I. Overview

　　Quality study of new TCMs refers to the process of determining critical quality attributes of the TCMs by studying relevant factors related to drug safety and efficacy by using various technologies, methods and means under the guidance of TCM theories. The purpose of quality study is to determine the quality control indicators and their acceptable ranges, and provide basis for manufacturing process control and quality standards establishment of the TCMs, so as to guarantee the safety, efficacy and quality control of the TCMs.

　　Based on characteristics of the multi-component complex system of TCMs, the quality study of new TCMs should be oriented by clinical value and needs, abide by TCM theories, insist on integrating inheritance and innovation, and utilize new physical, chemical or biological technologies and methods to study and analyze quality characteristics of the TCMs from multiple perspectives. In the meantime, quality study should also reflect the concepts of quality by design, whole-process quality control and risk management. Through studies of quantitative and qualitative transfer of medicinal substances and critical quality attributes across TCM crude drugs, prepared slices/decoction pieces, intermediates (intermediate products) and preparations in different stages, as well as the interaction between medicinal substances and excipients/pharmaceutical packaging materials, the quality control level of TCMs is constantly improved.

　　This guideline aims to provide reference for the quality study of new TCMs, and relevant contents will continue to be improved in accordance with scientific researches and the development of TCM.

　　II. Basic Principles

　　(I) Abiding by the guidance of TCM theories

　　TCMs have complex medicinal substances, especially compound preparations. Therefore, the quality study should respect traditional theories and practices of TCM, and various study technologies and methods should be selected in accordance with characteristics of different medicines to conduct targeted quality studies and reflect the overall quality of TCMs.

　　(II) Laying equal emphasis on traditional quality control methods and modern quality study methods

　　Traditional experience and method are of important significance to TCM quality study and quality control, and in the meantime, application of modern science and technology in TCM quality study is also encouraged. In accordance with characteristics of the medicines, physical, chemical, biological or other modern study methods should be utilized to analyze quality characteristics of the TCMs, study characterization methods of the quality characteristics, critical quality attributes, quality evaluation method, and quantitative and qualitative transfer laws, to effectively reflect the quality of TCMs.

　　(III) Taking the medicinal substances as important study contents

　　During the quality study process of new TCMs, study on medicinal substances should be guided by TCM theories and clinical practices, and pay attention to association study of safety and efficacy. Studies on relevant attributes of medicinal substances should be carried out to provide scientific support for manufacturing process control and quality standard development.

　　(IV) Taking safety, efficacy and quality controllability as the objective

　　Quality control method and indicators of new TCMs should be able to reflect the safety, efficacy, stability and quality controllability of the TCMs. Medicinal substances and critical quality attributes, and quantitative and qualitative transfer laws of TCM crude drugs, prepared slices/decoction pieces, intermediates and preparations, as well as the interaction between medicinal substances and excipients/pharmaceutical packaging materials are main contents for quality study. Appropriate study methods and quality control indicators should be selected centering on the safety and efficacy, to objectively characterize TCM quality characteristics and provide scientific basis for TCM quality control.

　　(V) Running throughout the whole life cycle of the TCMs

　　Quality study of the TCMs should not be only embodied in the entire manufacturing process including the quality of medicinal substances and excipients, manufacturing processes and equipment selection, process control and management, development of quality standards for preparations, risk control and assessment, etc., and should also run throughout the whole life cycle of the TCMs. Post-market quality studies of the TCMs should be strengthened to constantly improve product quality, establish a quality control system aligned with TCM characteristics that spans the entire process and whole life cycle, thus guaranteeing the quality controllability, stability and uniformity of new TCMs.

　　III. Main Contents

　　(I) TCM crude drugs and prepared slices/decoction pieces

　　As the source of preparations, the quality of TCM crude drugs and prepared slices/decoction pieces has a direct influence on drug quality. Therefore, quality research and control of the entire manufacturing process for TCM crude drugs and prepared slices/decoction pieces should be strengthened, and modern information technologies are encouraged to be applied to establish a traceability system of TCM crude drugs and prepared slices/decoction pieces.

　　The quality control of TCM crude drugs and prepared slices/decoction pieces used in new TCMs should be performed in reference to their systematic study results and in combination with TCM crude drugs and prepared slices/decoction pieces of specific products, as well as study results of its relevance to the intermediates and preparations, to determine the quality control indicators and their ranges of TCM crude drugs, prepared slices/decoction pieces, so as to meet quality design requirements for new TCMs.

　　Attention should be paid to impacts on the safety of TCM crude drugs from pesticide residues, heavy metals and harmful elements, and mycotoxin, etc. introduced during planting and cultivation, manufacturing, processing, circulation and storage of TCM crude drugs. If the formula contains animal-derived ingredients, attention should be paid to the possibility of introducing pathogens; in the meantime, attention should be paid to use of hormones and antibiotics in animal-derived ingredients, as well as mycotoxin contamination from some TCM crude drugs due to being infected with toxic fungi, and special safety control methods should be established when necessary; if the formula contains realgar, cinnabar and other mineral ingredients, reasonable purity control indicator of minerals should also be set, and safety influence of the valence state of its heavy metals and harmful elements that may be dissolved and absorbed in human body should also be studied; in addition, if the formula contains toxic ingredients, attention should be paid to its safety and efficacy, and reasonable limits or content ranges should be established as appropriate.

　　(II) Intermediates

　　Study on intermediates is one of the important contents of the quality study of new TCMs. The quality of the intermediates (such as powdered prepared slices/ decoction pieces, concentrates, and extracts, etc.) should be studied, especially the intermediates directly used for TCM preparations, combined with the preparation process characteristics. In accordance with different characteristics of the TCMs, their physiochemical properties, chemical components, and bioactivity, etc. and influence factors related to safety and efficacy should be studied.

　　1. Physiochemical properties

　　Physiochemical properties are of important significance for intermediate quality control and subsequent preparation study, etc. For compound preparations of TCMs with complex chemical components and unclear active components, attention should be paid to studies on overall physiochemical properties of intermediates.

　　For fluids and semi-solids, critical quality attributes influencing the drug quality should be determined in accordance with the subsequent preparation needs and studies of medicinal substance composition, from quality information of description, relative density, pH value, clarity, flowability, and total solids, etc.

　　For powdered prepared slices/decoction pieces used directly as medicine, special attention should be paid to its particle size, particle size distribution and mixing uniformity, etc.

　　For extract powder, flowability, bulk density, solubility and hygroscopicity, etc. should be studied, and its critical quality attributes should be determined in accordance with properties of the medicine itself and subsequent preparation requirements.

　　2. Chemical components

　　TCMs have complex and diverse chemical components, and therefore, focused and systematic research on chemical components should be conducted based on the characteristics of new TCMs.

　　2.1 Compound preparations

　　For quality studies of compound preparations, a systematic study of chemical components should be conducted under the guidance of TCM theories and in combination with functions and indications, and previous use conditions.

　　Emphasis should be laid on literature research on chemical components of ingredients, to understand chemical categories, structures, contents, assay and measurement methods, etc. for various components.

　　Attention should be paid to chemical components related to TCM safety and efficacy, and to chemical components of sovereign drug, precious drugs, toxic drugs or ingredients with large dose in the formula.

　　Targeted studies should be conducted toward medicinal substances obtained from the confirmed manufacturing process, to identify critical quality attributes.

　　2.2 Extracts obtained from single plant, animal or mineral materials and their preparations

　　Since these extracts have been enriched with chemical components related to pharmaceutical effect during the preparation process, emphasis should be placed on systematic research on the composition and chemical component content, etc. of the extracts, and providing full characterization via multiple means of single component content, major chemical classes contents, and fingerprint/characteristic chromatogram, etc.

　　Categories of other components contained in the extracts should also be studied, to guarantee the stability and uniformity of the medicinal substances of the extracts.

　　3. Safety-related factors

　　3.1 Endogenous toxic components

　　If the formula contains toxic ingredients, the endogenous toxicity should be analyzed in combination with toxicology study results, and in the meantime, attention should also be paid to ingredients containing structurally similar components with discovered toxic ingredients, as well as the ingredients belonging to the same family and genus with known toxic ingredients.

　　For ingredients containing known toxic components, limit test methods of toxic components should be established, to define safety limits or non-detection criteria; while if the toxic components are also active, content ranges (upper and lower limits) of such toxic components should be set in accordance with literature report and study results of safety and efficacy.

　　For ingredients with known toxicity but unclear toxic components, the safety dose range should be studied and determined in accordance with TCM theories and traditional clinical use, or the definitive study on toxic components and in-depth toxicology study on medicinal substances could be conducted, to strengthen quality control.

　　3.2 Exogenous pollutants

　　Exogenous pollutants primarily include pesticide residues (including plant growth regulators and their degradants), heavy metals, harmful elements, mycotoxin and sulfur dioxide, etc. introduced from TCM crude drugs and prepared slices/decoction pieces, and also include organic solvent residues and resin residues, etc. introduced during the extraction and processing, as well as the microorganisms grown during the storage process (if applicable). In addition, attention should also be paid to possible pollutants from the equipment and its components.

　　By the systematic study and analysis of the exogenous pollutants contained in the intermediates, for any pesticide residues, heavy metals, harmful elements and mycotoxin that might be introduced from TCM crude drugs and prepared slices/decoction pieces, their retention in intermediates should be analyzed, and necessary test methods should be studied and established.

　　If resin and/or organic solvent are used during the extraction and processing, their residue or enrichment in intermediates should be studied and analyzed, safety risks should be evaluated, and reasonable control methods should be established.

　　4. Bioactivity

　　It is encouraged to carry out studies on exploring bioactivity assay for new TCMs. It is suggested to combine pharmacological or toxicological research results to establish bioactivity assay method as alternatives or supplements to conventional physical and chemical methods, so as to improve the correlation between quality evaluation and functions and indications (indications for use), and safety of new TCMs.

　　(III) Preparations

　　In accordance with characteristics of new TCMs, based on studies on TCM crude drugs and prepared slices/decoction pieces, intermediates, the manufacturing process of preparations and stability, etc., and in combination with studies on medicinal substances, and safety and efficacy study results, the preparation quality study should be conducted with emphasis on the following aspects:

　　1. Dosage form

　　Dosage form is one of the important factors influencing the quality of new TCMs. For new TCMs, the administration route is selected and dosage form determined generally based on clinical use needs, and by comprehensively considering formula composition, physiochemical properties of medicinal substances, drug loading quantity of different dosage forms, clinical administration dose, and patient compliance, etc.

　　For new TCMs, corresponding quality control items should be studied and established according to the characteristics and requirements of different dosage forms, to characterize the characteristics of the dosage form selected. For different types of preparations, it is generally required to set key control indicators in reference to regulations in the General Rules on Preparations in Chinese Pharmacopoeia, e.g., disintegration time for oral solid preparations and softening time for suppositories, etc.

　　2. Formula and molding process of preparations

　　The formula of preparations should be determined in reference to study results of physiochemical properties, chemical components and bioactivity of intermediates. The properties of intermediates, functions of selected excipients and interaction between medicinal substances and excipients should also be considered comprehensively in combination with characteristics of the dosage form, to study impacts of the molding process on medicinal substances and the quality control method.

　　It should be noted that medicinal substances are affected by solvents, excipients and various processing conditions during the preparation process. In particular, loss and other changes of active components, volatile components, heat-sensitive components, and other unstable components may be induced by excessive temperature or heating time during drying and sterilization.

　　The critical control points and control objectives of the manufacturing process of preparations should be determined in reference to the stability of medicinal substances, to guarantee stable quality of the medicine.

　　3. Microorganism control

　　Microbial contamination (including primary contamination and secondary contamination) may occur during the manufacturing process of TCM crude drugs and prepared slices/decoction pieces and their preparations. Appropriate microbial control measures or appropriate microorganism removal method (e.g., autoclave, instantaneous high temperature) should be studied and taken into consideration based on ingredients, processing or manufacturing process characteristics, administration route, and drug properties, etc. Methods for removing microorganisms should be validated and ensure that they have no significant impact on the medicinal substances.

　　Microbiological tests must be carried out toward the preparations, and the microbial limit depends on the dosage form and administration route. The microbial limit test should conform to relevant regulations in the Chinese Pharmacopoeia.

　　4. Others

　　For new TCMs using extracts from single plants, animals, minerals, or other substances, it is suggested to conduct dissolution studies according to the requirements of dosage form and establish corresponding dissolution test method; moreover, it is encouraged to carry out relevant studies on other types of innovative TCMs in accordance with their own characteristics. For medicinal substances with low content in the preparations or accounting for a small proportion in the formula of preparations, attention should be given to their content uniformity, and relevant study and validation should be performed.

　　(IV) Relevance of quality study

　　1. Relevance to safety and efficacy

　　The quality study of new TCMs should aim to guarantee the safety and efficacy of the TCMs, and specific study methods and quality control indicators are chosen to characterize quality characteristics of new TCMs.

　　2. Relevance to manufacturing process study

　　Different preparation processes will get different medicinal substances with different properties, directly affecting the safety and efficacy of the medicine. Quality study should run through the entire process of the manufacturing process study and manufacturing quality control, to ensure consistent quality of the products.

　　3. Relevance to stability study

　　Stability study is also an important content of quality study. The stability study indicators should be able to reflect the intrinsic quality changes of the medicine and also reflect the quality study results.

　　Quality study should pay attention to changes in volatile, heat-sensitive, easily oxidized and other unstable components, and active components, especially changes in toxic components. Attention should be paid to changes in mycotoxin and other pollutants of powdered prepared slices/decoction pieces directly used as medicine, TCM crude drugs and prepared slices/decoction pieces with relatively high contamination risk from fermentation process, etc., and their preparations during storage process, and then corresponding control measures should be taken.

　　Note: In the event of any discrepancy between the English and Chinese versions, the Chinese version shall prevail.