Safety, effectiveness and quality control are the basic attributes of drugs, and also the core content of drug research and evaluation. Drug research and development is a systematic project integrating pharmacy, efficacy, toxicology, clinic, statistics and other disciplines, with long cycle, high investment and high risk. . The content of pharmaceutical research in each stage before listing is to provide a basis for further research. The biggest characteristic of traditional Chinese medicine is that it comes from clinical practice and carries out systematic research on the basis of respecting clinical medication experience. Pharmaceutical research is the foundation of stable and controllable quality of traditional Chinese medicine industrialization, and also the guarantee of drug safety and effectiveness. At present, although the guiding principles or technical requirements of traditional Chinese medicine pharmaceutical research cover the whole process of research on raw materials, processes, preparations, stability, changes and so on, they do not reflect the content of phased requirements. In this paper, the focus of pharmaceutical research in different stages of the registration and application of traditional Chinese medicine is elaborated, aiming to provide reference for the R & D personnel, in order to improve the efficiency of R & D and reduce the risk of R & D.
1 The background of the phase of pharmaceutical research
In order to improve the ability of innovative research and development of drugs and accelerate the review and approval of drugs for marketing, the State Council issued the opinions of the State Council on reforming the review and approval system of drugs and medical devices (Guo Fa 〔2015〕44No.)[1]The general office of the CPC Central Committee and the general office of the State Council issued the "report on deepening the review and evaluation ofOpinions on the reform of approval system to encourage the innovation of drugs and medical devices（Office 〔2017〕42No）[2]，propose“Focusing on the clinical value of drugs”. The former State Food and Drug Administration issued the announcement on several policies for the review and approval of drug registration（2015Year230No.)[3]It is clear that "the application for clinical trials of new drugs shall be approved at one time, and the method of application by stages and review and approval by stages shall no longer be adopted; the review shall focus on the scientificity of the clinical trial scheme and the control of safety risks, so as to ensure the safety of subjects." the State Drug Administration has successively issued the "on adjusting drug clinical trialsAnnouncement of review and approval procedures（2018Year50No.)[4]Communication and exchange measures for drug R & D and technical review（2018Year74No.)[5]And other documents to clearly apply for the implementation of drug clinical trials60The reform measures, such as tacit permission, communication and exchange with applicants at key nodes, encourage drug innovation and speed up drug review and approval.
According to this, although the new drug registration application has adjusted the concept of technical evaluation and optimized the evaluation procedure, pharmaceutical research, as an effective and controllable guarantee of drug quality and safety, the content of basic research work is unchanged. On the basis of respecting the law of drug research and development, developers should establish the concept that quality comes from design, pay attention to the source control of raw materials and production process control, so as to ensure the consistency of the quality of listed drugs and drugs verified by clinical trials[6]According to the current measures for the administration of drug registration, the application for new drug registration is divided into application for clinical trials and application for production2The three stages can be divided into pre clinical trial, clinical trial period, listing application and post listing research according to the key nodes of R & D and registration application. The main research contents of each stage should be focused on.
2 Main contents of pharmaceutical research on new drugs of traditional Chinese Medicine
Pharmaceutical research on new drugs of traditional Chinese medicine mainly includes the source and quality control of medicinal materials, production process research and process validation, quality research and quality standard formulation, drug stability research, and the selection of packaging materials and containers in direct contact with drugs. After the approval and listing of new drugs, with the expansion of scale and the development of science and technology, pharmaceutical research work such as the source and guarantee of raw and auxiliary materials, the improvement of production technology and equipment, the improvement of quality control and standards, the improvement of packaging materials and the improvement of stability will still accompany the whole life cycle of drugs.
According to the characteristics of traditional Chinese medicine, the pharmaceutical research of traditional Chinese medicine should pay attention to the source control and process control, study the key links and control methods that affect the quality of traditional Chinese medicine, and establish an effective quality control system according to the characteristics of traditional Chinese medicine and the quantity and quality transmission Research of the production process, so as to ensure the stability and controllability of the quality of traditional Chinese medicine. These contents not only run through the whole process of new drug research and development, but also have different emphases in different research stages. Pre clinical trial research and evaluation focus on the safety of clinical trial samples, so as to ensure the quality, safety and controllability of clinical trial samples; Pharmaceutical research continued to improve during clinical trials; Pre marketing research and evaluation focus on the feasibility of large-scale production of the improved production process, which is consistent with the quality of drugs verified by clinical safety and effectiveness trials, and ensures stable and controllable quality; .
3 Key contents of pharmaceutical research at various stages
3.1 Preclinical phase
. The main purpose of pharmaceutical research is toI、IIPhase I clinical trial research provides samples with stable and controllable quality to meet the needs of clinical trials. At the same time, samples produced in pilot scale are used for the research and evaluation of safety and effectiveness of non clinical trials. Therefore, the drug prescription and route of administration must be fixed at this stage; The base of medicinal materials should be accurate; The processing technology of decoction pieces is basically fixed; The process before the formulation is basically fixed; .
3.1.1 Prescription ingredients The raw materials of traditional Chinese medicine include medicinal materials, decoction pieces and extracts. At this stage, we should pay attention to the accuracy of the medicinal material base, and the processing method of decoction pieces is basically clear. For the use of wild Chinese herbal medicines, we must pay attention to the relevant regulatory requirements for protected species and the sustainable utilization of Chinese herbal medicine resources. Establish a preliminary quality control method for raw materials. If the prescription raw materials are not included in the legal standards, relevant research needs to be completed and the corresponding quality standards need to be established. Pay attention to the safety research and evaluation of raw material quality, and feed it after passing the inspection according to the quality standard. For decoction pieces that need to be crushed and fed, research on the crushing method should be carried out; . For irradiation sterilization, the necessity of using this method should be considered, and further research should be carried out on this basis to ensure the rationality of using this method.
3.1.2 technology In the stage of small-scale trial production in the laboratory, the designed process route and method are improved and perfected through batch trial production, and the process route and preliminary process parameters suitable for pilot production are formulated. The optimal process route should focus on the key issues affecting production, and comprehensively consider the production cycle, yield, equipment conditions, raw material supply and other factors. The material preparation process before the formation of the preparation, including the extraction, separation, purification, concentration, drying process, etc., is basically fixed for the process methods and steps that may affect the material base, such as the extraction method and times, the type of solvent, etc., and effective control and evaluation methods are formulated, such as the concentration degree of the extract is controlled by the relative density, and the purification degree of the active ingredient is controlled by the transfer rate and content of the active ingredient, and the extract yield. All process parameters, including temperature, time, pressure, etc., can be properly adjusted according to equipment conditions on the basis of clear material basis. Molding process based on the clear nature of the raw materials of the preparation, the formulation design and molding process research are carried out, and the types and dosage of auxiliary materials, as well as the molding process methods and process parameters are basically determined.
. It is suggested that pilot studies should not be limited to10Times the prescribed amount3For batch samples, the influence of factors such as the actual production quality fluctuation of medicinal materials and the expansion of equipment scale on the material basis of drugs should be taken into account, so as to accumulate data and improve the research. Such as volatile oil extraction, inclusion process, resin column purification process and other processes that are greatly affected by the scale, the key quality attributes should be fully studied to design reasonable process parameters to ensure the consistency of the material base. Pay attention to the variation range of extraction rate of each process route to make the amount of extract fluctuate within a reasonable range.
3.1.3 Quality research and quality standards Quality research should focus on the safety and effectiveness of drugs, establish preliminary quality standards according to the characteristics of drugs, preparation characteristics and key quality attributes, and the inspection methods should be scientific, reasonable and feasible. The samples used to formulate quality standards shall be those produced in pilot scale. For easily confused medicinal materials, it is suggested to establish specific identification methods to ensure the accuracy of medicinal materials. . Research on heavy metals and harmful elements, pesticide residues, mycotoxins, organic solvent residues and endogenous toxic and harmful components in the production process shall be included in the quality standards as appropriate. On the basis of safe and effective research and evaluation, the selection of quality control indicators needs to consider the integrity. Select representative indicators for different process routes for quantitative control research, such as the process control of extracting volatile oil.
3.1.4 stability test The preliminary stability test should pay attention to whether there is enough research data to support that the expiration date and storage conditions of drugs can be coveredIPeriod andIIThe cycle of phase I clinical trials ensures that the quality of drugs is basically controllable and stable to meet the needs of clinical trials.
3.2 Clinical research stage
During the clinical study, the preparation prescription, dosage form, specification, process and its parameters, quality control indicators, etc. may change in the preliminary pharmaceutical research. If necessary, the corresponding research shall be carried out according to the "relevant guiding principles for the change of research technology of listed traditional Chinese medicine".IIIThe preparation process of samples for phase I clinical trials should be the production scale, providing the basis for the process data applied for production inspection in the later stage, so as to ensure that the quality of drugs after marketing is consistent with the quality of drugs that have been clinically verified to be safe and effective.
3.2.1 I、IIDuring phase I clinical trial IPeriod andIIDuring the phase I clinical trial, according to the clinical trial results, the formulation, dosage form and specification of the preparation can be reasonably changed according to the needs to meet the curative effect and clinical medication needs. It should be noted that if the administration route is changed at this stage, the corresponding pharmacodynamics and toxicology should also be studied. If the excipients and processes (including dosage forms) have changed greatly, relevant process scale-up studies and stability test studies should be carried out, which can further improve and perfect the drug quality standards, better control the drug quality, and ensure the consistency of drug quality. Continue to carry out long-term stability test research forIIITo provide the basis for clinical trials and the formulation of drug validity.
3.2.2 IIIBefore phase I clinical trial III. The formulation prescription, dosage form and specification of the drug shall be determined, and the drug shall be prepared in accordance withGMPUnder these conditions, the scale-up production of samples for clinical trials is carried out, and the production process and main process parameters are determined to ensureIIIThe quality consistency of drugs for clinical use in phase I and drugs produced on a large scale after marketing. For the quality standards determined at this stage, it should be noted that the quality control indicators of medicinal materials cannot be simply transferred to intermediates or finished products, but should be set according to the process characteristics and other targeted quality control indicators to build the overall quality standard system of medicinal materials, intermediates and preparations. .
3.3 Listing application stage
The research and evaluation of the application for production focus on the production process before clinical trialIIIPreparation process and mass production process of samples for phase I clinical trials3The second is the feasibility of large-scale production process and quality controllability to ensure the production of drugs consistent with the quality of samples used in clinical trials, that is, the quality of marketed drugs is consistent with the quality of drugs that have been proved to be safe and effective through clinical trials, and the quality between batches is stable[7]。
3.3.1 prescription Clarify the sources and standards of raw and auxiliary materials. . Those who use wild Chinese herbal medicine should explain the sustainable utilization of Chinese herbal medicine resources and carry out planting (breeding) technology research. It should be noted that the origin of medicinal materials should be determined in combination with the actual situation of clinical trials. Processing technology and process parameters of fixed decoction pieces.
3.3.2 technology By completing the process scale-up verification of multiple batches, fixing the production process, and specifying the process route and process parameters, we can ensure that the production process can meet the actual production after listing. The production process shall be consistent withIII.
3.3.3 Quality research and quality standards The formulation of quality standards is based on production scale samples, which effectively reflect the quality of drugs. Determine the quality standard system of raw materials, intermediates and preparations, set the limit (range), combine the measured results of clinical trial samples and the measured data accumulated in the study, comprehensively consider the influencing factors such as the quality fluctuation of medicinal materials and production scale, and reasonably draw up on the basis of conforming to the actual production, so as to ensure the stable and controllable quality of drugs. At the same time, the source and purity of the reference material shall be explained. If necessary, studies such as structure confirmation and purity analysis shall be completed.
3.3.4 Stability test and packaging materials in direct contact with drugs . According to the stability research results of clinical trial samples, determine the expiration date and storage conditions of drugs.
3.3.5 Instructions, packaging, labels Clarify the contents of "properties, specifications, storage, packaging, and expiration date" in the instructions, packaging, and labels of traditional Chinese medicine.
3.4 Post market stage
After the approval of drugs for marketing, the quality stability and traceability of the source of medicinal materials should be guaranteed, and the whole process quality control system of medicinal materials planting (breeding), decoction pieces processing and preparation production should be established to ensure the safety, effectiveness, stability and controllability of the quality of drugs. At the same time, through the process of enlarging the production scale and mature and stable technology, the measured data of multiple batches of samples were accumulated, and the drug quality standards were appropriately adjusted and revised in combination with the clinical use of drugs after marketing, so as to make the quality control items and limits more reasonable, and the stability of samples on the market and the influencing factors were continued to be investigated and studied. Due to a variety of reasons, the prescription, specification, process and other aspects of the preparation will be changed accordingly. The specific requirements refer to the "guiding principles for the change research technology of listed traditional Chinese medicine" for research.
4 epilogue
In this paper, the focus of pharmaceutical research at different stages of registration and application of traditional Chinese medicine is considered, in order to provide references for researchers and developers. Attach importance to the key link of the transition from laboratory to industrial production. 2008〕3No.) relevant requirements[8]If the adjustment may affect the effectiveness and safety, a supplementary application shall be submitted. The preparation process and quality of samples for clinical trials are the basis for determining the content of production process data for on-site inspection, especiallyIIIThe samples for phase I clinical trials should be large-scale production, which is the key to evaluate the feasibility of the process. IIIPharmaceutical communication before phase I clinical trials can reduce R & D risks, improve R & D efficiency, and speed up the listing of new drugs.
References (omitted)
Come Source:Zhao Wei, maxiujing, tupengfei Thinking on pharmaceutical research of new Chinese medicine [j]. Chinese herbal medicine, 2019, 50 (23): 5872-5875