Quality control method of Beijing medicine compound preparation

Abstract

The invention discloses a quality control method of a Beijing medicine compound preparation, and particularly relates to the field of quality control methods. Comprising the steps of comprehensive detection of medicinal materials, multi-component content determination, biological activity evaluation, quality consistency evaluation and the like. The quality stability of the medicinal materials is guaranteed from the source by determining the medicinal material producing area, the harvesting time and the processing technology preset standard; a biological activity detection model related to efficacy is established, and the quality standard and the efficacy are tightly combined; a compound preparation quality database is constructed, principal component analysis and clustering analysis are used for regular review analysis, and quality control standards and methods are dynamically adjusted and optimized; and a quality early warning mechanism is formulated, and quality problems are handled in time. According to the method, the quality is comprehensively controlled from multiple dimensions, the quality stability of preparations in different batches is ensured, the disjunction of the quality and the efficacy is effectively avoided, and the safety and the effectiveness of the Beijing medicine compound preparation are ensured.

Description

Technical Field

[0001] This invention relates to the field of quality control methods, and in particular to a quality control method for a compound preparation of Beijing medicine. Background Technology

[0002] Currently, the Jing ethnic group is mainly distributed on three small islands—Wanwei, Wutou, and Shanxin—in Jiangping Town. Their unique geographical location, surrounded by the ocean, makes transportation extremely inconvenient. This special island environment allowed the Jing ancestors to gradually accumulate and summarize valuable medical experience in their struggle against disease, forming a distinctive local medical system. At present, research on Jing medicine is still in its early stages, lacking multi-directional and in-depth research results. Establishing a theoretical system for Jing medicine remains a long and arduous task.

[0003] Jing ethnic medicine is an important component of Chinese ethnic medicine, integrating traditional Chinese medicine theory with the medicinal experience and regional characteristics of the Jing people. The Jing people live in an area rich in medicinal resources, especially unique marine medicinal resources, which provided a theoretical foundation for the origin and development of Jing medicine. The integration of traditional Chinese medicine principles, methods, prescriptions, and medicines further promoted the development of Jing medicine. Jing medicine compound preparations often use local herbs and marine drugs as formulas, optimized according to clinical needs, forming a synergistic effect of multiple components and targets. However, due to the complex composition and unclear pharmacodynamic material basis of Jing medicine compound preparations, their quality control has long faced multiple challenges. First, compound preparations are usually composed of multiple medicinal materials. For example, a formula for treating colds and flu includes four medicinal materials: perilla leaves, mugwort leaves, mint, and wampee leaves. These include both traditional Chinese medicine and wampee leaves, a specialty of the Jing region. Their chemical components encompass hundreds of compounds, including volatile oils, flavonoids, terpenes, phenylpropanoids, polysaccharides, organic acids, coumarins, and amides. Traditional quality control methods often rely on the determination of the content of a single or a few components, which makes it difficult to fully reflect the overall quality of the preparation. This method may result in a situation where the quality is qualified but the clinical efficacy is unstable.

[0004] Secondly, the quality of Chinese medicinal herbs and local Jing ethnic medicinal herbs is significantly affected by factors such as origin, harvesting time, and processing techniques, further exacerbating the difficulty of quality control. For example, the content of catalpol in "Huai Di Huang" produced in Jiaozuo, Henan, is 2-3 times higher than that in other producing areas, and the content of paeonol in peony bark harvested in autumn is 30% higher than that in spring. If enterprises do not establish strict procurement standards, the component content of the same compound preparation may vary too much between different batches, making it difficult to guarantee the consistency of efficacy. In addition, the complexity of processing technology is also a key issue. The processing methods of compound preparations involve multiple steps such as extraction, concentration, drying, and granulation. Even slight changes in different process parameters can cause significant differences in component dissolution rate and stability. If the processing technology lacks scientific optimization and process control, the quality of the product will ultimately be difficult to stabilize.

[0005] Finally, there is a disconnect between current quality standards and efficacy. Currently, the quality standards for most compound preparations in the Chinese Pharmacopoeia only include appearance, identification, testing (such as moisture and ash content), and content determination of a few components, lacking bioactivity evaluation. For example, a batch of heat-clearing and detoxifying compound preparations may meet the standards for baicalin and chlorogenic acid content, but if the components degrade or unknown toxic substances are present during the production process, the chemical indicators may not reflect this, potentially leading to the risk of "qualified quality but questionable safety." Therefore, establishing scientific and comprehensive quality control methods has become an urgent need to ensure the safety and efficacy of Beijing Pharmaceutical's compound preparations. Summary of the Invention

[0006] The present invention aims to provide a quality control method for compound preparations of Beijing pharmaceutical companies, which solves the problem that existing quality control methods for compound preparations are unscientific.

[0007] To achieve the above objectives, the technical solution of the present invention is as follows: A quality control method for a compound preparation of Beijing pharmaceuticals, comprising the following steps: S1. Conduct comprehensive quality testing on the medicinal materials used in the compound preparation. The testing content includes the origin of the medicinal materials, the harvesting time, and the processing technology to ensure that the medicinal materials used meet the preset standards. The preset standards are the quality standards of the medicinal materials after being processed by a specific processing technology within a specific origin and harvesting time range. S2. For compound preparations made from medicinal materials that meet quality standards, the content of multiple components shall be determined. No less than five key components in the preparation shall be selected and determined by high performance liquid chromatography to ensure that the content of each key component is within the specified range. S3. Establish a bioactivity detection model related to the efficacy of compound preparations, and evaluate the efficacy of the preparations by detecting the bioactivity indicators of the preparations in the model. S4. Conduct a quality consistency evaluation on different batches of compound preparations, compare the multi-component content and bioactivity indicators of each batch of preparations, and determine whether the quality differences between batches are within the allowable range. S5. Establish a quality database for compound preparations, and record the source of medicinal materials, the results of multi-component content determination, the results of bioactivity evaluation, and the results of quality consistency evaluation for each batch of preparations; S6. Based on the data in the quality database, regularly review and analyze the quality control methods, summarize the patterns and causes of quality problems, and dynamically adjust and optimize the quality control standards and methods. S7. Establish a quality early warning mechanism for compound preparations. When the results of multi-component content determination, bioactivity evaluation, or quality consistency evaluation exceed the preset threshold, an early warning signal should be issued in a timely manner, and quality investigation and improvement measures should be initiated.

[0008] Furthermore, the preset standards for step S1 are: the heavy metal content of the medicinal material in the soil of a specific production area is lower than the heavy metal limit standard for the soil of the medicinal material production area as stipulated in the Chinese Pharmacopoeia; the specific harvesting time is within three days before and after the effective component content of the medicinal material reaches its peak; and the specific processing technology is to operate in accordance with the processing time, temperature and amount of excipients specified in the processing method of the medicinal material as stipulated in the Chinese Pharmacopoeia.

[0009] Furthermore, the preset standards in step S1 are as follows: the heavy metal content of the medicinal material in the soil of a specific production area is lower than the heavy metal limit standard for the soil of the medicinal material production area as stipulated in the Chinese Pharmacopoeia; the specific harvesting time is within three days before and after the effective component content of the medicinal material reaches its peak; and the specific processing technology is to operate in accordance with the processing time, temperature and amount of excipients specified in the processing method of the medicinal material as stipulated in the Chinese Pharmacopoeia.

[0010] Furthermore, in step S3, if the compound preparation's efficacy is to clear heat and detoxify, and the bioactivity detection model is an in vitro anti-inflammatory model, the bioactivity index is determined by detecting the inhibition rate of the preparation against inflammatory factors such as tumor necrosis factor-α and interleukin-6. The preparation is required to have an inhibition rate of at least 30% against tumor necrosis factor-α and at least 25% against interleukin-6 at a specific concentration. If the compound preparation's efficacy is to replenish qi and nourish blood, and the bioactivity detection model is an animal anemia model, the efficacy is assessed by detecting the increase in hemoglobin content and red blood cell count after administration. The increase in hemoglobin content after administration is required to be at least 15 g / L, and the increase in red blood cell count is required to be at least 0.5 × 10⁻⁶ g / L. 12 / L.

[0011] Furthermore, in step S4, the allowable range is determined based on the standard deviation of the multi-component content determination results and the coefficient of variation of the bioactivity index. The standard deviation of the multi-component content determination results is calculated using test data from at least 30 batches of formulations, and the coefficient of variation of the bioactivity index is calculated using test data from at least 30 batches of formulations. When the deviation of the content of each key component from the average content in the multi-component content determination results of each batch of formulation does not exceed ±15%, and the deviation of the bioactivity index from the average value does not exceed ±20%, the quality difference between batches is determined to be within the allowable range.

[0012] Furthermore, in step S5, the compound preparation quality database adopts a MySQL database management system, which has the functions of data entry, storage, query, statistical analysis and report generation. When entering data, the origin coordinates of the medicinal materials, the supplier name, the content values ​​of each component in the multi-component content determination results, the bioactivity index values ​​of the bioactivity evaluation results, and the batch-to-batch difference values ​​of the quality consistency evaluation results are recorded in detail and accurately.

[0013] Furthermore, in step S6, the data in the quality database is processed using principal component analysis and cluster analysis once a quarter during the review analysis. The patterns and causes of quality problems are summarized. Based on the analysis results, the adjustment range of component content in the quality control standards is not more than ±10%, the adjustment range of bioactivity index thresholds is not more than ±15%, and the detection method parameters and bioactivity detection model conditions in the quality control methods are optimized.

[0014] Furthermore, in step S7, the preset threshold is determined based on historical data of multi-component content determination results, historical data of bioactivity evaluation results, and historical data of quality consistency evaluation results. The preset threshold for multi-component content determination results is the average value of each key component content ±12%, the preset threshold for bioactivity evaluation results is the average value of bioactivity indicators ±18%, and the preset threshold for quality consistency evaluation results is the average value of batch-to-batch differences ±16%. The quality investigation includes a comprehensive review of medicinal material procurement records, production process records, and storage environment records. Improvement measures include changing medicinal material suppliers, adjusting production equipment parameters to improve equipment operating accuracy to within ±2%, and improving storage facility conditions so that the temperature fluctuation range of the storage environment does not exceed ±1℃ and the humidity fluctuation range does not exceed ±3%.

[0015] Compared with existing technologies, the beneficial effects of this solution are: 1. This invention not only conducts comprehensive quality testing on the medicinal materials used in compound preparations, covering key factors such as the origin, harvesting time, and processing techniques of the medicinal materials, but also performs multi-component content determination on compound preparations made from compliant medicinal materials. It selects no fewer than five key components and employs various advanced detection methods to ensure that the content of each key component is within the specified range. Simultaneously, it establishes a bioactivity detection model to evaluate the efficacy of the preparations and conducts quality consistency evaluations. This comprehensive quality control from multiple dimensions effectively avoids the problem of qualified quality but unstable clinical efficacy due to incomplete quality testing.

[0016] 2. This invention ensures the stability of medicinal material quality from the source by clearly defining pre-set standards for the origin, harvesting time, and processing techniques of medicinal materials, such as the heavy metal content requirements in the soil of specific medicinal materials in specific origins, specific harvesting time ranges, and specific processing operation specifications. Furthermore, it conducts quality consistency evaluations on different batches of preparations, judging whether the quality differences between batches are within the allowable range based on the deviations in multi-component content determination results and bioactivity indicators, further ensuring the stability of the quality of different batches of compound preparations.

[0017] 3. This invention establishes a bioactivity detection model related to the efficacy of compound preparations, and sets corresponding bioactivity indicators according to different efficacies. For example, the heat-clearing and detoxifying effect corresponds to the inhibition rate of inflammatory factors in the in vitro anti-inflammatory model, and the qi-tonifying and blood-nourishing effect corresponds to the increase in hemoglobin content and red blood cell count in the animal anemia model. This closely combines quality standards with efficacy, effectively avoiding the risk of "quality qualified but safety questionable".

[0018] 4. This invention establishes a quality database for compound preparations, records the various test and evaluation results of each batch of preparations, and regularly reviews and analyzes the quality control methods. It uses data processing methods such as principal component analysis and cluster analysis to summarize the patterns and causes of quality problems, and dynamically adjusts and optimizes the quality control standards and methods. This allows the quality control methods to be continuously improved with the deepening of production practice and research, so as to better ensure the quality of Beijing Pharmaceutical's compound preparations. Detailed Implementation

[0019] The present invention will be further described in detail below through specific embodiments: Example

[0020] A quality control method for a compound preparation of traditional Chinese medicine from Beijing, specifically targeting the quality control of a compound preparation for dispelling wind and dampness. This compound preparation for dispelling wind and dampness from Beijing uses locally characteristic vine-like medicinal materials recorded in the *Beijing Ethnic Medicine*, such as *Piper kadsura*, *Vine kuanjinteng*, and *Spatholobus suberectus*, as its main ingredients, and also contains traditional Chinese medicinal materials such as *Saposhnikovia divaricata* and *Angelica pubescens*, used to treat symptoms such as rheumatic pain and difficulty in joint flexion and extension. The method includes the following steps: S1. Quality Testing of Medicinal Materials: *Piper kadsura* (sea pine) from specific islands along the Guangxi coast was selected, and the heavy metal content in the soil of its production area was detected using atomic absorption spectrometry (AAS). The test results showed that the lead content was 0.3 mg / kg and the cadmium content was 0.01 mg / kg, both lower than the heavy metal limits for the soil of this medicinal material's production area stipulated in the Chinese Pharmacopoeia (lead ≤ 5 mg / kg, cadmium ≤ 0.1 mg / kg). The content of lignans in *Piper kadsura* was continuously monitored by high-performance liquid chromatography (HPLC), and it was found that the content reached its peak (3.2%) when the stems and branches matured in autumn. Therefore, the harvesting time was determined to be within three days before and after the peak content of lignans. Following the traditional processing methods recorded in *Jingzu Medicine*, *Piper kadsura* was washed, cut into sections, and sun-dried. The moisture content of the processed medicinal material was ≤12% (determined by the drying method). Similarly, the production area, harvesting time, and processing techniques of *Vitis thunbergii*, *Spatholobus suberectus*, *Saposhnikovia divaricata*, and *Angelica pubescens* were tested to ensure compliance with the preset standards.

[0021] S2. Determination of Multiple Component Content: Five key components were selected for determination: representative lignans from *Piper kadsura*, anthraquinones from *Tinospora sinensis*, flavonoids from *Spatholobus suberectus*, chromogens from *Saposhnikovia divaricata*, and coumarins from *Angelica pubescens*. High-performance liquid chromatography (HPLC) was used, with a methanol-water mixture as the mobile phase. The volume ratio was optimized based on the properties of different components. The flow rate was set to 1.0 mL / min, and the column temperature was controlled at 30℃. The results showed that the content of each key component met the preset standards and was within the specified range.

[0022] S3. Bioactivity Assay: Using a rat adjuvant-induced arthritis model, rats were randomly divided into a model group, a formulation group (low, medium, and high doses), and a positive control group (dexamethasone). After inducing arthritis with Freund's complete adjuvant, the rats were administered the medication continuously for 21 days. The degree of joint swelling and joint diameter were observed, and the efficacy of the formulation was evaluated by the joint swelling inhibition rate. Results showed that at a medium dose, the formulation achieved a joint swelling inhibition rate of 38% (≥35%), meeting the requirements.

[0023] S4. Quality Consistency Evaluation: Thirty batches of formulations were tested, and the standard deviation (SD) of the multi-component content determination results and the coefficient of variation (CV) of the bioactivity index were calculated. In each batch of formulations, the SD and CV of the key component content were within a reasonable range, the deviation of the content of all key components from the average content was ≤±15%, and the deviation of the bioactivity index from the average value was ≤±20%. The batch-to-batch quality differences were determined to be within the allowable range.

[0024] S5. Quality Database Establishment and Management: A MySQL database management system is used to establish a table structure that includes the source of medicinal materials (origin coordinates, supplier), content of multiple components (HPLC determination value), bioactivity indicators (joint swelling inhibition rate), and quality consistency evaluation results (SD / CV). Detailed and accurate records are kept of relevant data for each batch of preparations.

[0025] S6. Review, Analysis, and Optimization: Principal component analysis (PCA) and cluster analysis (HCA) are performed quarterly on the multi-component content and bioactivity data in the database to identify the main sources of batch-to-batch differences. Based on the analysis results, the component content ranges (adjustment range ≤ ±10%) and bioactivity index thresholds in the quality control standards are adjusted (adjustment range ≤ ±15%). The detection method parameters and bioactivity detection model conditions in the quality control methods are optimized.

[0026] S7. Quality warning mechanism: The preset thresholds are determined based on historical data. The preset threshold for the determination results of multi-component contents is the average value of the contents of each key component ± 12%, the preset threshold for the results of biological activity evaluation is the average value of biological activity indicators ± 18%, and the preset threshold for the results of quality consistency evaluation is the average value of batch-to-batch differences ± 16%. When the content of the key component or the biological activity index of a certain batch of preparation exceeds the preset threshold, a warning signal is sent in a timely manner, a quality investigation is initiated, and corresponding improvement measures are taken according to the cause of the problem. Example

[0027] A quality control method for a Jing medicine compound preparation. This example is for the quality control of a compound preparation for promoting digestion and resolving food stagnation. A certain Jing medicine compound preparation for promoting digestion and resolving food stagnation uses traditional Chinese medicinal materials such as Clausena excavata Burm. f., Areca catechu L., Hawthorn, and Fructus Hordei Germinatus as the main components, and is used to treat symptoms such as food retention and abdominal distension. The method includes the following steps: S1. Detection of the quality of medicinal materials: Select Clausena excavata Burm. f. produced in a specific area of Guangxi, and use AAS to detect the heavy metal content in the soil of its origin. After detection, the mercury content is 0.02 mg / kg and the arsenic content is 0.1 mg / kg, both of which are lower than the heavy metal limit standards for the soil of the origin of this medicinal material specified in the Chinese Pharmacopoeia (mercury ≤ 0.2 mg / kg, arsenic ≤ 2 mg / kg). The content of flavonoid components in Clausena excavata Burm. f. is monitored by HPLC, and it is found that the content is the highest (2.8%) when the fruit is ripe. Therefore, the harvesting time is determined as the fruit ripening period. According to the traditional processing method, Clausena excavata Burm. f. is washed, de-nucleated, and dried, and the water content of the processed medicinal material ≤ 10%. Similarly, the origin, harvesting time, and processing technology of Areca catechu L., Hawthorn, and Fructus Hordei Germinatus are detected to ensure compliance with the preset standards. S2. Determination of multi-component contents: Select five key components, namely, the flavonoid representative component in Clausena excavata Burm. f., the alkaloid component in Areca catechu L., the organic acid component in Hawthorn, and the amylase component in Fructus Hordei Germinatus in the preparation for determination. The high-performance liquid chromatography method is used, and the mobile phase is a mixed solution of acetonitrile - phosphate buffer solution. The volume ratio is adjusted according to the characteristics of the components, the flow rate is set at 0.9 mL / min, and the column temperature is controlled at 28°C. The determination results show that the contents of each key component meet the preset standards and are within the specified range.

[0028] S3. Biological activity detection: The mouse gastric emptying experiment model is used. The mice are randomly divided into a model group, a preparation group (low, medium, and high doses), and a positive control group (domperidone). After intragastric administration of the preparation to the mice, the amount of residual food in the stomach is measured, and the efficacy of the preparation is evaluated by the gastric emptying rate. The results show that: at the medium dose, the increase in the gastric emptying rate of the preparation reaches 25% (≥ 20%), meeting the requirements.

[0029] S4. Quality Consistency Evaluation: 35 batches of formulations were tested, and the standard deviation of the multi-component content determination results and the coefficient of variation of the bioactivity indicators were calculated. For each batch of formulations, the deviation of the key component content from the average content was ≤±15%, and the deviation of the bioactivity indicators from the average value was ≤±20%, indicating that the quality differences between batches were within the allowable range.

[0030] S5. Quality Database Establishment and Management: A MySQL database management system will be used to establish a table structure that includes information on the source of medicinal materials, content of multiple components, bioactivity indicators, and quality consistency evaluation results. An entry field for animal experimental data (gastric emptying rate) will be added. Detailed and accurate records will be kept of relevant data for each batch of preparations.

[0031] S6. Retrospective Analysis and Optimization: A retrospective analysis of the data in the quality database is conducted quarterly. PCA and HCA analyses are used to examine the correlation between the content of multiple components and bioactivity indicators, identifying key components affecting the digestive and stagnation-relieving effects. Based on the analysis results, quality control standards and methods are adjusted and optimized accordingly.

[0032] S7. Quality Early Warning Mechanism: The preset threshold is determined based on historical data. When the content of key components or bioactivity indicators of a batch of preparations exceeds the preset threshold, an early warning signal is issued in a timely manner, a quality investigation is initiated, and improvement measures such as adjusting the production process and changing the supplier of medicinal materials are taken. Example

[0033] A quality control method for a compound preparation of traditional Chinese medicine from Beijing, specifically targeting the quality control of a compound preparation for calming the mind and promoting sleep. This particular compound preparation from Beijing uses characteristic medicinal materials with calming effects recorded in the *Beijing Traditional Medicine*, such as Albizia bark and Polygonum multiflorum stem, as well as traditional Chinese medicinal materials such as Ziziphus jujuba seed and Poria cocos, as its main ingredients. It is used to treat symptoms such as insomnia and excessive dreaming. The method includes the following steps: S1. Quality Testing of Medicinal Materials: Albizia bark from a specific coastal area of ​​Guangxi was selected, and the heavy metal content in the soil of its production area was tested using AAS. The test results showed that the lead content was 0.4 mg / kg and the cadmium content was 0.015 mg / kg, both lower than the heavy metal limits for the soil of this medicinal material's production area stipulated in the Chinese Pharmacopoeia (lead ≤ 5 mg / kg, cadmium ≤ 0.1 mg / kg). HPLC monitoring of the saponin content in the Albizia bark revealed that its content was higher (2.5%) when the bark was collected in autumn. Therefore, the harvesting time was determined to be autumn. Following traditional processing methods, the Albizia bark was washed, shredded, and sun-dried, resulting in a moisture content of ≤11%. Similarly, the origin, harvesting time, and processing techniques of Polygonum multiflorum, Ziziphus jujuba var. spinosa, and Poria cocos were tested to ensure compliance with preset standards.

[0034] S2. Determination of Multiple Component Content: Five key components were selected for determination: representative saponins from Albizia bark, flavonoids from Polygonum multiflorum, saponins from Ziziphus jujuba seed, and polysaccharides from Poria cocos. High-performance liquid chromatography (HPLC) was used. The mobile phase was a methanol-water-glacial acetic acid mixture, with the volume ratio adjusted according to the component properties. The flow rate was set to 1.1 mL / min, and the column temperature was controlled at 32℃. The results showed that the content of each key component met the preset standards and was within the specified range.

[0035] S3. Bioactivity Assay: A mouse spontaneous activity test model was used. Mice were randomly divided into a model group, a formulation group (low, medium, and high doses), and a positive control group (diazepam). After administration, mice were placed in a spontaneous activity testing device at a certain time, and the number of mouse movements was recorded over a specific period. The efficacy of the formulation was assessed by the reduction rate of movement frequency. Results showed that at the medium dose, the formulation reduced mouse movement frequency by 30% (≥25%), meeting the requirements.

[0036] S4. Quality Consistency Evaluation: Forty batches of formulations were tested, and the standard deviation of the multi-component content determination results and the coefficient of variation of the bioactivity index were calculated. For each batch of formulations, the deviation of the key component content from the average content was ≤±15%, and the deviation of the bioactivity index from the average value was ≤±20%, indicating that the quality differences between batches were within the allowable range.

[0037] S5. Quality Database Establishment and Management: A MySQL database management system will be used to establish a table structure that includes information on the source of medicinal materials, content of multiple components, bioactivity indicators, and quality consistency evaluation results. An entry field for animal experimental data (reduction rate of mouse activity) will be added. Detailed and accurate records will be kept of relevant data for each batch of preparations.

[0038] S6. Retrospective Analysis and Optimization: A retrospective analysis of the data in the quality database is conducted quarterly. PCA and HCA analyses are used to examine the correlation between the content of multiple components and bioactivity indicators, identifying key components affecting the calming and sleep-aiding effects. Based on the analysis results, quality control standards and methods are adjusted and optimized accordingly.

[0039] S7. Quality Early Warning Mechanism: The preset threshold is determined based on historical data. When the content of key components or bioactivity indicators of a batch of preparations exceeds the preset threshold, an early warning signal is issued in a timely manner, a quality investigation is initiated, and improvement measures such as improving production processes and strengthening the quality control of medicinal materials are taken.

[0040] The above are merely embodiments of the present invention, and common knowledge such as specific structures and / or characteristics in the solutions are not described in detail here. It should be noted that those skilled in the art can make various modifications and improvements without departing from the structure of the present invention, and these should also be considered within the scope of protection of the present invention. These modifications and improvements will not affect the effectiveness of the implementation of the present invention or the practicality of the patent. The scope of protection claimed in this application should be determined by the content of its claims, and the specific embodiments described in the specification can be used to interpret the content of the claims.

Claims

1. A quality control method of a Beijing compound preparation, characterized in that, Comprise the following steps: S1, the medicinal materials used in the compound preparation are comprehensively quality tested, the test contents include the medicinal material producing area, the harvesting time, the processing technology, and it is ensured that the medicinal materials used meet the preset standards, wherein the preset standards are the quality standards of the medicinal materials in the specific producing area, within the specific harvesting time range and treated by the specific processing technology; S2, the compound preparation prepared from the medicinal materials meeting the quality standards is subjected to multi-component content determination, at least five key components in the preparation are selected, and high performance liquid chromatography is used for determination, so as to ensure that the contents of the key components are within the specified range; S3, a biological activity detection model related to the efficacy of the compound preparation is established, the biological activity index of the preparation in the model is detected, and the efficacy of the preparation is evaluated; S4, the quality consistency of different batches of compound preparations is evaluated, the multi-component content and the biological activity index of each batch of preparation are compared, and it is judged whether the quality difference between batches is within the allowable range; S5, a compound preparation quality database is established, and the medicinal material sources, multi-component content determination results, biological activity evaluation results and quality consistency evaluation results of each batch of preparation are recorded; S6, according to the data in the quality database, the quality control method is reviewed and analyzed regularly, the rules and reasons of quality problems are summarized, and the quality control standards and methods are dynamically adjusted and optimized; S7, a quality warning mechanism for the compound preparation is established, when the multi-component content determination results, biological activity evaluation results or quality consistency evaluation results exceed the preset threshold, a warning signal is sent in time, and quality investigation and improvement measures are started.

2. The quality control method of the Beijing compound preparation according to claim 1, characterized in that: The preset standards of step S1 are that the heavy metal content of the medicinal materials in the soil of the specific producing area is lower than the heavy metal limit standard of the soil of the medicinal material producing area specified in the Chinese Pharmacopoeia, the specific harvesting time is within three days before and after the peak value of the content of the effective components of the medicinal materials, and the specific processing technology is to operate according to the processing time, temperature and auxiliary material amount specified in the processing method of the medicinal materials in the Chinese Pharmacopoeia.

3. The quality control method of the Beijing compound preparation according to claim 1, characterized in that: The key components in step S2 are determined according to the main efficacy of the compound preparation and clinical application experience, when high performance liquid chromatography is used, the mobile phase is a mixture of acetonitrile and water with a volume ratio of 40:60-60:40, the flow rate is set to 0.9-1.1 mL / min, and the column temperature is controlled at 28-32℃.

4. The quality control method of the Beijing compound preparation according to claim 1, characterized in that: In step S3, if the compound preparation has the efficacy of clearing heat and resolving toxins, the biological activity detection model is an in vitro anti-inflammatory model, the inhibition rate of the preparation on inflammatory factors such as tumor necrosis factor-α and interleukin-6 is detected as a biological activity index, and the preparation is required to have an inhibition rate on tumor necrosis factor-α of not less than 30% and an inhibition rate on interleukin-6 of not less than 25% at a specific concentration; if the compound preparation has the efficacy of tonifying qi and nourishing blood, the biological activity detection model is an animal anemia model, the increase in the hemoglobin content and red blood cell count of the animal after administration is detected to evaluate the efficacy of the preparation, and the preparation is required to have an increase in the hemoglobin content of the animal after administration of not less than 15 g / L and an increase in the red blood cell count of not less than 0.5 x 10 12 / L.

5. The quality control method of the Beijing compound preparation according to claim 1, characterized in that: In step S4, the allowable range is determined according to the standard deviation of the multi-component content determination results and the coefficient of variation of the biological activity index, the standard deviation of the multi-component content determination results is calculated from the detection data of at least 30 batches of preparations, the coefficient of variation of the biological activity index is calculated from the detection data of at least 30 batches of preparations, when the deviation of the content of each key component in the multi-component content determination results of each batch of preparation from the average content is not more than ±15%, and the deviation of the biological activity index from the average value is not more than ±20%, it is determined that the quality difference between batches is within the allowable range.

6. The quality control method of the Beijing compound preparation according to claim 1, characterized in that: In step S5, the compound preparation quality database adopts MySQL database management system, with data entry, storage, query, statistical analysis and report generation functions. The data entry records the origin coordinates of medicinal materials, supplier name, multi-component content determination results, biological activity evaluation results and batch difference values in detail and accurately.

7. The quality control method of the Beijing compound preparation according to claim 1, characterized in that: In step S6, the review analysis is carried out once every quarter. The principal component analysis and cluster analysis are used to process the data in the quality database, summarize the rules and reasons of quality problems, and adjust the component content range in the quality control standard by not more than ±10%, adjust the biological activity index threshold by not more than ±15%, and optimize the detection method parameters and biological activity detection model conditions in the quality control method.

8. The quality control method of the Beijing compound preparation according to claim 7, characterized in that: In step S7, the preset threshold is determined according to the historical data of multi-component content determination results, biological activity evaluation results and quality consistency evaluation results. The preset threshold of multi-component content determination results is the average value of the content of each key component ±12%, the preset threshold of biological activity evaluation results is the average value of the biological activity index ±18%, and the preset threshold of quality consistency evaluation results is the average value of the batch difference ±16%. The quality investigation includes comprehensive review of medicinal material procurement records, production process records and storage environment records. The improvement measures include replacing the medicinal material supplier, adjusting the production equipment parameters to improve the equipment operation accuracy to within ±2%, and improving the storage facility conditions to make the storage environment temperature fluctuation range not more than ±1℃ and the humidity fluctuation range not more than ±3%.