Under the deployment of the State Drug Administration, the drug approval center organized and formulated the guiding principles for pharmaceutical research technology at all stages of new drug research of traditional Chinese medicine (Trial) (Annex 1). According to the requirements of the notice of the General Department of the State Food and Drug Administration on printing and distributing the procedures for issuing the technical guidelines for drugs (yjzyg [2020] No. 9), and with the approval of the State Drug Administration, it is hereby issued and shall take effect from the date of issuance.
It is hereby notified.
Drug evaluation center of the State Drug Administration
October 27, 2020
Guiding principles for pharmaceutical research technology at all stages of new Chinese Medicine Research (Trial)
1、 Overview
The research on new drugs of traditional Chinese medicine is a systematic project involving multi-disciplinary research such as pharmacy, pharmacology and toxicology, and clinic. . Under the guidance of traditional Chinese medicine theory, according to the characteristics of traditional Chinese medicine, the general law of new drug research and development and the main purpose of different research stages, targeted research should be carried out to implement the whole life cycle management of drugs, promote the inheritance and innovation of traditional Chinese medicine, and ensure the safety, effectiveness and quality control of drugs.
This guiding principle mainly puts forward the basic requirements for the main pharmaceutical research contents to be completed at each stage of the application for clinical trial, phase III clinical trial, application for marketing license and post marketing research of new Chinese medicine, and provides a reference for the research of new Chinese medicine. For specific products, it is not necessary to adhere to the phased requirements proposed in this guiding principle, and the research content should be arranged scientifically and reasonably according to the product characteristics.
2、
（1） Follow the guidance of traditional Chinese medicine theory
Under the guidance of traditional Chinese medicine theory, traditional experience and clinical practice should be respected, and modern science and technology should be encouraged to carry out research and innovation.
（2） In line with the characteristics of traditional Chinese medicine and the law of research and development
According to the characteristics of traditional Chinese medicine and the general law of new drug research and development, we should fully understand the complexity of traditional Chinese medicine, the gradualness of new drug research and development and the main research purposes of different stages, carry out the corresponding research work in stages, reflect that the quality originates from the design concept, pay attention to the integrity and systematicness of research, improve the quality and efficiency of new drug research and development, and promote the inheritance and innovative development of traditional Chinese medicine.
（3） Practice life cycle management
Pharmaceutical research on new drugs of traditional Chinese medicine should reflect the whole life cycle management, strengthen the quality control research of the whole process of medicinal materials, decoction pieces, intermediates, preparations, etc., establish and improve the whole process quality control system in line with the characteristics of traditional Chinese medicine, and with the improvement of product cognition and the continuous progress of science and technology, continue to improve the drug production process, quality control methods and means, and promote the continuous improvement of drug quality.
3、
（1） Application for clinical trial
The following pharmaceutical research work should be completed to provide basically stable quality samples for clinical trials to meet the needs of clinical trials. The research content includes fixed prescription drug taste and route of administration; ; Establish quality standards, basically complete safety related quality control research, and achieve basically controllable quality; Ensure the stability of sample quality for clinical trials.
1. flavor and quality of prescription drugs
The prescription flavor of new Chinese medicine (including Chinese medicine decoction pieces, extracts, etc.) should be fixed. Clarify the origin, medicinal parts, quality requirements, processing methods and quality standards of herbal pieces. Pay attention to the place of origin of medicinal materials and the collection period (including the collection period and time, the same below).
In order to ensure the stability of the quality of traditional Chinese medicine, we should pay attention to the quality of the used medicinal materials and the sustainable utilization of resources, and carry out resource evaluation research on wild medicinal materials according to the relevant requirements. .
2. dosage form and preparation process
Under the guidance of the theory of traditional Chinese medicine, combined with human experience, the physicochemical properties and pharmacological effects of the chemical components contained in each medicine flavor, the research on the preparation process of new Chinese medicine was carried out.
Dosage form selection, process route and main process parameters should be studied to clarify dosage form and preparation process and explain the rationality of its selection. . Carry out formulation design and molding process research, and clarify the auxiliary materials used, molding process and main process parameters.
The preparation process should be determined through pilot scale-up study, and the main process parameters should be defined. Consider the feasibility and adaptability of commercial scale production equipment.
Samples for non clinical safety test shall be of pilot scale or above.
3. quality research and quality standards
Carry out quality control research on new medicinal materials / decoction pieces, intermediates, preparations and excipients of traditional Chinese medicine, and establish quality standards. Quality research should be carried out around the safety and effectiveness of drugs, focusing on quality control projects that affect safety, such as toxic ingredients and their control, and establishing quality control methods. With the deepening of research, quality research and quality standards should be gradually improved.
4. stability study
Conduct preliminary stability research, select appropriate packaging materials / containers that directly contact drugs, study and determine storage conditions, and ensure the quality stability of samples for clinical trials.
（2） Before phase III clinical trial
Samples used in clinical trials should generally be samples prepared on a production scale, and the production should meet the requirements of drug production quality management norms.
1. flavor and quality of prescription drugs
On the basis of the previous research on the basis of fixed medicinal materials, medicinal parts and processing methods of decoction pieces, through the systematic research (including literature research) on the influence of the origin, harvest time and processing of the origin, production mode (wild, planting and breeding, other ways), storage methods and conditions of prescription Chinese medicinal materials on the quality of medicinal materials, improve and determine the relevant information of medicinal materials, and ensure the stability of the quality of medicinal materials. The quality standards of medicinal materials and decoction pieces should be continuously studied and improved. For those who really need to use rare and endangered wild medicinal materials, research on planting and breeding technology should be carried out.
2. production process
According to the pre clinical trials and research results, complete the large-scale production research, fix the production process and specify the detailed process parameters to ensure the stable quality of samples for phase III clinical trials. On the premise that the process route and key process parameters remain unchanged, if it is necessary to change the process parameters, forming process, auxiliary materials, specifications, etc., the research work shall be carried out according to the actual changes, with reference to the relevant technical guidelines, to explain its rationality and necessity, and make supplementary applications when necessary.
3. quality research and quality standards
We will continue to carry out quality research and improve quality standards, such as adding specific identification of drug flavor and content determination of multiple indicators. According to the specific situation of the product, carry out the research on safety related indicators (such as heavy metals and harmful elements, pesticide residues, mycotoxins), and list the results into the standard according to the results, so as to better control the product quality.
4. stability study
Continue to conduct stability research to ensure the stable quality of samples for confirmatory clinical trials.
（3） Application for marketing license
All pharmaceutical research work should be completed, the reasonable range of production process and key process parameters should be clarified, and basically perfect quality control methods should be established to ensure that the quality of post marketing drugs is consistent with that of samples for confirmatory clinical trials.
1. flavor and quality of prescription drugs
According to the situation of the medicinal materials / decoction pieces used in the samples for non clinical safety test and clinical test, and in combination with the relevant research results of medicinal materials / decoction pieces, the base of medicinal materials, medicinal parts, origin, collection date, processing method and processing parameters of decoction pieces were fixed. According to the clinical trials and preparation needs, the quality standards of medicinal materials and decoction pieces should be improved.
; The rare and endangered wild medicinal materials used should meet the needs of post marketing production.
2. production process
According to the preparation process of samples for confirmatory clinical trials, establish the control indicators of the production process, complete the verification of the production process on a commercial scale, determine the production process and process parameters for the application for listing, and determine the yield / yield range of intermediates (such as extracts), so as to better control the consistency of product quality. The production process should be stable and feasible, and the production conditions should meet the requirements of the drug production quality management specification. The auxiliary materials used shall meet the relevant requirements of the relevant review and approval.
3. quality research and quality standards
We should strengthen the quality research of medicinal materials / decoction pieces, intermediates, preparations and excipients, and packaging materials / containers in direct contact with drugs, pay attention to the quality changes in the production process, build a perfect quality standard system, and realize the whole process quality control of drugs.
The formulation of preparation quality standards should reflect the quality status of samples for clinical trials according to the test results of samples for confirmatory clinical trials, and the detection indicators such as content determination should be formulated within a reasonable range to ensure the stability of preparation quality. According to the product characteristics, explore and establish fingerprint or characteristic spectrum, biological activity detection and other projects.
4. stability study
According to the stability inspection results of production scale samples, the expiration date and storage conditions are determined.
Clarify the packaging materials / containers that directly contact the samples and their quality control requirements. .
（4）
. With the progress of science and technology, the update of production equipment and the deepening understanding of products, carry out relevant research; According to the actual production and clinical use, we should continue to accumulate relevant data, pay attention to the effectiveness, safety and quality controllability of drugs, establish and improve the whole process quality control system, and promote the continuous improvement of drug quality.