Technical guidelines for change research of listed traditional Chinese medicine (1)

Food and Drug Administration of all provinces, autonomous regions and municipalities directly under the central government (Drug Administration): in order to scientifically regulate and guide the research on the change of listed traditional Chinese medicine and ensure the quality of research, the State Administration has organized and formulated the technical guidelines for the change of listed traditional Chinese Medicine (I), which is hereby printed and distributed for reference Appendix: technical guidelines for research on change of listed traditional Chinese medicine (1) appendix of the State Food and Drug Administration on November 16, 2011: Technical guidelines for the change of research on listed traditional Chinese medicine (I) contents I, overview II, basic principles and requirements III, change of drug specifications or packaging specifications IV, change of excipients with existing pharmaceutical requirements in drug prescriptions 5 Change of production process 6 Change of validity or storage conditions 7 Change of packaging materials and containers 8 Reference 9 Technical guidelines for the change of listed traditional Chinese medicine by the author 1 Overview The guiding principles are mainly used to guide the applicant to carry out the change research on the production, quality control and use of the listed traditional Chinese medicine preparation The applicant shall carry out corresponding technical research according to the impact of the change on the safety, effectiveness and quality controllability of the drugs, and submit a supplementary application to the drug regulatory department after completing the relevant work The application for change of clinical trial research shall be implemented after approval At present, the guiding principles mainly involve the following items: change of drug specifications or packaging specifications, change of excipients with existing pharmaceutical requirements in drug prescriptions, change of production process, change of drug validity or storage conditions, change of drug packaging materials and containers, change of drug production site, etc For other changes, corresponding work shall be carried out according to the specific conditions and the basic principles of the guiding principles According to the impact of changes on the basis of medicinal substances or absorption and utilization of drugs, the guiding principles divide the changes into three categories: Category I changes are minor changes, which will not cause changes in the basis of medicinal substances, will not have a significant impact on the absorption and utilization of drugs, and will not cause significant changes in safety and effectiveness; category II changes are moderate changes Moreover, the change has an impact on the basis of medicinal substances or on the absorption and utilization of drugs, but the change is not significant; category III change is a major change, which will cause a significant change in the basis of medicinal substances, or may have a significant impact on the absorption and utilization of drugs The purpose of classification is to help the applicant to determine the content of change research, effectively carry out change research, evaluate and declare However, in the specific research, the category boundary may not be obvious, so it is necessary to determine the category according to the specific situation and research results Due to the complexity of the change situation, the applicant, as the main body responsible for the change research, shall carry out the research and verification according to the characteristics of the product in accordance with the basic requirements of the guiding principles and the relevant provisions of the drug registration management This guideline only describes the relevant research and verification work that should be considered when changing the listed traditional Chinese medicine from the perspective of technical evaluation The specific requirements for each research work mentioned in the guidelines can be found in the corresponding guidelines The applicant may adopt other appropriate methods according to the specific characteristics of the varieties and the basic research situation, but shall explain the methods adopted and their reliability Due to the particularity of traditional Chinese medicine injection, the guiding principle of research on the change of the listed traditional Chinese medicine injection will be formulated separately 2 Basic principles and requirements (1) "necessary, scientific and reasonable" principle changes of listed traditional Chinese medicine should reflect the necessity, scientificity and rationality of changes The proposal and research of change is based on the understanding of the drugs to be changed, and is based on the research and data accumulation in the previous drug registration stage and the actual production process The more systematic and in-depth the research work in the registration stage and its early stage, the more sufficient the data accumulated in the production process, and the more helpful it will be to the research of post listing changes Therefore, the research results of change application should be based on the understanding of the product to be changed and the scientific and reasonable judgment made by comparing with the change content As the main body of the change research work is the applicant, the applicant has a comprehensive and accurate understanding of the R & D and production of its products and the nature of its products The reason, degree and necessity of the change should be clear, the quality, stability and biological properties of the products before and after the change should be comprehensively studied, the research results should be comprehensively analyzed, and the drugs should be targeted at the change The impact of safety, effectiveness and quality controllability shall be comprehensively evaluated, and the necessity, scientificity and rationality of change shall be explained through the research data provided (2) the principle of "safety, effectiveness and quality control" shall be applied to the change of listed traditional Chinese medicine to ensure its safety, effectiveness and quality control The applicant needs to investigate and evaluate the impact of change on drug safety, effectiveness and quality controllability through certain research work The specific research work should be determined according to the specific situation of change If the controllability of quality standards for drug quality is low and it is difficult to evaluate the impact of changes, research on quality and quality standards should be carried out to improve the controllability of quality standards for drug quality For the change of listed traditional Chinese medicine, full consideration shall be given to the possible risks Any omission or lack of any link may have adverse effects on the safety, effectiveness and quality control of the medicine Systematic research and evaluation shall be strengthened (3) for the research verification of the change of listed traditional Chinese medicine required by the sample for research, the sample with the scale of pilot test or above shall be used Production scale samples shall be used for the study of changes such as significant changes in process The comparative study of drug quality before and after the change is generally carried out with three batches of production scale samples before the change and three batches of samples after the change Generally, three batches of samples are used for accelerated test and long-term stability inspection for 3-6 months after the change, and the stability data of three batches of production scale samples before the change are compared (4) the application for change of associated change may only involve changes in one situation, or changes in multiple situations For example, the change of drug specifications may be accompanied by the change of auxiliary materials, or the change of drug packaging materials For the convenience of description, other changes accompanying or caused by a change are called associated changes in the guidelines For related changes, the research work should be considered comprehensively according to the basic ideas of the change research work in the guiding principles, and relevant research should be carried out As these changes may have different effects on the quality, safety and effectiveness of drugs, it is generally necessary to study according to the change categories with higher technical requirements (5) for the change of the prescription containing toxic medicinal materials, the requirements for the preparation containing toxic medicinal materials should pay attention to the impact of the change on the drug safety, especially the safety of the following types of preparation changes, and carry out relevant research (1) Preparations containing highly toxic medicinal materials; (2) preparations containing medicinal materials found to be seriously toxic by modern research; (3) preparations classified as toxic medicinal materials and used by paediatric, pregnant and lactating women; (4) preparations containing medicinal materials prohibited or used with caution by pregnant women and mainly used by pregnant and lactating women Highly toxic medicinal materials refer to 28 kinds of toxic medicinal materials published in the measures for the administration of toxic drugs for medical use (1988) issued by the State Council and those marked as highly toxic (or highly toxic) in various editions of Chinese Pharmacopoeia, standards issued by the Ministry, standards for imported medicinal materials and standards for local medicinal materials Toxic medicinal materials refer to the medicinal materials marked as toxic in various editions of Chinese Pharmacopoeia, standards issued by the Ministry, standards for imported medicinal materials and standards for local medicinal materials If the toxicity classification of the standard Chinese herbal medicines in each province (district or city) is inconsistent, the classification standard with high toxicity shall be taken as the basis 3 Change of drug specifications or packaging specifications refers to the weight, volume or concentration of drugs in a unit preparation or in a single packaging container Generally, the specifications of tablets, capsules, suppositories, pills, etc are expressed by the weight of each tablet, capsule, pill, etc.; while the specifications of granules, ointments, syrups, etc are expressed by the weight or volume of drugs in a single packaging container In addition to the above-mentioned changes in the specifications of different dosage forms of drugs, changes in the packaging specifications of drugs may also involve changes in multi dose packaging, single dose packaging and other packaging specifications The change of auxiliary materials shall refer to the relevant requirements of the change of auxiliary materials The change of specifications shall be based on scientific, reasonable and necessary basis, and shall follow the principle of convenient clinical use The specifications shall be reasonably determined according to the usage and dosage of drugs, generally within the scope of usage and dosage of clinical use The research work needs to pay attention to the consistency between the changed drug specifications and the original specifications in terms of prescription, process, daily dosage / dosage, etc (I) class I change Such changes will not cause changes in the basis of pharmaceutical substances, and will not have a significant impact on the absorption and utilization of drugs, mainly including the following situations: only involving changes in the minimum packaging drug loading in drug packaging, such as changes in packaging specifications of granules, decoctions, syrups, pills, etc.; changing the tablet weight size, packaging specifications of capsules, etc The research work is mainly based on the consistency between the changed specifications and the original specifications, such as the formulation, process, daily dosage / dosage, etc According to the characteristics of dosage forms and drug properties, it is advisable to select appropriate items to carry out comparative study on the changed drugs and the original drugs Generally, the following information shall be provided: 1 Reasons for the change, specifying the specific situation, necessity and rationality of the change 2 If necessary, provide quality comparison test and research data before and after the change, test data and literature data of quality research work, and quality standards 3 Inspection report of three consecutive batches of samples after change 4 Stability research data, including comparison with the stability of products before change In the first case, if the change of packaging material is not involved, it may not be provided generally; however, if the factors affecting the stability of drugs such as the size of packaging container space are involved, the stability research data shall be provided (II) class III changes such changes may cause significant changes in the basis of pharmaceutical substances, or may have significant impact on the absorption and utilization of drugs For sustained-release / controlled-release preparations, pharmacokinetic research data shall be provided and clinical trials shall be conducted according to the research situation This kind of drug specification change needs more comprehensive research work: 1 The reason of the change, the specific situation of the change, the necessity and rationality of the change 2 If necessary, provide research data of preparation prescription 3 Quality comparison test and research data before and after the change, test data and literature data of quality research work, and quality standard 4 Inspection report of three consecutive batches of samples after change