Production process and quality control method of sugar-free levocarnitine oral solution based on production efficiency and quality

Abstract

The invention discloses a production process and a quality control method of a sugar-free levocarnitine oral solution based on production efficiency and quality, and relates to the technical field of medicine production quality detection. The levocarnitine oral solution quality control method based on production efficiency and quality comprises the following steps: preparing a sample; monitoring relative density; and adjusting the sample loading amount. According to the invention, the process parameters of the to-be-prepared sample in the preparation process are monitored in real time to judge whether to send the relative density monitoring instruction, and then the density change condition of the to-be-prepared sample in the relative density monitoring process is monitored in real time to judge whether to send the automatic loading volume adjusting instruction; and finally, based on the obtained adjustment stability index, judging whether to send an adjustment loading qualified instruction, so that the effect of improving the quality control efficiency in the loading adjustment process of the small-specification levocarnitine oral solution is achieved, and the problem of low quality control efficiency in the loading adjustment process of the small-specification levocarnitine oral solution in the prior art is solved.

Description

Technical Field

[0001] The invention relates to the technical field of drug production quality detection, and in particular to a production process of a sugar-free L-carnitine oral solution based on production efficiency and quality and a quality control method thereof. Background Art

[0002] With the continuous progress of medical technology and the improvement of people's health awareness, L-carnitine oral solution, as an important pharmaceutical product, has a growing market demand. L-carnitine oral solution is mainly used to prevent and treat L-carnitine deficiency, such as L-carnitine deficiency caused by hemodialysis in patients with chronic renal failure, and can also improve myocardial ischemia, anti-angina pectoris, etc. However, the traditional L-carnitine oral solution production process has problems such as low production efficiency and unstable quality control, which is difficult to meet the growing market demand. In order to solve these problems, it is particularly important to study and develop a sugar-free L-carnitine oral solution production process and its quality control method based on production efficiency and quality.

[0003] The existing technology monitors the operating status of the automated production equipment in real time, and uses high performance liquid chromatography to determine the content of L-carnitine in the L-carnitine oral solution, and then uses HPLC to check it. Finally, by comparing the ratio of the peak area of ​​each impurity peak in the sample chromatogram to the main peak area in the reference substance chromatogram, it is determined whether the impurity content meets the requirements.

[0004] For example, the invention patent announcement with announcement number: CN117890496B discloses a method for detecting related substances in a compound preparation of guaiac bromide oral solution, which includes: detecting related substances in the compound preparation of guaiac bromide oral solution by high performance liquid chromatography, and calculating the content of related substances in the compound preparation of guaiac bromide oral solution by area normalization method.

[0005] For example, the quality control method of diastereoisomers in arformoterol tartrate inhalation solution disclosed in the invention patent with publication number CN116298046B includes: determining the content of diastereoisomers in arformoterol tartrate inhalation solution by high performance liquid chromatography; if the content of diastereoisomers in arformoterol tartrate inhalation solution is greater than 1.0%, it is considered that the content of diastereoisomers in arformoterol tartrate inhalation solution does not meet the quality control standard.

[0006] However, in the process of implementing the technical solution of the invention in the embodiments of the present application, the present application found that the above technology has at least the following technical problems:

[0007] In the prior art, due to the poor thermal stability of small-sized preparations, small-sized preparations usually require low-temperature dissolution operations, which helps to reduce the generation of impurities, but the dissolution process of raw materials and excipients slows down, and the small dissolution difference of the small-sized preparations easily leads to a larger difference in the amount or content; and the process time required for conventional full dissolution is relatively long. The prior art often does not take into account the real-time changes of key parameters in the dissolution process, and cannot be automatically adjusted in time, resulting in the problem of low quality control efficiency during the adjustment of the amount of small-sized L-carnitine oral solution. Summary of the invention

[0008] The embodiment of the present application solves the problem of low quality control efficiency in the process of adjusting the filling amount of small-sized L-carnitine oral solutions in the prior art by providing a production process and quality control method of a sugar-free L-carnitine oral solution based on production efficiency and quality, thereby improving the quality control efficiency in the process of adjusting the filling amount of small-sized L-carnitine oral solutions.

[0009] The embodiment of the present application provides a production process of a sugar-free L-carnitine oral solution based on production efficiency and quality, including: weighing of raw and auxiliary materials, preparation of concentrated liquid samples, filling amount adjustment and packaging and warehousing; the weighing of raw and auxiliary materials is used to ensure that various raw materials and auxiliary materials required for the production of each batch of L-carnitine oral solution are weighed according to a preset ratio; the concentrated liquid sample preparation is used to mix and dissolve the weighed raw and auxiliary materials according to a preset process flow to form a uniform prepared sample; the filling amount adjustment is used to transport qualified prepared samples to a filling production line to automatically adjust the filling amount of each bottle of L-carnitine oral solution; the packaging and warehousing is used to automatically perform light inspection, packaging and warehousing on the filled L-carnitine oral solution.

[0010] The embodiment of the present application provides a quality control method for a production process of a sugar-free L-carnitine oral solution based on production efficiency and quality, which is used for the production process of the sugar-free L-carnitine oral solution based on production efficiency and quality, and comprises the following steps: step one, real-time monitoring of process parameters of the sample to be prepared during the preparation process to determine whether to send a relative density monitoring instruction; step two, real-time monitoring of density changes of the sample to be prepared during the relative density monitoring process to determine whether to send an automatic filling quantity adjustment instruction; step three, real-time monitoring of the filling quantity adjustment state of the sample to be filled and adjusted on the filling production line to obtain an adjustment stability index, and judging whether to send an adjustment filling quantity qualified instruction based on the obtained adjustment stability index, wherein the adjustment stability index is used to quantify the stability of the filling quantity adjustment of the sample to be filled and adjusted on the filling production line.

[0011] Furthermore, the specific steps of real-time monitoring the density change of the sample to be prepared during the relative density monitoring process include: after a preset preparation time period, obtaining the dissolving temperature of the sample to be prepared at the current preparation time and judging whether it is within the allowable range of the dissolving temperature in the database, if so, obtaining the clarity of the solution, otherwise sending a temperature adjustment instruction, the temperature adjustment instruction including a temperature reduction instruction and a temperature increase instruction; real-time monitoring of the stirring speed of the corresponding stirring equipment at the current preparation time during the preparation process of the sample to be prepared, and at the same time real-time monitoring of the solute in the sample to be prepared at the current preparation time. solubility and pH value; obtaining a preparation uniformity compliance index according to the obtained preparation parameters and in combination with the reference preparation parameters in the database, the preparation parameters including dissolution temperature, solution clarity, stirring speed, solubility and pH value, the reference preparation parameters including preparation uniformity compliance weight factor, maximum allowable dissolution temperature, reference stirring speed, reference pH value and reference pH deviation value, the preparation uniformity compliance weight factor including dissolution temperature weight factor, pH value weight factor and stirring speed weight factor, the preparation uniformity compliance index is used to quantify the degree of uniformity of the sample to be prepared during the preparation process.

[0012] Furthermore, the real-time monitoring of the density change of the sample to be prepared during the relative density monitoring process also includes obtaining the amount of purified water added according to the acquired relative density. The specific process is: L1, judging whether the acquired relative density is equal to the target relative density, if so, the amount of purified water added is recorded as 0, otherwise execute L2; L2, judging whether the acquired relative density is greater than the target relative density, if so, obtaining the amount of purified water added, otherwise sending a preparation failure instruction; the purified water addition amount represents the ratio of the product of the initial volume of the sample to be prepared before preparation and the relative density deviation to the target relative density; the relative density deviation represents the difference between the relative density and the target relative density.

[0013] Furthermore, the specific steps of real-time monitoring of the density change of the sample to be prepared during the relative density monitoring process include: when the obtained preparation uniformity compliance index is greater than the preparation uniformity compliance index preset in the database, obtaining the stirring speed and stirring frequency of the corresponding stirring equipment in the pH adjustment process at the current monitoring time, and simultaneously obtaining the relative density recovery time at the end of the current monitoring period, and combining the obtained purified water addition amount and the reference monitoring data in the database to obtain a relative density evaluation score; the relative density evaluation score is used to evaluate the relative density recovery efficiency of the sample to be prepared after adding purified water; the relative density recovery time indicates the time corresponding to the relative density deviation equal to 0 after adding purified water; the reference monitoring data includes a relative density evaluation weight factor as well as a reference stirring speed, a reference stirring frequency and a maximum allowable relative density recovery time; the relative density evaluation weight factor includes a stirring speed weight factor, a stirring frequency weight factor, a relative density recovery time weight factor, a first relative density evaluation weight factor and a second relative density evaluation weight factor.

[0014] Furthermore, the specific steps for obtaining the adjustment stability index are as follows: when the obtained relative density evaluation score is greater than the relative density evaluation score preset in the database, batch numbering is performed on the samples to be adjusted for quantity, and the adjustment response time score and the adjustment quantity score of the samples to be adjusted for quantity in the specified batch during the automated filling adjustment process are obtained; a preset adjustment stability weight factor is obtained from the database, and the adjustment stability index is obtained by combining the obtained adjustment stability data; the adjustment response time score represents the ratio of the absolute value of the difference between the adjustment response time and the reference adjustment response time to the reference adjustment response time; the adjustment response time score represents the ratio of the absolute value of the difference between the adjustment response time and the reference adjustment response time. The response time is used to reflect the response rate of the controller on the corresponding filling production line when the volume of the designated batch of samples to be filled and adjusted changes; the adjusted volume score represents the ratio of the absolute value of the difference between the actual adjusted volume and the reference adjusted volume to the reference adjusted volume; the adjustment stability weight factor includes the volume adjustment response time score weight factor, the adjustment volume score weight factor, the preparation uniformity compliance index weight factor, the relative density evaluation score weight factor, the first adjustment stability weight factor and the second adjustment stability weight factor; the adjustment stability data includes the volume adjustment response time score, the adjustment volume score, the preparation uniformity compliance index and the relative density evaluation score.

[0015] Furthermore, the specific limiting expression of the adjustment stability index is:

[0016]

[0017] Where i is the batch number of the sample to be filled, i = 1, 2, ..., U, U is the total number of batches of the sample to be filled, e is a natural constant, JW represents the adjustment stability index of the sample to be filled on the filling production line, y 5 represents the first adjustment stability weight factor, y 1 represents the weight factor of the response time of loading adjustment, X i represents the fraction of the response time of the i-th batch of samples to be filled during the automatic filling adjustment process, y 2 represents the weight factor for adjusting the loading fraction, J i represents the adjusted filling volume fraction of the i-th batch of samples to be filled in the automated filling volume adjustment process, y 6 represents the second adjustment stability weight factor, y 3 represents the preparation uniformity index weight factor, PY represents the preparation uniformity index of the sample to be prepared during the preparation process, y 4 represents the relative density assessment score weight factor, and XD represents the relative density assessment score of the sample to be prepared during the relative density monitoring process.

[0018] In the absence of additional instructions, the "L-carnitine oral solution" described in the present invention refers to a small-size L-carnitine oral solution prepared from L-carnitine, DL-malic acid, sodium saccharin, sodium benzoate, pH regulator (hydrochloric acid aqueous solution) and purified water, wherein the amount of L-carnitine is 100g / 1000ml. The product specifications are 2.5ml / tube or 10ml / tube.

[0019] One or more technical solutions provided in the embodiments of the present application have at least the following technical effects or advantages:

[0020] 1. By real-time monitoring of the process parameters of the sample to be prepared during the preparation process to determine whether to send a relative density monitoring instruction, then real-time monitoring of the density change of the sample to be prepared during the relative density monitoring process to determine whether to send an automatic adjustment filling instruction, and finally determining whether to send an adjustment filling qualified instruction based on the obtained adjustment stability index, the stability of the automatic adjustment filling of the sample to be filled is improved, and the quality control efficiency in the adjustment filling process of the small-size L-carnitine oral solution is improved, which effectively solves the problem of low quality control efficiency in the adjustment filling process of the small-size L-carnitine oral solution in the prior art.

[0021] 2. By obtaining the stirring speed and stirring frequency of the corresponding stirring equipment at the current monitoring time during the pH adjustment process, and at the same time obtaining the relative density recovery time at the end of the current monitoring period, and combining the obtained purified water addition amount and the reference monitoring data in the database to obtain the relative density evaluation score, the accuracy of obtaining the relative density evaluation score is improved, thereby achieving a more accurate evaluation of the relative density recovery efficiency of the sample to be prepared.

[0022] 3. By batch numbering the samples for the amount to be adjusted, and then obtaining the filling adjustment response time score and the adjustment filling score of the specified batch of samples for the amount to be adjusted during the automated filling adjustment process, finally obtaining the preset adjustment stability weight factor from the database, and combining the obtained adjustment stability data to obtain the adjustment stability index, thereby achieving an improved accuracy in obtaining the adjustment stability index, and further achieving a more accurate evaluation of the filling adjustment stability of the samples for the amount to be adjusted. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 A flow chart of a quality control method for a production process of a sugar-free L-carnitine oral solution based on production efficiency and quality provided in an embodiment of the present application;

[0024] Figure 2 A specific flow chart of the quality control of the L-carnitine oral solution provided in the embodiments of the present application;

[0025] Figure 3 This is the HPLC chromatogram of the prepared small-scale L-carnitine oral solution provided in the examples of the present application. DETAILED DESCRIPTION

[0026] The embodiment of the present application solves the problem of low quality control efficiency in the process of adjusting the filling amount of small-sized L-carnitine oral solutions in the prior art by providing a production process and quality control method of a sugar-free L-carnitine oral solution based on production efficiency and quality. The process parameters of the sample to be prepared in the preparation process are monitored in real time to obtain a preparation uniformity compliance index, and at the same time, based on the obtained preparation uniformity compliance index, it is determined whether to send a relative density monitoring instruction. Then, the concentration change of the sample to be concentrated in the relative density monitoring process is monitored in real time to obtain a relative density evaluation score, and at the same time, based on the obtained relative density evaluation score, it is determined whether to send an automatic adjustment filling amount instruction. Finally, the filling amount adjustment state of the sample to be adjusted on the filling production line is monitored in real time to obtain an adjustment stability index, and at the same time, based on the obtained adjustment stability index, it is determined whether to send an adjustment filling amount qualified instruction, thereby achieving an improvement in the quality control efficiency in the process of adjusting the filling amount of small-sized L-carnitine oral solutions.

[0027] The technical solution in the embodiment of the present application is to solve the problem of low quality control efficiency during the adjustment and filling process of the above-mentioned small-sized L-carnitine oral solution. The overall idea is as follows:

[0028] By real-time monitoring of the process parameters of the sample to be prepared during the preparation process to determine whether to send a relative density monitoring instruction, and then real-time monitoring of the density change of the sample to be prepared during the relative density monitoring process to determine whether to send an automatic adjustment filling instruction, and finally based on the obtained adjustment stability index, it is determined whether to send an adjustment filling qualified instruction, thereby achieving the effect of improving the quality control efficiency in the adjustment filling process of small-size L-carnitine oral solution.

[0029] In order to better understand the above technical solution, the above technical solution will be described in detail below in conjunction with the accompanying drawings and specific implementation methods.

[0030] The embodiment of the present application provides a production process of L-carnitine oral solution based on production efficiency and quality, including: weighing of raw and auxiliary materials, preparation of concentrated liquid samples, filling amount adjustment and packaging and warehousing; the weighing of raw and auxiliary materials is used to ensure that various raw materials and auxiliary materials required for the production of each batch of L-carnitine oral solution are weighed according to a preset ratio; the concentrated liquid sample preparation is used to mix and dissolve the weighed raw and auxiliary materials according to a preset process flow to form a uniform prepared sample; the filling amount adjustment is used to transport qualified prepared samples to a filling production line to automatically adjust the filling amount of each bottle of L-carnitine oral solution; the packaging and warehousing is used to automatically perform light inspection, packaging and warehousing on the L-carnitine oral solution after filling.

[0031] In this embodiment, the specific process of the production process of L-carnitine oral solution is as follows:

[0032] (1) Weighing of raw and auxiliary materials: According to the production instructions, weigh the raw and auxiliary materials required for production, label the materials and keep them ready for use.

[0033] (2) Preparation of concentrated liquid samples: Prepare the sample in a concentrated liquid tank, and add purified water accounting for about 80% of the total volume of the sample to the liquid preparation tank. During the preparation process, the temperature of the purified water and the stirring frequency of the agitator in the stirring device need to be monitored in real time to keep the temperature of the purified water at 10°C-30°C and the stirring frequency of the agitator in the stirring device at 30Hz-50Hz.

[0034] Add sodium benzoate, rinse the container with an appropriate amount of purified water and add it to the preparation tank, stir for 10 minutes until the solution becomes clear.

[0035] Add L-carnitine, rinse the container with an appropriate amount of purified water and add it to the preparation tank, stir for 15 minutes until the solution becomes clear.

[0036] Add D-malic acid, rinse the container with an appropriate amount of purified water and add it to the preparation tank, stir for 10 minutes until the solution is clear.

[0037] Add saccharin sodium, rinse the container with an appropriate amount of purified water and add it to the preparation tank, stir for 10 minutes until the solution is clear.

[0038] Use 5 mol / L hydrochloric acid solution to adjust the solution pH to the target range of 4.50-4.65, continue stirring for 30 minutes, and take the relative density of the sample to be prepared.

[0039] According to the relative density of the sample to be prepared, add purified water to the total preparation amount. After circulating stirring for 30 minutes, take the middle sample to be prepared for testing.

[0040] (3) Filling volume adjustment: The drug solution is filtered through a 5μm titanium rod filter for 30 minutes until the solution clarity is qualified. After the intermediate sample to be prepared is qualified (i.e., the sample to be adjusted in filling volume), the drug solution is filtered to the filling production line for automatic adjustment of filling volume, filling, and capping.

[0041] (4) Qualified products (i.e. small batches of L-carnitine oral solution) filled with 2.5ml:0.25g or 10ml:1g are inspected by light, packaged, and stored.

[0042] This preparation process is the best process obtained after the method and system are optimized. In terms of process preparation efficiency, the preparation time of each batch of products is shortened by about 2 hours. In terms of the difference in active drug content between product batches, the content difference is 1-2% (less than 5%) of the specified content (100g / 1000ml); in terms of impurity content, the total impurity content is less than 0.5%. The chromatographic conditions for related substance detection and active drug content detection are the same as the quality standard for L-carnitine in the Pharmacopoeia of the People's Republic of China.

[0043] like Figure 1 As shown, it is a flow chart of a quality control method for a production process of a sugar-free L-carnitine oral solution based on production efficiency and quality provided in an embodiment of the present application. A quality control method for a production process of a sugar-free L-carnitine oral solution based on production efficiency and quality provided in an embodiment of the present application is used for a production process of a sugar-free L-carnitine oral solution based on production efficiency and quality, and includes the following steps: step one, real-time monitoring of process parameters of the sample to be prepared during the preparation process to determine whether to send a relative density monitoring instruction; step two, real-time monitoring of density changes of the sample to be prepared during the relative density monitoring process to determine whether to send an automatic filling amount adjustment instruction; step three, real-time monitoring of the filling amount adjustment state of the sample to be filled on the filling production line to obtain an adjustment stability index, and judging whether to send an adjustment filling amount qualified instruction based on the obtained adjustment stability index, and the adjustment stability index is used to quantify the stability of the filling amount adjustment of the sample to be filled on the filling production line.

[0044] In this embodiment, the small-size batch of L-carnitine oral solution in this example is a 2.5 ml:0.25 g or 10 ml:1 g batch of L-carnitine oral solution; the process parameters include but are not limited to stirring speed, dissolution temperature, preparation time, solute pH and solution clarity, wherein the stirring speed is directly displayed on the digital display screen on the tachometer, the dissolution temperature is measured by an infrared thermometer, the preparation time is recorded by a timer, the solute pH is measured by a pH meter, and the solution clarity is measured by a spectrophotometer.

[0045] like Figure 2 As shown, it is a specific flow chart of the quality control of the L-carnitine oral solution provided in the embodiment of the present application. The quality control method of this example focuses more on preventive quality control. Through real-time monitoring and automatic adjustment, intervention can be carried out before problems occur, thereby avoiding rework and cost increase caused by quality problems. Secondly, by quantifying the adjustment stability index of the sample to be filled on the filling production line, the stability of the production process can be more accurately evaluated, which helps to timely discover and solve potential quality problems, ensure the stability and consistency of the final product, and realize precise control of the production process. While ensuring the stability of the filling adjustment, the production efficiency and product quality are effectively improved, thereby realizing the improvement of the quality control efficiency in the process of adjusting the filling amount of small-sized L-carnitine oral solution.

[0046] Furthermore, the specific steps of real-time monitoring the density change of the sample to be prepared during the relative density monitoring process include: after a preset preparation time period, obtaining the dissolution temperature of the sample to be prepared at the current preparation time and determining whether it is within the allowable range of the dissolution temperature in the database, if so, obtaining the clarity of the solution, otherwise sending a temperature adjustment instruction, the temperature adjustment instruction including a temperature reduction instruction and a temperature increase instruction; real-time monitoring of the stirring speed of the stirring device corresponding to the sample to be prepared at the current preparation time during the preparation process, and real-time monitoring of the solubility and pH value of the solute in the sample to be prepared at the current preparation time; obtaining a preparation uniformity compliance index based on the obtained preparation parameters and in combination with the reference preparation parameters in the database, the preparation parameters including dissolution temperature, solution clarity, stirring speed, solubility and pH value, the reference preparation parameters including preparation uniformity compliance weight factor, maximum allowable dissolution temperature, reference stirring speed, reference pH value and reference pH deviation value, the preparation uniformity compliance weight factor including dissolution temperature weight factor, pH value weight factor and stirring speed weight factor, and the preparation uniformity compliance index is used to quantify the uniformity degree of the sample to be prepared during the preparation process.

[0047] Among them, the specific limiting expression for the uniform compliance index is:

[0048]

[0049] Where n is the number of the current preparation time in the preparation process, n = 1, 2, ..., N, N is the total number of the current preparation time in the preparation process, PY represents the preparation uniformity index of the sample to be prepared in the preparation process, β 1 represents the melting temperature weight factor, W n represents the melting temperature of the sample to be prepared at the current preparation time n, W max Indicates the maximum allowable melting temperature, β 2 represents the pH weight factor, H n It represents the pH value of the solute in the sample to be prepared at the current preparation time n, H 0 Indicates the reference pH value, ΔH 0 Indicates the reference pH deviation value, β 3 represents the stirring speed weight factor, C n Indicates the solution clarity of the sample to be prepared at the current preparation time n, S n It indicates the stirring speed of the stirring device at the current preparation time n during the preparation process of the sample to be prepared, S 0 represents the reference stirring speed, b n It indicates the solubility of the solute in the sample to be prepared at the current preparation time n.

[0050] In this embodiment, the preset personnel prepare a series of solutions of different concentrations, oscillate them to equilibrium under constant temperature conditions (such as room temperature 22° C.), and then measure the actual concentration of the solute in the sample to be prepared, thereby obtaining the solubility of the solute in the sample to be prepared.

[0051] The maximum allowable dissolution temperature represents the maximum value of the historical dissolution temperatures of the samples to be prepared in the database at each historical preparation time. The reference pH value and the reference pH deviation value are respectively represented by the sum and average of the historical pH values ​​and historical pH deviation values ​​of the solutes in the samples to be prepared in the database at each historical preparation time. The reference stirring speed is represented by the sum and average of the historical stirring speeds of the corresponding stirring equipment at each historical preparation time during the preparation process of the samples to be prepared in the database.

[0052] The database stores preset weight factors that are closely related to the preparation uniformity compliance index. A predefined mapping relationship is established between these weight factors and the corresponding evaluation indicators. It is worth noting that this mapping is not set arbitrarily. It can be an accurate one-to-one correspondence or a flexible many-to-one relationship. In practical applications, when it is necessary to evaluate the preparation and mixing effect of the prepared sample, the real-time dissolution temperature, pH value and stirring speed can be directly input into this preset mapping relationship, which can quickly and accurately extract the dissolution temperature weight factor, pH value weight factor and stirring speed weight factor that match the current preparation uniformity compliance index.

[0053] It is particularly important that, in order to ensure the consistency and comparability of the evaluation, the value ranges of the dissolution temperature weight factor, the pH value weight factor and the stirring speed weight factor are strictly limited to between 0 and 1, and the sum of the three is 1.

[0054] The aforementioned database is a database for storing various set data established before the design of the quality control method of the production process of the sugar-free L-carnitine oral solution based on production efficiency and quality. The database includes but is not limited to the allowable range of dissolution temperature, the preset preparation uniformity compliance index, the preset relative density evaluation score, the preset adjustment stability index and the current monitoring period. The various values ​​therein are directly set by technical personnel. Among them, the setting basis of the allowable range of dissolution temperature can be determined according to the actual preparation scenario of the sample to be concentrated. For example, the allowable range of dissolution temperature represents the range corresponding to the maximum and minimum values ​​of the historical dissolution temperature of the sample to be concentrated at each preparation time in the database. In addition, various values ​​in the database can be set and fine-tuned by technical personnel according to actual debugging.

[0055] Specifically, the allowable range of the dissolution temperature in this example includes the maximum and minimum values ​​of the historical dissolution temperature; the solubility factor and the stirring speed fraction (i.e. ) is limited to a value range of 0 to 1; the trigger condition for the temperature reduction instruction is that the melt temperature is less than the minimum value of the historical melt temperature in the database, which is usually used to prompt the preset personnel to reduce the melt temperature by increasing the number of cooling equipment; the temperature increase instruction is that the melt temperature is greater than the maximum value of the historical melt temperature in the database, which is usually used to prompt the preset personnel to increase the melt temperature by increasing the number of heating equipment.

[0056] It should be understood that the formulation uniformity index increases with the increase of dissolution temperature and solution clarity, and decreases with the pH deviation (i.e. |H n -H 0 |) and stirring speed deviation (i.e. |S n -S 0 |) increases, and the reference pH deviation value and the reference stirring speed are not equal to 0.

[0057] It should be noted that the dissolution temperature also indirectly affects the value of the stirring speed deviation. When the dissolution temperature decreases, the viscosity of the sample solution to be prepared will increase, and the agitator will need to exert greater force to overcome the resistance for stirring, which may lead to reduced stirring efficiency or even failure to achieve the expected stirring effect. In this case, the stirring speed deviation may also increase because the agitator may not be able to run at a constant speed.

[0058] The clarity of the solution also indirectly affects the value of the reference pH deviation. When the clarity of the solution increases, it means that there are fewer suspended matter or impurities in the sample solution to be prepared, which helps to more accurately measure the pH value of the sample to be prepared. When the clarity of the solution decreases, there are more suspended matter or impurities in the sample solution to be prepared. These substances may react with the pH indicator or interfere with the contact between the electrode of the pH meter and the solution, thereby causing the deviation of the pH measurement value to increase, that is, the pH deviation value increases.

[0059] By considering the above-mentioned indirect influence mechanism, the relationship between the preparation uniformity compliance index and each variable can be more comprehensively understood, which helps the preset personnel to reduce the pH measurement deviation and ionic strength interference by improving the clarity of the solution and reducing the content of suspended matter or impurities, thereby improving the quality and stability of the product, thereby achieving the improvement of the quality control efficiency in the process of adjusting the filling amount of small-sized L-carnitine oral solution, and effectively solving the problem of low quality control efficiency in the process of adjusting the filling amount of small-sized L-carnitine oral solution in the prior art.

[0060] Furthermore, the specific process for determining whether to send a relative density monitoring instruction is as follows: determine whether the obtained preparation uniformity compliance index is greater than the preparation uniformity compliance index preset in the database: if the obtained preparation uniformity compliance index is greater than the preparation uniformity compliance index preset in the database, it indicates that the preparation uniformity of the prepared sample meets the expected requirements and a relative density monitoring instruction is sent; if the obtained preparation uniformity compliance index is not greater than the preparation uniformity compliance index preset in the database, a solution adjustment pH check instruction is sent and the pH is re-adjusted; the relative density monitoring instruction is used to obtain the relative density of the sample to be prepared; the relative density is used to reflect the ratio of the solution density in the sample to be prepared to the density of purified water; the solution adjustment pH check instruction is used to prompt the preset personnel to test the pH of the adjusted solution to determine whether it is within the target pH range.

[0061] In this embodiment, the preset preparation uniformity compliance index is represented by the result of summing and averaging the historical preparation uniformity compliance indexes of the samples to be prepared in the historical preparation process in the database; when the obtained preparation uniformity compliance index is greater than the preset preparation uniformity compliance index in the database, it indicates that the sample to be prepared is qualified. Figure 3 As shown, it is the HPLC chromatogram of the small-scale L-carnitine oral solution after preparation provided in the embodiment of the present application, which shows the separation of the two main components in the 2.5ml:0.25g L-carnitine oral solution on the chromatographic column, wherein the first peak represents the main component in the sample to be prepared - L-carnitine, and the marked "16.573" represents the retention time of L-carnitine, and "mAU" is the vertical coordinate unit of the chromatogram -.

[0062] The second peak represents the impurity component in the sample to be prepared, and its labeled "19.645" also indicates the retention time of the impurity in the chromatogram. In addition, the chromatogram is also labeled with the time unit "min", indicating that the time scale of the horizontal axis is in minutes. As a typical chromatogram of the oral liquid prepared by the optimal process obtained after the preparation process is optimized by the method and system, the total impurity content calculated by the peak area of ​​the external standard method is less than 0.5%.

[0063] Comprehensive analysis shows that the HPLC (High Performance Liquid Chromatography) chromatogram shows that the prepared small-scale L-carnitine oral solution contains both the main ingredient L-carnitine and a certain amount of impurities. In order to ensure the quality and safety of the drug, the impurity content in the solution needs to be strictly controlled to meet the relevant pharmacopoeia regulations or quality standards.

[0064] The adjustment solution in this example is a 5 mol / L hydrochloric acid solution, and the target pH range is usually 4.50-4.65. pH adjustment is usually used to add 5 mol / L hydrochloric acid solution to the prepared sample and continue stirring for 30 minutes. This example avoids the subjectivity and uncertainty that may be caused by manual judgment through automated judgment and instruction sending processes, thereby improving quality control efficiency.

[0065] Furthermore, the density change of the sample to be prepared during the relative density monitoring process is monitored in real time, which also includes obtaining the amount of purified water added according to the obtained relative density. The specific process is: L1, judging whether the obtained relative density is equal to the target relative density, if so, the amount of purified water added is recorded as 0, otherwise execute L2; L2, judging whether the obtained relative density is greater than the target relative density, if so, obtaining the amount of purified water added, otherwise sending a preparation failure instruction; the amount of purified water added represents the ratio of the product of the initial volume of the sample to be prepared before preparation and the relative density deviation to the target relative density; the relative density deviation represents the difference between the relative density and the target relative density.

[0066] In this embodiment, by real-time monitoring of the relative density of the sample to be prepared and calculating the amount of purified water to be added based on the result, the waste caused by blindly adding purified water is avoided, and the waste of raw materials and time caused by unqualified preparation is also reduced. Secondly, the process realizes intelligent control and management of the production process of the sample to be prepared through real-time monitoring, automatic calculation and instant feedback.

[0067] Furthermore, the specific steps of real-time monitoring of the density change of the sample to be prepared during the relative density monitoring process include: when the obtained preparation uniformity compliance index is greater than the preparation uniformity compliance index preset in the database, obtaining the stirring speed and stirring frequency of the corresponding stirring equipment at the current monitoring time during the pH adjustment process, and at the same time obtaining the relative density recovery time at the end of the current monitoring period, and combining the obtained purified water addition amount and the reference monitoring data in the database to obtain the relative density evaluation score; the relative density evaluation score is used to evaluate the relative density recovery efficiency of the sample to be prepared after adding purified water; the relative density recovery time indicates the time corresponding to the relative density deviation equal to 0 after adding purified water; the reference monitoring data includes a relative density evaluation weight factor as well as a reference stirring speed, a reference stirring frequency and a maximum allowable relative density recovery time; the relative density evaluation weight factor includes a stirring speed weight factor, a stirring frequency weight factor, a relative density recovery time weight factor, a first relative density evaluation weight factor and a second relative density evaluation weight factor.

[0068] Among them, the specific limiting expression of the relative density evaluation score is:

[0069]

[0070] Wherein, m is the number of the current monitoring moment in the current monitoring period, m = 1, 2, ..., M, M is the total number of the current monitoring moments in the current monitoring period, e is a natural constant, XD represents the relative density evaluation score of the sample to be prepared during the relative density monitoring process, and a 4 represents the first relative density assessment weight factor, a 1 represents the stirring speed weight factor, V m Indicates the stirring speed of the corresponding stirring device at the current monitoring time m during the pH adjustment process, V 0 Indicates the reference stirring speed, a 2 represents the stirring frequency weight factor, L m Indicates the stirring frequency of the corresponding stirring device at the current monitoring time m during the pH adjustment process, L 0 represents the reference stirring frequency, a 5 represents the second relative density assessment weight factor, BU represents the amount of purified water added to the sample to be prepared at the beginning of relative density monitoring, a 3 represents the relative density recovery time weight factor, T represents the relative density recovery time of the sample to be prepared at the end of the current monitoring period, T max Indicates the maximum allowable relative density recovery time, PY indicates the uniformity index of the sample to be prepared during the preparation process, PY 0 Indicates the preset configuration uniformity index.

[0071] In this embodiment, the stirring frequency is obtained by a frequency sensor, the relative density recovery time is obtained by recording a timer, the reference stirring frequency is represented by the sum and average of the historical stirring frequencies of the corresponding stirring equipment at each historical monitoring time during the pH adjustment process in the data, and the maximum allowable relative density recovery time represents the maximum value of the historical relative density recovery time of the sample to be prepared in the database at the end of each historical monitoring period.

[0072] The stirring speed weight factor, stirring frequency weight factor and relative density recovery time weight factor are the influence of the stirring speed, stirring frequency and relative density recovery time preset in the database on the relative density assessment score acquisition process. Specifically, the database stores preset weight factors corresponding to the stirring speed, stirring frequency and relative density recovery time. There is a pre-set mapping relationship between these weight factors and the stirring speed, stirring frequency and relative density recovery time. This mapping relationship can be one-to-one or many-to-one. In practical applications, the real-time stirring speed, stirring frequency and relative density recovery time can be input into this mapping relationship to quickly obtain the corresponding weight factor, which provides an important quantitative indicator for evaluating the accuracy and reliability of the relative density recovery efficiency, and then more accurately calculates the relative density assessment score.

[0073] In this example, the value ranges of the stirring speed weight factor, the stirring frequency weight factor, and the relative density recovery time weight factor are all limited to between 0 and 1, and the sum of the three is 1.

[0074] The first relative density assessment weight factor and the second relative density assessment weight factor are respectively a first relative density assessment score (i.e. ) and the second relative density evaluation score (i.e. ) respectively affect the relative density assessment score acquisition process. Specifically, preset weight factors corresponding to the first relative density assessment score and the second relative density assessment score are stored in the database. There is a pre-set mapping relationship between these weight factors and the first relative density assessment score and the second relative density assessment score. This mapping relationship can be one-to-one or many-to-one. In practical applications, the real-time first relative density assessment score and the second relative density assessment score can be input into this mapping relationship, so as to quickly obtain the corresponding weight factors, which provides an important quantitative indicator for evaluating the accuracy and reliability of relative density recovery efficiency, and then more accurately calculates the relative density assessment score.

[0075] In this example, the value ranges of the first relative density evaluation score and the second relative density evaluation score are both limited to between 0 and 1, and the sum of the two is 1.

[0076] It should be understood that the relative density assessment score increases with the increase of stirring speed and stirring frequency, and decreases with the increase of purified water addition amount and relative density recovery time. Among them, the stirring speed and stirring frequency also indirectly affect the value of the purified water addition amount. When the stirring speed increases, the collision frequency between the solute molecules and the solvent molecules in the solution increases, thereby accelerating the dissolution process of the solute. Since the stirring speed affects the dissolution rate and the uniformity of the solution, that is, when the stirring speed increases, less purified water may be needed to achieve the target relative density. Similarly, when the stirring frequency increases, the corresponding purified water addition amount also decreases accordingly.

[0077] The amount of purified water added also indirectly affects the value of the relative density recovery time. When the amount of purified water added is increased, the purified water will dilute the solutes in the solution, thereby reducing the relative density. Therefore, the amount of purified water added directly affects the change in relative density. When the amount of purified water added increases, it will take a longer time to reach the target relative density again because more solutes are needed to balance the newly added water molecules.

[0078] By considering the above-mentioned indirect influence mechanism, it is helpful to avoid excessive or insufficient addition of water, thereby maintaining the stability of relative density, which helps to improve the accuracy and efficiency of the preparation process, thereby achieving the improvement of the quality control efficiency in the process of adjusting the filling amount of small-sized L-carnitine oral solution, and effectively solving the problem of low quality control efficiency in the process of adjusting the filling amount of small-sized L-carnitine oral solution in the prior art.

[0079] Furthermore, the specific process for determining whether to send an automatic adjustment filling quantity instruction is as follows: determine whether the obtained relative density assessment score is greater than the relative density assessment score preset in the database: if the obtained relative density assessment score is greater than the relative density assessment score preset in the database, the corresponding sample to be prepared will be recorded as a sample to be adjusted in filling quantity, and an automatic adjustment filling quantity instruction will be sent; if the obtained relative density assessment score is not greater than the relative density assessment score preset in the database, a relative density detection failure instruction will be sent, and relative density monitoring will be performed again.

[0080] In this embodiment, the preset relative density assessment score is represented by the sum and average of the historical relative density assessment scores of the samples to be prepared in the database during the historical relative density monitoring process; this example automatically determines whether to send an automatic adjustment filling quantity instruction, which helps to improve product quality, production efficiency and resource allocation efficiency, reduce human errors and production costs, and at the same time, provides strong support for the digital transformation and intelligent upgrading of the pharmaceutical industry.

[0081] Furthermore, the specific steps for obtaining the adjustment stability index are as follows: when the obtained relative density evaluation score is greater than the relative density evaluation score preset in the database, the samples to be adjusted for loading are batch-numbered, and the loading adjustment response time score and the adjustment loading score of the samples to be adjusted for loading in the specified batch during the automated loading adjustment process are obtained; a preset adjustment stability weight factor is obtained from the database, and the adjustment stability index is obtained by combining the obtained adjustment stability data; the loading adjustment response time score represents the ratio of the absolute value of the difference between the loading adjustment response time and the reference loading adjustment response time to the reference loading adjustment response time; the loading adjustment response time score represents the ratio of the absolute value of the difference between the loading adjustment response time and the reference loading adjustment response time. The response time is used to reflect the response rate of the controller on the corresponding filling production line when the filling volume of the designated batch of samples to be filled and adjusted changes; the adjustment filling volume score represents the ratio of the absolute value of the difference between the actual adjustment filling volume and the reference adjustment filling volume to the reference adjustment filling volume; the adjustment stability weight factor includes the filling volume adjustment response time score weight factor, the adjustment filling volume score weight factor, the preparation uniformity compliance index weight factor, the relative density assessment score weight factor, the first adjustment stability weight factor and the second adjustment stability weight factor; the adjustment stability data includes the filling volume adjustment response time score, the adjustment filling volume score, the preparation uniformity compliance index and the relative density assessment score.

[0082] Among them, when the obtained relative density evaluation score is greater than the relative density evaluation score preset in the database, the specific restriction expression for adjusting the stability index is:

[0083]

[0084] Where i is the batch number of the sample to be filled, i = 1, 2, ..., U, U is the total number of batches of the sample to be filled, e is a natural constant, JW represents the adjustment stability index of the sample to be filled on the filling production line, y 5 represents the first adjustment stability weight factor, y 1 represents the weight factor of the response time of loading adjustment, X i Indicates the fraction of the response time of the i-th batch of samples to be filled during the automatic filling adjustment process, X1 i Indicates the response time of the i-th batch of samples to be filled during the automatic filling adjustment process, X1 0 Indicates the reference loading adjustment response time, y 2 represents the weight factor for adjusting the loading fraction, J i J1 represents the adjusted filling volume score of the i-th batch of samples to be filled in the automatic filling volume adjustment process, i Indicates the actual adjusted loading volume of the i-th batch of samples to be loaded during the automated loading volume adjustment process, J1 0 Indicates reference adjustment loading, y 6represents the second adjustment stability weight factor, y 3 represents the preparation uniformity index weight factor, PY represents the preparation uniformity index of the sample to be prepared during the preparation process, y 4 represents the relative density assessment score weight factor, and XD represents the relative density assessment score of the sample to be prepared during the relative density monitoring process.

[0085] In this embodiment, the response time for adjusting the loading quantity is recorded by a time measuring instrument, the actual adjusted loading quantity is measured by a liquid level meter, and the reference loading quantity adjustment response time and the reference adjusted loading quantity are respectively represented by the sum and average of the historical loading quantity adjustment response time and the historical adjusted loading quantity of each batch of samples to be adjusted in the database in the historical automated loading quantity adjustment process.

[0086] The database stores preset weight factors closely related to the adjustment stability index. A pre-defined mapping relationship is established between these weight factors and the corresponding loading adjustment response time score, adjustment loading score, preparation uniformity compliance index and relative density assessment score. It is worth noting that this mapping is not set arbitrarily. It can be one-to-one or many-to-one. In actual applications, when it is necessary to conduct a stability assessment on the samples to be adjusted during the loading adjustment process, the real-time loading adjustment response time score, adjustment loading score, preparation uniformity compliance index and relative density assessment score can be directly input into this preset mapping relationship, so that the loading adjustment response time score weight factor, adjustment loading score weight factor, preparation uniformity compliance index weight factor and relative density assessment score weight factor that match the adjustment stability index can be quickly and accurately extracted.

[0087] What is particularly important is that in order to ensure the consistency and comparability of the evaluation, the value ranges of the loading adjustment response time score weight factor, the loading adjustment score weight factor, the preparation uniformity compliance index weight factor and the relative density assessment score weight factor in this example are strictly limited to between 0 and 1, and the sum of the four is 1.

[0088] The first adjustment stability weight factor and the second adjustment stability weight factor are respectively the corresponding weight factors in the process of obtaining the adjustment stability index in the preset database, which represent the numerical values ​​corresponding to the degree of influence of the first adjustment stability index and the second adjustment stability index on the adjustment stability index. When used, the corresponding weight factors can be directly obtained from the database, and the corresponding relationship can be a pre-set mapping relationship. For example, the first adjustment stability index corresponding to the first adjustment stability index in the process of obtaining the adjustment stability index and the weight factor corresponding to the first adjustment stability index in the database form a mapping set, and the real-time first adjustment stability index is input into the mapping set to obtain the corresponding first adjustment stability index weight factor. Similarly, the real-time second adjustment stability index is input into the mapping set to obtain the corresponding second adjustment stability index weight factor, and the mapping relationship can be one-to-one or many-to-one. In this example, the value ranges of the first adjustment stability index weight factor and the second adjustment stability index weight factor are both [0,1], and the sum of the two is 1.

[0089] Specifically, the statistical table of changes in the adjustment stability index is shown in Table 1:

[0090] Table 1 Statistics of changes in regulation stability indicators

[0091]

[0092] It should be understood that, from the first, second and third groups of data in Table 1, it can be seen that the adjustment stability index increases with the increase of the preparation uniformity compliance index and the relative density evaluation score. From the fourth and fifth groups of data in Table 1, it can be seen that the adjustment stability index decreases with the increase of the filling adjustment response time score and the adjustment filling score. Among them, the filling adjustment response time score increases with the filling adjustment response time deviation (i.e., |X1 i -X1 0 |) increases, and the adjustment loading score increases with the adjustment loading deviation (i.e. |J1 i -J1 0 |) increases with the increase of.

[0093] It should be noted that the relative density assessment score also indirectly affects the value of the filling volume adjustment response time score. When the relative density of the solution changes, its fluidity may be affected. For example, if the solution becomes too viscous, the speed of pumping or transferring the solution may slow down during the filling volume adjustment process, resulting in an increase in the filling volume adjustment response time. Therefore, changes in the relative density assessment score will indirectly affect the filling volume adjustment response time score by affecting the fluidity of the solution. If the relative density assessment score decreases, it indicates that the solution may not be uniform or the concentration is low, which may lead to poor fluidity and thus increase the filling volume adjustment response time.

[0094] The filling quantity adjustment response time score also indirectly affects the value of the adjustment filling quantity score. When the filling quantity adjustment response time increases, it may cause stagnation or delay of the production line, which will not only reduce production efficiency, but also affect the accuracy of the adjustment filling quantity, because long waiting or delays may increase the instability of the solution and cause the filling quantity deviation to increase. Therefore, the change of the filling quantity adjustment response time score will indirectly affect the adjustment filling quantity score by affecting production efficiency.

[0095] By considering the above-mentioned indirect influence mechanism, the quality control problem in the process of adjusting the filling amount of small-sized L-carnitine oral solution can be better understood. The preset personnel can ensure the uniformity and fluidity of the solution by accurately controlling the relative density of the solution, shorten the response time, reduce the filling amount deviation, and improve the accuracy of adjusting the filling amount, thereby achieving the improvement of the quality control efficiency in the process of adjusting the filling amount of small-sized L-carnitine oral solution, and effectively solving the problem of low quality control efficiency in the process of adjusting the filling amount of small-sized L-carnitine oral solution in the prior art.

[0096] Furthermore, the specific process of judging whether to send a qualified instruction for adjusting the filling quantity based on the obtained adjustment stability index is as follows: judging whether the obtained adjustment stability index is greater than the adjustment stability index preset in the data: if the obtained adjustment stability index is greater than the adjustment stability index preset in the data, then sending a qualified instruction for adjusting the filling quantity and recording the corresponding batch of adjustment samples for the completed adjustment filling quantity as samples for packaging and storage; if the obtained adjustment stability index is not greater than the adjustment stability index preset in the data, then sending a filling parameter adjustment instruction and re-performing automatic filling adjustment; the filling parameter adjustment instruction is used to control the stability of the filling quantity adjustment of the specified batch of adjustment samples for the waiting to be filled.

[0097] In this embodiment, the preset adjustment stability index is represented by the result of summing and averaging the historical adjustment stability indexes of the samples of the amount to be filled in the database during the historical filling adjustment process; the filling parameter is usually a filling adjustment value, wherein the filling adjustment value is the difference between the preset adjustment stability index and the adjustment stability index. When the filling adjustment value is equal to 0, the preset personnel is prompted to check the filling amount of the specified batch of samples of the amount to be filled, and when the filling adjustment value is not equal to 0, the preset personnel is prompted to increase the stability of the filling amount adjustment by reducing the filling amount adjustment speed on the display screen of the controller on the canning production line, thereby achieving more precise control of the filling amount adjustment of the samples of the amount to be filled in the specified batch, thereby achieving improved quality control efficiency in the process of adjusting the filling amount of small-size L-carnitine oral solution.

[0098] In summary, the embodiment of the present application monitors the process parameters of the sample to be prepared in real time during the preparation process to determine whether to send a relative density monitoring instruction, then monitors the density change of the sample to be prepared in real time during the relative density monitoring process to determine whether to send an automatic adjustment filling instruction, and finally determines whether to send an adjustment filling qualified instruction based on the obtained adjustment stability index, thereby achieving an improvement in the stability of the automatic adjustment filling of the sample to be filled, and then achieving an improvement in the quality control efficiency during the adjustment filling process of the small-sized L-carnitine oral solution, effectively solving the problem of low quality control efficiency during the adjustment filling process of the small-sized L-carnitine oral solution in the prior art.

[0099] Those skilled in the art will appreciate that embodiments of the present invention may be provided as methods, systems, or computer program products. Therefore, the present invention may take the form of a complete hardware embodiment, a complete software embodiment, or an embodiment combining software and hardware. Moreover, the present invention may take the form of a computer program product implemented on one or more computer-usable storage media (including but not limited to disk storage, CD-ROM, optical storage, etc.) containing computer-usable program code.

[0100] The present invention is described with reference to flowcharts and / or block diagrams of methods, devices (systems), and computer program products according to embodiments of the present invention. It should be understood that each process and / or block in the flowchart and / or block diagram, as well as the combination of processes and / or blocks in the flowchart and / or block diagram, can be implemented by computer program instructions. These computer program instructions can be provided to a processor of a general-purpose computer, a special-purpose computer, an embedded processor, or other programmable data processing device to produce a machine, so that the instructions executed by the processor of the computer or other programmable data processing device generate instructions for implementing the processes in the flowchart and / or block diagram. Figure 1 A process or multiple processes and / or boxes Figure 1 A device that provides the functions specified in a block or multiple blocks.

[0101] These computer program instructions may also be stored in a computer-readable memory capable of directing a computer or other programmable data processing device to operate in a specific manner, so that the instructions stored in the computer-readable memory produce an article of manufacture comprising an instruction device, which implements the process Figure 1 A process or multiple processes and / or boxes Figure 1 A function specified in one or more boxes.

[0102] These computer program instructions can also be loaded onto a computer or other programmable data processing device so that a series of operating steps are executed on the computer or other programmable device to produce a computer-implemented process, thereby providing instructions for implementing the process. Figure 1A process or multiple processes and / or boxes Figure 1 The steps for the functions specified in one or more boxes.

[0103] Although the preferred embodiments of the present invention have been described, those skilled in the art may make other changes and modifications to these embodiments once they have learned the basic creative concept. Therefore, the appended claims are intended to be interpreted as including the preferred embodiments and all changes and modifications that fall within the scope of the present invention.

[0104] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include these modifications and variations.

Claims

1. A production process for sugar-free L-carnitine oral solution based on production efficiency and quality, characterized in that: include: Weighing of raw and auxiliary materials, preparation of concentrated liquid samples, adjustment of loading volume, and packaging and storage; The weighing of raw and auxiliary materials is used to ensure that the various raw materials and auxiliary materials required for the production of each batch of L-carnitine oral solution are weighed according to the preset ratio; The concentrated liquid sample preparation is used to mix and dissolve the weighed raw and auxiliary materials according to a preset process flow to form a uniform prepared sample; The filling amount adjustment is used to deliver qualified prepared samples to the filling production line to automatically adjust the filling amount of each bottle of L-carnitine oral solution; The packaging and warehousing is used to automatically perform light inspection, packaging and warehousing of the filled L-carnitine oral solution.

2. A quality control method for the production process of a sugar-free L-carnitine oral solution based on production efficiency and quality, used for the production process of a L-carnitine oral solution based on production efficiency and quality as claimed in claim 1, characterized in that: The following steps are involved: Step 1: real-time monitoring of the process parameters of the sample to be prepared during the preparation process to determine whether to send a relative density monitoring instruction; Step 2: Real-time monitoring of the density change of the sample to be prepared during the relative density monitoring process to determine whether to send an automatic adjustment loading instruction; Step three, monitor the filling quantity adjustment status of the sample to be filled and adjusted on the filling production line in real time to obtain the adjustment stability index, and judge whether to send the adjustment filling quantity qualification instruction based on the obtained adjustment stability index. The adjustment stability index is used to quantify the stability of the filling quantity adjustment of the sample to be filled and adjusted on the filling production line.

3. A quality control method for the production process of a sugar-free L-carnitine oral solution based on production efficiency and quality as claimed in claim 2, characterized in that: The specific steps of real-time monitoring the density change of the sample to be prepared during the relative density monitoring process include: After the preset preparation time period, the dissolving temperature of the sample to be prepared at the current preparation time is obtained and it is determined whether it is within the allowable range of the dissolving temperature in the database. If so, the clarity of the solution is obtained, otherwise a temperature adjustment instruction is sent, and the temperature adjustment instruction includes a temperature reduction instruction and a temperature increase instruction; Real-time monitoring of the stirring speed of the stirring device corresponding to the sample to be prepared at the current preparation time during the preparation process, and real-time monitoring of the solubility and pH value of the solute in the sample to be prepared at the current preparation time; A preparation uniformity compliance index is obtained according to the obtained preparation parameters and combined with the reference preparation parameters in the database, wherein the preparation parameters include dissolution temperature, solution clarity, stirring speed, solubility and pH value, the reference preparation parameters include preparation uniformity compliance weight factor, maximum allowable dissolution temperature, reference stirring speed, reference pH value and reference pH deviation value, the preparation uniformity compliance weight factor includes dissolution temperature weight factor, pH value weight factor and stirring speed weight factor, and the preparation uniformity compliance index is used to quantify the degree of uniformity of the sample to be prepared during the preparation process.

4. A quality control method for the production process of a sugar-free L-carnitine oral solution based on production efficiency and quality as claimed in claim 3, characterized in that: The specific process of determining whether to send a relative density monitoring instruction is as follows: Determine whether the obtained uniform conformity index is greater than the uniform conformity index preset in the database: If the obtained preparation uniformity compliance index is greater than the preparation uniformity compliance index preset in the database, a relative density monitoring instruction is sent; If the obtained preparation uniformity compliance index is not greater than the preparation uniformity compliance index preset in the database, a pH adjustment solution check instruction is sent and pH adjustment is performed again; The relative density monitoring instruction is used to obtain the relative density of the sample to be prepared; The relative density is used to reflect the ratio of the density of the solution in the sample to be prepared to the density of purified water; The pH check instruction for the adjusted solution is used to prompt a preset person to test the pH of the adjusted solution to determine whether it is within a target pH range.

5. A quality control method for the production process of a sugar-free L-carnitine oral solution based on production efficiency and quality as claimed in claim 2, characterized in that: The real-time monitoring of the density change of the sample to be prepared during the relative density monitoring process also includes obtaining the amount of purified water added according to the obtained relative density. The specific process is as follows: L1, determine whether the obtained relative density is equal to the target relative density. If so, the amount of purified water added is recorded as 0, otherwise execute L2; L2, determine whether the obtained relative density is greater than the target relative density. If so, obtain the amount of purified water to be added, otherwise send a preparation failure instruction; The amount of purified water added represents the ratio of the product of the initial volume of the sample to be prepared before preparation and the relative density deviation to the target relative density; The relative density deviation represents the difference between the relative density and the target relative density.

6. A quality control method for the production process of a sugar-free L-carnitine oral solution based on production efficiency and quality as claimed in claim 2, characterized in that: The specific steps of real-time monitoring the density change of the sample to be prepared during the relative density monitoring process include: When the obtained preparation uniformity compliance index is greater than the preparation uniformity compliance index preset in the database, the stirring speed and stirring frequency of the corresponding stirring equipment at the current monitoring time during the pH adjustment process are obtained, and the relative density recovery time at the end of the current monitoring period is obtained, and the relative density evaluation score is obtained by combining the obtained purified water addition amount and the reference monitoring data in the database; The relative density evaluation score is used to evaluate the relative density recovery efficiency of the sample to be prepared after adding purified water; The relative density recovery time refers to the time corresponding to the relative density deviation being equal to 0 after adding purified water; The reference monitoring data includes a relative density assessment weight factor, a reference stirring speed, a reference stirring frequency, and a maximum allowable relative density recovery time; The relative density assessment weight factors include a stirring speed weight factor, a stirring frequency weight factor, a relative density recovery time weight factor, a first relative density assessment weight factor and a second relative density assessment weight factor.

7. A quality control method for the production process of a sugar-free L-carnitine oral solution based on production efficiency and quality as claimed in claim 6, characterized in that: The specific process of determining whether to send an automatic adjustment load quantity instruction is as follows: Determine whether the obtained relative density evaluation score is greater than the relative density evaluation score preset in the database: If the obtained relative density evaluation score is greater than the relative density evaluation score preset in the database, the corresponding sample to be prepared is recorded as a sample to be adjusted in loading quantity, and an automatic loading quantity adjustment instruction is sent; If the obtained relative density assessment score is not greater than the relative density assessment score preset in the database, a relative density detection failure instruction is sent and relative density monitoring is performed again.

8. A quality control method for the production process of a sugar-free L-carnitine oral solution based on production efficiency and quality as claimed in claim 2, characterized in that: The specific steps for obtaining the adjustment stability index are: When the relative density evaluation score obtained is greater than the relative density evaluation score preset in the database, the samples to be loaded and adjusted are batch-numbered, and the response time score and the adjusted loading score of the specified batch of samples to be loaded and adjusted in the process of automatic loading and adjustment are obtained; Obtaining a preset adjustment stability weight factor from a database, and obtaining an adjustment stability index in combination with the obtained adjustment stability data; The loading quantity adjustment response time fraction represents the ratio of the absolute value of the difference between the loading quantity adjustment response time and the reference loading quantity adjustment response time to the reference loading quantity adjustment response time; The filling quantity adjustment response time is used to reflect the response rate of the controller on the corresponding filling production line when the filling quantity of the samples to be filled quantity adjusted in a specified batch changes; The adjustment filling amount fraction represents the ratio of the absolute value of the difference between the actual adjustment filling amount and the reference adjustment filling amount to the reference adjustment filling amount; The adjustment stability weight factor includes a loading adjustment response time fraction weight factor, an adjustment loading fraction weight factor, a preparation uniformity compliance index weight factor, a relative density assessment fraction weight factor, a first adjustment stability weight factor, and a second adjustment stability weight factor; The adjustment stability data include the filling adjustment response time score, the adjustment filling score, the formulation uniformity compliance index and the relative density evaluation score.

9. A quality control method for the production process of a sugar-free L-carnitine oral solution based on production efficiency and quality as claimed in claim 8, characterized in that: The specific limiting expression of the adjustment stability index is: Where i is the batch number of the sample to be filled, i=1,2,...,U, U is the total number of batches of the sample to be filled, e is a natural constant, JW represents the adjustment stability index of the sample to be filled on the filling production line, y5 represents the first adjustment stability weight factor, y1 represents the weight factor of the response time of the filling adjustment, X i represents the response time score of the i-th batch of samples to be loaded in the process of automatic loading adjustment, y2 represents the weight factor of the adjustment loading score, J i It represents the adjustment filling score of the i-th batch of samples to be filled during the automated filling adjustment process, y6 represents the second adjustment stability weight factor, y3 represents the preparation uniformity compliance index weight factor, PY represents the preparation uniformity compliance index of the samples to be prepared during the preparation process, y4 represents the relative density assessment score weight factor, and XD represents the relative density assessment score of the samples to be prepared during the relative density monitoring process.

10. A quality control method for the production process of a sugar-free L-carnitine oral solution based on production efficiency and quality as claimed in claim 2, characterized in that: The specific process of judging whether to send a qualified adjustment loading quantity instruction based on the obtained adjustment stability index is as follows: Determine whether the obtained adjustment stability index is greater than the adjustment stability index preset in the data: If the obtained adjustment stability index is greater than the adjustment stability index preset in the data, an adjustment filling qualified instruction is sent and the adjustment samples to be filled corresponding to the batch of completed adjustment filling are recorded as samples to be packaged and put into storage; If the obtained adjustment stability index is not greater than the adjustment stability index preset in the data, a filling parameter adjustment instruction is sent and the automatic filling quantity adjustment is performed again; The filling parameter adjustment instruction is used to control the stability of the filling amount adjustment of the samples to be filled in a specified batch.

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