An online combined dilution dispensing method

Abstract

This invention relates to the field of biopharmaceutical technology and discloses an online combined dilution preparation method. The method includes: preparing multiple high-concentration mother liquors; using multiple independent pumps to extract corresponding high-concentration mother liquors according to preset initial flow rates, and delivering the extracted high-concentration mother liquors to a mixing device for online mixing and dilution to form an initial process solution; real-time monitoring of the physicochemical parameters of the initial process solution, the physicochemical parameters including at least pH and conductivity; comparing the real-time monitored physicochemical parameters with preset parameter ranges; and automatically adjusting the flow rate of at least one independent pump when the physicochemical parameters deviate from the preset parameter ranges to obtain the target process solution. This invention, through the above technical solution, solves the technical problems of high equipment dependence, large space occupation, long process cycles, and complex cleaning validation in related technologies.

Description

Technical Field

[0001] This invention relates to the field of biopharmaceutical technology and discloses an online combined dilution preparation method. Background Technology

[0002] Online combination dilution and solution preparation is a crucial step in biopharmaceutical processes, used to provide compliant process solutions for unit operations such as cation chromatography. In the production of biopharmaceuticals such as monoclonal antibodies, polyclonal antibodies, and fusion proteins, large quantities of various process solutions, including equilibration buffers, elution buffers, and preservation solutions, are required. The pH value, conductivity, and other parameters of these solutions directly affect the chromatographic separation effect and product quality.

[0003] Currently, existing solutions preparation methods typically employ traditional manual batch processing, which suffers from long process cycles and difficulty in achieving real-time monitoring and precise control, making it difficult to guarantee the accuracy and compliance of solution preparation. Summary of the Invention

[0004] In view of this, this application provides an online combined dilution and preparation method to achieve efficient, accurate, and controllable continuous preparation, solving the technical problems of high equipment dependence, large space occupation, long process cycle, and difficulty in guaranteeing preparation accuracy and compliance in the prior art.

[0005] To solve the above problems, the present invention adopts the following technical solution: An online combined dilution preparation method, comprising: Prepare multiple high-concentration mother liquors; Multiple independent pumps are used to extract high-concentration mother liquor according to a preset initial flow rate ratio, and the extracted high-concentration mother liquor is transported to a mixing device for online mixing and dilution to form an initial process solution. Real-time monitoring of the physicochemical parameters of the initial process solution, including at least pH and conductivity; The real-time monitored physicochemical parameters are compared with the preset parameter range; When the physicochemical parameters deviate from the preset parameter range, the flow rate of at least one independent pump is automatically adjusted to obtain the target process solution.

[0006] Optionally, multiple independent pumps include pump A1, pump B1, pump B2, pump B3, pump C1, and pump D1; High-concentration mother liquors include acidic, alkaline, and neutral mother liquors; acidic mother liquors include 0.3M citric acid solution; alkaline mother liquors include 2.5M sodium hydroxide solution, 0.1M sodium hydroxide solution, and 0.3M sodium citrate solution; neutral mother liquors include WFI water for injection and 3M sodium chloride solution. Pumps A1 and D1 are neutral pumps, corresponding to WFI water for injection and 3M sodium chloride solution, respectively; pumps B1, B2, and B3 are alkaline pumps, corresponding to 2.5M sodium hydroxide solution, 0.1M sodium hydroxide solution, and 0.3M sodium citrate solution, respectively; and pump C1 is an acidic pump, corresponding to 0.3M citric acid solution.

[0007] Optionally, the target process solution includes at least a 0.5M sodium hydroxide solution, a cation balance solution, a cation eluent, a 0.01M sodium hydroxide solution, and a 0.1M sodium hydroxide solution.

[0008] Optionally, when preparing a 0.5M sodium hydroxide solution, the preset initial flow rate ratio is: 80% for pump A1 and 20% for pump B2. When preparing the cation balance solution, the preset initial flow rate ratio is: A1 pump 93.33%, B2 pump 3.95%, C1 pump 2.72%; When preparing the cation eluent, the preset initial flow rate ratio is: A1 pump 87.69%, B1 pump 4.58%, C1 pump 2.09%, and D1 pump 5.64%. When preparing a 0.01M sodium hydroxide solution, the preset initial flow rate ratio is: 90% for pump A1 and 10% for pump B3. When preparing a 0.1M sodium hydroxide solution, the preset initial flow rate ratio is: 96% for pump A1 and 4% for pump B2.

[0009] Optionally, when the physicochemical parameters deviate from the preset parameter range, the flow rate of at least one independent pump is automatically adjusted, including: When the initial process solution pH value is higher than the upper limit of the preset range, the feed rate of the acid pump is increased. And / or, when the initial process solution pH value is lower than the preset lower limit, the alkaline pump delivery flow rate is increased as a feedback mechanism.

[0010] Optional, also includes: When the conductivity of the initial process solution deviates from the preset range, the flow rate of the salt solution pump is automatically adjusted. Specifically, when the conductivity value deviates from the preset range due to adjusting the flow rate of the acid pump or the alkaline pump, the adjustment of the acid pump or the alkaline pump is paused, and the flow rate of the pump delivering the salt solution is adjusted first, until the conductivity value returns to the preset range.

[0011] Optionally, the salt solution pump is a D1 pump.

[0012] Optionally, the flow rate of the acid or alkaline pump can be increased by feedback and adjusted in preset steps. After each adjustment, a preset time is waited before monitoring is performed again until the pH value returns to the preset range or the preset number of adjustments is reached.

[0013] Optional, automatic flow rate adjustment of the brine solution pump includes: When the conductivity value is higher than the upper limit of the preset range, reduce the flow rate of pump D1; And / or, when the conductivity value is below the lower limit of the preset range, increase the flow rate of pump D1.

[0014] Optionally, a process solution switching step may also be included: When it is necessary to switch from the current target process solution to another target process solution, shut down all pumps for the current formulation and turn on pump A1 to flush the pipeline. The conductivity value of the fluid in the pipeline is monitored in real time. When the conductivity value drops below the preset threshold, the pipeline is determined to be emptied. The corresponding pump is started according to the preset initial flow rate ratio of another target process solution. After the real-time monitored physicochemical parameters reach the preset range, the target process solution is obtained.

[0015] In summary, due to the adoption of the above technical solutions, the beneficial effects of the present invention include at least the following: By replacing traditional large-scale dispensing and storage tanks with online mixing and dilution, the equipment investment cost is significantly reduced, and the space occupied in cleanrooms is minimized, solving the problems of high equipment dependence and large space occupation in existing technologies. Simultaneously, the on-demand online preparation mode eliminates the need for solution preparation several days in advance, removing transfer waiting time and significantly shortening the process cycle, thus solving the problem of long process cycles in existing technologies. Furthermore, by using online sensors to monitor pH and conductivity values ​​in real time and combining this with automatic feedback adjustment, the physicochemical parameters of the output solution are ensured to remain stable within the preset range, solving the problem of difficulty in guaranteeing dispensing accuracy in existing technologies. In addition, the entire process automatically records monitoring data and adjustment events, achieving complete data traceability and meeting compliance requirements, thus solving the problem of difficulty in guaranteeing compliance in existing technologies. Attached Figure Description

[0016] To more clearly illustrate the technical solutions in the embodiments of this application or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only embodiments of this application. For those skilled in the art, other drawings can be obtained based on the provided drawings without creative effort.

[0017] Figure 1 The present invention provides a method flowchart. Detailed Implementation

[0018] The technical solutions of the embodiments of this application will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of this application, and not all embodiments. Based on the embodiments of this application, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this application.

[0019] In this application, relational terms such as "first" and "second" are used merely to distinguish one entity or operation from another, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Furthermore, the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, article, or apparatus. Without further limitation, an element defined by the phrase "comprising one..." does not exclude the presence of other identical elements in the process, method, article, or apparatus that includes the element.

[0020] As can be seen from the background technology above, common solution preparation methods mostly adopt the traditional manual batch mode, that is, the process solution is prepared in advance in a large preparation tank according to the target volume and concentration, stored in a storage tank after passing the test, and then transported to the point of use via a transfer tank when needed. However, this solution preparation method has the following technical problems: First, there are many types of process solutions, and the preparation, testing, sterilization and storage need to be completed several days or even 1-2 weeks in advance. The transfer process can also introduce additional waiting time, resulting in a long process cycle; Second, there are many manual operation steps, and the data relies on paper records or manual entry, which cannot guarantee real-time monitoring and accurate control, and is prone to solution preparation accuracy problems, resulting in relatively high compliance risks.

[0021] Therefore, how to design an online solution preparation method that can realize the instant preparation of process solutions, monitor and precisely control solution parameters in real time, and have automatic data recording and traceability functions has become a technical problem that urgently needs to be solved in this field.

[0022] The following is in conjunction with the appendix Figure 1 The online combination dilution preparation method provided in this application will be described in detail through specific embodiments and application scenarios.

[0023] like Figure 1 As shown, this application provides an online combined dilution and preparation method, which includes the following steps: Prepare multiple high-concentration mother liquors. Specifically, prepare multiple high-concentration mother liquors in advance according to process requirements. The concentration of the high-concentration mother liquors is much higher than that of the target process solution, so that the required working concentration can be obtained through online dilution.

[0024] Multiple independent pumps extract corresponding high-concentration mother liquors according to preset initial flow rates, and then deliver the extracted high-concentration mother liquors to a mixing device for online mixing and dilution to form an initial process solution. Specifically, each independent pump starts simultaneously according to the formula of the target process solution and a preset initial flow rate ratio, delivering its extracted high-concentration mother liquors to the mixing device for rapid mixing and dilution during the flow process.

[0025] The physicochemical parameters of the initial process solution are monitored in real time, including at least pH and conductivity. Specifically, an online pH meter and conductivity meter are installed downstream of the mixing device to collect the pH and conductivity values ​​of the mixed and diluted fluid in real time, and the monitoring data is transmitted to the control system in real time.

[0026] The system compares the real-time monitored physicochemical parameters with preset parameter ranges. Specifically, the control system pre-stores the parameter ranges for each target process solution, and compares the real-time monitored pH and conductivity values ​​with the corresponding preset ranges.

[0027] When the physicochemical parameters deviate from the preset parameter range, the flow rate of at least one independent pump is automatically adjusted to obtain the target process solution. Specifically, if the monitored value is within the preset range, no adjustment is required, and the target process solution is directly output; if the monitored value deviates from the preset range, the feedback adjustment mechanism is triggered to adjust the flow rate of the corresponding pump, so that the physicochemical parameters return to the preset range.

[0028] Through the closed-loop control of online mixing and dilution with real-time feedback adjustment described above, this application transforms the traditional manual batch solution preparation mode into a continuous and automated online solution preparation mode. Online mixing and dilution replaces large solution preparation tanks and storage tanks, significantly reducing equipment investment costs and cleanroom space occupation; the on-demand preparation method eliminates the need to prepare solutions several days in advance, eliminating transfer waiting time and significantly shortening the process cycle; real-time monitoring and automatic feedback adjustment solve the problems of large errors in manual operation and difficulty in ensuring solution preparation accuracy; the entire process automatically records monitoring data and adjustment events, achieving complete data traceability and meeting compliance requirements.

[0029] In some embodiments, the plurality of independent pumps includes pump A1, pump B1, pump B2, pump B3, pump C1, and pump D1. The high-concentration mother liquor includes acidic mother liquor, alkaline mother liquor, and neutral mother liquor. Specifically, the acidic mother liquor includes a 0.3M citric acid solution; the alkaline mother liquor includes a 2.5M sodium hydroxide solution, a 0.1M sodium hydroxide solution, and a 0.3M sodium citrate solution; and the neutral mother liquor includes WFI water for injection and a 3M sodium chloride solution.

[0030] Specifically, pumps A1 and D1 are neutral pumps, corresponding to the extraction of WFI water for injection and 3M sodium chloride solution, respectively; pumps B1, B2, and B3 are alkaline pumps, corresponding to the extraction of 0.3M sodium citrate solution, 2.5M sodium hydroxide solution, and 0.1M sodium hydroxide solution, respectively; and pump C1 is an acidic pump, corresponding to the extraction of 0.3M citric acid solution.

[0031] By classifying high-concentration mother liquors into acidic, alkaline, and neutral categories, and assigning different categories of mother liquors to corresponding pumps, this application establishes a clear pump-mother liquor mapping relationship. The classification design of acidic, alkaline, and neutral pumps provides clear operational targets for subsequent pH and conductivity adjustments, making the feedback control logic clearer and easier to implement.

[0032] In some embodiments, the process solution includes at least a 0.5M sodium hydroxide solution, a cation balance solution, a cation eluent, a 0.01M sodium hydroxide solution, and a 0.1M sodium hydroxide solution.

[0033] Specifically, the preset initial flow rate ratios for each target process solution are set as follows: When preparing a 0.5M sodium hydroxide solution, the preset initial flow rate ratio is: 80% for pump A1, 20% for pump B2, and the remaining pumps are turned off.

[0034] When preparing the cation balance solution, the preset initial flow rate ratio is: A1 pump 93.33%, B2 pump 3.95%, C1 pump 2.72%, and the remaining pumps are turned off.

[0035] When preparing the cation eluent, the preset initial flow rate ratio is: A1 pump 87.69%, B1 pump 4.58%, C1 pump 2.09%, D1 pump 5.64%, and the remaining pumps are turned off.

[0036] When preparing a 0.01M sodium hydroxide solution, the preset initial flow rate ratio is: 90% for pump A1, 10% for pump B3, and the remaining pumps are turned off.

[0037] When preparing a 0.1M sodium hydroxide solution, the preset initial flow rate ratio is: A1 pump 96%, B2 pump 4%, and the remaining pumps are turned off.

[0038] Furthermore, the above proportions are determined based on material conservation calculations and experimental optimization, ensuring that the prepared process solution meets the preset quality standards. Specifically, the pH range of the cation balance solution is [missing information]. The conductivity value range is The pH range of the cationic eluent is: The conductivity value range is The concentration of the 0.5M sodium hydroxide solution is 20.00 g / L; the concentration of the 0.01M sodium hydroxide solution is 0.40 g / L; and the concentration of the 0.1M sodium hydroxide solution is 4.00 g / L. By pre-storing the formulations of various target process solutions in digital form in the control system, this application achieves rapid recall and flexible switching of formulations, significantly improving the standardization and ease of operation of the process.

[0039] In some embodiments, the automatic feedback adjustment of the flow rate of at least one independent pump when the physicochemical parameters deviate from the preset parameter range includes: when the pH value of the initial process solution is higher than the upper limit of the preset range, feedback increasing the delivery flow rate of the acid pump; and / or, when the pH value of the initial process solution is lower than the lower limit of the preset range, feedback increasing the delivery flow rate of the alkaline pump.

[0040] Specifically, when the pH value is higher than the upper limit of the preset range (e.g., pH > 5.05 for cation balance solution), the system determines that the solution is too alkaline, increases the flow rate of acid pump C1, and increases the amount of acid to lower the pH; when the pH value is lower than the lower limit of the preset range (e.g., pH < 4.85), the system determines that the solution is too acidic, increases the flow rate of alkaline pumps B1, B2, or B3, and increases the amount of alkali to raise the pH.

[0041] In some embodiments, the flow rate of the acid or alkaline pump is increased by feedback and adjusted in preset step sizes. After each adjustment, a preset time is waited before monitoring is performed again until the pH value returns to the preset range or the preset maximum number of adjustments is reached. Specifically, each adjustment step size can be set to a flow rate change of 0.5% to 1.0%. After adjustment, 15 to 30 seconds are waited for the fluid to flow through the pipeline to the sensor, and the pH value is read again for judgment. If the pH value still does not meet the standard after two consecutive adjustments, a fine adjustment mode is entered, and the step size is reduced to continue adjustment. If the standard is still not met after five consecutive adjustments, an alarm is triggered and the pipeline is automatically switched to discharge waste.

[0042] Through the pH adjustment logic described above, this application achieves precise closed-loop control of pH value. The preset step size and waiting time settings avoid overshoot and oscillation caused by excessive adjustment or detection lag, while the setting of the upper limit of adjustment times and alarm mechanism ensures the safety and robustness of the process.

[0043] In some embodiments, the method further includes: automatically adjusting the flow rate of the salt solution pump when the conductivity value of the initial process solution deviates from a preset range. Specifically, the salt solution pump is a D1 pump used to draw 3M sodium chloride solution.

[0044] In some embodiments, the automatic adjustment of the flow rate of the salt solution pump includes: reducing the flow rate of the D1 pump when the conductivity value is higher than the upper limit of a preset range; and / or increasing the flow rate of the D1 pump when the conductivity value is lower than the lower limit of a preset range.

[0045] In some embodiments, when the conductivity value deviates from a preset range due to adjusting the flow rate of the acid pump or the alkaline pump, the adjustment of the acid pump or the alkaline pump is paused, and the flow rate of the pump delivering the salt solution is adjusted first, until the conductivity value returns to the preset range.

[0046] Specifically, conductivity is primarily determined by the flow rate of the salt solution pump D1, and is also affected by the flow rates of the acid and alkaline pumps (because the addition of citric acid and sodium citrate also contributes ions). When conductivity deviates independently, the system directly adjusts the flow rate of pump D1 to correct it. When conductivity deviates due to pH adjustment, the system prioritizes conductivity, suspends pH adjustment, and instead adjusts pump D1 to restore conductivity. pH adjustment resumes only after conductivity stabilizes.

[0047] Through the aforementioned conductivity adjustment logic and pH-conductivity coupling control strategy, this application achieves precise control of multiple parameters in a coordinated manner. When pH adjustment and conductivity control conflict, the system prioritizes conductivity stability, avoiding the problem of conductivity runaway due to blind pH adjustment, and ensuring that the final quality of the output solution meets the requirements.

[0048] In some embodiments, the method further includes a process solution switching step: when it is necessary to switch from the current target process solution to another target process solution, all pumps of the current formulation are shut down, and the A1 pump is turned on to flush the pipeline; the conductivity value of the fluid in the pipeline is monitored in real time, and when the conductivity value drops below a preset threshold, it is determined that the pipeline purging is complete; the corresponding pump is started according to the preset initial flow rate ratio of the other target process solution, and the other target process solution is obtained after the real-time monitored physicochemical parameters reach the preset range.

[0049] Specifically, upon switching, the system automatically switches the pipeline outlet to the waste outlet, shuts down all mother liquor pumps for the current formulation, and only activates the A1 pump (WFI) to flush the pipeline at a higher flow rate. Because the old solution contains a large number of ions, its conductivity is typically... The conductivity of the solution is relatively high, while that of the WFI solution is extremely low (<1 μS / cm), showing a significant difference. An online conductivity meter continuously monitors the conductivity of the fluid in the tubing. When the conductivity drops to a preset threshold (e.g., ≤1 μS / cm) and stabilizes, the tubing is considered emptied. Subsequently, the system starts the corresponding mother liquor pump according to the new solution formula. Once the online sensor detects that both pH and conductivity have reached the preset range and stabilized, the tubing is switched back to the column inlet to resume liquid supply.

[0050] Through the above-described evacuation operation, this application achieves seamless switching between different process solutions, effectively preventing cross-contamination between new and old solutions. Using conductivity as the criterion for determining the completion of evacuation ensures a sensitive and accurate response, guaranteeing the reliability of the switching process and the continuity of the process.

[0051] In other preferred embodiments, the following optimization schemes can be adopted to further improve the adaptability and control performance of the system.

[0052] In some preferred embodiments, when the dilution factor of the target process solution is large (e.g., preparing a 0.01M sodium hydroxide solution from a 2.5M sodium hydroxide mother liquor, the dilution factor is as high as 250 times), direct one-step dilution will result in an extremely low flow rate ratio of the high-concentration mother liquor pump (e.g., the B3 pump only needs to be turned on at 0.4%). At this time, it is difficult to guarantee the control accuracy of the pump at low flow rates, and small flow fluctuations will be amplified, resulting in a large deviation in the final concentration and affecting the stability of the process.

[0053] To address the aforementioned issues, this preferred embodiment employs a multi-stage dilution strategy. Specifically, a premixing device is provided, independent of the main mixing device. Its inlet is connected to both the high-concentration mother liquor source and the WFI source, and its outlet is connected to the inlet of a corresponding independent pump via an intermediate mother liquor pipeline.

[0054] In the first stage of dilution, the high-concentration mother liquor and a portion of the WFI are transferred to a premixing device to prepare an intermediate-concentration mother liquor. For example, 2.5M sodium hydroxide and WFI are mixed at a ratio of 1:4 to prepare a 0.5M sodium hydroxide intermediate mother liquor. The premixing device is equipped with a stirrer or static mixing element to ensure uniform mixing. The intermediate mother liquor can be continuously prepared and temporarily stored in an intermediate mother liquor container.

[0055] In the second-stage dilution, the intermediate mother liquor is used as a new high-concentration mother liquor and mixed with WFI in a preset ratio in the main mixing unit to obtain the target process solution. For example, mixing 0.5M sodium hydroxide intermediate mother liquor with WFI at a ratio of 1:49 yields a 0.01M sodium hydroxide solution.

[0056] By employing the aforementioned multi-stage dilution strategy, the large dilution ratio of 250x is broken down into two stages: 5x and 50x. Each stage has a moderate dilution ratio, and the flow rates of each pump are within a controllable range, effectively solving the problem of insufficient control precision at low flow rates. Simultaneously, the intermediate mother liquor can be pre-prepared and stably stored, reducing the adjustment burden on the main dispensing pipeline and improving the overall stability and reliability of the dispensing system.

[0057] In some preferred embodiments, pure feedback regulation inherently suffers from hysteresis (the time it takes for fluid to flow through the pipeline). When the solution changes or the flow rate changes abruptly, overshoot or oscillation is likely to occur, requiring multiple adjustments to achieve stability. Different solutions have different response characteristics, and a fixed-step-size regulation strategy is difficult to adapt to all scenarios, resulting in low regulation efficiency.

[0058] To address the aforementioned issues, this preferred embodiment constructs a historical adjustment database to achieve adaptive feedforward adjustment. Specifically, the system records key data of adjustment events during each operation, including: the initial pH value at the time of deviation, the pump number used for adjustment, the adjustment step size, the adjustment direction, the monitoring values ​​at each time point after adjustment, the time required for final stabilization, the number of adjustments required for stabilization, and corresponding operating parameters such as the process solution type and total flow rate.

[0059] The system extracts features from historical data and calculates the optimal adjustment strategy for each solution and each deviation range. For example, for a cation equilibrium solution, historical data shows that when the pH deviates by 0.1 units, the optimal step size is 0.5%, which can be stabilized with a single adjustment; when the pH deviates by 0.3 units, the optimal step size is 1.0%, which may require two adjustments. The system establishes a mapping database of "deviation features - optimal adjustment parameters".

[0060] When the pH value deviates from the preset range, the system first obtains the current process solution type and the current deviation value. It then matches the historical event closest to the current operating condition from the mapping database and extracts the corresponding optimal initial step size. Next, the system performs feedforward adjustment using this optimal step size, applying the predicted optimal adjustment amount all at once, rather than gradually probing from fixed small step sizes. After adjustment, the system further fine-tunes based on sensor feedback.

[0061] Through the above-mentioned adaptive feedforward adjustment, this preferred embodiment upgrades the adjustment process from a passive cycle of "trial-feedback-retrial" to an active control of "prediction-execution-fine-tuning", which significantly reduces the number of adjustments and overshoot, and improves adjustment efficiency and process stability.

[0062] In some preferred embodiments, there is a coupling between pH and conductivity—adjusting the acid or alkaline pump changes not only the pH but also the total amount of ions in the solution, thus affecting conductivity; adjusting the salt solution pump only changes conductivity and does not affect pH. When both pH and conductivity deviate simultaneously, traditional sequential adjustment (adjusting pH first, then conductivity) may lead to repeated oscillations, long adjustment times, and low efficiency.

[0063] To address the aforementioned issues, this preferred embodiment establishes a decoupled control matrix to achieve parallel decoupled regulation. Specifically, during the system initialization phase, disturbance tests are performed on each actuator pump: under steady-state conditions, a small flow rate change (e.g., an increase of 0.5%) is applied to each adjustable pump, and the changes in pH and conductivity are recorded. The influence coefficients of each pump's flow rate change on pH and conductivity are calculated. This leads to the establishment of a 2×n transfer matrix M, where n is the number of adjustable pumps, and the matrix elements... This represents the effect coefficient of the j-th pump on pH. This represents the influence coefficient of the j-th pump on conductivity.

[0064] During operation, the system acquires pH deviation in real time. and conductivity deviation Construct the deviation vector Then, calculate the pseudo-inverse of the transfer matrix M. Solve for the control vector This yields the theoretical adjustment value for each pump. Control vector Each element corresponds to a pump adjustment value; a positive value indicates an increase in flow rate, and a negative value indicates a decrease in flow rate.

[0065] The theoretical adjustment amount is limited (not exceeding the pump's maximum / minimum flow limit) and fine-tuned according to priority (e.g., prioritizing the use of pumps that have a greater impact on pH to adjust pH, and pumps that have a greater impact on conductivity to adjust conductivity). Finally, the adjustment amount of each pump is output and executed in parallel.

[0066] Through the decoupled control matrix described above, this preferred embodiment achieves parallel regulation of pH and conductivity, correcting both parameters simultaneously with a single adjustment. This avoids repeated oscillations caused by sequential regulation, significantly shortens the regulation time, and improves control efficiency.

[0067] In some preferred embodiments, a dead volume exists in the piping from the pump outlet to the sensor (including the internal volume of the mixing device and connecting pipes), causing the parameters detected by the sensor to lag behind the actual adjustment action. Lag time .in Indicates dead volume; This represents the current total flow rate. When the flow rate changes, the lag time also changes. PID control with fixed parameters is difficult to adapt to, resulting in large overshoot and long settling time.

[0068] To address the aforementioned issues, this preferred embodiment introduces a Smith predictor for hysteresis compensation. Specifically, the dead volume V of the pipeline from each pump junction to the sensor is first accurately measured, which can be obtained through water injection weighing or impulse response methods.

[0069] The system monitors the total flow rate of each pump in real time. ,according to Calculate the current lag time. It updates in real time according to changes in flow rate.

[0070] Constructing a mathematical model of the controlled object This model describes the response characteristics of pH / conductance to pump flow rate. It can be obtained through system identification experiments, for example, using a first-order inertial plus pure hysteresis model. A hysteresis element is introduced. ,in For the Laplace operator, This refers to the time lag between real-time updates.

[0071] The output of the Smith predictor is .in, For gain, It is a time constant. For inherent lag time, For the Laplace operator.

[0072] The Smith predictor constructs a forecasting model without lags in the following way, and its output is: in, The Laplace transform of the controller output. This is a lag element that updates in real time. The predicted value is used to compensate for the lag in the actual feedback signal.

[0073] Compensated feedback signal measured by the sensor The result is obtained by superimposing the output of the predictor: The controller (such as a PID controller) receives the compensated feedback signal and compares it with the setpoint. Comparison generates control variables: This is the transfer function of the controller. This control variable acts simultaneously on the actual controlled object and the Smith predictor, forming a closed loop.

[0074] Through the Smith predictor compensation described above, this preferred embodiment effectively eliminates the impact of hysteresis on control stability, enabling the system to remain stable under conditions of large hysteresis, significantly reducing overshoot, shortening settling time, and improving control quality.

[0075] In some preferred embodiments, during continuous production, a failure of any single pump (such as motor damage, pipeline blockage, or depletion of mother liquor) will cause the entire system to shut down, resulting in batch failure and economic losses. Single point of failure is a bottleneck to the system's reliability.

[0076] To address the aforementioned issues, this preferred embodiment employs redundant pump sets and a fault self-healing mechanism. Specifically, redundant pump sets are configured for critical mother liquors. For example, the 2.5M sodium hydroxide mother liquor is equipped with pumps B2 and B2' connected in parallel. The inlets of both pumps are connected to the same mother liquor source, and their outlets are merged via a three-way valve before being connected to the mixing device. During normal operation, pump B2 runs while pump B2' is in standby mode.

[0077] The system monitors the operating status of each pump in real time, including motor current, speed feedback, and flow meter readings. Fault detection thresholds are set; for example, if the flow rate is below 80% of a set value for 3 seconds, it is considered a pump fault.

[0078] When a fault is detected in pump B2, the system immediately shuts down pump B2 and simultaneously starts pump B2', quickly adjusting its speed to achieve the same flow rate as the original pump B2. The entire switching process is completed within 1 second, with almost no flow fluctuation felt downstream, achieving seamless switching of the faulty pump.

[0079] When no redundant pumps are available (e.g., no redundant pumps are configured for non-critical mother liquor), the system employs a multi-pump collaborative compensation strategy. Taking the failure of pump B2 (2.5M sodium hydroxide) as an example, the system obtains the formulation data of the current target process solution and calculates the contribution of the mother liquor delivered by the failed pump to the formulation (i.e., the total demand for sodium hydroxide). Then, other available alkaline pumps (such as pump B3, 0.1M sodium hydroxide) are used at higher flow rates to compensate for the missing sodium hydroxide contribution, while adjusting the flow rates of other pumps to maintain pH balance. The system calculates new flow rate combinations for each pump through decoupling, enabling "operation with the fault" until the batch ends.

[0080] In addition, a level gauge or weight sensor is installed in the mother liquor container. When the liquid level is lower than the warning line, the operator is prompted to replace the mother liquor in advance. If the liquid level is lower than the danger line, the system automatically switches to the backup mother liquor container.

[0081] Through the above-mentioned redundant configuration and fault self-healing mechanism, this preferred embodiment upgrades the system from "single point of failure resulting in shutdown" to "fault self-healing and seamless switching", which significantly improves the system's reliability and continuous production capacity, and reduces the risk of batch failure due to equipment failure.

[0082] Although preferred embodiments of the invention have been described, those skilled in the art, upon learning the basic inventive concept, can make other changes and modifications to these embodiments. Therefore, the appended claims are intended to be interpreted as including both the preferred embodiments and all changes and modifications falling within the scope of the invention.

[0083] Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. Therefore, if these modifications and variations fall within the scope of the claims of this invention and their equivalents, this invention also intends to include these modifications and variations.

[0084] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any changes or substitutions that can be easily conceived by those skilled in the art within the scope of the technology disclosed in the present invention should be included within the scope of protection of the present invention.

Claims

1. An online combined dilution and solution preparation method, characterized in that, include: Prepare multiple high-concentration mother liquors; Multiple independent pumps are used to extract corresponding high-concentration mother liquors according to preset initial flow ratios, and the extracted high-concentration mother liquors are transported to a mixing device for online mixing and dilution to form an initial process solution. The physicochemical parameters of the initial process solution are monitored in real time, including at least pH value and conductivity value; The real-time monitored physicochemical parameters are compared with the preset parameter range; When the physicochemical parameters deviate from the preset parameter range, the flow rate of at least one independent pump is automatically adjusted to obtain the target process solution.

2. The online combined dilution and preparation method according to claim 1, characterized in that, The plurality of independent pumps include pump A1, pump B1, pump B2, pump B3, pump C1, and pump D1; The high-concentration mother liquor includes acidic mother liquor, alkaline mother liquor, and neutral mother liquor; the acidic mother liquor includes 0.3M citric acid solution; the alkaline mother liquor includes 2.5M sodium hydroxide solution, 0.1M sodium hydroxide solution, and 0.3M sodium citrate solution; the neutral mother liquor includes WFI water for injection and 3M sodium chloride solution. Pumps A1 and D1 are neutral pumps that draw water for injection (WFI) and sodium chloride solution (3M), respectively; pumps B1, B2, and B3 are alkaline pumps that draw 2.5M sodium hydroxide solution, 0.1M sodium hydroxide solution, and 0.3M sodium citrate solution, respectively; and pump C1 is an acidic pump that draws 0.3M citric acid solution.

3. The online combined dilution and preparation method according to claim 2, characterized in that, The target process solution includes at least a 0.5M sodium hydroxide solution, a cation balance solution, a cation eluent, a 0.01M sodium hydroxide solution, and a 0.1M sodium hydroxide solution.

4. The online combined dilution and preparation method according to claim 3, characterized in that: When preparing a 0.5M sodium hydroxide solution, the preset initial flow rate ratio is: 80% for pump A1 and 20% for pump B2. When preparing the cation balance solution, the preset initial flow rate ratio is: A1 pump 93.33%, B2 pump 3.95%, C1 pump 2.72%; When preparing the cation eluent, the preset initial flow rate ratio is: A1 pump 87.69%, B1 pump 4.58%, C1 pump 2.09%, and D1 pump 5.64%. When preparing a 0.01M sodium hydroxide solution, the preset initial flow rate ratio is: 90% for pump A1 and 10% for pump B3. When preparing a 0.1M sodium hydroxide solution, the preset initial flow rate ratio is: 96% for pump A1 and 4% for pump B2.

5. The online combined dilution and preparation method according to claim 1, characterized in that, When the physicochemical parameters deviate from the preset parameter range, the automatic feedback adjustment of the flow rate of at least one independent pump includes: When the pH value of the initial process solution is higher than the upper limit of the preset range, the flow rate of the acid pump is increased. And / or, when the pH value of the initial process solution is lower than the lower limit of a preset range, the flow rate of the alkaline pump is increased as a feedback.

6. The online combined dilution and preparation method according to claim 5, characterized in that, Also includes: When the conductivity value of the initial process solution deviates from the preset range, the flow rate of the salt solution pump is automatically adjusted; Specifically, when the conductivity value deviates from the preset range due to adjusting the flow rate of the acid pump or the alkaline pump, the adjustment of the acid pump or the alkaline pump is paused, and the flow rate of the pump delivering the salt solution is adjusted first, until the conductivity value returns to the preset range.

7. The online combined dilution and preparation method according to claim 6, characterized in that, The salt solution pump is a D1 pump.

8. The online combined dilution and preparation method according to claim 5, characterized in that, The feedback increases the delivery flow rate of the acid or alkaline pump, and is adjusted according to a preset step size. After each adjustment, a preset time is waited before monitoring is performed again until the pH value returns to the preset range or the preset number of adjustments is reached.

9. The online combined dilution and preparation method according to claim 7, characterized in that, The automatic flow rate adjustment of the salt solution pump includes: When the conductivity value is higher than the upper limit of the preset range, reduce the flow rate of pump D1; And / or, when the conductivity value is lower than the lower limit of the preset range, increase the flow rate of pump D1.

10. The online combined dilution and preparation method according to claim 2, characterized in that, It also includes the process solution switching step: When it is necessary to switch from the current target process solution to another target process solution, shut down all pumps for the current formulation and turn on pump A1 to flush the pipeline. The conductivity value of the fluid in the pipeline is monitored in real time. When the conductivity value drops below a preset threshold, it is determined that the pipeline purging is complete. The corresponding pump is started according to the preset initial flow rate ratio of another target process solution. After the real-time monitored physicochemical parameters reach the preset range, the target process solution is obtained.

Images