Online traceability method and system for multi-parameter magnitude of synthetic bioreactor

Abstract

The invention discloses a synthetic bioreactor multi-parameter magnitude online traceability method and system, and belongs to the field of biological process control. The core of the method is that working and standard double measurement channels are configured for key parameters of a reactor, deviation is calculated in real time by synchronously comparing data of the working and standard double measurement channels, and a working measurement value is corrected accordingly; meanwhile, monitoring deviation to carry out credibility early warning; and finally, precise process control is realized based on the corrected high-credibility true value. The system correspondingly comprises paired sensor groups and an intelligent processing control unit. According to the method, the metering calibration process is online and normalized, the problems of measurement misalignment and control precision reduction caused by sensor drift are effectively solved, and the stability of the synthetic biological fermentation process, the consistency of product quality and the production intelligence level are remarkably improved.

Description

Technical Field

[0001] This invention relates to the field of bioprocess control and metrology, and in particular to a method and system for real-time measurement, online calibration and data correction of multiple parameters in a synthetic bioreactor. Background Technology

[0002] In synthetic biotechnology manufacturing, such as the fermentation production of succinic acid using genetically engineered bacteria, the accurate measurement of key process parameters within the bioreactor, such as temperature, pH, and dissolved oxygen, is fundamental to ensuring stable product yield and quality. Currently, industrial applications rely on single online sensors for monitoring and control. However, these sensors are prone to performance drift and inaccuracy in the long-term, complex fermentation environment, causing measured values ​​to deviate from the true values. Existing technologies primarily rely on periodic shutdowns and offline testing for sensor calibration, which fails to address the reliability of real-time data during production and cannot promptly detect and correct drift, becoming a key bottleneck affecting process controllability and product quality consistency. Therefore, there is an urgent need for a technology that enables uninterrupted online traceability, calibration, and verification of measured values ​​during normal reactor operation. Summary of the Invention

[0003] The purpose of this invention is to provide a method and system for online traceability of multiple parameters in synthetic bioreactors, so as to solve the problems mentioned in the background art.

[0004] To achieve the above objectives, the present invention provides the following technical solution: The present invention aims to solve the problems in existing synthetic bioreactor monitoring technology, such as inaccurate measurement of process parameters, decreased control accuracy, product quality fluctuations, and poor data reliability caused by the inability to obtain and correct sensor online drift in real time.

[0005] To solve the above-mentioned technical problems, the present invention provides the following technical solution: In a first aspect, a method for online traceability of multiple parameters in a synthetic bioreactor is characterized by comprising the following steps: S1. Dual-channel synchronous measurement: During reactor operation, two independent measurement channels are activated simultaneously for each key process parameter to be monitored: the first channel is the working measurement channel, which acquires the real-time measurement value of the process parameter through a working sensor that is permanently installed on the reactor; the second channel is the standard reference channel, which synchronously acquires the reference standard value of the parameter through a standard sensor that is directly related to the parameter being measured and has higher measurement accuracy or known metrological characteristics; the key process parameters include at least fermentation broth temperature, pH value, and dissolved oxygen concentration; S2. Online error calculation and real-time correction: Calculate the deviation between the real-time measured value and the reference standard value of the same parameter in real time; based on the deviation value, perform mathematical compensation on the real-time measured value to generate the corrected true value for process control; S3. Dynamic verification of measurement reliability: Set a deviation alarm threshold for each parameter; continuously monitor the deviation value, and if its absolute value exceeds the corresponding alarm threshold, automatically trigger an early warning signal to indicate that the measurement reliability of the corresponding working sensor has exceeded the acceptable range; S4. Closed-loop control based on reliable data: The corrected true value is used as a feedback signal and input to the reactor's process control system (such as PLC or DCS) to drive the actuators (such as heat exchange units, acid and alkali pumps, and venting valves) to make adjustments, thereby achieving precise and stable control of process conditions.

[0006] Secondly, a multi-parameter online traceability system for synthetic bioreactors implementing the above method is characterized by comprising: Dual-channel sensing unit: Consists of paired sensor groups, each group including a working sensor and a standard sensor that measures the same physical or chemical quantity; the standard sensor is superior to the working sensor in terms of accuracy, stability, or traceability chain. Integrated calibration access unit: provides an online, process-interrupted access point for the standard sensor. This unit can be a calibration interface with a sealed valve reserved in the reactor body, a bypass circulation system connected in parallel with the main process pipeline, or a multi-way valve group that can realize automatic sensor switching. Intelligent processing and control unit: electrically connected to the dual-channel sensing unit, its built-in processor is configured to perform the following functions: a) Synchronously acquire and receive signals from the working sensor and the standard sensor; b) Calculate the deviation and apply the correction algorithm to output the corrected true value; c) Compare deviations with thresholds and manage early warning outputs; d) Send the corrected truth value to the downstream controller or generate control commands directly.

[0007] Compared with the prior art, the beneficial effects of the present invention are: By making the principle of "standard comparison" in metrology online and routine, production process data has real-time traceability, which fundamentally ensures the accuracy and reliability of the data.

[0008] Control based on real-time calibrated true values ​​eliminates the influence of sensor latent errors on the control loop, enabling the reactor to operate stably within the optimal process window for a long period, significantly improving the yield and quality consistency of target products (such as succinic acid).

[0009] By transforming "regular preventive maintenance" into "condition predictive maintenance," the system can diagnose the health status of sensors on its own, provide timely warnings, avoid unplanned production stoppages and losses caused by instrument failures, and reduce operation and maintenance costs.

[0010] By ensuring the accuracy and reliability of measurement and control, batch adjustments, rework, or product downgrades caused by parameter fluctuations are reduced, thereby improving the overall operational efficiency and economic benefits of the production line.

[0011] The system automatically generates and saves complete records of measurement values, standard values, deviations, and corrections, providing objective and continuous electronic evidence for production process validation and compliance with regulations such as Good Manufacturing Practices (GMP). Attached Figure Description

[0012] Figure 1 This is a schematic diagram of the fermenter structure of the present invention. Detailed Implementation

[0013] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be described in a non-limiting detail below with reference to specific and most preferred embodiments. For example... Figure 1 As shown, this embodiment uses the fermentation process of Escherichia coli that produces succinic acid as the application scenario.

[0014] System Construction: This invention was implemented on a standard 50L stainless steel fermenter. A dual-channel sensing unit was constructed for the three most critical parameters (temperature, pH, and dissolved oxygen): For temperature: the working sensor is an installed Class A platinum resistance thermometer (PT100); the standard sensor is a high-precision PT100 of the same model that is inserted through the sanitary quick-connect calibration port reserved on the top of the tank and is within the calibration period. Its probe and the working probe are placed at different depths in the same temperature measuring sleeve to ensure that they sense the same temperature field.

[0015] For pH values: the working sensor is a conventional composite pH electrode; the standard sensor is a laboratory-grade high-precision pH electrode installed with a dedicated insert-type sealing kit, with the sensing parts of both electrodes located at the same radial position above the stir bar.

[0016] For dissolved oxygen (DO): the working sensor is the original polarographic dissolved oxygen probe; the standard sensor is a high-precision dissolved oxygen meter probe that uses the optical fluorescence principle and is installed through another independent interface.

[0017] All standard sensor signal lines are connected to a dedicated data acquisition module, which is synchronized with the existing distributed control system (DCS) input module that connects to the working sensors via a precise clock to ensure the simultaneity of data acquisition.

[0018] The intelligent processing and control unit is implemented by an industrial computer (ICC). Customized software runs within the ICC, which reads the "real-time measurement values" of the working sensors from the DCS via the OPC protocol, and simultaneously reads the "reference standard values" of the standard sensors from a dedicated acquisition module.

[0019] Workflow (corresponding methods and steps): Dual-channel synchronous measurement (S1): After fermentation starts, the software synchronously acquires the "real-time measurement value" (such as pH_work) and "reference standard value" (such as pH_std) of three sets of parameters at a frequency of once per second.

[0020] Online error calculation and real-time correction (S2): The software calculates the deviation ΔpH = pH_work - pH_std in real time. Assuming that at a certain moment pH_work = 7.12 and pH_std = 7.05, then ΔpH = +0.07. The correction algorithm uses direct compensation: the corrected true value pH_true = pH_work - ΔpH = 7.05. This pH_true value is updated in real time to the DCS control loop database, replacing the original pH_work value.

[0021] Dynamic verification of measurement reliability (S3): The system presets the pH deviation alarm threshold to ±0.1. If |ΔpH|>0.1 for 5 consecutive sampling cycles, the industrial control computer will send an audible and visual alarm message to the central control room: "pH working electrode deviation exceeds the limit, verification recommended", and the abnormal time period will be highlighted in the trend graph.

[0022] Closed-loop control based on reliable data (S4): The DCS PID controller uses pH_true=7.05 as the current feedback value, compares it with the set value of 7.0, calculates the control quantity to drive the ammonia water addition pump, and thus accurately maintains the pH of the fermentation broth near the set point.

[0023] Effect verification: To verify the effectiveness of this invention, comparative experiments were conducted using the same bacterial strain, culture medium, and process formulation: Control group: Traditional single-sensor monitoring and control were used.

[0024] Experimental group: The dual-channel online traceability system of this invention was used.

[0025] The experimental results show that: Process stability: Throughout the fermentation process, the fluctuation range (standard deviation) of the temperature, pH, and DO used for control in the experimental group was reduced by more than 60% on average compared with the control group.

[0026] Product quality: The relative standard deviation (RSD) of the concentration of the succinic acid product finally obtained in the experimental group decreased from 5.2% in the control group to 1.8%, and the purity consistency was significantly improved.

[0027] Operational efficiency: The experimental group, through system alerts, detected and replaced a slowly drifting pH working electrode during the 15th batch of fermentation, avoiding a potential batch reduction due to control inaccuracies. In contrast, the control group experienced a decrease in product yield of approximately 10% in two batches within the same period due to undetected sensor drift.

[0028] The above embodiments fully demonstrate that the method and system described in this invention can effectively solve the problem of online sensor drift, achieve real-time self-calibration of parameters and data reliability assurance, and ultimately achieve the invention objective of improving the robustness of synthetic bio-fermentation processes and product quality.

Claims

1. A method for online traceability of multiple parameters in a synthetic bioreactor, characterized in that, Includes the following steps: Simultaneously acquire working sensor measurements and higher-precision standard sensor reference values ​​for the same process parameters; The deviation between the two is calculated in real time, and the measured value of the working sensor is corrected based on the deviation to obtain the corrected true value; Monitor whether the deviation exceeds the limit, and issue an early warning when the limit is exceeded; The reactor process is controlled based on the corrected true value.

2. The method according to claim 1, characterized in that: The process parameters include at least two of the following: fermentation broth temperature, pH value, and dissolved oxygen concentration.

3. The method according to claim 1, characterized in that: The correction is to subtract the deviation value from the measured value of the working sensor.

4. The method according to claim 1, characterized in that: The standard sensor is connected and measured online through a calibration interface on the reactor body, a parallel process bypass, or an automatic switching valve.

5. An online traceability system for multiple parameters of a synthetic bioreactor, used to implement the method described in any one of claims 1-4, characterized in that, include: Multiple sets of paired sensors, each set containing a working sensor and a standard sensor that measures the same parameter; A processing control unit is used to synchronously receive signals from sensor pairs, calculate deviations and make corrections, manage early warnings, and output control commands based on the corrected true values.

6. The system according to claim 5, characterized in that: The processing control unit is also used to record and analyze historical data of the deviation in order to assess the trend of sensor performance changes.

7. The application of the system according to claim 5 or 6 in the fermentation of genetically engineered bacteria to prepare organic acids.

8. The application according to claim 7, characterized in that: The genetically engineered bacteria is *Escherichia coli* that produces succinic acid, and the organic acid is succinic acid.

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