Circular of the drug approval center of the State Food and Drug Administration on the issuance of three guiding principles, including the "technical guiding principles for the quality control research of new medicinal materials of traditional Chinese medicine (Trial)" (No. 31, 2020)
 

Drug evaluation center of the State Drug Administration

October 10, 2020

Technical guidelines for research on quality standards of new Chinese medicines (Trial)

    1、 Overview

The quality standard of traditional Chinese medicine is an important content in the research of new drugs of traditional Chinese medicine. The research on quality standards of traditional Chinese medicine should follow the development law of traditional Chinese medicine, adhere to the combination of inheritance and innovation, and embody the concept of drug quality life cycle management; On the basis of in-depth research, modern science and technology should be used to establish scientific, reasonable and feasible quality standards to ensure the controllable quality of drugs.

Researchers should select and determine quality standard control indicators according to the prescription composition, preparation process, physicochemical properties of medicinal substances, characteristics and stability of preparations of new Chinese medicine. In addition, researchers should continue to improve the content of quality standards and improve the quality control level of new Chinese medicine in combination with the development of relevant science and technology,Ensure the safety and effectiveness of drugs。

This guiding principle aims to provide technical guidance for the research on the quality standards of new traditional Chinese medicines in China, focusing on the basic requirements for the research and formulation of the quality standards of new traditional Chinese medicines. The quality standards of natural drugs can also be referred to this guiding principle.

    2、 Basic principles

   （1） The quality standard should reflect the quality of traditional Chinese Medicine

. It is encouraged to adopt various forms to carry out exploratory research on the active ingredients of traditional Chinese medicine, and establish corresponding identification methods for all drug flavors in the prescription; Generally, the effective (active) ingredients, toxic ingredients and other chemical ingredients with obvious index characteristics should be selected as the detection indicators. The establishment of quality standards should evaluate the scientificity and rationality of inspection items and their standard settings, and the applicability and feasibility of inspection methods. In the process of quality standard research, it is encouraged to explore the correlation between the results of clinical trials and non clinical studies and the index components in the test samples, carry out quality research related to the safety and effectiveness of traditional Chinese medicine, and provide sufficient basis for the rationality of the determination of the indicators in the quality standard.

   （2） Relevance of quality standard research

The quality standards of traditional Chinese medicine decoction pieces or extracts, intermediate products, preparations and other quality standards constitute the quality standard system of traditional Chinese medicine preparations, and a perfect quality standard system is the basis for drug quality traceability; It reflects the transfer process of quantitative or quality controllable medicinal substances from decoction pieces or extracts, intermediates to preparations in the production process of traditional Chinese medicine preparations. This quantity and quality transfer process conforms to the quality control characteristics of traditional Chinese medicine preparations, and also reflects the relationship between the quality standards of traditional Chinese medicine preparations and process design, quality research, stability research, etc.

   （3） Quality standard research should reflect the characteristics of the preparation

The quality standard should be combined with the prescription composition, active ingredients or index ingredients, excipients and dosage form characteristics of the preparation to carry out targeted research. The medicinal material basis of different pharmaceutical preparations is different, and the detection indicators, methods and related requirements of their quality standards should also reflect their different characteristics. The quality control methods of traditional Chinese medicine should be selected according to the drug conditions, and the integration of multiple methods should be encouraged. The ingredients of traditional Chinese medicine compound preparations are closely related to their prescriptions and processes, and the inspection and detection items of multiple indicators should be established in their quality standards. The limits and ranges of various indicators of quality standards should be determined according to the research data of samples for clinical trials.

   （4） Quality standards should be scientific, standardized and feasible

The quality standard of new traditional Chinese medicine should meet the requirements of Chinese Pharmacopoeia, general principles of preparations and various inspection and detection methods. The quality standard research should refer to the specifications of the national drug standard working manual, and carry out systematic research and verification according to the requirements of the guiding principles for the validation of analytical methods of drug quality standards in Chinese Pharmacopoeia, so as to prove the rationality and feasibility of the analytical methods. The samples for quality standard research should be representative, and the inspection and detection methods should be simple and feasible. According to the needs of inspection and detection, the reference materials should be selected reasonably, and the control extract should be encouraged to be selected for the study of the content determination method of multi index components. .

   （5） Periodicity of quality standard research

The research on the quality standards of new drugs of traditional Chinese medicine is a process of gradual improvement with the continuous advancement of new drug research. In the research stage before clinical trial, we should focus on the research and establishment of the inspection and detection methods of the main indicators including toxic components, and the indicators related to safety in the quality standard should be as comprehensive as possible. During clinical trials, we should study and establish indicators and methods that comprehensively reflect the quality of preparations to improve the controllability of drug quality. In the pre marketing research phase of new drugs, the consistency of various indicators of the preparation quality standard and the corresponding indicators of the confirmatory clinical trial sample quality standard should be considered. Based on the consideration of risk assessment, reasonably select the inspection and detection items included in the quality standard, and formulate reasonable limits and content ranges according to the inspection and detection data of samples for clinical trials. .

   （6） Quality standards should be advanced

The method used in the quality standard shall be scientific, advanced and practical, and meet the requirements of simplicity, sensitivity, accuracy and reliability. The development of modern science and technology has provided more new technologies and methods for the quality standard research of new Chinese medicine. If the achievements of the development of modern science and technology meet the actual needs of the quality standard research and inspection of traditional Chinese medicine, we should encourage the rational use of relevant new technologies and methods in the quality standard, so as to better reflect the internal quality of traditional Chinese medicine. For the research on improving and perfecting the quality standard, if there is a case that the original method in the standard is replaced by a new method, a comparative study of the two should be carried out to reasonably determine the quality control requirements of relevant indicators.

IIIprimary coverage

The content of the quality standard for new drugs of traditional Chinese medicine generally includes: drug name, prescription, preparation method, character, identification, inspection, extract, fingerprint/Characteristic map, content determination, function and indications, usage and dosage, attention, specification, storage, etc. The following is a brief description of the main research contents and general requirements of some items in the quality standards of new Chinese medicine:

（1） Drug name

Including the correct name of drugs and the name in Chinese pinyin. The name should conform to the relevant provisions of the state drug regulatory department.

    （2） Prescription

The prescription includes the name and dosage of the medicinal flavor such as the decoction pieces and extracts of the prescription. The order of the medicinal flavor of the compound preparation should generally be in the order of monarch, minister, assistant and envoy. The dosage unit of solid medicine flavor is g（g）, the dosage unit of liquid medicine flavor is g（g）Or ml（ml）. The amount of each drug in the prescription is generally1000Preparation units (tablets, granulesg、ml; Except for special cases, the value of each drug taste quantity generally adopts integer digits.

. If there are pieces and extracts of traditional Chinese medicine without national drug standards and without drug registration standards, the quality standard of the flavor should be established separately and attached to the preparation standard. The quality standard of the extract should include its preparation process.

    （3） Preparation method

The preparation method is a brief description of the production process, which generally includes the process and main process parameters of pretreatment, extraction, purification, concentration, drying and molding. The format and wording of the formulation description can be standardized with reference to the format and wording of Chinese Pharmacopoeia and the national drug standards manual, requiring accurate words, concise language, rigorous logic, and avoiding the use of sentences that are prone to misunderstanding or ambiguity.

    （4） Character

. Generally, the color difference range describing the appearance color should not be too wide. The description of composite color should be that the secondary color comes first and the primary color comes second, such as yellowish brown, which is mainly brown. Other content requirements of trait items should refer to the examples in Chinese Pharmacopoeia.

    （5） Identification

The common methods of identification include microscopic identification, chemical reaction, chromatography, spectroscopy and biological methods. Generally, the identification test should adopt the methods with strong specificity, high sensitivity, good reproducibility, fast and convenient operation, and encourage the research and establishment of a method to identify multiple drug flavors at the same time.

If there is crude drug powder directly used in the preparation, a microscopic identification method should generally be established; If the preparation contains a variety of crude drug powders directly used in medicine, the specificity of each drug flavor should be described separately in the microscopic identification method. The chemical reaction identification method is generally applicable to the identification of large categories of chemical components containing mineral drug flavor and similar structural characteristics in the preparation. Chromatography mainly includes thin-layer chromatography（TLC/HPTLC）, gas chromatography（GC）And HPLC（HPLC/UPLC）Et al.TLCThe method can be identified by the specific shift value and color development characteristics, and the number of characteristic spots, specific shift value, spot color, UV absorption/The consistency of fluorescence characteristics with reference materials shall be described in detail;HPLCLawGCThe method can be identified by chromatographic characteristics such as retention time. If the prescription contains animal derived drug flavor and only its protein, polypeptide and other biological macromolecular components in the preparation have recognition characteristics, the corresponding specific inspection and detection methods should be established.

    （6） Inspection

1. Inspection items related to dosage form

According to the characteristics of the dosage form and the needs of clinical medication, the inspection method reflecting the characteristics of the preparation should be established with reference to the corresponding provisions of the general principles of Chinese Pharmacopoeia. If there are two or more methods for the examination items related to dosage forms in the general principles of Chinese Pharmacopoeia as options, a reasonable choice should be made according to the characteristics of the preparation, and the reasons should be explained.

2. Safety related inspection items

If the prescription contains drug flavor that is easily contaminated by heavy metals and harmful elements, or the equipment, auxiliary materials, separation materials used in the production process may introduce harmful elements, the corresponding limit inspection methods for heavy metals and harmful elements should be established, and the reasonable limits should be formulated on the basis of full research and risk assessment, and should conform to the relevant provisions of Chinese Pharmacopoeia and other standards.

If organic solvents (except ethanol) are used for extraction and processing in the preparation process, an organic solvent residue inspection method should be established in the quality standard; If macroporous adsorption resin is used for separation and purification, the limit inspection method for possible resin organic residues in the extract should be established according to the type of resin, the possible degradation products of resin and the use of solvents. For example, the possible degradation products of styrene macroporous adsorption resin mainly include but are not limited to benzene, n-hexane, toluene, xylene, styrene, diethylbenzene, etc. （ICH）Relevant requirements of.

If the drug flavor in the prescription contains one or a class of toxic ingredients rather than effective ingredients, a limit inspection method for toxic ingredients should be established for the drug flavor, and the limit can be reasonably formulated according to the corresponding toxicology or literature research data.

3. Inspection items related to drug characteristics

Targeted inspection items should be established according to the characteristics of drugs. For example, the inspection methods for relevant substances and dissolution should be established for the extracted natural single ingredient oral solid preparations; For oral solid preparations containing poorly soluble extracts, the dissolution should be checked and studied. .

4. Determination of inspection limits

The quality standard shall specify the inspection methods and limits of each inspection. Generally, for the inspection items listed in the quality standard, the rationality of the inspection method and its limits should be fully demonstrated from the aspects of safety and production practice. The set inspection limit, especially the inspection limit of hazardous substances, shall be within the level range supported by the safety data.

    （7） Leachables

The extract check can be used as an indicator to control the consistency of the total amount of extract. . The influence of various influencing factors on the detection of leachables, such as the influence of excipients, should be systematically investigated. The type and dosage of solvent, determination method and temperature parameters shall be indicated in the detection method of leachables, and a reasonable limit range of leachables shall be specified.

    （8） Fingerprint/Characteristic Atlas

Traditional Chinese medicine and new drug preparations (except natural single ingredient preparations extracted) should generally be fingerprinted/. The contents generally include the establishment of analytical methods, identification of chromatographic peaks, establishment of reference spectra, data analysis and evaluation.

fingerprint/Various chromatographic methods are generally used for characteristic spectra, such asHPLC/UPLCLawHPTLCLawGCFA et al. A suitable preparation method for the test article should be established according to the properties of the main ingredients contained. If the drug contains a variety of different types of ingredients with large differences in physical and chemical properties, consider preparing test samples for different types of ingredients and establishing multiple fingerprints/. If one method cannot fully reflect the characteristics of the ingredients contained in the test article, two or more methods can be used to obtain different fingerprints/The characteristic maps were analyzed.

fingerprint/. Generally, one or more main active ingredients or index ingredients that are easy to obtain are selected as references; If there is no suitable reference, the stable chromatographic peak in the spectrum can also be selected as the reference peak, and it should be identified as far as possible.

 By fingerprinting representative samples/For the analysis of characteristic chromatograms, the chromatographic peaks that appear in each batch of samples are selected as the common peaks. /. fingerprint/During the study of characteristic chromatograms, the main chromatographic peaks in the chromatograms should be identified as far as possible.

fingerprint/The similarity or the relative retention time of characteristic peaks and the ratio of peak area are generally used as the detection indicators of the characteristic map. According to the detection results of multiple batches of samples, the fingerprint similarity evaluation system computer software can be used to obtain the mode of common peaks, establish the control fingerprint, use the above software to analyze and compare the similarity between the fingerprint of the test article and the control fingerprint, and pay attention to the characteristics of non common peaks. . The evaluation shall be carried out on the basis of the sample detection data, and the fingerprint shall be formulated/The similarity or relative retention time, peak area ratio and its range of the characteristic map.

    （9） Assay

 1. Selection of content determination index

The prescription composition of the preparation is different, and the selection of content determination indicators is also different.Extracted natural single ingredient. For the extract preparation with basically clear composition, the content determination method of one or more main index components should be established, and the content determination method of major components should be studied and established.

As far as possible, compound preparations should study and establish the content determination method of multiple drug flavors in the prescription. According to their functions and indications, the chemical components related to the safety and effectiveness of drugs should be preferred, and generally the effective ones should be preferred/Active ingredients, toxic ingredients, and the index ingredients contained in the drug are the content determination indicators. In addition, it is necessary to consider the correlation between the content determination index and the process and stability, and establish a multi-component or multi-component content determination method as far as possible. /Content determination method of active ingredients or index ingredients; If there is a process for extracting volatile oil, the determination method of the total amount of volatile oil or the corresponding index components shall be studied and listed in the standard according to the situation; If there is a clear thermal sensitive component, the content determination method that can reflect the heating degree and stability of the material in the production process should be studied and listed in the standard according to the situation.

2. Content determination method

The content determination methods include volumetric (titration) method, chromatographic method, spectrometric method, etc., and the chromatographic method includesGCLaw andHPLC/UPLCMethod, etc., volatile components can be given priorityGCLaw orGC-MSMethod, non-volatile components can be given priorityHPLC/UPLCMethod. The inorganic components of mineral medicine flavor can be determined by volumetric method and atomic absorption spectrometry（AAS）Inductively coupled plasma atomic emission spectrometry（ICP-AES）Inductively coupled plasma mass spectrometry（ICP-MS）And other methods.

The method used for content determination shall be verified by methodology.

3. Content range

The extracted natural single ingredient and its preparation shall generally specify the content range of the main ingredient; According to its content and the requirements of the preparation, the percentage range of the ingredient in the unit preparation equivalent to the marked amount shall be specified.

The quality standard of the extract shall specify the content range of the major components and main index components, which can be one or several components; According to the content of the extract and the requirements of the preparation, the content range of major components and main index components shall be specified.

The establishment of multiple content determination indicators for compound preparations is encouraged, and the content range of each content determination indicator is specified. If the prescription contains drug flavor that may be both effective and toxic ingredients, the content shall be determined and the content range shall be specified.

    （10） Biological activity assay

Biological activity determination methods generally include biological potency determination method and biological activity limit determination method. Because the existing conventional physicochemical methods have certain limitations in the control of drug quality, it is encouraged to explore and carry out the research of biological activity determination, and establish the biological activity determination method as an alternative or supplement to the conventional physicochemical methods.

The biological activity determination method should conform to the basic principles of randomization, control and repetition of pharmacological research. The established method should be simple, accurate, feasible and controllable, and have clear judgment criteria. The selection of test system is closely related to the experimental principle and the formulation of indicators. The test system with clear background information, few influencing factors, sensitive detection indicators and high cost performance should be selected. The content (potency) determination method characterizing the biological activity intensity of drugs should be verified according to the requirements of the biological activity determination method. For the detailed requirements of the bioactivity determination methods of different drugs, please refer to the relevant guiding principles.

    （11） Specifications

The formulation specification shall refer to the relevant requirements of the technical guidelines for specification expression of Chinese patent medicine.

    （12） Storage

The contents of storage items are the basic requirements for drug storage and storage. The stability of drugs is not only related to their own properties, but also disturbed by many external factors. The packaging materials and storage conditions of direct contact with medicinal materials (decoction pieces), extracts and preparations should be systematically investigated, and the storage conditions should be determined according to the stability influencing factors and the test results of drug stability investigation.

    4、 Main references

1State Drug Administration.Technical requirements for the research of new drugs of traditional Chinese medicine,1999year.

2State Food and Drug Administration.Technical requirements for new drug research of natural drugs,2013year.

3National Pharmacopoeia Commission.Working manual of national drug standards,2012year.