CN114749076A - Biological vaccine intelligent preparation control method and equipment based on microfluidic technology - Google Patents
Biological vaccine intelligent preparation control method and equipment based on microfluidic technology Download PDFInfo
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- CN114749076A CN114749076A CN202210672004.9A CN202210672004A CN114749076A CN 114749076 A CN114749076 A CN 114749076A CN 202210672004 A CN202210672004 A CN 202210672004A CN 114749076 A CN114749076 A CN 114749076A
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Abstract
The invention relates to a biological vaccine intelligent preparation control method and equipment based on a microfluidic technology, wherein an intelligent microfluidic preparation system for biological vaccines is adopted, the preparation system comprises at least two-phase infusion pipelines, at least two microfluidic chips connected in parallel between the infusion pipelines, a main control module, a monitoring module for monitoring flow rate, pressure and temperature, a pump for supplying liquid, a valve for opening and closing the pipelines and a temperature control module for adjusting temperature, and the control method of the production mode of the preparation system comprises the following steps: setting parameters and starting preparation; the monitoring module monitors real-time parameters; the main control module compares the real-time parameters with the set parameters and controls the pump, the valve and the temperature control module to adjust; and stopping preparation when the liquid actually participating in the preparation reaches a set value, and then performing cleaning and stopping operation. The invention can automatically regulate and control the technological parameters in real time in the preparation process, realizes the accurate, efficient and controllable intelligent preparation of the biological vaccine and provides guarantee for industrial linear amplification.
Description
Technical Field
The invention relates to a biological vaccine intelligent preparation control method and equipment based on a microfluidic technology, which are applicable to the technical field of medical biology.
Background
Biological vaccines as preventive drugs for various major diseases are always concerned with human health, and many sudden diseases are usually died along with the successful development of targeted vaccines. Therefore, the development of biological vaccines has been the focus of great importance in the pharmaceutical field. The traditional preparation process of the biological vaccine usually focuses on solving the problem of how to express and efficiently separate and extract protein or nucleic acid, the involved process steps and equipment are very mature, after the protein or nucleic acid is prepared as API, the subsequent preparation link generally only needs to be subjected to conventional adsorption with an adjuvant, and the research on a higher-end drug delivery system (such as Liposome, Lipid Nanoparticle and the like) is not mature. With the marketing of mRNA-LNP vaccines, the high-efficiency prevention effect of the mRNA-LNP vaccines using Lipid Nanoparticles (LNP) as a delivery system is receiving wide social attention. With the rapid development and application of micro-nano preparations such as liposome, lipid nanoparticle, nanocrystal and microsphere, the quality requirements of the market on the preparations are higher and higher. However, the conventional preparation method is usually a batch method, needs multi-step operation, is complicated in process, and is difficult to complete high-quality linear amplification in a short time; the existing preparation process is mostly simple scattered equipment which needs manual operation, is difficult to control and cannot ensure accurate control of fluid; in addition, the existing preparation process and equipment have poor compatibility, and limited preparation conditions are difficult to meet the application working condition of high flow rate production.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention provides a biological vaccine intelligent preparation control method and equipment based on a microfluidic technology. The technical scheme adopted by the invention is as follows: an intelligent preparation control method of biological vaccines based on a microfluidic technology adopts an intelligent microfluidic preparation system for the biological vaccines, the preparation system comprises a preparation unit and a control unit, the preparation unit comprises at least two infusion pipelines for inputting liquid phase, pumps which are the same in number as the infusion pipelines and supply liquid to the infusion pipelines in a one-to-one correspondence manner, at least two microfluidic chips which are connected in parallel between the two infusion pipelines and used for liquid phase mixing, reaction and incubation, and a product outlet which is communicated with the microfluidic chip and used for outputting products. Specifically, the pump is arranged at the input end of the corresponding infusion pipeline, the corresponding stock solution participating in preparation can be conveyed to the infusion pipeline, different stock solutions are conveyed to the microfluidic chip through the infusion pipelines to be mixed and incubated, and the different stock solutions are conveyed to a product outlet from the microfluidic chip to be collected after incubation is completed, so that the production and preparation of the biological vaccine are completed. The microfluidic chip can be arranged in parallel, so that a plurality of chips can be started for production and preparation when the capacity needs to be expanded, and the parallel chips can be started to maintain the production process when a certain microfluidic chip is blocked and damaged.
The control unit comprises a main control module for controlling the operation of the preparation system, a monitoring module for monitoring the flow rate, pressure and temperature of the liquid in each infusion pipeline, a plurality of valves for respectively controlling the on-off of each infusion pipeline and a temperature control module for controlling the temperature of the liquid in each infusion pipeline. Specifically, the upstream and the downstream of each microfluidic chip are provided with valves, so that the microfluidic chips can be conveniently and respectively controlled to be switched between a working state and a standby state. The monitoring module can monitor and collect the flow speed, pressure and temperature parameters of liquid in the infusion pipeline in the vaccine production and preparation process in real time, the main control module automatically analyzes and controls the flow speed, pressure and temperature parameters, and the main control module controls corresponding pumps, valves and temperature control modules in real time according to the collected real-time parameters to perform corresponding adjustment, so that the automation, the accuracy and the controllability of the production and preparation of the biological vaccine are realized. Furthermore, the temperature control module can cool or heat the liquid in the microfluidic chip and the infusion pipeline by arranging the jacket on the microfluidic chip and the infusion pipeline, introducing water flow into the jacket and controlling the temperature of the water.
The preparation system has a production mode in which at least one of the microfluidic chips connected in parallel is in an operating state and at least one is in a standby state, and a control method of the production mode includes:
s1, starting preparation after setting parameters of liquid in each phase of infusion pipeline are respectively set in a preparation system, wherein each phase of infusion pipeline is provided with a group of setting parameters, each group of setting parameters comprises flow rate values V1, V2, V3 and V4 which are sequentially set from small to large corresponding to the phase of infusion pipeline, pressure values P1, P2, P3 and P4 which are sequentially set from small to large corresponding to the phase of infusion pipeline, temperature values C1 and C2 which are sequentially set from small to large corresponding to the phase of infusion pipeline, and a volume value S of the liquid which needs to be conveyed corresponding to the phase of infusion pipeline;
s2, the main control module controls the monitoring module to monitor real-time parameters of liquid in each phase of the infusion pipeline respectively and generate corresponding real-time data, wherein the real-time data comprise real-time flow velocity v, real-time pressure p, real-time temperature c and volume value S of actually conveyed liquid corresponding to each phase of the infusion pipeline;
s3, the main control module compares the real-time data of each phase of infusion pipeline with the set parameters:
if V is not less than V2 and not more than V3, P is not less than P2 and not more than P3, and C is not more than C1, executing step S4;
if V is more than or equal to V1 and less than V2 or V3 and more than V and less than or equal to V4, the main control module controls the corresponding pump to adjust the liquid flow rate in the infusion pipeline, and then the step S3 is executed repeatedly; if V is less than V1 or V is more than V4, the main control module controls the preparation system to stop and gives an alarm;
if P is more than or equal to P1 and less than P2, the main control module compares the real-time flow rate of the corresponding infusion pipeline with the set flow rate: if V is less than V3, the main control module controls the corresponding pump to adjust the liquid flow rate in the infusion pipeline, and then the step S3 is executed repeatedly; if V is larger than or equal to V3, the main control module controls the preparation system to stop and gives an alarm;
if P is more than P3 and less than or equal to P4, the real-time flow rate of the corresponding infusion pipeline is compared with the set flow rate by the main control module: if V is less than or equal to V2, the main control module controls the corresponding valve to be opened so that at least one micro-fluidic chip connected with the infusion pipeline and in a standby state is switched to a working state, and then the step S3 is repeatedly executed; if V is greater than V2, the main control module controls the corresponding pump to adjust the liquid flow rate in the infusion pipeline, and then the step S3 is executed repeatedly;
if P is less than P1 or P is more than P4, the main control module controls the preparation system to stop and gives an alarm;
if C is more than C1 and less than or equal to C2, the main control module controls the temperature control module to adjust the temperature of the liquid in the corresponding infusion pipeline and gives an alarm, and then the step S3 is repeatedly executed; if C is larger than C2, the main control module controls the preparation system to stop and gives an alarm;
s4, the main control module compares the volume value S of the liquid which is actually conveyed with the volume value S of the liquid which is set to be conveyed, if S is less than S, the step S3 is executed; if the delivery pipeline S of any phase is larger than or equal to S, the main control module controls all the pumps to stop delivering liquid, and executes the step S5 after the time t;
and S5, the main control module controls the preparation system to execute the cleaning process and then finishes the preparation.
Furthermore, an integer N is more than or equal to 1, the infusion pipeline has N +1 phases and is divided into N stages, the first stage is provided with two-phase infusion pipelines, the microfluidic chip is divided into N stages, each stage is provided with a group of microfluidic chips, each group is provided with at least two microfluidic chips which are connected in parallel, and the input end of the first stage microfluidic chip is respectively connected with the two-phase first-stage infusion pipelines in a way of being communicated or disconnected through corresponding valves; when N is more than or equal to 2, all the other stages except the first stage of the infusion pipeline are respectively provided with a phase of infusion pipeline, the input end of the nth stage of the microfluidic chip is respectively connected with the output end of the nth-1 stage of the microfluidic chip and the nth stage of the infusion pipeline in a way of being communicated or disconnected through corresponding valves, and N is more than or equal to 2 and less than or equal to N; the output end of each micro-fluidic chip is connected with the product outlet in a connection or disconnection way through a corresponding valve. Specifically, in the vaccine preparation process, the liquid incubated in the upper stage microfluidic chip can be introduced into the lower stage microfluidic chip according to a specific process, and mixed and incubated with the liquid in the other phase of infusion pipeline again, so as to meet the requirements of different preparation processes.
Furthermore, the preparation system also comprises a cleaning module for cleaning and sterilizing the preparation unit and a cleaning outlet which is connected with the product outlet in parallel and used for discharging cleaning water, a conductivity monitoring module is arranged at the upstream of the cleaning outlet, and when the preparation system is cleaned and sterilized, the main control module controls the corresponding valve to open the cleaning outlet and close the product outlet. Specifically, the input intercommunication of clean module and infusion pipeline can let in purified water, injection water, washing liquid and high temperature steam respectively in to the infusion pipeline, conveniently washs and disinfect the preparation unit, realizes aseptic control, microorganism load control and heat source control in the preparation of biological bacterin for whole preparation system satisfies aseptic requirement, avoids appearing the condition that microbiological contamination or endotoxin exceed standard in preparing the production process, ensures that preparation production accomplishes smoothly. The cleaning module can also introduce dry air into the infusion pipeline, so that the preparation unit is convenient to purge, and liquid is prevented from being remained in the pipeline, and bacteria are further bred.
Further, in step S5, the cleaning process specifically includes:
1) cleaning after cleaning parameters are set in the preparation system, wherein the cleaning parameters comprise qualified purified water conductivity G1, qualified injection water conductivity G2, cleaning liquid cleaning time T1 and purging time T2;
2) the main control module controls the cleaning module to introduce purified water into the preparation unit for pre-cleaning, and controls the conductivity monitoring module to monitor the real-time conductivity g1 of the purified water;
3) the main control module compares the real-time conductivity G1 of the purified water with the conductivity G1 of the purified water, if G1 is not more than G1, the step 4) is executed, and if not, the step 3) is repeatedly executed;
4) the main control module controls the cleaning module to stop introducing purified water, and then a cleaning solution is introduced into the preparation unit for cleaning for a duration of T1;
5) after T1 time, the main control module controls the cleaning module to introduce injection water into the preparation unit for flushing, and controls the conductivity monitoring module to monitor the real-time conductivity g2 of the injection water;
6) the main control module compares the real-time conductivity G2 of the injection water with the qualified conductivity G2 of the injection water, if G2 is not more than G2, the step 7) is executed, and if not, the step 6) is repeatedly executed;
7) and the main control module controls the cleaning module to stop introducing the injection water, then performs purging on the preparation unit, and finishes the cleaning process after the duration of T2.
Still further, the preparation system is further provided with a sterilization mode, and the control method of the sterilization mode comprises the following steps:
a. sterilizing is started after sterilization parameters are set in the preparation system, wherein the sterilization parameters comprise: setting a sterilization temperature C3, a lower temperature limit C4, a pressure maintaining temperature C5 and a sterilization time T3;
b. the main control module controls the cleaning module to introduce steam into the preparation unit, and controls the monitoring module to monitor the real-time temperature c1 in the preparation unit;
c. the main control module compares the real-time temperature C1 with the set sterilization temperature C3, and when C1 is more than or equal to C3, the main control module starts to record the actual sterilization time t1 and executes the step d;
d. the main control module compares the real-time temperature C1 with a set lower temperature limit C4, if C1 is not less than C4, step e is executed, otherwise, sterilization is finished and an alarm is given out;
e. the main control module compares the actual sterilization time T1 with the set sterilization time T3, if T1 is more than or equal to T3, step f is executed, otherwise step d is executed;
f. the main control module controls the cleaning module to stop introducing steam, then performs purging on the preparation unit, and controls the monitoring module to monitor the actual pressure maintaining temperature c 2;
g. and the main control module compares the actual pressure maintaining temperature C2 with the set pressure maintaining temperature C5, when C2 is not more than C5, the main control module controls the corresponding valve to close the preparation unit for pressure maintaining, otherwise, the step f is executed.
Further, the preparation system has a normal state and a regulated state when the preparation is performed: if V is not less than V2 and not more than V3, P is not less than P2 and not more than P3, and C is not less than C1, the preparation system is in a normal state, if not, the preparation system is in a regulation state, the preparation system further comprises a waste liquid outlet which is connected in parallel with the product outlet and is used for discharging the product prepared when the preparation system is in the regulation state, when the preparation system starts to prepare, the product outlet is in a closed state, and the waste liquid outlet is in an open state.
Furthermore, in step S3, when the preparation system is switched from the regulation state to the normal state, the main control module controls the corresponding valve to open the product outlet after time t', and closes the waste liquid outlet, so as to ensure that the defective products prepared by the preparation system in the regulation state are discharged completely through the waste liquid outlet, thereby further preventing the defective products from affecting the product quality; when the preparation system is switched to the regulation state from the conventional state, the main control module controls the corresponding valve to close the product outlet after the time t' and open the waste liquid outlet, so that after the collection of the remaining good products in the preparation pipeline is completed, the subsequent defective products are collected through the waste liquid outlet, and the waste is avoided.
The invention also provides a biological vaccine intelligent device which adopts the biological vaccine intelligent preparation control method based on the microfluidic technology.
Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:
according to the intelligent preparation control method and equipment for the biological vaccine based on the microfluidic technology, the intelligent microfluidic preparation system for the biological vaccine is adopted, the preparation process of the LNP carrier of the biological vaccine DDS delivery system is accurate, automatic and controllable, the parameters such as the flow velocity, the temperature and the pressure of each phase fluid in the preparation process can be monitored in real time, and real-time regulation and control are performed, so that the intelligent preparation of the biological vaccine which is accurate, efficient and controllable is realized, the preparation effect is prevented from being influenced by the density and the viscosity difference of different phases, and the problems of error and uncontrollable easily caused by manual operation are also prevented; meanwhile, the restriction of the traditional sectional machining on industrial linear amplification caused by complicated operation and complex process is avoided.
Drawings
Some specific embodiments of the invention will be described in detail hereinafter, by way of illustration and not limitation, with reference to the accompanying drawings. The same reference numbers in the drawings identify the same or similar elements or components. Those skilled in the art will appreciate that the drawings are not necessarily drawn to scale. In the drawings:
FIG. 1 is a process flow diagram of one embodiment of the present invention;
FIG. 2 is a logic control diagram of a production mode in the embodiment of FIG. 1;
FIG. 3 is a logic control diagram of the cleaning process in the embodiment of FIG. 1;
FIG. 4 is a control diagram of the logic for the sterilization mode in the embodiment of FIG. 1;
FIG. 5 is a process flow diagram of another embodiment of the present invention;
wherein the reference numerals are as follows:
1. a liquid delivery pipeline; 2. a product outlet; 3. a monitoring module; 4. cleaning an outlet; 5. a conductivity monitoring module; 6. a waste liquid outlet; 7. and (4) a valve.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the accompanying drawings, and it should be understood that the described embodiments are some, but not all embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
In addition, the technical features involved in the different embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.
Example one
Referring to fig. 1-4, this embodiment provides a method and an apparatus for controlling the intelligent preparation of a biological vaccine based on a microfluidic technology, which employs an intelligent microfluidic preparation system for a biological vaccine, where the preparation system includes a preparation unit and a control unit.
The preparation unit comprises two infusion pipelines 1 used for inputting liquid phase, pumps which are the same in quantity as the infusion pipelines 1 and supply liquid to the infusion pipelines 1 in a one-to-one correspondence mode, at least two micro-fluidic chips which are connected between the two infusion pipelines 1 in parallel and used for liquid phase mixing, reaction and incubation, and a product outlet 2 which is communicated with the micro-fluidic chips and used for outputting products. Specifically, referring to fig. 1, the pump is disposed at the input end of the corresponding infusion pipeline 1, and can deliver the corresponding stock solution participating in preparation to the infusion pipeline 1, and different stock solutions are delivered to the microfluidic chip via the infusion pipelines 1 to be mixed and incubated, and are delivered to the product outlet 2 from the microfluidic chip after incubation is completed for collection, thereby completing production and preparation of the biological vaccine. The microfluidic chips can be arranged in parallel, so that the production preparation can be conveniently carried out by simultaneously starting the chips when the capacity needs to be expanded, and the production process can be conveniently maintained by starting the chips which are connected in parallel when one microfluidic chip is blocked and damaged.
The control unit comprises a main control module for controlling the operation of the preparation system, a monitoring module 3 for monitoring the flow rate, pressure and temperature of the liquid in each infusion pipeline 1, a plurality of valves 7 for respectively controlling the on-off of each infusion pipeline 1 and a temperature control module for controlling the temperature of the liquid in the infusion pipeline 1. Specifically, the upstream and the downstream of each microfluidic chip are provided with valves 7, so that each microfluidic chip can be conveniently and respectively controlled to be switched between a working state and a standby state. Can monitor and gather the velocity of flow, pressure and the temperature parameter of liquid in the infusion pipeline 1 in the vaccine production preparation process in real time through monitoring module 3 to carry out analysis and control by host system is automatic, corresponding adjustment is carried out according to the real-time parameter real time control corresponding pump, valve 7 and the temperature control module of gathering to host system, realizes automation, the accuracy and the controllability of biological vaccine production preparation. Furthermore, the temperature control module can be used for setting a jacket on the microfluidic chip and the infusion pipeline 1, introducing water into the jacket, and cooling or heating the liquid in the microfluidic chip and the infusion pipeline 1 by controlling the water temperature.
The preparation system also comprises a cleaning module for cleaning and sterilizing the preparation unit, a cleaning outlet 4 which is connected with the product outlet 2 in parallel and used for discharging cleaning water, a conductivity monitoring module 5 is arranged at the upstream of the cleaning outlet 4, and when the preparation system is used for cleaning and sterilizing, the main control module controls the corresponding valve 7 to open the cleaning outlet 4 and close the product outlet 2. Specifically, the cleaning module is communicated with the input end of the infusion pipeline 1, purified water, injection water, cleaning fluid and high-temperature steam can be respectively introduced into the infusion pipeline 1, the preparation unit is convenient to clean and sterilize, aseptic control, microbial load control and heat source control in the preparation of the biological vaccine are realized, the whole preparation system meets the aseptic requirement, the condition that bacteria contamination or endotoxin exceeds the standard in the preparation production process is avoided, and the smooth completion of preparation production is ensured. The cleaning module can also be used for introducing dry air into the infusion pipeline 1, so that the preparation unit is convenient to purge, and liquid is prevented from being remained in the pipeline, and bacteria are further bred.
The preparation system has a production mode in which at least one of the microfluidic chips connected in parallel is in an operating state and at least one is in a standby state, and the control method of the production mode includes:
s1, respectively setting set parameters of liquid in each phase of infusion pipeline 1 in a preparation system, and then starting preparation, wherein each phase of infusion pipeline 1 is provided with a group of set parameters, each group of set parameters comprises flow rate values V1, V2, V3 and V4 which are sequentially set from small to large corresponding to the phase of infusion pipeline 1, pressure values P1, P2, P3 and P4 which are sequentially set from small to large corresponding to the phase of infusion pipeline 1, temperature values C1 and C2 which are sequentially set from small to large corresponding to the phase of infusion pipeline 1, and a volume value S of the liquid which needs to be conveyed corresponding to the phase of infusion pipeline 1; V2-V3 and P2-P3 are respectively a normal flow speed range and a normal pressure range, and C1 is a normal temperature upper limit value; v1 and V4, P1 and P4, C2 are respectively a flow rate alarm value, a pressure alarm value and a temperature alarm value;
s2, the master control module controls the monitoring module 3 to monitor real-time parameters of the liquid in each phase of the infusion pipeline 1 and generate corresponding real-time data, wherein the real-time data comprise real-time flow velocity v, real-time pressure p, real-time temperature c and volume value S of the actually conveyed liquid of each phase of the infusion pipeline 1;
s3, the main control module compares the real-time data of each phase of the infusion pipeline 1 with the set parameters:
if V is more than or equal to V2 and less than or equal to V3, P is more than or equal to P2 and less than or equal to P3, and C is less than or equal to C1, executing step S4;
if V is more than or equal to V1 and less than V2 or V is more than V3 and less than or equal to V4, the main control module controls the corresponding pump to adjust the flow rate of the liquid in the infusion pipeline 1, and then the step S3 is executed repeatedly; if V is less than V1 or V is more than V4, the main control module controls the preparation system to stop and gives an alarm; specifically, when the real-time flow rate exceeds the normal range of the flow rate but does not exceed the warning range of the flow rate, the main control module regulates and controls the flow rate on the premise that the real-time pressure and the real-time temperature do not exceed the normal range; when the real-time flow rate exceeds the warning range, the main control module judges that the system is in failure and controls the preparation system to stop and alarm;
if P is more than or equal to P1 and is less than P2, the main control module compares the real-time flow rate of the corresponding infusion pipeline 1 with the set flow rate: if V is less than V3, the main control module controls the corresponding pump to adjust the liquid flow rate in the infusion pipeline 1, and then the step S3 is executed repeatedly; if V is larger than or equal to V3, the main control module controls the preparation system to stop and gives an alarm; specifically, when the real-time pressure is lower than the normal pressure range, the main control module can judge the real-time flow rate, and if the real-time flow rate is lower than the normal upper limit value, the main control module controls the corresponding pump to increase the liquid flow rate within the normal range, so that the real-time pressure is increased; if the real-time flow rate reaches or is higher than the upper limit of the normal flow rate, the main control module judges that the system has a fault and controls the preparation system to stop and alarm;
if P3 is greater than P and less than or equal to P4, the main control module compares the real-time flow rate of the corresponding infusion pipeline 1 with the set flow rate: if V is less than or equal to V2, the main control module controls the corresponding valve 7 to be opened so that at least one micro-fluidic chip connected with the infusion pipeline 1 and in a standby state is switched to a working state, and then the step S3 is repeatedly executed; if V is greater than V2, the main control module controls the corresponding pump to adjust the flow rate of the liquid in the infusion pipeline 1, and then the step S3 is executed repeatedly; specifically, when the real-time pressure is higher than the normal pressure range, the main control module determines the real-time flow rate, and if the real-time flow rate reaches or is lower than the lower limit value of the normal flow rate, the main control module controls the corresponding valve 7 to open the standby chip for shunting and relieving pressure, so that the preparation process is ensured to be carried out smoothly; if the real-time flow rate is higher than the lower limit value of the normal flow rate, the main control module controls the corresponding pump to reduce the liquid flow rate within a normal range, so that the real-time pressure is reduced conveniently;
if P is less than P1 or P is more than P4, the main control module controls the preparation system to stop and gives an alarm; specifically, when the real-time pressure exceeds the pressure warning range, the main control module judges that the system is in fault and controls the preparation system to stop and alarm;
if C is more than C1 and less than or equal to C2, the main control module controls the temperature control module to adjust the temperature of the liquid in the corresponding infusion pipeline 1 and gives an alarm, and then the step S3 is repeatedly executed; if C is larger than C2, the main control module controls the preparation system to stop and gives an alarm; specifically, when the vaccine preparation process does not require, the preparation temperature is usually room temperature, the real-time temperature in the preparation process can be increased along with the increase of the real-time flow rate and the real-time pressure, when the real-time temperature exceeds a normal upper limit value but does not exceed a temperature warning value, the main control module controls the temperature control module to cool through cooling water arranged in the infusion pipeline 1 and a micro-fluidic chip jacket, and when the real-time temperature exceeds the temperature warning value, the main control system judges that the system fails and controls the preparation system to stop alarming;
s4, the main control module compares the volume value S of the liquid which is actually conveyed with the volume value S of the liquid which is set to be conveyed, if S is less than S, the step S3 is executed; if the delivery pipeline S of any phase is larger than or equal to S, the main control module controls all the pumps to stop delivering liquid, and the step S5 is executed after the time t; specifically, the volume value s of the actually delivered liquid = the liquid flow rate x the flow time of the pipeline cross-sectional area x, when the actual volume value s reaches a set volume value, the main control module controls all the pumps to stop delivering the liquid, and waits for time t, so that the residual liquid in the infusion pipeline 1 is conveniently and completely mixed and incubated, and then is output as a product;
and S5, the main control module controls the preparation system to execute the cleaning process and then finishes the preparation.
Further, the cleaning process specifically comprises:
1) cleaning after cleaning parameters are set in the preparation system, wherein the cleaning parameters comprise qualified purified water conductivity G1, qualified injection water conductivity G2, cleaning liquid cleaning time T1 and purging time T2;
2) the main control module controls the cleaning module to introduce purified water into the preparation unit for pre-cleaning, and controls the conductivity monitoring module 5 to monitor the real-time conductivity g1 of the purified water;
3) the main control module compares the real-time conductivity G1 of the purified water with the conductivity G1 of the purified water, if G1 is not more than G1, the step 4) is executed, and if not, the step 3) is repeatedly executed;
4) the main control module controls the cleaning module to stop introducing purified water, and then a cleaning solution is introduced into the preparation unit for cleaning for a time duration of T1;
5) after T1 time, the main control module controls the cleaning module to introduce injection water into the preparation unit for flushing, and controls the conductivity monitoring module 5 to monitor the real-time conductivity g2 of the injection water;
6) the main control module compares the real-time conductivity G2 of the injection water with the qualified conductivity G2 of the injection water, if G2 is not more than G2, step 7) is executed, and if not, step 6) is executed repeatedly;
7) and the main control module controls the cleaning module to stop introducing the injection water, then performs purging on the preparation unit, and finishes the cleaning process after the duration of T2.
The control method is used for monitoring and regulating the flow speed, temperature and pressure parameters of each phase of fluid in real time in the biological vaccine preparation process, so that the precise, efficient and controllable intelligent preparation of the biological vaccine is realized, the LNP carrier preparation process of the biological vaccine DDS delivery system is precise, automatic and controllable, and the restriction of the traditional sectional type manual operation on industrial linear amplification is avoided.
In a more preferred embodiment, the preparation system further has a sterilization mode, and the control method of the sterilization mode includes:
a. sterilizing is started after sterilization parameters are set in the preparation system, wherein the sterilization parameters comprise: setting a sterilization temperature C3, a lower temperature limit C4, a pressure maintaining temperature C5 and a sterilization time T3;
b. the main control module controls the cleaning module to introduce steam into the preparation unit, and controls the monitoring module 3 to monitor the real-time temperature c1 in the preparation unit;
c. the main control module compares the real-time temperature C1 with the set sterilization temperature C3, and when C1 is more than or equal to C3, the main control module starts to record the actual sterilization time t1 and executes the step d;
d. the main control module compares the real-time temperature C1 with a set lower temperature limit C4, if C1 is not less than C4, step e is executed, otherwise, sterilization is finished and an alarm is given out;
e. the main control module compares the actual sterilization time T1 with the set sterilization time T3, if T1 is more than or equal to T3, step f is executed, otherwise step d is executed;
f. the main control module controls the cleaning module to stop introducing steam, then performs purging on the preparation unit, and controls the monitoring module 3 to monitor the actual pressure maintaining temperature c 2;
g. and the main control module compares the actual pressure maintaining temperature C2 with the set pressure maintaining temperature C5, when C2 is not more than C5, the main control module controls the corresponding valve 7 to close the preparation unit for pressure maintaining, otherwise, the step f is executed.
In a more preferred embodiment, the preparation system has a normal state and a regulated state when it is prepared: if V is more than or equal to V2 and less than or equal to V3, P is more than or equal to P2 and less than or equal to P3, and C is less than or equal to C1, the preparation system is in a normal state, and if not, the preparation system is in a regulation state. The preparation system further comprises a waste liquid outlet 6 which is connected with the product outlet 2 in parallel and used for discharging products prepared by the preparation system in a regulation state, when the preparation system starts to prepare, the product outlet 2 is in a closed state, the waste liquid outlet 6 is in an open state, the products prepared when the liquid parameters in the initial preparation stage are unstable can be discharged from the waste liquid outlet 6 and then collected separately, and the influence of defective products prepared in the initial stage on the subsequent quality of good products is prevented.
In a more preferred embodiment, in step S3, when the preparation system is switched from the regulation state to the normal state, the main control module controls the corresponding valve 7 to open the product outlet 2 and close the waste liquid outlet 6 after time t', so as to ensure that the defective products prepared by the preparation system in the regulation state are discharged completely through the waste liquid outlet 6, and further prevent the quality of the products from being affected by the defective products; when the preparation system is switched to the regulation state from the conventional state, the main control module controls the corresponding valve 7 to close the product outlet 2 after time t' and open the waste liquid outlet 6, so that after the collection of the remaining good products in the infusion pipeline 1 is completed, subsequent defective products are collected through the waste liquid outlet 6, and waste is avoided.
Example two
Referring to fig. 5, the difference between the first embodiment and the second embodiment is that the infusion pipeline 1 is more than two phases, assuming that N is an integer greater than or equal to 2, the infusion pipeline 1 has N +1 phases and is divided into N stages, the first stage has the two-phase infusion pipeline 1, and each of the other stages except the first stage infusion pipeline 1 has the one-phase infusion pipeline 1; the micro-fluidic chip is divided into N stages, each stage is provided with a group of micro-fluidic chips, each group is provided with at least two micro-fluidic chips which are connected in parallel, the input end of the first-stage micro-fluidic chip is respectively connected with the two first-stage infusion pipeline 1 in a way of being communicated or disconnected through a corresponding valve 7, the input end of the nth-stage micro-fluidic chip is respectively connected with the output end of the nth-1-stage micro-fluidic chip and the nth-stage infusion pipeline 1 in a way of being communicated or disconnected through a corresponding valve 7, and N is more than or equal to 2 and less than or equal to N. The output of each microfluidic chip is connected to the product outlet 2 via a corresponding valve 7, which can be switched on and off. During preparation, several stages of infusion pipelines and microfluidic chips can be selected according to requirements to participate in preparation.
In the present embodiment, N =2 is taken as an example for explanation. When only the primary infusion pipeline 1 and the micro-fluidic chip are needed to participate in preparation, the valves 7 on the upstream and downstream of the secondary micro-fluidic chip b are closed, and the preparation and control process is the same as that of the first embodiment. When two stages of the transfusion pipelines 1 and the micro-fluidic chips are required to participate in preparation, the corresponding valves 7 are closed to disconnect the first stage micro-fluidic chip a from the product outlet 2, and the corresponding valves 7 are opened to connect the first stage micro-fluidic chip a with the second stage micro-fluidic chip b. Different stock solutions are conveyed to the first-stage micro-fluidic chip a through the first-stage infusion pipeline 1 to be mixed and incubated, then are introduced into the next-stage micro-fluidic chip b, are mixed and incubated with the stock solution in the second-stage infusion pipeline 1 again, and then a product is formed. In the production mode, at least one of the microfluidic chips at the same stage is in an operating state and at least one is in a standby state.
In step S3, if P3 is greater than or equal to P4 and V is greater than or equal to V2, the main control module controls the corresponding valve 7 to open so as to switch at least one of the micro-fluidic chips connected to the infusion pipeline 1 in the standby state to the operating state, that is, at least one of the micro-fluidic chips in the same stage as the infusion pipeline 1 in the standby state to the operating state, and then step S3 is repeatedly executed.
The invention also provides a biological vaccine intelligent device which adopts the biological vaccine intelligent preparation control method based on the microfluidic technology.
Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:
according to the intelligent preparation control method and equipment for the biological vaccine based on the microfluidic technology, the intelligent microfluidic preparation system for the biological vaccine is adopted, the LNP carrier preparation process of the biological vaccine DDS delivery system is accurate, automatic and controllable, parameters such as flow speed, temperature and pressure of each phase fluid in the preparation process can be monitored in real time, real-time regulation and control are performed, the intelligent preparation of the precise, efficient and controllable biological vaccine is realized, the preparation effect is prevented from being influenced due to density and viscosity difference of different phases, and the problems of error and uncontrollable which are easily generated by manual operation are also prevented; meanwhile, the restriction of the complicated operation and the complicated process of the traditional sectional machining on the linear amplification of the industry is avoided.
The above embodiments are merely illustrative of the technical concept and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the content of the present invention and implement the invention, and not to limit the scope of the invention, and all equivalent changes or modifications made according to the spirit of the present invention should be covered by the scope of the present invention.
Claims (8)
1. The method is characterized in that an intelligent micro-fluidic preparation system for biological vaccines is adopted, the preparation system comprises a preparation unit and a control unit, the preparation unit comprises at least two infusion pipelines (1) used for inputting liquid phases, pumps which are the same in quantity as the infusion pipelines (1) and supply liquid to the infusion pipelines (1) in a one-to-one correspondence manner, at least two micro-fluidic chips which are connected in parallel between the two infusion pipelines (1) and used for mixing, reacting and incubating liquid phases, and a product outlet (2) which is communicated with the micro-fluidic chip and used for outputting products, the control unit comprises a main control module used for controlling the operation of the preparation system, a monitoring module (3) used for monitoring the flow rate, pressure and temperature of the liquid in each infusion pipeline (1), The temperature control module is used for controlling the temperature of liquid in each infusion pipeline (1); when the micro-fluidic chip is communicated with the infusion pipeline (1), the micro-fluidic chip is in a working state, and when the micro-fluidic chip is disconnected from the infusion pipeline (1), the micro-fluidic chip is in a standby state;
the preparation system is provided with a production mode, in which at least one of the microfluidic chips connected in parallel is in a working state and at least one of the microfluidic chips is in a standby state, and the control method of the production mode comprises the following steps:
s1, setting parameters of liquid in each phase of the infusion pipeline (1) in the preparation system respectively, and then starting preparation, wherein each phase of the infusion pipeline (1) has a set of setting parameters, each set of setting parameters comprises flow rate values V1, V2, V3 and V4 which are set from small to large corresponding to the phase of the infusion pipeline (1), pressure values P1, P2, P3 and P4 which are set from small to large corresponding to the phase of the infusion pipeline (1), temperature values C1 and C2 which are set from small to large corresponding to the phase of the infusion pipeline (1), and a volume value S of the liquid to be conveyed corresponding to the phase of the infusion pipeline (1);
s2, the main control module controls the monitoring module (3) to monitor real-time parameters of liquid in each phase of the infusion pipeline (1) respectively and generate corresponding real-time data, and the real-time data comprise real-time flow velocity v, real-time pressure p, real-time temperature c and volume value S of actually conveyed liquid of each phase of the infusion pipeline (1);
s3, the main control module compares the real-time data of each phase of the infusion pipeline (1) with the set parameters:
if V is not less than V2 and not more than V3, P is not less than P2 and not more than P3, and C is not more than C1, executing step S4;
if V is greater than or equal to V1 and less than V2 or V3 and less than or equal to V4, the main control module controls the corresponding pump to adjust the liquid flow rate in the infusion pipeline (1), and then the step S3 is repeatedly executed; if V is less than V1 or V is more than V4, the main control module controls the preparation system to stop and gives an alarm;
if P is not less than P1 and is less than P2, the real-time flow rate of the corresponding infusion pipeline (1) is compared with a set flow rate by the main control module: if V is less than V3, the main control module controls the corresponding pump to adjust the liquid flow rate in the infusion pipeline (1), and then the step S3 is repeatedly executed; if V is larger than or equal to V3, the main control module controls the preparation system to stop and gives an alarm;
if P3 is more than or equal to P4, the real-time flow rate of the corresponding infusion pipeline (1) is compared with a set flow rate by the main control module: if V is less than or equal to V2, the main control module controls the corresponding valve (7) to be opened so that at least one micro-fluidic chip connected with the infusion pipeline (1) and in a standby state is switched to a working state, and then the step S3 is repeatedly executed; if V is greater than V2, the main control module controls the corresponding pump to adjust the liquid flow rate in the infusion pipeline (1), and then the step S3 is repeatedly executed;
if P is less than P1 or P is more than P4, the main control module controls the preparation system to stop and gives an alarm;
if C is more than C1 and less than or equal to C2, the main control module controls the temperature control module to adjust the temperature of the liquid in the corresponding infusion pipeline (1) and gives an alarm, and then the step S3 is repeatedly executed; if C is larger than C2, the main control module controls the preparation system to stop and gives an alarm;
s4, the main control module compares the volume value S of the liquid which is actually conveyed with the volume value S of the liquid which is set to be conveyed, if S is less than S, the step S3 is executed; if the delivery pipeline S of any phase is larger than or equal to S, the main control module controls all the pumps to stop delivering liquid, and executes the step S5 after the time t;
and S5, the main control module controls the preparation system to execute the cleaning process and then finishes the preparation.
2. The intelligent preparation control method of biological vaccine based on micro-fluidic technology according to claim 1, characterized in that, the integer N is more than or equal to 1, the infusion pipeline (1) has N +1 phases and is divided into N stages, the first stage has two-phase infusion pipeline (1), the micro-fluidic chip is divided into N stages, each stage has a group of the micro-fluidic chips, each group has at least two parallel micro-fluidic chips, the input end of the micro-fluidic chip of the first stage is connected with the two-phase first stage infusion pipeline through the corresponding valve (7) in a way of connection or disconnection; when N is more than or equal to 2, the other stages except the first stage of the transfusion pipeline (1) are respectively provided with a phase of the transfusion pipeline (1), the input end of the nth stage of the microfluidic chip is respectively connected with the output end of the nth-1 stage of the microfluidic chip and the nth stage of the transfusion pipeline (1) in a way of being communicated or disconnected through the corresponding valve (7), and N is more than or equal to 2 and less than or equal to N; the output end of each microfluidic chip is connected with the product outlet (2) through the corresponding valve (7) in a connection or disconnection mode.
3. The intelligent preparation control method of biological vaccines based on microfluidic technology according to claim 1, wherein the preparation system further comprises a cleaning module for cleaning and sterilizing the preparation unit, a cleaning outlet (4) connected in parallel with the product outlet (2) and used for discharging cleaning water, a conductivity monitoring module (5) is arranged upstream of the cleaning outlet (4), and when the preparation system is cleaning and sterilizing, the main control module controls the corresponding valve (7) to open the cleaning outlet (4) and close the product outlet (2).
4. The intelligent preparation control method of biological vaccines based on microfluidic technology as claimed in claim 3, wherein in step S5, the cleaning process specifically comprises:
1) cleaning after cleaning parameters are set in the preparation system, wherein the cleaning parameters comprise qualified conductivity G1 of purified water, qualified conductivity G2 of injection water, cleaning time T1 of cleaning liquid and purging time T2;
2) the main control module controls the cleaning module to introduce purified water into the preparation unit for pre-cleaning, and controls the conductivity monitoring module (5) to monitor the real-time conductivity g1 of the purified water;
3) the main control module compares the real-time conductivity G1 of the purified water with the conductivity G1 of the purified water, if G1 is not more than G1, the step 4) is executed, and if not, the step 3) is repeatedly executed;
4) the main control module controls the cleaning module to stop introducing purified water, and then a cleaning solution is introduced into the preparation unit for cleaning for a time T1;
5) after T1 time, the main control module controls the cleaning module to introduce injection water into the preparation unit for flushing, and controls the conductivity monitoring module (5) to monitor the real-time conductivity g2 of the injection water;
6) the main control module compares the real-time conductivity G2 of the injection water with the qualified conductivity G2 of the injection water, if G2 is not more than G2, the step 7) is executed, and if not, the step 6) is repeatedly executed;
7) and the main control module controls the cleaning module to stop introducing the injection water, then purges the preparation unit, and finishes the cleaning process after the duration of time T2.
5. The intelligent preparation control method of biological vaccines based on microfluidic technology as claimed in claim 3, wherein the preparation system further has a sterilization mode, and the control method of the sterilization mode comprises:
a. initiating sterilization after setting sterilization parameters in the preparation system, the sterilization parameters comprising: setting a sterilization temperature C3, a lower temperature limit C4, a pressure maintaining temperature C5 and a sterilization time T3;
b. the main control module controls the cleaning module to introduce steam into the preparation unit, and controls the monitoring module (3) to monitor the real-time temperature c1 in the preparation unit;
c. the main control module compares the real-time temperature C1 with a set sterilization temperature C3, and when C1 is more than or equal to C3, the main control module starts to record the actual sterilization time t1 and executes the step d;
d. the main control module compares the real-time temperature C1 with a set lower temperature limit C4, if C1 is not less than C4, step e is executed, otherwise, sterilization is finished and an alarm is given out;
e. the main control module compares the actual sterilization time T1 with the set sterilization time T3, if T1 is more than or equal to T3, step f is executed, otherwise step d is executed;
f. the main control module controls the cleaning module to stop introducing steam, then performs purging on the preparation unit, and controls the monitoring module (3) to monitor the actual pressure maintaining temperature c 2;
g. and the main control module compares the actual pressure maintaining temperature C2 with the set pressure maintaining temperature C5, when C2 is not more than C5, the main control module controls the corresponding valve (7) to close the preparation unit for pressure maintaining, otherwise, the step f is executed.
6. The intelligent preparation control method of biological vaccines based on microfluidic technology as claimed in claim 1, wherein the preparation system has a normal state and a regulation state when being prepared: if V is more than or equal to V2 and is less than or equal to V3, P is more than or equal to P2 and is less than or equal to P3, and C is less than or equal to C1, the preparation system is in a normal state, if not, the preparation system is in a regulation state, the preparation system further comprises a waste liquid outlet (6) which is connected with the product outlet (2) in parallel and used for discharging products prepared when the preparation system is in the regulation state, when the preparation system starts to prepare, the product outlet (2) is in a closed state, and the waste liquid outlet (6) is in an open state.
7. The intelligent preparation control method of biological vaccines based on microfluidic technology as claimed in claim 6, wherein in step S3, when the preparation system is switched from the regulation state to the normal state, the main control module controls the corresponding valve (7) to open the product outlet (2) and close the waste liquid outlet (6) after time t'; when the preparation system is switched from the conventional state to the regulation state, the main control module controls the corresponding valve (7) to close the product outlet (2) and open the waste liquid outlet (6) after time t'.
8. An intelligent preparation device of biological vaccines, which is characterized in that the intelligent preparation control method of biological vaccines based on the microfluidic technology of any one of claims 1 to 7 is adopted.
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