drying, packaging and the like.
The operations of sterilization and inoculation of the fermentation medium can be carried out in a pharmaceutical fermenter. The conventional method is to introduce high-temperature steam into the fermentation medium in a pharmaceutical fermentation tank, and utilize the strong penetration capacity of the high-temperature steam to release heat energy through the steam, so that chemical bonds (especially hydrogen bonds) inside various bacteria, fungal proteins, enzymes and nucleic acid molecules are destroyed, irreversible denaturation is caused, and microorganisms are killed.
In the sterilization treatment process, in the traditional operation process, the valves and the mechanical monitoring instruments on the pharmaceutical fermentation tank are manually operated, steam is manually added, or the valves are manually and remotely controlled to be opened and closed, and then the operation result is judged according to the fixed sterilization time, however, due to the uncertainty of control in the modes, the defects of operation lag, misoperation, single valve opening and the like can exist, the pressure and the temperature in the tank are easily overhigh, and equipment damage and personal safety risks are generated; or the local temperature rise is too fast, and the effective ingredients of the materials are damaged; or the heating effect is not good, so that the disinfection and sterilization effect is not controllable; meanwhile, because the existing control mode has large uncertainty, and excessive use of steam is easily caused in order to pursue the effect of complete sterilization, the fermentation culture medium is greatly damaged, the loss of nutrient components is caused, not only is a large amount of energy wasted, but also the sterilization time is too long, and the production efficiency is low.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides an improved pharmaceutical fermentation tank which can reduce the damage to a fermentation culture medium, needs less heating energy and has high sterilization production efficiency on the basis of ensuring the sterilization effect and is suitable for industrial automation large-scale application.
The invention also provides a fermentation control system comprising the pharmaceutical fermentation tank.
In order to achieve the purpose, the invention adopts the technical scheme that: a pharmaceutical fermentation tank, comprising: a fermentation tank body;
the first heating mechanism is partially arranged on the outer wall of the fermentation tank body and is used for conducting heat to the interior of the fermentation tank body;
a pressure maintaining and ventilating mechanism which is communicated with the fermentation tank body;
the second heating mechanism comprises a first sub-heating component and a second sub-heating component, the first sub-heating component is communicated with the fermentation tank body, and the second sub-heating component is kept to be communicated with the ventilation mechanism and the fermentation tank body through the pressure;
the cooling mechanism is partially arranged on the outer wall of the fermentation tank body and is used for cooling the interior of the fermentation tank body;
a control module in communication with the first heating mechanism, the pressure maintenance and ventilation mechanism, the second heating mechanism, and the cooling mechanism, respectively;
the heating heat source of the first heating mechanism, the heating heat source of the first sub-heating assembly and the heating heat source of the second sub-heating assembly are respectively steam;
the fermentation tank comprises a sterilization state, when the fermentation tank is in the sterilization state, a fermentation culture medium is added into the fermentation tank body, and sterilization treatment is carried out according to the following procedures:
step (i): the theoretical sterilization time T, T = (1/K). times.ln (M) was obtained from the formula (1)0/MT) Formula (1), M0The number of bacteria before sterilization; mTK is a reaction rate constant for the number of residual bacteria after sterilization;
step (ii): the heating amounts of the first heating mechanism, the first sub-heating assembly and the second sub-heating assembly in unit time are respectively and independently controlled, when the temperature in the fermentation tank body is raised to a first temperature, the pressure maintaining and ventilating mechanism is started, and the pressure in the fermentation tank body is maintained at a first pressure;
when the temperature in the fermentation tank body is raised to a second temperature, the heating amounts of the first heating mechanism and the first sub-heating assembly in unit time are respectively reduced;
when the temperature inside the fermentation tank body is increased to a third temperature, the heating amount of the second sub-heating assembly in unit time is adjusted so as to keep the temperature inside the fermentation tank body at the third temperature;
the third temperature is a sterilization temperature, the first temperature is 10-30 ℃ lower than the third temperature, and the second temperature is 2-8 ℃ lower than the third temperature;
step (iii): and after the third temperature is continuously kept for the theoretical sterilization time T, the sterilization is finished, and the temperature is reduced by the cooling mechanism.
According to some preferred and specific aspects of the present invention, in the step (i), the reaction rate constant K is obtained by the following formula (2):
K=Ae-Ea/RTain the formula (2), A is an Arrhenius constant, Ea is an experimental activation energy constant, R is a molar gas constant, and Ta is an absolute temperature.
According to some preferred aspects of the invention, in the step (i), the sterilization treatment is performed with an enhanced sterilization time T1 instead of the theoretical sterilization time T to enhance the sterilization effect, and T1 is 1.05 to 1.25 times T.
According to some preferred aspects of the invention, in step (i), when a plurality of bacteria are contained in the fermentation medium, each bacteria has a theoretical sterilization time, and the theoretical sterilization time having the longest duration is used as the theoretical sterilization time actually used for sterilizing the fermentation medium.
According to some preferred and specific aspects of the present invention, in the step (ii), when the bacteria in the fermentation medium include one or more of Bacillus subtilis, Clostridium sp, and Thermus stearothermophilus, the first temperature is 100-.
According to some preferred aspects of the invention, in step (ii), the first pressure is 0.12-0.3 MPa.
According to some preferred and specific aspects of the present invention, the first heating mechanism comprises a heating jacket, a first steam inlet pipe, a drain pipe, a first steam regulating valve arranged on the first steam inlet pipe, and a drain regulating valve arranged on the drain pipe, the heating jacket is respectively communicated with the first steam inlet pipe and the drain pipe, the heating jacket is arranged on the outer wall of the fermentation tank body, and the first steam regulating valve and the drain regulating valve are respectively communicated with the control module.
According to some preferred and specific aspects of the present invention, the pressure maintenance and ventilation mechanism comprises: the fermentation tank comprises a compressed air inlet pipe communicated with the lower part of the fermentation tank body, and a compressed air flow meter and a compressed air regulating valve which are arranged on the compressed air inlet pipe in sequence respectively, wherein the compressed air flow meter is in communication connection with the compressed air regulating valve respectively.
According to some preferred and specific aspects of the present invention, the first sub-heating assembly comprises: the second steam inlet pipe is communicated with the bottom of the fermentation tank body, and the steam flow meter and the second steam regulating valve are respectively and sequentially arranged on the second steam inlet pipe;
the second sub-heating assembly comprises a third steam inlet pipe and a third steam regulating valve arranged on the third steam inlet pipe, one end of the third steam inlet pipe is communicated with the second steam inlet pipe, the other end of the third steam inlet pipe is communicated with the compressed air inlet pipe, the communication joint of the third steam inlet pipe and the second steam inlet pipe is positioned between the steam flow meter and the second steam regulating valve, and the communication joint of the third steam inlet pipe and the compressed air inlet pipe is positioned between the compressed air regulating valve and the fermentation tank body;
the steam flow meter, the second steam regulating valve and the third steam regulating valve are respectively in communication connection with the control module.
According to some preferred and specific aspects of the invention, the pharmaceutical fermenter further comprises: the fermentation tank comprises an in-tank temperature sensor and an in-tank pressure sensor which are respectively in communication connection with the control module, and a disinfection exhaust regulating valve and a cultivation exhaust regulating valve which are respectively arranged at the upper part of the fermentation tank body and are communicated with the inside of the fermentation tank body.
In the invention, the disinfection exhaust regulating valve and the culture exhaust regulating valve are respectively communicated with different external treatment environments.
According to some preferred aspects of the invention, the specific steps of process step (ii) comprise:
opening the drainage regulating valve with the opening degree of 20-40%, and opening the first steam regulating valve with the opening degree of 20-40%; after delaying for 20-40s, respectively closing the drainage regulating valve and the first steam regulating valve; opening the second steam regulating valve, wherein the opening degree is 20-40%, and closing after delaying for 20-40 s;
opening the third steam regulating valve, wherein the opening degree is 50-70%, and the opening is controlled to be 4-6% every 5 s;
when the temperature in the fermentation tank body is monitored to be increased to a fourth temperature through the in-tank temperature sensor, the opening degree of the third steam regulating valve is regulated to 75-85%, and the opening degree is controlled to be 4-6% every 5 s;
when the temperature in the fermentation tank body is monitored to be increased to a fifth temperature through the in-tank temperature sensor, the second steam regulating valve and the first steam regulating valve are respectively opened, the opening degrees are respectively 75-85%, 4-6% is respectively controlled to be opened every 5s, and the opening degree of the disinfection exhaust regulating valve is adjusted to 80-100%;
when the temperature inside the fermentation tank body is monitored to be increased to a first temperature through the in-tank temperature sensor, the compressed air regulating valve is opened, the opening degree is 80-100%, and the pressure inside the fermentation tank body is kept at the first pressure by regulating the opening degree of the disinfection exhaust gas regulating valve;
when the temperature in the fermentation tank body is monitored to be increased to a second temperature through the in-tank temperature sensor, the opening degrees of the second steam regulating valve and the first steam regulating valve are respectively regulated to 20-40%, and the closing is respectively controlled to be 1-3% every 10 s;
when the temperature inside the fermentation tank body is monitored to be increased to the sterilization temperature through the in-tank temperature sensor, the temperature inside the fermentation tank body is kept at the sterilization temperature by controlling the opening degree of the third steam regulating valve.
Further, in the step (ii), the fourth temperature is 85 to 95 ℃, the fifth temperature is 95 to 105 ℃, and the fifth temperature is higher than the fourth temperature and lower than the first temperature.
According to some preferred aspects of the present invention, in the step (iii), when the temperature inside the fermenter body monitored by the in-tank temperature sensor is equal to or higher than the sterilization temperature, timing is started, when the temperature inside the fermenter body monitored by the in-tank temperature sensor is lower than the sterilization temperature and equal to or higher than the second temperature, timing is suspended, when the temperature inside the fermenter body monitored by the in-tank temperature sensor is lower than the second temperature, timing is cleared, and then timing operation is restarted after the monitored temperature inside the fermenter body reaches a corresponding temperature requirement until the third temperature continuously maintains the theoretical sterilization time.
According to some preferred aspects of the present invention, in the step (iii), after the sterilization is finished, the opening degree of the compressed air regulating valve is adjusted to 20 to 40%, the opening degree of the sterilization exhaust regulating valve is fixed to 40 to 60%, and the second steam regulating valve and the third steam regulating valve are respectively closed; then after 20-40s, adjusting the opening degree of the first steam regulating valve to 80-100%, and then opening and adjusting the opening degree of the disinfection exhaust regulating valve to keep the pressure inside the fermentation tank body at a second pressure;
and reducing the temperature through the cooling mechanism, closing the disinfection exhaust regulating valve when the temperature is reduced to the sixth temperature and maintained, opening the culture exhaust regulating valve, and maintaining the pressure inside the fermentation tank body at the second pressure by adjusting the opening size of the culture exhaust regulating valve.
According to some preferred aspects of the invention, the second pressure is 0.01 to 0.1 MPa.
According to some preferred aspects of the invention, the sixth temperature is 40-50 ℃.
According to some preferred and specific aspects of the present invention, the steam is a high temperature supersaturated steam at a temperature of 140 ℃ and 160 ℃.
According to some preferred and specific aspects of the present invention, the cooling mechanism employs process water as a heat sink.
The invention provides another technical scheme that: the application of the fermentation tank for pharmacy in sterilization of fermentation medium for pharmacy is provided.
The invention provides another technical scheme that: a fermentation control system comprising the above-mentioned pharmaceutical fermentation tank is adopted to ferment pharmacy.
Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:
the invention innovatively provides an improved pharmaceutical fermentation tank based on the defects of uncontrollable sterilization effect, overlong sterilization time, large energy waste, large damage to a fermentation medium and the like caused by various uncertain problems of the conventional pharmaceutical fermentation tank in the process of sterilizing the fermentation medium, and the like, the pharmaceutical fermentation tank realizes comprehensive and balanced heating, temperature rise and sterilization of the fermentation medium by combining various heating modes and heating positions and combining components such as a pressure maintaining and ventilating mechanism, a control module and the like, particularly combines improved heating and temperature control steps and a theoretical sterilization time with basis derived from a formula, abandons the conventional control mode of judging an operation result and uncertainty according to fixed empirical sterilization time, can simultaneously realize coarse adjustment and fine adjustment of the sterilization process, and not only obtains excellent sterilization effect, but also reduces the damage of heating and temperature control sterilization processes to the fermentation medium, correspondingly reduces the sterilization time, reduces the demand on heating energy, greatly saves the energy, has high sterilization production efficiency, can be automatically controlled, and has safer production process.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to these drawings without inventive exercise.
FIG. 1 is a schematic diagram of the configuration of a pharmaceutical fermentation tank used in an embodiment of the present invention;
wherein, 11, a first steam leading-in pipe; 12. a drain pipe; 13. a first steam regulating valve; 14. a drain regulating valve; 21. a compressed air inlet pipe; 22. a compressed air flow meter; 23. a compressed air regulating valve; 31. a second steam introduction pipe; 32. a steam flow meter; 33. a second steam regulating valve; 41. a third steam introduction pipe; 42. a third steam regulating valve; 5. a fermentation tank body; 51. an in-tank temperature sensor; 52. a tank internal pressure sensor; 53. a sterilizing exhaust regulating valve; 54. culturing an exhaust regulating valve; 55. a culture medium liquid inlet adjusting valve; 56. a tank bottom liquid outlet adjusting valve; 6. a control module; 71. circulating cooling water inlet regulating valve; 72. and a circulating cooling water return regulating valve.
Detailed Description
The concept of the invention mainly comprises: the traditional fixed experience sterilization time is changed into the sterilization time deduced from a formula theory by depending on a pharmaceutical fermentation tank with a specific structure, a plurality of heating modes (such as indirect heat conduction and direct contact) and different heating positions are combined, and then a specific temperature rise and control process is adopted, so that the heating process is effective and controllable, coarse adjustment and fine adjustment can be realized, a barrier film or a heat insulation layer for wrapping microorganisms is not easy to form in the presence of the changed heating modes and acting forces of different positions on a fermentation medium, the sterilization effect is better, meanwhile, the damage to the fermentation medium is greatly avoided, in addition, the sterilization time is greatly shortened, the consumption of steam resources is reduced, particularly, the whole ordered process is controllable, the uncertainty factor is few, and the intelligent control and large-scale application are facilitated.
Further, the present invention provides a pharmaceutical fermentation tank comprising: a fermentation tank body; the first heating mechanism is partially arranged on the outer wall of the fermentation tank body and is used for conducting heat to the interior of the fermentation tank body; a pressure maintaining and ventilating mechanism which is communicated with the fermentation tank body; the second heating mechanism comprises a first sub-heating component and a second sub-heating component, the first sub-heating component is communicated with the fermentation tank body, and the second sub-heating component is kept to be communicated with the ventilation mechanism and the fermentation tank body through the pressure; the cooling mechanism is partially arranged on the outer wall of the fermentation tank body and is used for cooling the interior of the fermentation tank body; a control module in communication with the first heating mechanism, the pressure maintenance and ventilation mechanism, the second heating mechanism, and the cooling mechanism, respectively; the heating heat source of the first heating mechanism, the heating heat source of the first sub-heating assembly and the heating heat source of the second sub-heating assembly are respectively steam;
the fermentation tank comprises a sterilization state, when the fermentation tank is in the sterilization state, a fermentation culture medium is added into the fermentation tank body, and sterilization treatment is carried out according to the following procedures:
step (i): the theoretical sterilization time T, T = was determined from the formula (1)（1/K）×ln(M0/MT) Formula (1), M0The number of bacteria before sterilization; mTK is a reaction rate constant for the number of residual bacteria after sterilization;
when the fermentation medium contains a plurality of bacteria, each bacteria has a theoretical sterilization time, and the theoretical sterilization time with the longest duration is taken as the theoretical sterilization time actually adopted when the fermentation medium is sterilized;
step (ii): the heating amounts of the first heating mechanism, the first sub-heating assembly and the second sub-heating assembly in unit time are respectively and independently controlled, when the temperature in the fermentation tank body is raised to a first temperature, the pressure maintaining and ventilating mechanism is started, and the pressure in the fermentation tank body is maintained at a first pressure;
when the temperature in the fermentation tank body is raised to a second temperature, the heating amounts of the first heating mechanism and the first sub-heating assembly in unit time are respectively reduced;
when the temperature inside the fermentation tank body is increased to a third temperature, the heating amount of the second sub-heating assembly in unit time is adjusted so as to keep the temperature inside the fermentation tank body at the third temperature;
the third temperature is a sterilization temperature, the first temperature is 10-30 ℃ lower than the third temperature, and the second temperature is 2-8 ℃ lower than the third temperature;
step (iii): and after the third temperature is continuously kept for the theoretical sterilization time T, the sterilization is finished, and the temperature is reduced by the cooling mechanism.
Further, in the sterilization process of the fermentation medium, the reaction speed constant K, K = Ae, is innovatively calculated by combining the Allen-Wus law-Ea/RTaA is an Arrhenius constant, Ea is an experimental activation energy constant, R is a molar gas constant, Ta is an absolute temperature, and practice proves that the calculated reaction rate constant K is applied to the formula (1) to obtain the theoretical sterilization time T so as to meet the sterilization requirement.
In the invention, a plurality of heating structures are arranged, the combination mode of the heating structures and the fermentation tank body has difference, steam is used as a heating heat source, the characteristics of indirect heat conduction and direct heat conduction are realized through the steam, each heating structure has different heating capacities and heating modes, the heating process is endowed with variability, the heating process can be finely regulated and controlled through a control module, further, specific temperature rising and control procedures can be combined, sterilization time control with too large uncertainty factor of fixed empirical sterilization time is replaced under the guidance of theoretical sterilization time deduced by a formula, the temperature rising process is more gentle by adopting a mode of combining coarse adjustment and fine adjustment in the temperature rising and control processes, the temperature rising speed in the fermentation medium is more balanced, and different action modes (indirect heat transfer, common introduction and independent introduction with gas) of the steam can be utilized, make the fermentation medium difficult for forming the barrier film or insulating layer etc. of parcel microorganism, and then make the sterilization effect better, the while sterilization time shortens relatively, reduces the consumption of steam energy, and whole process is more controllable, and the security is better.
The invention is further described below with reference to the accompanying drawings. Referring to fig. 1, the fermentation tank for pharmaceutical production comprises a fermentation tank body 5, a first heating mechanism, a pressure maintaining and ventilating mechanism, a second heating mechanism, a cooling mechanism and control module 6, an in-tank temperature sensor 51, an in-tank pressure sensor 52, and a sterilization exhaust regulating valve 53, a culture exhaust regulating valve 54 and a tank bottom liquid regulating valve 56 which are respectively arranged at the upper part of the fermentation tank body 5 and communicated with the interior of the fermentation tank body 5.
The first heating mechanism comprises a heating jacket, a first steam inlet pipe 11, a drain pipe 12, a first steam regulating valve 13 arranged on the first steam inlet pipe 11 and a drain regulating valve 14 arranged on the drain pipe 12, the heating jacket is respectively communicated with the first steam inlet pipe 11 and the drain pipe 12, and the heating jacket is arranged on the outer wall of the fermentation tank body 5; the first heating mechanism conducts heat from the outside to the inside of the fermentation tank body 5 in an indirect heat transfer mode, and heats or keeps the temperature of the fermentation medium inside;
the pressure maintaining and air exchanging mechanism comprises a compressed air inlet pipe 21 communicated with the lower part of the fermentation tank body 5, and a compressed air flow meter 22 and a compressed air regulating valve 23 which are respectively and sequentially arranged on the compressed air inlet pipe 21;
the first sub-heating component comprises a second steam leading-in pipe 31 communicated with the bottom of the fermentation tank body 5, and a steam flow meter 32 and a second steam regulating valve 33 which are respectively and sequentially arranged on the second steam leading-in pipe 31;
the second sub-heating assembly comprises a third steam leading-in pipe 41 and a third steam regulating valve 42 arranged on the third steam leading-in pipe 41, one end of the third steam leading-in pipe 41 is communicated with the second steam leading-in pipe 31, the other end of the third steam leading-in pipe 41 is communicated with the compressed air inlet pipe 21, the communication connection position of the third steam leading-in pipe 41 and the second steam leading-in pipe 31 is positioned between the steam flow meter 32 and the second steam regulating valve 33, and the communication connection position of the third steam leading-in pipe 41 and the compressed air inlet pipe 21 is positioned between the compressed air regulating valve 23 and the fermentation tank body 5;
the first steam regulating valve 13, the drainage regulating valve 14, the compressed air flow meter 22, the compressed air regulating valve 23, the steam flow meter 32, the second steam regulating valve 33, the third steam regulating valve 42, the tank temperature sensor 51, the tank pressure sensor 52, the disinfection exhaust regulating valve 53, the culture exhaust regulating valve 54, the culture medium inlet regulating valve 55 and the tank bottom liquid regulating valve 56 are respectively in communication connection with the control module 6, so that automatic regulation is realized.
Further, in the present invention, in order to avoid introducing new bacteria, it is preferable to use clean compressed air, and the second sub-heating assembly is also configured to sterilize the compressed air.
Further, when the pharmaceutical fermentation tank is in a sterilized state, a fermentation medium is added to the fermentation tank 5, and the sterilization treatment is performed according to the following steps:
step (1): the theoretical sterilization time T, T = (1/K). times.ln (M) was obtained from the formula (1)0/MT) Formula (1), K = Ae-Ea/RTa，M0The number of bacteria before sterilization; mTIn order to finish the sterilization, the number of the residual bacteria is K, A is a reaction rate constant, Ea is an experimental activation energy constant, R is a molar gas constant,ta is the absolute temperature; performing sterilization treatment by using intensified sterilization time T1 instead of the theoretical sterilization time T to intensify sterilization effect, wherein T1 is 1.05-1.25 times of T, i.e. T1= (1.05-1.25) T = (1.05-1.25) × (1/K) × ln (M)0/MT)=（1.05-1.25）×（2.7636/K）×log10(M0/MT)；
When the fermentation medium contains a plurality of bacteria, each bacteria has a theoretical sterilization time, and the theoretical sterilization time with the longest duration is taken as the theoretical sterilization time actually adopted when the fermentation medium is sterilized;
step (2): opening a culture medium inlet regulating valve 55, and adding a fermentation culture medium into the fermentation tank body 5;
step (3): closing all valves;
step (4): opening the circulating cooling water return regulating valve 72 with an opening degree of 100% (namely opening the circulating cooling water inlet regulating valve 71 at any time when needed to perform cooling water circulation cooling); opening the culture exhaust regulating valve 54, opening 100%, and closing the delay time of 100 and 120 s;
step (5): opening the drainage regulating valve 14 with the opening degree of 20-40%, opening the first steam regulating valve 13 with the opening degree of 20-40%, and respectively delaying for 20-40s and then closing;
step (6): opening the second steam regulating valve 33, wherein the opening degree is 20-40%, and closing after delaying for 20-40 s;
step (7): slowly opening the third steam regulating valve 42, wherein the opening degree is 50-70%, and controlling the opening degree to be 4-6% every 5 s;
when the temperature in the fermentation tank body 5 is monitored to be increased to a fourth temperature through the in-tank temperature sensor 51, the opening degree of the third steam regulating valve 42 is slowly regulated to 75-85%, and the opening is controlled to be 4-6% every 5 s; wherein the fourth temperature is 85-95 ℃;
when the temperature in the fermentation tank body 5 is monitored to be increased to a fifth temperature through the in-tank temperature sensor 51, the second steam regulating valve 33 and the first steam regulating valve 13 are respectively and slowly opened, the opening degrees are respectively 75-85%, the opening degrees are respectively controlled to be 4-6% every 5s, and the opening degree of the disinfection exhaust regulating valve 53 is adjusted to 80-100%; wherein the fifth temperature is 95-105 ℃, and the fifth temperature is higher than the fourth temperature and lower than the first temperature;
when the temperature inside the fermentation tank body 5 is monitored to be increased to a first temperature through the in-tank temperature sensor 51, the compressed air regulating valve 23 is opened, the opening degree is 80-100%, the opening degree of the disinfection exhaust regulating valve 53 is adjusted to keep the pressure inside the fermentation tank body 5 at a first pressure, the first pressure is 0.12-0.3MPa, the disinfection exhaust regulating valve 53 and the in-tank pressure sensor 52 can be interlocked, the opening degree of the disinfection exhaust regulating valve 53 is adjusted in real time, namely the interlocking means that the pressure inside the fermentation tank body 5 is kept at the first pressure through controlling the opening degree of the disinfection exhaust regulating valve 53, and the first pressure is monitored in real time through the in-tank pressure sensor 52; in the following description, when a certain control valve is interlocked with the in-tank pressure sensor 52, the same means that the pressure inside the fermenter 5 is maintained at a certain set pressure by controlling the opening of the certain control valve;
when the temperature in the fermentation tank body 5 is monitored to be increased to a second temperature through the in-tank temperature sensor 51, the opening degrees of the second steam regulating valve 33 and the first steam regulating valve 13 are respectively and slowly regulated to 20-40%, and the closing is respectively controlled to be 1-3% every 10 s;
when the temperature inside the fermenter body 5 is monitored to be raised to the sterilization temperature by the in-tank temperature sensor 51, the opening degree of the third steam regulating valve 42 is controlled to keep the temperature inside the fermenter body 5 at the sterilization temperature, so that the third steam regulating valve 42 and the in-tank temperature sensor 51 can be interlocked, and the opening degree of the third steam regulating valve 42 is adjusted in real time, namely the interlocking means that the temperature inside the fermenter body 5 is kept at the sterilization temperature by controlling the opening degree of the third steam regulating valve 42, and the sterilization temperature is monitored in real time by the in-tank temperature sensor 51; in the following description, the case where a certain control valve is interlocked with the in-tank temperature sensor 51 means that the inside temperature of the fermenter 5 is maintained at a certain set temperature by controlling the opening degree of the certain control valve.
Step (8): when the temperature inside the fermentation tank body 5 monitored by the in-tank temperature sensor 51 is greater than or equal to the sterilization temperature, timing is started, when the temperature inside the fermentation tank body 5 monitored by the in-tank temperature sensor 51 is less than the sterilization temperature and greater than or equal to a second temperature, timing is suspended, when the temperature inside the fermentation tank body 5 monitored by the in-tank temperature sensor 51 is less than the second temperature, timing is cleared, timing operation is restarted after the monitored temperature inside the fermentation tank body 5 reaches a corresponding temperature requirement until a third temperature continuously keeps a theoretical sterilization time T, and an excellent sterilization effect can be ensured by the method;
after the sterilization is finished, the opening degree of the compressed air regulating valve 23 is adjusted to 20-40%, the opening degree of the sterilizing exhaust regulating valve 53 is fixed at 40-60%, and the second steam regulating valve 33 and the third steam regulating valve 42 are respectively closed; then after 20-40s, the opening degree of the first steam regulating valve 13 is adjusted to 80-100%, then the opening degree of the disinfection exhaust regulating valve 53 is opened and adjusted to keep the pressure in the fermentation tank body 5 at a second pressure, wherein the second pressure is 0.01-0.1MPa, the disinfection exhaust regulating valve 53 and the tank pressure sensor 52 can be interlocked, and the opening degree of the disinfection exhaust regulating valve 53 can be adjusted in real time;
the temperature is reduced by adjusting the opening of the circulating cooling water return regulating valve 72, when the temperature is reduced to the sixth temperature and is kept (the circulating cooling water return regulating valve 72 can be interlocked with the in-tank temperature sensor 51 in a keeping mode, the opening of the circulating cooling water return regulating valve 72 is adjusted in real time), the disinfection exhaust regulating valve 53 is closed, the culture exhaust regulating valve 54 is opened, the pressure in the fermentation tank body 5 is kept at the second pressure by adjusting the opening of the culture exhaust regulating valve 54, the in-tank pressure sensor 52 can be interlocked with the culture exhaust regulating valve 54, and the opening of the culture exhaust regulating valve 54 is adjusted in real time; meanwhile, the flow rate of the compressed air can be kept at the flow rate set value by controlling the opening degree of the compressed air regulating valve 23, and the flow rate set value can be 400-500Nm3The flow set value can be monitored and fed back through the compressed air flow meter 22 in real time, the opening of the compressed air regulating valve 23 is further adjusted in real time, the pressure is maintained, positive pressure inside the fermentation tank body 5 is kept, and influence caused by entering of impurities containing bacteria such as air unclean outside and the like is avoidedSterilization results of fermentation media.
The steam is high-temperature supersaturated steam with the temperature of 140-160 ℃, and the cooling mechanism adopts process water as a cold source.
In some embodiments, when the bacteria in the fermentation medium comprise one or more of Bacillus subtilis, Clostridium, and Thermus stearothermophilus, the first temperature is 100-.
The above-described scheme is further illustrated below with reference to specific examples; it is to be understood that these embodiments are provided to illustrate the general principles, essential features and advantages of the present invention, and the present invention is not limited in scope by the following embodiments; the implementation conditions used in the examples can be further adjusted according to specific requirements, and the implementation conditions not indicated are generally the conditions in routine experiments.
Not specifically illustrated in the following examples, all starting materials are commercially available or prepared by methods conventional in the art.
Example 1
This example provides a fermentation tank for pharmaceutical use having the structure shown in FIG. 1, and the fermentation medium (commercially available medium, and the main nutrients include. alpha. -aminobutyric acid, D-threonine, etc.) is sterilized according to the sterilization process.
Wherein, the pharmaceutical liquid fermentation tank is 15m3The sterilization temperature is 128 ℃, and the absolute temperature is converted into 401.15 open-type temperature.
In the step (1), the reaction rate constant K = Ae is calculated according to the Arrhenius law-Ea/RTaA is an Allen-meus constant, Ea is an experimental activation energy constant, R is a molar gas constant 8.314J/(mol.K), and Ta is a sterilization absolute temperature 401.15 open degree;
theoretical sterilization time T =1/K × ln (M)0/MT)；
Intensive sterilization time T1= T1.2 =1.2/K ln (M)0/MT1)=2.7636/K*log10(M0/MT1) Wherein M is0=1.0168*104，MT1=10-3。
Step (2): opening a culture medium inlet regulating valve 55, and adding a fermentation culture medium into the fermentation tank body 5;
step (3): closing all valves;
in the step (4), the time is delayed by 110 s;
step (5): opening the drainage regulating valve 14 with the opening degree of 30%, opening the first steam regulating valve 13 with the opening degree of 30%, and respectively delaying for 28s and then closing the first steam regulating valve and the second steam regulating valve;
step (6): the second steam regulating valve 33 is opened, the opening degree is 30%, and the second steam regulating valve is closed after the delay of 28 s;
step (7): slowly opening the third steam regulating valve 42, wherein the opening degree is 60%, and the opening degree is controlled to be 5% every 5 s;
when the temperature inside the fermenter 5 is monitored to rise to a fourth temperature (90 ℃) by the in-tank temperature sensor 51, the opening degree of the third steam control valve 42 is slowly adjusted to 80%, and is controlled to be opened 5% every 5 seconds;
when the temperature in the fermentation tank body 5 is monitored to be increased to a fifth temperature (100 ℃) by the in-tank temperature sensor 51, the second steam regulating valve 33 and the first steam regulating valve 13 are respectively and slowly opened, the opening degrees are respectively 80%, 5% opening every 5s is respectively controlled, and the disinfection exhaust regulating valve 53 is fully opened;
when the temperature inside the fermentation tank body 5 is monitored to be increased to a first temperature (105 ℃) through the in-tank temperature sensor 51, the compressed air regulating valve 23 is opened, the opening degree is 100%, the pressure inside the fermentation tank body 5 is kept at a first pressure through regulating the opening degree of the disinfection exhaust regulating valve 53, and the first pressure is 0.17MPa, so that the disinfection exhaust regulating valve 53 and the in-tank pressure sensor 52 can be interlocked, and the opening degree of the disinfection exhaust regulating valve 53 is regulated in real time;
when the temperature in the fermentation tank body 5 is monitored to be increased to a second temperature (125 ℃) by the in-tank temperature sensor 51, the opening degrees of the second steam regulating valve 33 and the first steam regulating valve 13 are respectively and slowly regulated to 30%, and are respectively controlled to be closed by 2% every 10 s;
when the temperature inside the fermenter 5 is monitored to be raised to the sterilization temperature (128 ℃) by the in-tank temperature sensor 51, the opening of the third steam control valve 42 is controlled to keep the temperature inside the fermenter 5 at the sterilization temperature, so that the third steam control valve 42 and the in-tank temperature sensor 51 can be interlocked, and the opening of the third steam control valve 42 can be adjusted in real time.
Step (8): when the temperature inside the fermentation tank body 5 is monitored to be greater than or equal to the sterilization temperature (128 ℃) through the in-tank temperature sensor 51, timing is started, when the temperature inside the fermentation tank body 5 is monitored to be less than the sterilization temperature and greater than or equal to a second temperature (125 ℃), timing is suspended, when the temperature inside the fermentation tank body 5 is monitored to be less than the second temperature through the in-tank temperature sensor 51, timing is cleared, timing operation is restarted after the monitored temperature inside the fermentation tank body 5 meets the corresponding temperature requirement, and the excellent sterilization effect can be ensured by the method;
after the sterilization is finished, the opening degree of the compressed air regulating valve 23 is adjusted to 30%, the opening degree of the sterilizing exhaust regulating valve 53 is fixed at 50%, and the second steam regulating valve 33 and the third steam regulating valve 42 are respectively closed; then after 30s, the opening degree of the first steam regulating valve 13 is regulated to 100%, then the opening degree of the disinfection exhaust regulating valve 53 is opened and regulated to keep the pressure in the fermentation tank body 5 at a second pressure (0.08 MPa), the disinfection exhaust regulating valve 53 is interlocked with the tank pressure sensor 52, and the opening degree of the disinfection exhaust regulating valve 53 is regulated in real time;
reducing the temperature by adjusting the opening of the circulating cooling water return regulating valve 72, closing the sterilizing exhaust regulating valve 53, opening the culturing exhaust regulating valve 54, and adjusting the opening of the culturing exhaust regulating valve 54 to keep the pressure inside the fermentor body 5 at the second pressure by interlocking the circulating cooling water return regulating valve 72 with the in-tank temperature sensor 51 in a maintaining manner and adjusting the opening of the circulating cooling water return regulating valve 72 in real time when the temperature is reduced to the sixth temperature (45 ℃) and maintained (the opening of the circulating cooling water return regulating valve 72 is adjusted in real time); meanwhile, the flow rate of the compressed air is kept at a flow rate set value of 450Nm by controlling the opening degree of the compressed air regulating valve 233And h, monitoring and feeding back the flow set value through the compressed air flow meter 22 in real time, further adjusting the opening of the compressed air adjusting valve 23 in real time, maintaining the pressure to be favorable for keeping the positive pressure inside the fermentation tank body 5, and avoiding impurities containing bacteria, such as air which is not clean outside, from entering and influencing the sterilization result of the fermentation medium.
The temperature of the steam is supersaturated steam of 150 ℃, and the cooling mechanism adopts process water as a cold source.
Based on the measurements on the fermentation medium, the relevant parameters of the bacteria were calculated, with the following characteristics, as shown in table 1:
the maximum sterilization time 1008.4s is taken as the theoretical sterilization time actually adopted in the embodiment, and the reinforced sterilization time is calculated as follows: 1210.1 s.
According to the experimental procedure, the actual sterilization time and the amount of steam used in the sterilization phase were measured as shown in table 2 below:
the measured actual sterilization time is the same as the intensified sterilization time derived theoretically, and the temperature of the sterilization process basically has no fluctuation.
Sampling a fermentation liquid culture medium after sterilization, randomly sampling 5 bottles of diagonal lines in a fermentation tank, performing 30-degree constant-temperature culture in an incubator, checking a mold-free bacterial colony after 7 days of culture, and verifying that sterilization is completely finished.
The sterilized fermentation medium was tested as follows, and the loss of nutrients was found in the following Table 3:
as can be seen from Table 3 above, the loss rate of the nutritional ingredients alpha-aminobutyric acid and D-threonine is low, and the nutritional ingredients are basically and effectively preserved after sterilization.
Example 2
Basically, the method is the same as the method of the embodiment 1, and the method only differs from the method in that: pharmacy liquid fermentation tank 100m3The sterilization temperature is 121 ℃, and the absolute temperature is converted into 394.15 open-type temperature.
Wherein the reaction rate constant K = Ae is calculated according to the Allen-Wus' law-Ea/RTaA is an Arrhenius constant, Ea is an experimental activation energy constant, R is a molar gas constant 8.314J/(mol. K), and Ta is a sterilization absolute temperature 394.15 open degree.
Theoretical sterilization time T =1/K × ln (M)0/MT)；
Intensive sterilization time T1= T1.2 =1.2/K ln (M)0/MT1)=2.7636/K*log(M0/MT1) Wherein M is0=1.0157*104，MT1=10-3。
Based on the measurements on the fermentation medium, the relevant parameters of the bacteria were calculated, with the following characteristics, as shown in table 4:
the maximum sterilization time 1344.5s is taken as the theoretical sterilization time actually adopted in the embodiment, and the reinforced sterilization time is calculated as follows: 1613.4 s.
According to the experimental procedure, the actual sterilization time and the amount of steam used in the sterilization phase were measured as shown in table 5 below:
the measured actual sterilization time is the same as the intensified sterilization time derived theoretically, and the temperature of the sterilization process basically has no fluctuation.
Sampling a fermentation liquid culture medium after sterilization, randomly sampling 5 bottles of diagonal lines in a fermentation tank, performing 30-degree constant-temperature culture in an incubator, checking a mold-free bacterial colony after 7 days of culture, and verifying that sterilization is completely finished.
The sterilized fermentation medium was tested as follows, and the loss of nutrients was found in the following Table 6:
as can be seen from Table 6 above, the loss rate of the nutritional ingredients alpha-aminobutyric acid and D-threonine is low, and the nutritional ingredients are basically and effectively preserved after sterilization.
Comparative example 1
Pharmacy liquid fermentation cylinder 15m3The same fermentation medium as in example 1 was sterilized by a conventional sterilization method at 128 ℃ for 2400 s.
The traditional heating up and heating mode is as follows: the steam and air release control valves adopt hand valves, the temperature and the pressure are detected by adopting a mechanical expression field, and the operators manually operate the valves on the spot.
The actual experimental data are shown in table 7 below:
the steam consumption is significantly increased.
Sampling a fermentation liquid culture medium after sterilization, randomly sampling 5 bottles of diagonal lines in a fermentation tank, performing 30-degree constant-temperature culture in an incubator, checking a mold-free bacterial colony after 7 days of culture, and verifying that sterilization is completely finished.
The following tests were carried out on the sterilized fermentation medium, and the loss of nutrients was found in the following Table 8:
as can be seen from Table 8 above, the loss rate of the nutritional components alpha-aminobutyric acid and D-threonine is high, and the loss of the nutritional components after sterilization is large.
Comparative example 2
Pharmacy liquid fermentation tank 100m3The sterilization temperature was 121 ℃ and the sterilization time was conventionally fixed at 2400s, which was the same as in example 1The fermentation medium of (2) is sterilized.
The actual experimental data are shown in table 9 below:
the steam consumption is significantly increased.
Sampling a fermentation liquid culture medium after sterilization, randomly sampling 5 bottles of diagonal lines in a fermentation tank, performing 30-degree constant-temperature culture in an incubator, checking a mold-free bacterial colony after 7 days of culture, and verifying that sterilization is completely finished.
The sterilized fermentation medium was tested as follows, and the loss of nutrients was found in the following Table 10:
as can be seen from Table 10 above, the loss rate of the nutritional components alpha-aminobutyric acid and D-threonine is high, and the loss of the nutritional components after sterilization is large.
Comparative example 3
Basically, the method is the same as the method of the embodiment 1, and the method only differs from the method in that: the second heating mechanism does not comprise a second sub-heating component, and in the process of sterilization treatment,
wherein, the pharmaceutical liquid fermentation tank is 15m3The sterilization temperature is 128 ℃, and the absolute temperature is converted into 401.15 open-type temperature.
In the step (a), the reaction rate constant K = Ae is calculated according to Allen's Law-Ea/RTaA is an Arrhenius constant, Ea is an experimental activation energy constant, R is a molar gas constant 8.314J/(mol. K), and Ta is a sterilization absolute temperature 401.15 open degree.
Theoretical sterilization time T =1/K × ln (M)0/MT)；
Intensive sterilization time T1= T1.2 =1.2/K ln (M)0/MT1)=2.7636/K*log10(M0/MT1) Wherein M is0=1.0168*104，MT1=10-3。
A step (b): opening a culture medium inlet regulating valve 55, and adding a fermentation culture medium into the fermentation tank body 5;
a step (c): closing all valves;
in the step (d), the time is delayed by 110 s;
a step (e): opening the drainage regulating valve 14 with the opening degree of 30%, opening the first steam regulating valve 13 with the opening degree of 30%, and respectively delaying for 28s and then closing the first steam regulating valve and the second steam regulating valve;
a step (f): slowly opening the second steam regulating valve 33, wherein the opening degree is 60%, and the opening degree is controlled to be 5% every 5 s;
when the temperature inside the fermenter 5 is monitored to rise to a fourth temperature (90 ℃) by the in-tank temperature sensor 51, the opening degree of the second steam control valve 33 is slowly adjusted to 80%, and is controlled to be opened 5% every 5 seconds;
when the temperature inside the fermenter 5 is monitored to be raised to a fifth temperature (100 ℃) by the in-tank temperature sensor 51, the first steam regulating valve 13 is slowly opened, the opening degree is 80%, 5% opening is controlled every 5s, and the sterilizing exhaust regulating valve 53 is fully opened;
when the temperature inside the fermentation tank body 5 is monitored to be increased to a first temperature (105 ℃) through the in-tank temperature sensor 51, the compressed air regulating valve 23 is opened, the opening degree is 100%, the pressure inside the fermentation tank body 5 is kept at a first pressure through regulating the opening degree of the disinfection exhaust regulating valve 53, and the first pressure is 0.17MPa, so that the disinfection exhaust regulating valve 53 and the in-tank pressure sensor 52 can be interlocked, and the opening degree of the disinfection exhaust regulating valve 53 is regulated in real time;
when the temperature inside the fermenter 5 is monitored to be increased to a second temperature (125 ℃) by the in-tank temperature sensor 51, the opening degree of the first steam adjusting valve 13 is slowly adjusted to 30%, and the control is performed to close 2% every 10 s;
when the temperature inside the fermenter 5 is monitored to be raised to the sterilization temperature (128 ℃) by the in-tank temperature sensor 51, the second steam control valve 33 and the in-tank temperature sensor 51 can be interlocked by controlling the opening of the second steam control valve 33 so as to keep the temperature inside the fermenter 5 at the sterilization temperature, and the opening of the second steam control valve 33 can be adjusted in real time.
Step (g): when the temperature inside the fermentation tank body 5 monitored by the in-tank temperature sensor 51 is greater than or equal to the sterilization temperature, timing is started, when the temperature inside the fermentation tank body 5 monitored by the in-tank temperature sensor 51 is less than the sterilization temperature and greater than or equal to a second temperature, timing is suspended, when the temperature inside the fermentation tank body 5 monitored by the in-tank temperature sensor 51 is less than the second temperature, timing is cleared, and then timing operation is restarted after the monitored temperature inside the fermentation tank body 5 meets the corresponding temperature requirement;
after the sterilization is finished, the opening degree of the compressed air regulating valve 23 is adjusted to 30%, the opening degree of the sterilizing exhaust regulating valve 53 is fixed at 50%, and the second steam regulating valve 33 is closed; then after 30s, the opening degree of the first steam regulating valve 13 is regulated to 100%, and then the opening degree of the disinfection exhaust regulating valve 53 is opened and regulated to keep the pressure in the fermentation tank body 5 at a second pressure (0.08 MPa), so that the disinfection exhaust regulating valve 53 and the tank pressure sensor 52 can be interlocked, and the opening degree of the disinfection exhaust regulating valve 53 can be regulated in real time;
the rest is the same as example 1.
The actual sterilization time and the steam dosage in the sterilization stage are detected, in the example, the temperature in the fermentation tank body is reduced to below 125 ℃ 2 times after reaching 128 ℃, and the sterilization time needs to be cleared after each reduction, so that the actual sterilization time reaches 1524.3s, which is far greater than the strengthened sterilization time deduced by theory, and the steam dosage in the sterilization stage is 77.56 kg.
Sampling a fermentation liquid culture medium after sterilization, randomly sampling 5 bottles of diagonal lines in a fermentation tank, performing 30-degree constant-temperature culture in an incubator, checking a mold-free bacterial colony after 7 days of culture, and verifying that sterilization is completely finished.
The sterilized fermentation medium was examined as follows, and the loss of nutrients was found in the following Table 11:
as can be seen from the above, compared to example 1, the sterilization stability was lowered, the sterilization time was significantly increased, the steam dosage was significantly increased, and the nutrient loss rate was relatively increased.
The above embodiments are merely illustrative of the technical ideas and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.
The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value, and such ranges or values should be understood to encompass values close to those ranges or values. For ranges of values, between the endpoints of each of the ranges and the individual points, and between the individual points may be combined with each other to give one or more new ranges of values, and these ranges of values should be considered as specifically disclosed herein.
Claims (15)
1. The utility model provides a pharmacy fermentation cylinder, this pharmacy fermentation cylinder includes the fermentation tank body, and its characterized in that, this pharmacy fermentation cylinder still includes:
the first heating mechanism is partially arranged on the outer wall of the fermentation tank body and is used for conducting heat to the interior of the fermentation tank body;
a pressure maintaining and ventilating mechanism which is communicated with the fermentation tank body;
the second heating mechanism comprises a first sub-heating component and a second sub-heating component, the first sub-heating component is communicated with the fermentation tank body, and the second sub-heating component is kept to be communicated with the ventilation mechanism and the fermentation tank body through the pressure;
the cooling mechanism is partially arranged on the outer wall of the fermentation tank body and is used for cooling the interior of the fermentation tank body;
a control module in communication with the first heating mechanism, the pressure maintenance and ventilation mechanism, the second heating mechanism, and the cooling mechanism, respectively;
the heating heat source of the first heating mechanism, the heating heat source of the first sub-heating assembly and the heating heat source of the second sub-heating assembly are respectively steam;
the fermentation tank comprises a sterilization state, when the fermentation tank is in the sterilization state, a fermentation culture medium is added into the fermentation tank body, and sterilization treatment is carried out according to the following procedures:
step (i): the theoretical sterilization time T, T = (1/K). times.ln (M) was obtained from the formula (1)0/MT) Formula (1), M0The number of bacteria before sterilization; mTK is a reaction rate constant for the number of residual bacteria after sterilization;
step (ii): the heating amounts of the first heating mechanism, the first sub-heating assembly and the second sub-heating assembly in unit time are respectively and independently controlled, when the temperature in the fermentation tank body is raised to a first temperature, the pressure maintaining and ventilating mechanism is started, and the pressure in the fermentation tank body is maintained at a first pressure;
when the temperature in the fermentation tank body is raised to a second temperature, the heating amounts of the first heating mechanism and the first sub-heating assembly in unit time are respectively reduced;
when the temperature inside the fermentation tank body is increased to a third temperature, the heating amount of the second sub-heating assembly in unit time is adjusted so as to keep the temperature inside the fermentation tank body at the third temperature;
the third temperature is a sterilization temperature, the first temperature is 10-30 ℃ lower than the third temperature, and the second temperature is 2-8 ℃ lower than the third temperature;
step (iii): and after the third temperature is continuously kept for the theoretical sterilization time T, the sterilization is finished, and the temperature is reduced by the cooling mechanism.
2. The pharmaceutical fermentation tank of claim 1, wherein in step (i), the reaction rate constant K is determined by the following equation (2):
K=Ae-Ea/RTaformula (2), A is ArrheniusNumber, Ea is the experimental activation energy constant, R is the molar gas constant, and Ta is the absolute temperature.
3. The pharmaceutical fermentation tank of claim 1, wherein in step (i), during the sterilization treatment, the sterilization treatment is performed with an enhanced sterilization time T1 instead of the theoretical sterilization time T, wherein T1 is 1.05-1.25 times T; and/or, in the step (i), when a plurality of bacteria are contained in the fermentation medium, each bacteria has a theoretical sterilization time, and the theoretical sterilization time with the longest duration is taken as the theoretical sterilization time actually adopted when the fermentation medium is sterilized.
4. The fermentation tank of claim 1, wherein in step (ii), when the bacteria in the fermentation medium include one or more of Bacillus subtilis, Clostridium and Thermus stearothermophilus, the first temperature is 110-.
5. The pharmaceutical fermentation tank of claim 1, wherein in step (ii), said first pressure is 0.12-0.3 MPa.
6. The pharmaceutical fermentation tank of claim 1, wherein the first heating mechanism comprises a heating jacket, a first steam inlet pipe, a drain pipe, a first steam regulating valve disposed on the first steam inlet pipe, and a drain regulating valve disposed on the drain pipe, the heating jacket is respectively communicated with the first steam inlet pipe and the drain pipe, the heating jacket is disposed on the outer wall of the fermentation tank body, and the first steam regulating valve and the drain regulating valve are respectively in communication connection with the control module.
7. The pharmaceutical fermenter of claim 6, wherein the pressure maintaining and venting mechanism comprises: the fermentation tank comprises a compressed air inlet pipe communicated with the lower part of the fermentation tank body, and a compressed air flow meter and a compressed air regulating valve which are arranged on the compressed air inlet pipe in sequence respectively, wherein the compressed air flow meter is in communication connection with the compressed air regulating valve respectively.
8. The pharmaceutical fermenter of claim 7, wherein the first sub-heating assembly comprises: the second steam inlet pipe is communicated with the bottom of the fermentation tank body, and the steam flow meter and the second steam regulating valve are respectively and sequentially arranged on the second steam inlet pipe;
the second sub-heating assembly comprises a third steam inlet pipe and a third steam regulating valve arranged on the third steam inlet pipe, one end of the third steam inlet pipe is communicated with the second steam inlet pipe, the other end of the third steam inlet pipe is communicated with the compressed air inlet pipe, the communication joint of the third steam inlet pipe and the second steam inlet pipe is positioned between the steam flow meter and the second steam regulating valve, and the communication joint of the third steam inlet pipe and the compressed air inlet pipe is positioned between the compressed air regulating valve and the fermentation tank body;
the steam flow meter, the second steam regulating valve and the third steam regulating valve are respectively in communication connection with the control module.
9. The pharmaceutical fermentation tank of claim 8, further comprising: the fermentation tank comprises an in-tank temperature sensor and an in-tank pressure sensor which are respectively in communication connection with the control module, and a disinfection exhaust regulating valve and a cultivation exhaust regulating valve which are respectively arranged at the upper part of the fermentation tank body and are communicated with the inside of the fermentation tank body.
10. The pharmaceutical fermentation tank of claim 9, wherein step (ii) comprises the steps of:
opening the drainage regulating valve with the opening degree of 20-40%, and opening the first steam regulating valve with the opening degree of 20-40%; after delaying for 20-40s, respectively closing the drainage regulating valve and the first steam regulating valve;
opening the second steam regulating valve, wherein the opening degree is 20-40%, and closing after delaying for 20-40 s;
opening the third steam regulating valve, wherein the opening degree is 50-70%, and the opening is controlled to be 4-6% every 5 s;
when the temperature in the fermentation tank body is monitored to be increased to a fourth temperature through the in-tank temperature sensor, the opening degree of the third steam regulating valve is regulated to 75-85%, and the opening degree is controlled to be 4-6% every 5 s; wherein the fourth temperature is 85-95 ℃;
when the temperature in the fermentation tank body is monitored to be increased to a fifth temperature through the in-tank temperature sensor, the second steam regulating valve and the first steam regulating valve are respectively opened, the opening degrees are respectively 75-85%, 4-6% is respectively controlled to be opened every 5s, and the opening degree of the disinfection exhaust regulating valve is adjusted to 80-100%; wherein the fifth temperature is 95-105 ℃, and the fifth temperature is higher than the fourth temperature and lower than the first temperature;
when the temperature inside the fermentation tank body is monitored to be increased to a first temperature through the in-tank temperature sensor, the compressed air regulating valve is opened, the opening degree is 80-100%, and the pressure inside the fermentation tank body is kept at the first pressure by regulating the opening degree of the disinfection exhaust gas regulating valve;
when the temperature in the fermentation tank body is monitored to be increased to a second temperature through the in-tank temperature sensor, the opening degrees of the second steam regulating valve and the first steam regulating valve are respectively regulated to 20-40%, and the closing is respectively controlled to be 1-3% every 10 s;
when the temperature inside the fermentation tank body is monitored to be increased to the sterilization temperature through the in-tank temperature sensor, the temperature inside the fermentation tank body is kept at the sterilization temperature by controlling the opening degree of the third steam regulating valve.
11. The pharmaceutical fermentation tank of claim 10, wherein in step (iii), when the temperature inside the fermentation tank body monitored by the in-tank temperature sensor is equal to or higher than the sterilization temperature, timing is started, when the temperature inside the fermentation tank body monitored by the in-tank temperature sensor is less than the sterilization temperature and equal to or higher than the second temperature, timing is suspended, when the temperature inside the fermentation tank body monitored by the in-tank temperature sensor is less than the second temperature, timing is cleared, and then timing operation is restarted after the temperature inside the fermentation tank body monitored reaches the corresponding temperature requirement until the third temperature continuously maintains the theoretical sterilization time.
12. The fermenter according to claim 10 or 11, wherein in step (iii), after the sterilization is completed, the opening of the compressed air control valve is adjusted to 20-40%, the opening of the sterilization vent gas control valve is fixed to 40-60%, and the second steam control valve and the third steam control valve are closed, respectively; then after 20-40s, adjusting the opening degree of the first steam regulating valve to 80-100%, and then opening and adjusting the opening degree of the disinfection exhaust regulating valve to keep the pressure inside the fermentation tank body at a second pressure;
and reducing the temperature through the cooling mechanism, closing the disinfection exhaust regulating valve when the temperature is reduced to the sixth temperature and maintained, opening the culture exhaust regulating valve, and maintaining the pressure inside the fermentation tank body at the second pressure by adjusting the opening size of the culture exhaust regulating valve.
13. The pharmaceutical fermentation tank of claim 12, wherein the second pressure is 0.01-0.1 MPa; and/or the sixth temperature is 40-50 ℃.
14. The fermentation tank of claim 1, wherein the steam is a supersaturated steam with a temperature of 140 ℃ and 160 ℃; and/or the cooling mechanism adopts process water as a cold source.
15. A fermentation control system comprising a pharmaceutical fermentation tank according to any one of claims 1 to 14.
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