Continuous flow production system, process and related devices for lipid nanoparticles

Abstract

The application provides a continuous flow preparation system, process and related device of lipid nanoparticles, wherein the system comprises: a plurality of peristaltic pump devices configured to pump a plurality of fluid channels required for preparing lipid nanoparticles respectively; each peristaltic pump device comprises: at least one driving motor and a plurality of rollers driven thereby; wherein the phases of the plurality of rollers are different, so that the periodic flow pulsations generated by the plurality of rollers at least partially cancel each other out in the output pump pipe of the peristaltic pump device; and a controller in communication connection with the plurality of peristaltic pump devices and configured to adjust the operating parameters of the corresponding peristaltic pump device based on the output flow of each peristaltic pump device respectively, so as to suppress the periodic flow pulsations of the peristaltic pump device, wherein the operating parameters include the rotating speed of the driving motor of the peristaltic pump device. The application can suppress the inherent periodic flow pulsations of the peristaltic pump device, meet the characteristics that the LNP preparation is very sensitive to the pulse, and break through the technical prejudice that the peristaltic pump is not suitable for LNP preparation.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of biopharmaceuticals, in particular, to a continuous flow preparation system, process and related device of lipid nanoparticles. BACKGROUND

[0002] The preparation of lipid nanoparticles (LNP) is a key link in biopharmaceuticals, and its core is to quickly and uniformly mix the organic phase containing lipids (such as ethanol) with the aqueous phase containing the effective components to be wrapped (such as mRNA) in multiple flow fluids. One of the core requirements of LNP preparation is to use a disposable delivery scheme to meet the strict pharmaceutical production specifications and ensure product purity, prevent cross-contamination between batches and the introduction of foreign impurities. Especially for advanced therapies such as personalized cancer vaccines (PCV), a disposable delivery scheme is a necessary condition to ensure product independence and patient safety.

[0003] However, the existing disposable delivery scheme faces severe challenges. If traditional pumping methods such as centrifugal pumps are used, either the flow path system has dead corners that cannot be cleaned, making it difficult to achieve complete disposability and causing cross-contamination, or the cost is too high, requiring the replacement of the entire pump cavity for one-time use, making it difficult to be applied on a large scale. If a low-cost peristaltic pump is used, although it can achieve isolation of the pump body and the fluid, and only needs to replace the pipeline to meet the one-time requirement; but the inherent pulse delivery of the peristaltic pump will produce periodic flow fluctuations, and LNP preparation is very sensitive to pulses, so using a peristaltic pump will have a serious adverse effect on the particle size uniformity, encapsulation efficiency and batch consistency of lipid nanoparticles. As a result, there is a consensus in the industry that peristaltic pumps are not suitable for LNP preparation and will seriously affect the mixing efficiency and stability.

[0004] It should be noted that the information disclosed in the above background section is only used to strengthen the understanding of the background of the present application, and therefore can include information that does not constitute prior art known to those of ordinary skill in the art. SUMMARY

[0005] The present application provides a continuous flow preparation system, process and related device of lipid nanoparticles, which realizes a high-precision microfluidic mixing scheme based on a peristaltic pump that meets the requirements of one-time use and effectively suppresses flow pulsation, breaking the technical prejudice that peristaltic pumps are not suitable for LNP preparation.

[0006] According to an aspect of the present application, there is provided a continuous flow preparation system for lipid nanoparticles, comprising: a plurality of peristaltic pump devices configured to pump a plurality of fluid streams required for preparation of lipid nanoparticles, respectively; wherein each peristaltic pump device comprises: at least one driving motor; a plurality of rollers driven by the corresponding driving motor and acting on a pump tube; wherein the plurality of rollers have different phases such that the periodic flow pulsations generated by the plurality of rollers at least partially cancel each other out in an output pump tube of the peristaltic pump device; and a controller communicatively connected to the plurality of peristaltic pump devices and configured to adjust operating parameters of the corresponding peristaltic pump device based on an output flow rate of each peristaltic pump device, respectively, to suppress the periodic flow pulsations of the peristaltic pump device, wherein the operating parameters comprise rotational speeds of the driving motors of the peristaltic pump device.

[0007] In some embodiments, each peristaltic pump device comprises: one driving motor; a plurality of roller groups driven by the driving motor, wherein each roller group comprises at least one roller, each roller group acts on an independent pump tube, and the pump tubes of the plurality of roller groups converge to an output pump tube of the peristaltic pump device; wherein the plurality of roller groups have different phases such that the periodic flow pulsations generated by the plurality of roller groups at least partially cancel each other out in the output pump tube.

[0008] In some embodiments, each peristaltic pump device comprises: a plurality of pumping units, each pumping unit comprising one driving motor and at least one roller driven by the driving motor; wherein the rollers of the plurality of pumping units collectively act on an output pump tube of the peristaltic pump device, and the rollers of the plurality of pumping units have different phases such that the periodic flow pulsations generated by the plurality of pumping units at least partially cancel each other out in the output pump tube; wherein the operating parameters further comprise operating phase differences of the driving motors of the plurality of pumping units.

[0009] In some embodiments, each peristaltic pump device comprises: a plurality of peristaltic pump units, each peristaltic pump unit comprising one driving motor and at least one roller driven by the driving motor; wherein the rollers of each peristaltic pump unit act on an independent pump tube, and the pump tubes of the plurality of peristaltic pump units converge to an output pump tube of the peristaltic pump device; wherein the plurality of peristaltic pump units have different phases such that the periodic flow pulsations generated by the plurality of peristaltic pump units at least partially cancel each other out in the output pump tube; wherein the operating parameters further comprise operating phase differences of the driving motors of the plurality of peristaltic pump units.

[0010] In some embodiments, the continuous flow preparation system further comprises: a non-contact flow sensor arranged at an outlet position of each peristaltic pump device and configured to monitor an output flow rate of each peristaltic pump device.

[0011] In some embodiments, the continuous flow preparation system further comprises a microfluidic chip configured to receive and mix the multiple streams of fluid to prepare the lipid nanoparticles, wherein each of the peristaltic pump devices is connected to a fluid inlet of the microfluidic chip.

[0012] According to yet another aspect of the present application, there is provided a continuous flow preparation process of lipid nanoparticles, implemented based on the continuous flow preparation system of any of the above embodiments, the continuous flow preparation process comprising: monitoring the output flow rate of each of the peristaltic pump devices during pumping of the multiple streams of fluid required for preparing the lipid nanoparticles; and adjusting the operating parameters of each of the peristaltic pump devices based on the output flow rate of the peristaltic pump device, respectively, by a pulse suppression strategy to suppress the periodic flow pulsation of the peristaltic pump device; wherein the pulse suppression strategy comprises a phase difference control strategy and / or a rotational speed compensation strategy.

[0013] In some embodiments, the phase difference control strategy comprises adjusting the phase difference of operation of the multiple driving motors of the peristaltic pump device to cause the periodic flow pulsation generated by the multiple driving motors to at least partially cancel each other to control the error between the output flow rate of the peristaltic pump device and the target flow rate of the corresponding stream of fluid.

[0014] In some embodiments, the phase difference control strategy is implemented based on a multi-axis synchronous control algorithm.

[0015] In some embodiments, the rotational speed compensation strategy comprises adjusting the rotational speed of the driving motor of the peristaltic pump device to cause the peristaltic pump device to generate a compensation flow to at least partially cancel the periodic flow pulsation of the peristaltic pump device to control the error between the output flow rate of the peristaltic pump device and the target flow rate of the corresponding stream of fluid.

[0016] In some embodiments, the rotational speed compensation strategy comprises detecting a peak and a trough of the output flow rate of the peristaltic pump device; synchronously reducing the rotational speed of the driving motor of the peristaltic pump device when a peak is detected; and synchronously increasing the rotational speed of the driving motor of the peristaltic pump device when a trough is detected.

[0017] In some embodiments, a peak is detected when the output flow rate of the peristaltic pump device is sampled to be higher than a set value or a plurality of consecutive sampling points of the output flow rate of the peristaltic pump device are local maximum values; and a trough is detected when the output flow rate of the peristaltic pump device is sampled to be lower than a set value or a plurality of consecutive sampling points of the output flow rate of the peristaltic pump device are local minimum values; wherein the local maximum value and the local minimum value are determined by comparing the current sampling point with the previous and subsequent sampling points.

[0018] In some embodiments, the rotation speed compensation strategy is implemented based on a proportional-integral-derivative control algorithm.

[0019] In some embodiments, the rotation speed compensation strategy is implemented according to the following formula:

[0020] ;

[0021] wherein Q meas is the output flow rate of the peristaltic pump device, Q set is the target flow rate of the corresponding fluid, n now is the current rotation speed of the driving motor of the peristaltic pump device, n target is the target rotation speed of the driving motor of the peristaltic pump device, K p is the proportional gain.

[0022] In some embodiments, during implementation of the rotation speed compensation strategy, one or more of the following are followed: the sampling frequency of the output flow rate of the peristaltic pump device is greater than or equal to 100 Hz; the rotation speed adjustment interval of the driving motor of the peristaltic pump device is greater than the sampling frequency; the target rotation speed of the driving motor of the peristaltic pump device is adjusted within a rated rotation speed range.

[0023] According to still another aspect of the present application, there is provided an electronic device comprising: a processor; a memory having stored therein executable instructions; wherein the executable instructions, when executed by the processor, implement the continuous flow preparation process of the lipid nanoparticle as described in any of the above embodiments.

[0024] According to still another aspect of the present application, there is provided a computer-readable storage medium for storing a program, which, when executed by a processor, implements the continuous flow preparation process of the lipid nanoparticle as described in any of the above embodiments.

[0025] According to still another aspect of the present application, there is provided a computer program product comprising a computer program, which, when executed by a processor, implements the continuous flow preparation process of the lipid nanoparticle as described in any of the above embodiments.

[0026] The present application has at least the following beneficial effects compared with the prior art:

[0027] The multiple peristaltic pump devices are used to pump multiple fluids respectively to meet the requirements of multiple inputs for LNP preparation. The fluid isolation characteristics of the peristaltic pump devices can avoid cross contamination and meet the requirements of one-time use to meet the strict drug production specifications and ensure product purity. In addition, the controller can dynamically adjust the operating parameters of the peristaltic pump device based on real-time flow feedback to actively suppress the periodic flow pulsation inherent in the peristaltic pump device and reduce the interference of flow fluctuation on the mixing process. In this way, the application can stabilize the output flow to ensure that the LNP preparation process continues and the flow is smooth, the mixing is uniform, and the stability is high, which breaks through the technical obstacles of peristaltic pumps in LNP preparation, meets the characteristics that LNP preparation is very sensitive to pulses, and makes the particle size uniformity, encapsulation efficiency and batch consistency of the lipid nanoparticles prepared meet the strict drug production requirements.

[0028] The continuous flow preparation scheme of the lipid nanoparticles of the application is particularly suitable for application fields with extremely high requirements for product purity, production flexibility and batch consistency, and can especially meet the production requirements of advanced therapies such as personalized tumor vaccines.

[0029] It should be understood that the above general description and the following detailed description are only exemplary and explanatory, and cannot limit the application. BRIEF DESCRIPTION OF DRAWINGS

[0030] The drawings incorporated into the specification and forming a part thereof show embodiments consistent with the application and, together with the specification, serve to explain the principles of the application. Obviously, the drawings in the following description are only some embodiments of the application, and other drawings can be obtained from these drawings without creative labor for those skilled in the art.

[0031] Figure 1 A structural schematic diagram of a continuous flow preparation system of lipid nanoparticles in an embodiment of the application is shown;

[0032] Figure 2 A structural schematic diagram of a peristaltic pump device in an embodiment of the application is shown;

[0033] Figure 3 A structural schematic diagram of another peristaltic pump device in an embodiment of the application is shown;

[0034] Figure 4 A structural schematic diagram of another peristaltic pump device in an embodiment of the application is shown;

[0035] Figure 5 A step schematic diagram of a continuous flow preparation process of lipid nanoparticles in an embodiment of the application is shown;

[0036] Figure 6A structural schematic diagram of an electronic device in an embodiment of the present application is shown. DETAILED DESCRIPTION

[0037] Example implementations will now be described more fully with reference to the accompanying drawings. Example implementations may, however, be implemented in many different forms and should not be construed as limited to the implementations set forth herein. Rather, these implementations are provided as non-limiting examples, so that this disclosure will fully convey the scope of the application to those skilled in the art.

[0038] The accompanying drawings are included to provide a further understanding of the present application and are incorporated in and constitute a part of this specification. The drawings illustrate embodiments of the present application and, together with the description, serve to explain the principles of the present application. In the drawings:

[0039] The flowcharts shown in the drawings are only exemplary illustrations and do not necessarily include all the steps. For example, some steps can be broken down, some steps can be combined or partially combined, and the actual execution order can be changed according to the actual situation. The terms "first", "second", and similar terms used in the specific description do not represent any order, number, or importance, but are only used to distinguish different components. The term "multiple" means two or more, unless otherwise explicitly specified and limited. In addition, in the description of the present application, unless otherwise explicitly specified and limited, the term "connection" should be understood broadly, for example, it can be a fixed connection, or a detachable connection, or an integral connection; it can be a mechanical connection, or an electrical connection; it can be directly connected, or indirectly connected through an intermediate medium, or internal communication between two elements.

[0040] It should be noted that the embodiments of the present application and the features in different embodiments can be combined with each other without conflict. Based on the embodiments of the present application, all other embodiments obtained by those of ordinary skill in the art without creative labor fall within the scope of protection of the present application.

[0041] Figure 1 A structure of a continuous flow preparation system of lipid nanoparticles is shown, and the continuous flow preparation system of lipid nanoparticles provided by the embodiments of the present application comprises: Figure 1 A structure of a continuous flow preparation system of lipid nanoparticles is shown, and the continuous flow preparation system of lipid nanoparticles provided by the embodiments of the present application comprises:

[0042] A plurality of peristaltic pump devices 100 (two are shown in the figure, but not limited thereto, and can be three or more) are configured to pump a plurality of fluids 200 required for preparation of lipid nanoparticles, respectively. Figure 1 A plurality of peristaltic pump devices 100 (two are shown in the figure, but not limited thereto, and can be three or more) are configured to pump a plurality of fluids 200 required for preparation of lipid nanoparticles, respectively.

[0043] The controller 300 (which can be arranged together with the peristaltic pump device 100 or deployed remotely) is communicatively connected with the plurality of peristaltic pump devices 100 and configured to adjust the operating parameters of the corresponding (i.e. determined to be in need of adjustment) peristaltic pump device 100 based on the output flow rate of each peristaltic pump device 100 respectively, so as to suppress the periodic flow pulsation of the peristaltic pump device 100.

[0044] The plurality of peristaltic pump devices 100 respectively pump the plurality of fluids 200, such as respectively pumping the lipid ethanol solution and the mRNA aqueous buffer, to meet the multi-path input requirement of LNP preparation. By virtue of the fluid isolation feature of the peristaltic pump device 100, the present application can avoid cross-contamination, meet the requirement of one-time use, and satisfy the strict pharmaceutical production specification and ensure the product purity. In addition, the present application dynamically adjusts the operating parameters (the operating parameters can include the phase and / or the rotation speed) of the peristaltic pump device 100 based on the real-time flow feedback by the controller 300, actively suppresses the inherent periodic flow pulsation of the peristaltic pump device 100, reduces the disturbance of flow fluctuation on the mixing process, and avoids affecting the LNP preparation. In this way, the present application can stabilize the output flow, ensure the continuous LNP preparation process and the smooth flow, uniform mixing, and high stability, break through the technical barrier of peristaltic pump in LNP preparation, meet the characteristics that LNP preparation is very sensitive to pulse, realize reliable LNP preparation, and make the particle size uniformity, encapsulation efficiency, and batch consistency of the lipid nanoparticles prepared meet the strict pharmaceutical production requirements.

[0045] The continuous flow preparation scheme of the lipid nanoparticles of the present application is particularly suitable for application fields with extremely high requirements for product purity, production flexibility, and batch consistency, such as being able to meet the production requirements of advanced therapies such as personalized tumor vaccines. Specifically, the personalized tumor vaccine is based on the tumor neoantigen specific to the patient, and its production has the characteristics of small batch size, unique sequence, and no cross-contamination.

[0046] The continuous flow preparation scheme of the lipid nanoparticles of the present application can precisely achieve:

[0047] Disposable fluid path: avoid cross-contamination between batches, and ensure the purity of the personalized tumor vaccine customized for each patient;

[0048] Pulse suppression and flow stability: ensure the particle size of the lipid nanoparticles to be highly uniform and the encapsulation efficiency to be stable, so as to realize the batch consistency and reliable efficacy of the personalized tumor vaccine;

[0049] Flexibility and scalability of the system: by virtue of the characteristic that the peristaltic pump only needs to replace the pipeline, different prescriptions and production quantities can be quickly switched to adapt to the production requirements of personalized tumors.

[0050] In some embodiments, the continuous flow preparation system of lipid nanoparticles can further comprise: a non-contact flow sensor 400, such as an ultrasonic flow sensor, disposed at the outlet position of each peristaltic pump device 100, configured to monitor the output flow of each peristaltic pump device 100. In this way, on the one hand, direct contact with the fluid is avoided, meeting the requirement of disposable use; on the other hand, the flow of each channel is monitored independently, realizing high-precision flow monitoring and providing reliable input for the control of each channel of fluid.

[0051] Further, in some embodiments, the continuous flow preparation system of lipid nanoparticles can further comprise: a microfluidic chip 500 configured to receive and mix the multiple channels of fluid 200 to prepare lipid nanoparticles, wherein each peristaltic pump device 100 is connected to a fluid inlet of the microfluidic chip 500, ensuring that each channel of fluid enters the microfluidic chip 500 at a stable flow rate. With the microfluidic chip 500, a fast and uniform mixing environment can be provided, realizing high-quality LNP preparation and meeting the requirements of uniform particle size, high encapsulation efficiency, etc.

[0052] In some embodiments, each peristaltic pump device 100 can comprise: at least one drive motor; a plurality of rollers driven by the corresponding drive motor and acting on the pump tube; wherein the phases of the plurality of rollers are different, so that the periodic flow pulsations generated by the plurality of rollers at least partially cancel each other out in the output pump tube of the peristaltic pump device 100.

[0053] Wherein the operating parameters of the corresponding peristaltic pump device 100 adjusted by the controller 300 include the rotation speed of the drive motor of the peristaltic pump device 100.

[0054] Figure 2 The structure of a peristaltic pump device is shown, where the Z-axis represents the axis direction of the rollers. In combination with Figure 1 and Figure 2 As shown in FIGS. 1 1 and 12, in some embodiments, each peristaltic pump device 100 comprises: one drive motor 110e; a plurality of roller groups (120e, 120f) driven by the drive motor 110e, wherein each roller group comprises at least one roller, each roller group acts on an independent pump tube, and the pump tubes (200e, 200f) of the plurality of roller groups (120e, 120f) converge into the output pump tube 200’ of the peristaltic pump device 100; wherein the phases of the plurality of roller groups (120e, 120f) are different, so that the periodic flow pulsations generated by the plurality of roller groups (120e, 120f) at least partially cancel each other out in the output pump tube 200’.

[0055] The mechanical structure of the peristaltic pump device 100 of the embodiment is simple, and the manufacturing cost is low. Through the design of driving the multiple groups of rollers (120e, 120f) with different phases by one driving motor 110e, the peak clipping effect is generated by the mechanical phase difference, the pulse suppression is realized, the dependence on the control algorithm is reduced, and the system stability is enhanced. Among them, the multiple groups of rollers (120e, 120f) are driven to rotate synchronously by the driving motor 110e, and the driving motor 110e and the multiple groups of rollers (120e, 120f) are integrated in one pump shell, which can save space and simplify installation.

[0056] In one specific example, the peristaltic pump device 100 can be configured with one driving motor 110e and two groups of rollers (such as the first group of rollers 120e and the second group of rollers 120f shown in the figure), and the number of rollers in each group of rollers can be set as needed. Figure 2 In one group of rollers: when two rollers are set, the two rollers can be arranged with a mechanical phase difference of 180°, and they can realize the alternating complementation of pulses during operation, form two opposite phase pulsating flows in the pump pipe, and superimpose the wave peak of one pulsating flow on the wave trough of the other pulsating flow in time, thereby effectively canceling the periodic flow pulsation generated by a single roller and improving the stability of the output flow of the peristaltic pump device 100. In one group of rollers: when M (M≥3) rollers are set, the M rollers can be uniformly arranged with a mechanical phase difference of 360° / M to achieve better flow smoothness. In actual application, the number of rollers can be selected by considering factors such as mechanical complexity, manufacturing cost, and operating power consumption.

[0057] In some cases, considering that the flow pulsation generated by a single roller may not be a sine wave, but contain harmonics caused by fluid inertia, pipeline rebound, etc., the multiple rollers in each group of rollers can also be arranged in a non-uniform phase arrangement to achieve targeted suppression of specific harmonic components, thereby obtaining a more stable flow output than the standard uniform phase. For example, three rollers are arranged in one group of rollers, and the three rollers can be arranged with a phase difference of 110°-130°-120°, which not only can cancel specific pulsation, but also can avoid periodic stress, resonance, etc.

[0058] In summary, by arranging the mechanical phase difference between the rollers, the pulsation amplitude that needs to be compensated by the controller 300 is reduced, the pulse suppression strategy based on flow monitoring of the controller 300 is simplified, so as to more quickly and accurately realize flow adjustment, and improve the response speed and stability of the continuous flow preparation system of the lipid nanoparticles.

[0059] Further, in the embodiment where the peristaltic pump device 100 comprises one driving motor 110e and multiple sets of rollers (120e, 120f), the controller 300 can adjust the rotation speed of the driving motor 110e based on the output flow rate of the peristaltic pump device 100 to suppress the periodic flow rate pulsation of the peristaltic pump device 100. For example, at the peak of the output flow rate of the peristaltic pump device 100, the rotation speed of the driving motor 110e can be reduced to provide negative compensation so that the instantaneous flow rate peak output by the peristaltic pump device 100 is reduced; at the trough of the output flow rate of the peristaltic pump device 100, the rotation speed of the driving motor 110e can be increased to provide positive compensation so that the instantaneous flow rate peak output by the peristaltic pump device 100 is increased. In this way, the output flow rate of the peristaltic pump device 100 is quickly stabilized to the target range.

[0060] Figure 3 Fig. 1 shows the structure of yet another peristaltic pump device, which is combined with Figure 1 and Figure 3 Fig. 1 shows the structure of yet another peristaltic pump device, which is combined with Figure 3 Fig. 1 shows the structure of yet another peristaltic pump device, which is combined with Figure 3 Fig. 1 shows the structure of yet another peristaltic pump device, which is combined with

[0061] Fig. 1 shows the structure of yet another peristaltic pump device, which is combined with

[0062] The rollers (120a, 120b) of the plurality of pumping units (100a, 100b) can be arranged in a uniform phase arrangement or a non-uniform phase arrangement. For details, please refer to the description of the above embodiments. By utilizing the mechanical phase difference between the rollers, the amplitude of the pulsation that needs to be compensated by the controller 300 can be reduced, and the pulsation suppression strategy based on flow monitoring of the controller 300 can be simplified, so as to more quickly and accurately achieve flow adjustment and improve the response speed and stability of the continuous flow preparation system of the lipid nanoparticles.

[0063] Further, in the embodiment in which the peristaltic pump device 100 includes a plurality of pumping units (100a, 100b), the controller 300 can adjust the operating phase difference between the driving motors (110a, 110b) of the plurality of pumping units (100a, 100b) and / or synchronously adjust the rotation speeds of the driving motors (110a, 110b) of the plurality of pumping units (100a, 100b) based on the output flow of the peristaltic pump device 100, so as to suppress the periodic flow pulsation of the peristaltic pump device 100. That is, in the present embodiment, the controller 300 has a multi-parameter adjustment capability, and by coordinating the operating phase difference and / or the rotation speed of the driving motor, it can cope with complex working conditions, dynamically optimize the pulsation suppression strategy, and ensure the stability of the output flow of the peristaltic pump device 100.

[0064] In a specific example, the coordinated control strategy of the controller over the phase difference and rotational speed of the drive motors (110a, 110b) of multiple pumping units (100a, 100b) may include the following process: When starting up or changing the fluid formula, the drive motors (110a, 110b) of the multiple pumping units (100a, 100b) are set to an initial phase difference, which preferably aligns the flow peaks generated by some pumping units with the flow troughs generated by other pumping units in time. Due to differences in pipeline characteristics, changes in fluid viscosity, etc., this initial phase difference cannot achieve complete pulse cancellation in practice. Therefore, during operation, the controller 300 continuously receives real-time flow signals from the non-contact flow sensor 400 and analyzes the pulse parameters (including amplitude and phase) of the output flow of the peristaltic pump device 100 using algorithms (e.g., Fourier analysis, zero-crossing detection, etc.). If a pulsation at a specific frequency is detected, the controller 300 can adjust the operating phase of one or more drive motors, for example, shifting the operating phase of one drive motor by 1°, to change the operating phase difference between the drive motors (110a, 110b) of multiple pumping units (100a, 100b), maintaining them in an optimal pulse cancellation state. Active cancellation is achieved through electronic control of the phase difference, which is more flexible than mechanical phase difference. The controller 300 can also further smooth the periodic flow pulsations output by the multiple pumping units (100a, 100b) through speed compensation. Specifically, the controller 300 can treat the multiple pumping units (100a, 100b) as a whole, calculate the error between their overall output flow and the target flow, and synchronously adjust the speed of all drive motors based on this error. If the output flow is too low, the speed of all drive motors can be increased synchronously; if the output flow is too high, the speed of all drive motors can be decreased synchronously. In addition, the controller 300 can also perform differentiated adjustment of the speed of a single or part of the drive motors. For example, when an instantaneous peak / trough is detected, the controller 300 can instantaneously reduce / increase the speed of the drive motor that caused the peak / trough in order to achieve targeted adjustment.

[0065] Figure 4 This diagram illustrates the structure of yet another type of peristaltic pump device, combined with... Figure 1 and Figure 4 As shown, in some embodiments, each peristaltic pump device 100 includes: a plurality of peristaltic pump units (100c, 100d) Figure 4Two, but not limited to), each peristaltic pump unit includes a drive motor and at least one roller driven by the drive motor. For example, the first peristaltic pump unit 100c includes a drive motor 110c and two rollers 120c driven by the drive motor 110c; the second peristaltic pump unit 100d includes a drive motor 110d and three rollers 120d driven by the drive motor 110d. Among them, the rollers of each peristaltic pump unit act on independent pump pipes, and the pump pipes (200c, 200d) of the plurality of peristaltic pump units (100c, 100d) converge into the output pump pipe 200' of the peristaltic pump device 100. Among them, the phases of the plurality of peristaltic pump units (100c, 100d) are different, which can be the running phase difference of the drive motor and / or the mechanical phase difference of the roller, so that the periodic flow pulsation generated by the plurality of peristaltic pump units (100c, 100d) at least partially cancels out in the output pump pipe 200'.

[0066] The embodiment utilizes a plurality of peristaltic pump units (100c, 100d), each having an independent pump housing and an independent drive motor, to achieve more flexible arrangement and more flexible control. Alternatively, the plurality of peristaltic pump units (100c, 100d) can be integrated in one pump housing. Through the coordinated action of the running phase difference between the drive motors (110c, 110d) of the plurality of peristaltic pump units (100c, 100d) and the mechanical phase difference between the rollers (120c, 120d), the flow adjustment can be accurately realized, and the preparation effect of the lipid nanoparticles is improved.

[0067] Further, in the embodiment in which the peristaltic pump device 100 includes a plurality of peristaltic pump units (100c, 100d), the controller 300 can adjust the running phase difference between the drive motors (110c, 110d) of the plurality of peristaltic pump units (100c, 100d) and / or synchronously adjust the rotation speed of the drive motors (110c, 110d) of the plurality of peristaltic pump units (100c, 100d) based on the output flow of the peristaltic pump device 100, to suppress the periodic flow pulsation of the peristaltic pump device 100. In this embodiment, the controller 300 also has multi-parameter adjustment capability, and by coordinating the running phase difference and / or rotation speed of the drive motors (110c, 110d), it can cope with complex working conditions, dynamically optimize the pulse suppression strategy, and ensure the stability of the output flow of the peristaltic pump device 100.

[0068] The embodiment of the present application also provides a continuous flow preparation process of lipid nanoparticles, which is realized based on the continuous flow preparation system of lipid nanoparticles described in any of the above embodiments. Figure 5 The main steps of the continuous flow preparation process of lipid nanoparticles are illustrated, and the reference is made to Figure 5In combination with the above embodiments, the continuous flow preparation process of the lipid nanoparticles provided by the embodiments of the present application comprises:

[0069] S610, during the pumping of the multiple flow fluids required for the preparation of the lipid nanoparticles by the multiple peristaltic pump devices, the output flow rate of each peristaltic pump device is monitored. Specifically, the instantaneous flow rate output by each peristaltic pump device can be monitored in real time by a high-response non-contact flow sensor.

[0070] S620, based on the output flow rate of each peristaltic pump device, the operating parameters of the corresponding peristaltic pump device are adjusted by a pulse suppression strategy to suppress the periodic flow pulsation of the peristaltic pump device; wherein the pulse suppression strategy comprises a phase difference control strategy and / or a speed compensation strategy.

[0071] By using the controller to dynamically adjust the phase and / or speed of the peristaltic pump device based on real-time flow feedback, the inherent periodic flow pulsation of the peristaltic pump device is actively suppressed, the disturbance of flow fluctuation to the mixing process is reduced, and the influence on LNP preparation is avoided. In this way, the present application can stabilize the output flow rate, ensure the continuous LNP preparation process and the smooth flow, uniform mixing and high stability, break through the technical barrier of peristaltic pump in LNP preparation, meet the characteristics that LNP preparation is very sensitive to pulse, realize reliable LNP preparation, and make the particle size uniformity, encapsulation efficiency and batch consistency of the lipid nanoparticles prepared meet the strict requirements of drug production. The continuous flow preparation scheme of the lipid nanoparticles of the present application is particularly suitable for application fields with extremely high requirements for product purity, production flexibility and batch consistency, such as being able to meet the production needs of advanced therapies such as personalized tumor vaccines.

[0072] In some embodiments, the phase difference control strategy comprises adjusting the operating phase difference of the multiple drive motors of the peristaltic pump device, so that the periodic flow pulsations generated by the multiple drive motors at least partially cancel each other out, to control the error between the output flow rate of the peristaltic pump device and the target flow rate of the corresponding flow fluid, and control the error within a reasonable range that does not affect LNP preparation.

[0073] The phase difference control strategy can be implemented based on a multi-axis synchronous control algorithm. For example, a virtual main shaft synchronous control algorithm can be used to generate a virtual and ideal main shaft motion trajectory inside the controller, and control all drive motors to follow the main shaft motion trajectory, wherein the target position of each drive motor has a certain phase offset relative to the virtual main shaft position. The controller can change or partially adjust the phase offset of the drive motors to adjust the operating phase difference between the drive motors.

[0074] In some embodiments, the rotation speed compensation strategy comprises adjusting the rotation speed of the driving motor of the peristaltic pump device, so that the peristaltic pump device generates a compensation flow that at least partially counteracts the periodic flow pulsation thereof, to control the error between the output flow of the peristaltic pump device and the target flow of the corresponding channel fluid, thereby smoothing the flow output, improving the mixing quality, and ultimately ensuring high-quality LNP preparation.

[0075] Specifically, the rotation speed compensation strategy can comprise detecting the peak and the trough of the output flow of the peristaltic pump device; when a peak is detected, synchronously reducing the rotation speed of the driving motor of the peristaltic pump device; when a trough is detected, synchronously increasing the rotation speed of the driving motor of the peristaltic pump device. In actual detection, when the output flow of the peristaltic pump device is sampled to be higher than a set value or a plurality of consecutive sampling points of the output flow of the peristaltic pump device are local maximum values, it can be judged that a peak is detected; at this time, it indicates that the instantaneous flow of the current pumping is too high, so the controller synchronously reduces the rotation speed of each driving motor (for example, the rotation speed of each driving motor is proportionally reduced), so that the instantaneous flow of the subsequent output is reduced, and the rising peak is flattened. When the output flow of the peristaltic pump device is sampled to be lower than a set value or a plurality of consecutive sampling points of the output flow of the peristaltic pump device are local minimum values, it can be judged that a trough is detected; at this time, it indicates that the instantaneous flow of the current pumping is insufficient, so the controller synchronously increases the rotation speed of each driving motor (for example, the rotation speed of each driving motor is proportionally increased), so that the instantaneous flow of the subsequent output is increased, and the falling peak is filled. In this way, the flow of each channel flowing into the microfluidic chip tends to be stable. Wherein, the local extreme value can be judged by comparing the current sampling point with the previous and subsequent sampling points. By using the rotation speed compensation strategy, the rotation speed of the driving motor is adjusted to regulate the instantaneous flow output by the peristaltic pump device, to resist the flow fluctuation caused by the periodicity inherent in the mechanical movement of the peristaltic pump device, so that the low-cost peristaltic pump solution can meet the application scenarios of LNP preparation and other extremely demanding applications requiring flow stability.

[0076] In some embodiments, the rotation speed compensation strategy is implemented based on a proportional-integral-derivative control algorithm. Specifically, the rotation speed compensation strategy can be executed according to the following formula:

[0077] ;

[0078] Wherein, Q meas is the output flow of the peristaltic pump device 100, Q set is the target flow of the corresponding channel fluid, n now is the current rotation speed of the driving motor 110 of the peristaltic pump device 100, n target is the target rotation speed of the driving motor 110 of the peristaltic pump device 100, K p is the proportional gain. The larger Kp is, the faster the response is, and the smaller Kp is, the better the system stability is.

[0079] Further, in the execution of the rotation speed compensation strategy, one or more of the following constraints can be followed. The sampling frequency of the output flow of the peristaltic pump device is greater than or equal to 100 Hz to ensure that the peaks / troughs can be captured; the detection of the peaks / troughs can be determined by comparing the current sampling point with the previous and subsequent sampling points to determine the local extreme value, or using a sliding window and first-order difference. The rotation speed adjustment interval of the driving motor of the peristaltic pump device is greater than the sampling frequency, that is, it is not necessary to adjust immediately after each sampling, and the minimum rotation speed adjustment interval (such as 0.5 s) can be set to control the rotation speed update rhythm. The target rotation speed of the driving motor of the peristaltic pump device is adjusted within the rated rotation speed range including the upper and lower limits (for example, the rated rotation speed range with the upper and lower limits of 20% and 120% of the current rotation speed), that is, the target rotation speed is limited to avoid abnormal jump. Through the constraints, the accurate rotation speed compensation strategy is realized, the characteristics that the LNP preparation is very sensitive to the pulse are met, and the LNP is stably prepared by using the peristaltic pump.

[0080] The embodiments of the present application also provide an electronic device including a processor and a memory, wherein the memory stores executable instructions, and the executable instructions are executed by the processor to implement the continuous flow preparation process of the lipid nanoparticles described in any of the embodiments.

[0081] The electronic device of the present application can be locally deployed in the continuous flow preparation system of the lipid nanoparticles, can be remotely deployed, or can be partially locally deployed and partially remotely deployed. When the electronic device of the present application executes the continuous flow preparation process of the lipid nanoparticles, it can realize real-time flow feedback-based dynamic adjustment of the phase and / or rotation speed of the peristaltic pump device, active inhibition of the periodic flow pulsation inherent in the peristaltic pump device, and stabilization of each flow into the microfluidic chip, thereby ensuring the continuous LNP preparation process and stable flow, uniform mixing, and high stability, breaking through the technical barrier of the peristaltic pump in LNP preparation, meeting the characteristics that the LNP preparation is very sensitive to the pulse, realizing reliable LNP preparation, and making the particle size uniformity, encapsulation efficiency, and batch consistency of the prepared lipid nanoparticles meet the strict pharmaceutical production requirements, thereby meeting the production needs of advanced therapies such as individualized tumor vaccines.

[0082] Figure 6 The structure of the electronic device is shown in Figure 6 As shown in FIG. 7, the electronic device 700 is in the form of a general computing device. The components of the electronic device 700 include, but are not limited to, at least one processing unit 710, at least one storage unit 720, a bus 730 connecting different platform components (including the storage unit 720 and the processing unit 710), etc.

[0083] The storage unit 720 stores program codes which can be executed by the processing unit 710 to cause the processing unit 710 to perform the continuous flow preparation process of the lipid nanoparticle described in any of the embodiments above. The storage unit 720 can include a readable medium in the form of a volatile storage unit, such as a random access memory and / or a cache memory, and can further include a read-only memory. The storage unit 720 can also include programs / utilities having one or more program modules, including but not limited to an operating system, one or more application programs, other program modules, and program data, each of which or some combination of which can include the implementation of a network environment.

[0084] The bus 730 can represent one or more of several types of bus structures, including a storage unit bus or storage unit controller, a peripheral bus, a graphics acceleration port, a processing unit, or a local bus using any of a variety of bus structures.

[0085] The electronic device 700 can also communicate with one or more external devices such as a keyboard, a pointing device, a Bluetooth device, or a device that enables a user to interact with the electronic device 700. The electronic device 700 can also communicate with one or more other computing devices, such as a router, a modem, or a network adapter. Such communication can occur via the input / output interface. The electronic device 700 can also communicate with one or more networks, such as a personal area network, a local area network, a wide area network, or the Internet, via the network adapter. The network adapter can communicate with the other modules of the electronic device 700 via the bus 730.

[0086] The embodiments of the present application also provide a computer-readable storage medium for storing a program, which, when executed, implements the continuous flow preparation process of the lipid nanoparticle described in any of the embodiments above.

[0087] The storage medium of the present application can be executed by a processor deployed locally and / or remotely in a continuous flow preparation system of the lipid nanoparticle, to achieve dynamic adjustment of the phase and / or rotational speed of the peristaltic pump device based on real-time flow feedback, to actively suppress the periodic flow pulsation inherent in the peristaltic pump device, to make the flow into the microfluidic chip stable, to ensure the continuous LNP preparation process and stable flow, uniform mixing, and high stability, to break through the technical barrier of the peristaltic pump in LNP preparation, to meet the characteristics of LNP preparation being very sensitive to pulses, to achieve reliable LNP preparation, to make the particle size uniformity, encapsulation efficiency, and batch consistency of the lipid nanoparticles prepared meet the strict requirements of pharmaceutical production, and to further meet the production needs of advanced therapies such as personalized tumor vaccines.

[0088] The storage medium can be a portable compact disc read only memory (CD-ROM), and can include a program code, and can be executed on a terminal device, such as a personal computer. However, the storage medium of the present application is not limited thereto, and can be any tangible medium that contains or stores a program that can be used by or in connection with an instruction execution system, apparatus, or device.

[0089] The storage medium can employ any combination of one or more of a readable medium or media. The readable medium can be a readable signal medium or a readable storage medium. The readable storage medium can be, for example, but not limited to, an electronic, magnetic, optical, electromagnetic, infrared, or semiconductor system, apparatus, or device, or any suitable combination of the above. More specific examples of a readable storage medium include, but are not limited to, an electrical connection having one or more wires, a portable disc, a hard disk, a random access memory (RAM), a read-only memory (ROM), an erasable programmable read-only memory (EPROM or flash memory), an optical fiber, a portable compact disc read-only memory (CD-ROM), an optical storage device, a magnetic storage device, or any suitable combination of the above.

[0090] The readable signal medium can include a data signal that is propagated in or on a baseband signal or a carrier wave that is propagated in or on a carrier wave. Such a propagated signal can take any of a variety of forms, including but not limited to electro-magnetic, optical, or any suitable combination thereof. The readable signal medium can also be any readable medium that is not a readable storage medium and that can communicate, propagate, or transport programming for use by or in connection with an instruction execution system, apparatus, or device.

[0091] The program code can be executed entirely on the user computing device, partially on the user device, as a stand-alone software package, partially on the user computing device and partially on a remote computing device, or entirely on a remote computing device or server. In the case of a remote computing device, the remote computing device can be connected to the user computing device through any kind of network, or can be connected to an external computing device, such as an Internet service provider, through the Internet.

[0092] The embodiments of the present application also provide a computer program product, including a computer program that, when executed by a processor, implements the continuous flow preparation process of the lipid nanoparticle as described in any of the above embodiments.

[0093] The computer program product of the present application, when running on a terminal device and / or a remote device, can realize dynamic adjustment of the phase and / or rotating speed of the peristaltic pump device based on real-time flow feedback, actively suppress the periodic flow pulsation inherent in the peristaltic pump device, make the flow into the microfluidic chip tend to be stable, and ensure that the LNP preparation process continues and the flow is stable, the mixing is uniform, and the stability is high, thereby breaking through the technical barrier of peristaltic pumps in LNP preparation, meeting the characteristics that LNP preparation is very sensitive to pulses, realizing reliable LNP preparation, making the particle size uniformity, encapsulation efficiency, and batch consistency of the lipid nanoparticles prepared meet the strict pharmaceutical production requirements, and further meeting the production needs of advanced therapies such as personalized tumor vaccines.

[0094] Finally, it should be noted that the above content is a further detailed description of the present application in combination with specific preferred embodiments, and the specific implementation of the present application cannot be limited to these descriptions. For ordinary skilled persons in the technical field to which the present application belongs, without departing from the concept of the present application, a number of simple deductions or substitutions can be made, and all of them should be regarded as falling within the protection scope of the present application.

Claims

1. A continuous flow preparation system for lipid nanoparticles, characterized in that, include: Multiple peristaltic pump devices are configured to pump the multiple fluids required for the preparation of lipid nanoparticles. Each peristaltic pump device includes: a drive motor; and multiple sets of rollers driven by the drive motor, wherein each set of rollers includes at least one roller, each set of rollers acts on an independent pump tube, and the pump tubes of the multiple sets of rollers converge to the output pump tube of the peristaltic pump device; wherein the multiple sets of rollers are in different phases, such that the periodic flow pulsations generated by the multiple sets of rollers at least partially cancel each other out in the output pump tube; The controller is communicatively connected to the plurality of peristaltic pump devices and is configured to adjust the operating parameters of the corresponding peristaltic pump device based on the output flow of each peristaltic pump device, so as to suppress the periodic flow pulsation of the peristaltic pump device. The operating parameters include the rotational speed of the drive motor of the peristaltic pump device, and the controller is configured to reduce the rotational speed of the drive motor at the peak of the output flow of the peristaltic pump device and increase the rotational speed of the drive motor at the trough of the output flow of the peristaltic pump device. A microfluidic chip configured to receive and mix the multiple fluid streams to prepare the lipid nanoparticles, wherein each of the peristaltic pump devices is connected to a fluid inlet of the microfluidic chip.

2. The continuous flow preparation system as described in claim 1, characterized in that, Each of the peristaltic pump devices includes: Multiple pumping units, each pumping unit including a drive motor and at least one roller driven by the drive motor; The rollers of the multiple pumping units work together on the output pump tube of the peristaltic pump device, and the rollers of the multiple pumping units have different phases, so that the periodic flow pulsations generated by the multiple pumping units at least partially cancel each other out in the output pump tube. The operating parameters also include the operating phase difference of the drive motors of the plurality of pumping units.

3. The continuous flow preparation system as described in claim 1, characterized in that, Each of the peristaltic pump devices includes: Multiple peristaltic pump units, each peristaltic pump unit including a drive motor and at least one roller driven by the drive motor; In this configuration, the roller of each peristaltic pump unit acts on an independent pump tube, and the pump tubes of the multiple peristaltic pump units converge to the output pump tube of the peristaltic pump device. The peristaltic pump units are in different phases, such that the periodic flow pulsations generated by the peristaltic pump units at least partially cancel each other out in the output pump tube. The operating parameters also include the operating phase difference of the drive motors of the plurality of peristaltic pump units.

4. The continuous flow preparation system as described in claim 1, characterized in that, Also includes: A non-contact flow sensor is disposed at the outlet of each of the peristaltic pump devices and configured to monitor the output flow of each of the peristaltic pump devices.

5. A continuous flow preparation process for lipid nanoparticles, characterized in that, The process is achieved using a continuous flow preparation system for lipid nanoparticles as described in any one of claims 1 to 4, wherein the continuous flow preparation process includes: During the process of pumping the multi-channel fluid required for the preparation of lipid nanoparticles through multiple peristaltic pump devices, the output flow rate of each peristaltic pump device was monitored; Based on the output flow rate of each of the peristaltic pump devices, the operating parameters of the corresponding peristaltic pump devices are adjusted through a pulse suppression strategy to suppress the periodic flow pulsation of the peristaltic pump devices; The pulse suppression strategy includes adjusting the rotational speed of the drive motor of the peristaltic pump device to generate a compensating flow that at least partially cancels out its periodic flow pulsations, thereby controlling the error between the output flow of the peristaltic pump device and the target flow of the corresponding fluid. The speed compensation strategy includes: detecting the peaks and troughs of the output flow of the peristaltic pump device; when a peak is detected, reducing the speed of the drive motor of the peristaltic pump device; and when a trough is detected, increasing the speed of the drive motor of the peristaltic pump device.

6. The continuous flow preparation process as described in claim 5, characterized in that, The pulse suppression strategy further includes a phase difference control strategy, which includes: The operating phase difference of the multiple drive motors of the peristaltic pump device is adjusted so that the periodic flow pulsations generated by the multiple drive motors at least partially cancel each other out, thereby controlling the error between the output flow of the peristaltic pump device and the target flow of the corresponding fluid.

7. The continuous flow preparation process as described in claim 6, characterized in that, The phase difference control strategy is implemented based on a multi-axis synchronous control algorithm.

8. The continuous flow preparation process as described in claim 5, characterized in that, When the output flow rate of the peristaltic pump device is higher than the set value, or when several consecutive sampling points of the output flow rate of the peristaltic pump device are local maxima, it is determined that a peak has been detected. When the output flow rate of the peristaltic pump device is lower than the set value or several consecutive sampling points of the output flow rate of the peristaltic pump device are local minima, it is determined that a trough has been detected. Local extrema are determined by comparing the current sampling point with the sampling points before and after.

9. The continuous flow preparation process as described in claim 5, characterized in that, The speed compensation strategy is implemented based on the proportional-integral-derivative control algorithm.

10. The continuous flow preparation process as described in claim 9, characterized in that, The speed compensation strategy is executed according to the following formula: ； Among them, Q meas Q is the output flow rate of the peristaltic pump device. set For the target flow rate of the corresponding fluid, n now n represents the current rotational speed of the drive motor of the peristaltic pump unit. target K is the target speed of the drive motor of the peristaltic pump unit. p This is the proportional gain.

11. The continuous flow preparation process according to any one of claims 5 to 10, characterized in that, The speed compensation strategy is executed in accordance with one or more of the following: The sampling frequency of the output flow of the peristaltic pump device is greater than or equal to 100Hz; The speed adjustment interval of the drive motor of the peristaltic pump device is greater than the sampling frequency; The target speed of the drive motor of the peristaltic pump device is adjustable within the rated speed range.

12. An electronic device, characterized in that, include: processor; A memory, wherein executable instructions are stored; When the executable instructions are executed by the processor, the continuous flow preparation process of lipid nanoparticles as described in any one of claims 5 to 11 is realized.

13. A computer-readable storage medium for storing a program, characterized in that, When the program is executed by the processor, it implements a continuous flow preparation process for lipid nanoparticles as described in any one of claims 5 to 11.

14. A computer program product, comprising a computer program, characterized in that, When the computer program is executed by the processor, it implements a continuous flow preparation process for lipid nanoparticles as described in any one of claims 5 to 11.

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