Some considerations on the quality study of respiratory compound preparations
2019-09-13 06:06:13
Abstract: Through the analysis of problems in the study of the quality of respiratory compound drug preparations, the emphasis should be placed on quality research. A brief description of the issues that need to be addressed during the identification, inspection, and determination of the quality study process.
Key words: quality study of respiratory system compound preparations Compound preparations account for a large proportion in respiratory medicines. Such pharmaceutical compositions typically comprise the compound preparation of medicament nasal decongestant pseudoephedrine hydrochloride, anti-allergy chlorpheniramine maleate, fexofenadine hydrochloride, loratadine, desloratadine, etc. Solutions Hot analgesic drugs such as aspirin, acetaminophen and the like. How to scientifically and reasonably evaluate the quality of these preparations, the author has accumulated relevant materials and materials through one year of review work, and at the same time, according to the guidelines of the center on quality research and impurity research, the quality evaluation of such preparations is carried out. With certain considerations, these considerations are summarized and summarized to facilitate the scientific development and evaluation of such preparations.
The quality study of the compound preparation should also be carried out in accordance with the relevant technical guidelines for quality research, but as a compound preparation, there are two or more main ingredients in the prescription, which is compared with the single composition preparation in the quality study. The big difference is sometimes more difficult in the quality research process. The following is a brief description of the concerns in the identification, examination and content determination in quality studies.
1. About the identification item: The main purpose of the identification item is to use the appropriate method to "identify" the specific drug. Identification of Compound Formulations Several methods are generally used to identify different components of a prescription. Commonly used identification methods are TLC (used to identify one or several main drugs in the prescription), chemical colorimetry (for the specific identification of a certain main drug), and HPLC method (using the reference method for identification) One or several major ingredients). In the quality study, different identification items should be studied to show that the method used has better specificity.
2, on the inspection items: generally focus on the dissolution, content uniformity, related substances and other items.
2.1 About the content uniformity test As a compound preparation, due to the characteristics of the prescription components, for the small-dose components in the prescription, if the prescription contains chlorpheniramine maleate, caffeine, artificial bezoar, etc., it should be carried out in accordance with the requirements of CP2005. Check the content uniformity and set the quality standard.
2.2 For the dissolution test, firstly combine the physical and chemical properties of the main drug in the prescription, check the conditions of different dissolution media (0.1mol/L hydrochloric acid, water or phosphate buffer solution of pH 6.8), slightly soluble or poorly soluble in the dissolution medium. The dissolution of the ingredients. Secondly, the corresponding ingredients in the prescription should be studied and examined accordingly. Whether the dissolution test is performed on one or several main drugs, the excipients and other components may have some influence and interference on the measurement, so a detailed method of validation of the dissolution test is required.
2.3 Inspection of related substances Due to the large number of impurities in the compound preparation and the diversity of its sources (caused by the main drug, possible interaction, production and preparation, and degradation under storage conditions), the impurities are Separation detection, qualitative and quantitative studies of impurities are more difficult and more complex than single-component impurity studies. Therefore, the common method for checking the impurity of the compound preparation is the HPLC method, and the detector is mostly a UV detector, a DAD detector, an evaporative light scattering detector, and the like. Among them, DAD detectors and evaporation tube scattering detectors have unique advantages in impurity inspection, so the research on impurities in compound preparations will increasingly use these new detectors.
Before the impurity research and inspection, the physicochemical properties of all the main drugs, the factors affecting the stability, etc. should be investigated in detail or necessary pre-tests, combined with the results of prescription screening and process research, to understand the main drugs in the various prescriptions. Stability, master the causes of the main drug impurities and the main degradation products, clear whether there are interactions between different components in the prescription conditions and production process, whether the auxiliary materials affect the stability of the main components. Then, based on this research or research, the main drug components with poor stability or easy degradation in the production and preparation process should be studied and checked with appropriate methods, and the impurity peaks must be assigned. If the acetaminophen in the prescription is easily degraded during the granulation process and produces toxic para-aminophenol, the inspection of the known degradation product, p-aminophenol, should be strictly controlled as a known impurity. The visual study results of the impurities of the more stable components in the prescription are not the key targets. For example, guaiacol glyceryl ether in the formulation (this ingredient is very stable and generally does not degrade under the conditions of manufacture and storage of the formulation) generally does not require inspection of its impurities in quality standards.
Because of the complexity of the study of impurity in compound preparations, if the chromatographic behavior of the main drug and each degradation product is quite different, two or more chromatographic conditions can be selected to check different degradation products separately, and these chromatographic conditions are separately performed. Detailed and complete method validation, method validation is very important in impurity research. In terms of measurement conditions, it should be ensured that the main drug can be separated well from each degradation product under the detection wavelength condition, and has a good detection limit and quantitative limit.
The setting of the impurity limit should be based on the impurity level of each raw material, the production process of the compound preparation, and the storage condition, and the results of the impurity inspection are comprehensively determined; for known impurities, the limit of the known impurity should be determined in the quality standard. .
3. Determination of content The method of content determination can be carried out by different methods (HPLC method, UV method or chemical titration method) or different chromatographic conditions. However, for different chromatographic conditions or different methods, detailed methodological verification should be carried out to illustrate the rationality and suitability of the selection method.
The above-mentioned problems in the preparation of respiratory medicines need to pay attention to the quality research process. Among them, the research on related substances only expounds the problems that must be paid attention to during the research process. Complex, these issues will be continuously accumulated and improved in the future review work, and summed up in a timely manner, better serve the drug registration applicant through the center's communication platform.
The above only represents personal opinions, and it is welcome to exchange and discuss this issue with drug registration applicants.
Key words: quality study of respiratory system compound preparations Compound preparations account for a large proportion in respiratory medicines. Such pharmaceutical compositions typically comprise the compound preparation of medicament nasal decongestant pseudoephedrine hydrochloride, anti-allergy chlorpheniramine maleate, fexofenadine hydrochloride, loratadine, desloratadine, etc. Solutions Hot analgesic drugs such as aspirin, acetaminophen and the like. How to scientifically and reasonably evaluate the quality of these preparations, the author has accumulated relevant materials and materials through one year of review work, and at the same time, according to the guidelines of the center on quality research and impurity research, the quality evaluation of such preparations is carried out. With certain considerations, these considerations are summarized and summarized to facilitate the scientific development and evaluation of such preparations.
The quality study of the compound preparation should also be carried out in accordance with the relevant technical guidelines for quality research, but as a compound preparation, there are two or more main ingredients in the prescription, which is compared with the single composition preparation in the quality study. The big difference is sometimes more difficult in the quality research process. The following is a brief description of the concerns in the identification, examination and content determination in quality studies.
1. About the identification item: The main purpose of the identification item is to use the appropriate method to "identify" the specific drug. Identification of Compound Formulations Several methods are generally used to identify different components of a prescription. Commonly used identification methods are TLC (used to identify one or several main drugs in the prescription), chemical colorimetry (for the specific identification of a certain main drug), and HPLC method (using the reference method for identification) One or several major ingredients). In the quality study, different identification items should be studied to show that the method used has better specificity.
2, on the inspection items: generally focus on the dissolution, content uniformity, related substances and other items.
2.1 About the content uniformity test As a compound preparation, due to the characteristics of the prescription components, for the small-dose components in the prescription, if the prescription contains chlorpheniramine maleate, caffeine, artificial bezoar, etc., it should be carried out in accordance with the requirements of CP2005. Check the content uniformity and set the quality standard.
2.2 For the dissolution test, firstly combine the physical and chemical properties of the main drug in the prescription, check the conditions of different dissolution media (0.1mol/L hydrochloric acid, water or phosphate buffer solution of pH 6.8), slightly soluble or poorly soluble in the dissolution medium. The dissolution of the ingredients. Secondly, the corresponding ingredients in the prescription should be studied and examined accordingly. Whether the dissolution test is performed on one or several main drugs, the excipients and other components may have some influence and interference on the measurement, so a detailed method of validation of the dissolution test is required.
2.3 Inspection of related substances Due to the large number of impurities in the compound preparation and the diversity of its sources (caused by the main drug, possible interaction, production and preparation, and degradation under storage conditions), the impurities are Separation detection, qualitative and quantitative studies of impurities are more difficult and more complex than single-component impurity studies. Therefore, the common method for checking the impurity of the compound preparation is the HPLC method, and the detector is mostly a UV detector, a DAD detector, an evaporative light scattering detector, and the like. Among them, DAD detectors and evaporation tube scattering detectors have unique advantages in impurity inspection, so the research on impurities in compound preparations will increasingly use these new detectors.
Before the impurity research and inspection, the physicochemical properties of all the main drugs, the factors affecting the stability, etc. should be investigated in detail or necessary pre-tests, combined with the results of prescription screening and process research, to understand the main drugs in the various prescriptions. Stability, master the causes of the main drug impurities and the main degradation products, clear whether there are interactions between different components in the prescription conditions and production process, whether the auxiliary materials affect the stability of the main components. Then, based on this research or research, the main drug components with poor stability or easy degradation in the production and preparation process should be studied and checked with appropriate methods, and the impurity peaks must be assigned. If the acetaminophen in the prescription is easily degraded during the granulation process and produces toxic para-aminophenol, the inspection of the known degradation product, p-aminophenol, should be strictly controlled as a known impurity. The visual study results of the impurities of the more stable components in the prescription are not the key targets. For example, guaiacol glyceryl ether in the formulation (this ingredient is very stable and generally does not degrade under the conditions of manufacture and storage of the formulation) generally does not require inspection of its impurities in quality standards.
Because of the complexity of the study of impurity in compound preparations, if the chromatographic behavior of the main drug and each degradation product is quite different, two or more chromatographic conditions can be selected to check different degradation products separately, and these chromatographic conditions are separately performed. Detailed and complete method validation, method validation is very important in impurity research. In terms of measurement conditions, it should be ensured that the main drug can be separated well from each degradation product under the detection wavelength condition, and has a good detection limit and quantitative limit.
The setting of the impurity limit should be based on the impurity level of each raw material, the production process of the compound preparation, and the storage condition, and the results of the impurity inspection are comprehensively determined; for known impurities, the limit of the known impurity should be determined in the quality standard. .
3. Determination of content The method of content determination can be carried out by different methods (HPLC method, UV method or chemical titration method) or different chromatographic conditions. However, for different chromatographic conditions or different methods, detailed methodological verification should be carried out to illustrate the rationality and suitability of the selection method.
The above-mentioned problems in the preparation of respiratory medicines need to pay attention to the quality research process. Among them, the research on related substances only expounds the problems that must be paid attention to during the research process. Complex, these issues will be continuously accumulated and improved in the future review work, and summed up in a timely manner, better serve the drug registration applicant through the center's communication platform.
The above only represents personal opinions, and it is welcome to exchange and discuss this issue with drug registration applicants.
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