Technical requirements and guiding principles for the development of Chinese medicine control preparation

[technical article of chinapharma.com] the reference material of traditional Chinese medicine is the physical control used in the detection of traditional Chinese medicine (including decoction pieces), extract and proprietary Chinese medicine It is used to determine the authenticity of traditional Chinese medicine, evaluate its quality, and play an important role in the control of drug production, improvement and assurance of drug quality, mainly including the chemical reference material of traditional Chinese medicine, the reference material and the reference extract Traditional Chinese medicine chemical reference material is a single or mixed component extracted and prepared from traditional Chinese medicine, animal and plant raw materials or natural products and calibrated for identification, inspection, content determination, etc Compared with the first and characteristic reference material form in China, it is a kind of original medicinal powder with clear basis and accurate medicinal parts, which is mainly used for thin-layer identification The control extract is a mixture of several main effective components or index components prepared by a specific extraction process of traditional Chinese medicine or natural products, which is mainly used for thin-layer or other chromatographic identification The Chinese Pharmacopoeia has been using chemical reference materials and reference materials of traditional Chinese medicine since 1985, and the reference extracts have been included in 2005 According to the provisions of the drug administration law and the measures for the administration of drug registration, CFDA is responsible for the calibration and management of national drug reference materials After more than 30 years' efforts, more than 630 kinds of chemical reference materials, 740 kinds of reference materials and 40 kinds of reference extracts have been established, which provides an effective material guarantee for the smooth implementation of national drug standards and the standardized production of traditional Chinese medicine However, with the development of drug analysis, the existing reference materials of traditional Chinese medicine can not fully meet the needs of traditional Chinese medicine research, new drug development and many other aspects In particular, as an organic whole, the multi-component characteristics of traditional Chinese medicine compound determine that a single or several index components are difficult to reflect the overall efficacy of traditional Chinese medicine, which makes it difficult to effectively control its quality, especially to evaluate its advantages and disadvantages In this situation, the traditional Chinese medicine reference preparation as a new form of Chinese medicine reference material came into being, showing a wide range of application prospects in the quality evaluation and control of traditional Chinese medicine In this paper, the definition of Chinese traditional medicine reference preparation is put forward, its development guidelines and technical requirements are introduced, and its application is prospected, in order to provide useful reference for drug quality supervision, inspection and research and development 1 Definition of Chinese medicine reference preparation Traditional Chinese medicine control preparation refers to the physical control prepared in strict accordance with the preparation method and the pharmaceutical production quality management standard, which is mainly used for the quality control of Chinese patent medicines, and to evaluate the authenticity of product feeding (whether the correct raw materials are fed) and the reliability of the feeding amount (whether the materials are fed according to the prescription amount) According to the use, the traditional Chinese medicine control preparation can be divided into qualitative control preparation and quantitative control preparation: the qualitative control preparation is mainly used for TLC identification, LC identification, GC identification, fingerprint / characteristic map or chromatographic peak location in content determination of traditional Chinese medicine; the quantitative control preparation is marked with multi-component content, which is directly quantitative for traditional Chinese medicine through content value transmission Due to the long history of Chinese patent medicine prescription, it is difficult to define the original manufacturers of some varieties On the other hand, the quality of drugs produced by the original manufacturers is not necessarily good Therefore, the research and development of traditional Chinese medicine reference preparation should not copy the method of selecting the original drugs as the reference preparation for the consistency evaluation of chemical drugs In recent two years, researchers have begun to focus on traditional Chinese medicine control agents Professor Sun Guoxiang's team used the internal standard quantitative fingerprint / characteristic spectrum method to select the standard preparation from the purchased samples for the quality control of Guanxinsuhe pills Furthermore, it is suggested that the basic method to ensure the consistency (equivalence) of Chinese medicine chemicals and the stability and consistency (equivalence) of curative effect is to establish the standard preparation control method of Chinese medicine The standard preparation of traditional Chinese medicine, also known as the background preparation of traditional Chinese medicine, has been proved to be a good prescription of traditional Chinese medicine and a standard preparation with constant chemical content and distribution proportion by pharmacodynamics and toxicology tests in the process of development and innovation of traditional Chinese medicine It can be directly used to control and test the quality of industrial products of traditional Chinese medicine and plant medicine In the actual production process of traditional Chinese medicine, pharmaceutical manufacturers can select standard preparations by different methods according to the actual situation and their own conditions, such as making strict standard preparations according to the prescription of Pharmacopoeia, selecting superior products produced by well-known manufacturers as standard preparations, and selecting standard preparations according to pharmacodynamics research Geng ting and others screened several batches of samples that passed the legal standard inspection, and each 10 batches were mixed into one batch to make their own control preparations, which were used for the internal control of Guizhi Fuling Capsule 2 Guidelines for the development of traditional Chinese medicine reference preparations The varieties of traditional Chinese medicine reference preparations shall be determined according to the needs of the formulation and revision of national drug standards Candidate samples shall meet the principles of applicability, representativeness and availability, their properties shall meet the requirements of use, and their uniformity, stability and corresponding characteristic value range shall be suitable for their specific use Select a reasonable preparation method and process flow to prevent the change of characteristic value and avoid pollution The candidate Chinese medicine control preparation shall be calibrated before distribution to confirm that the raw material is authentic and reliable, the exogenous impurities are controllable, and the components are evenly distributed In order to ensure the representativeness of the control preparation of traditional Chinese medicine, more than three batches of candidate samples should be prepared for the research of all the above items in the first batch of development For the control preparation used for content determination, after meeting the above requirements, it is necessary to set the value In addition, the stability of traditional Chinese medicine control preparation should be inspected regularly under the specified storage or use conditions 3.1 technical requirements for the development of traditional Chinese medicine reference preparation 3.1 the selection of raw and auxiliary materials is the basis for the development of reference preparation The research shows that the quality problems of traditional Chinese medicine and decoction pieces are the key factors affecting the quality of traditional Chinese medicine The quality risks of raw materials such as harmful residual pollution, adulteration, chemical dye dyeing may be transferred to the preparation According to the Executive Standards of the corresponding varieties of the control preparation, determine the raw materials (pieces), check the standards of collection, determine the legal basis and the method of collection and processing Through research and research, master the real estate area, medical resources and quality status of original plants / animals / minerals Purchase authentic medicinal materials (pieces) with correct base source, standard planting / Breeding and processing, and try to select medicinal materials planted according to gap standard and pieces produced by GMP manufacturers Understand the basic situation and potential quality risks of accessories, and purchase accessories from large enterprises with high reputation According to their respective legal standards (including supplementary inspection methods), the purchased raw materials (pieces of decoction) and auxiliary materials shall be inspected, and all items shall meet the requirements According to the research results, other tests were carried out to further eliminate the risks of heavy metals, pesticide residues, mycotoxins, sulfur dioxide, adulteration and dyeing As the reference preparation of traditional Chinese medicine may be more used in the prospective research of the quality standard of Chinese patent medicine in the future, it can provide key information including the transfer rate of chemical components (groups) from raw materials to preparations, so the raw materials (pieces of decoction) should be properly preserved, and the inspection and research results should be archived 3.2 the preparation of traditional Chinese medicine reference preparation is different from other traditional Chinese medicine reference materials In general, traditional Chinese medicine reference preparation should be prepared in GMP workshop at least in the scale of pilot test This is because there is a huge difference between laboratory operation and large-scale production in the extraction rate, etc., the former is difficult to reflect the real situation of the preparation The specifications of the prepared pieces shall meet the requirements of the actual process of the corresponding Chinese patent medicine varieties The dosage refers to the dosage after being chopped, broken or crushed as specified in the main text of the Chinese patent medicine variety standard [preparation method] The research and development unit of traditional Chinese medicine reference preparation can entrust enterprises with good reputation, standard technology, strong strength and strict requirements to produce in strict accordance with GMP regulations There are different specifications of preparations In the initial stage, only the mainstream specifications of the market can be prepared When evaluating the quality of other specifications of samples, the sample weight can be converted The internal and external packaging materials of the control preparation should be basically consistent with the market circulation products of the corresponding varieties, and the sub packaging specifications can be adjusted as needed The label and instructions shall indicate the reference material number, batch number, name, preparation date, purpose, use method, preparation unit, quantity value, storage conditions, loading capacity, precautions in use, etc As for the sterilization steps, the sterilization method in the approved process of each variety should be adopted However, for the preparation containing heat sensitive and volatile components and raw powder as medicine, the loss of heat sensitive active components (such as volatile oil, flavonoid glycosides, etc.) in the wet heat sterilization process is large, so at present, many traditional Chinese medicine factories generally adopt 60 Co - γ radiation sterilization For the varieties other than those allowed to be irradiated as stipulated in the Notice No [1997] issued by the Ministry of health and drug administration, the impact of irradiation on their effectiveness and safety is not clear When preparing the control preparation, it is not allowed to blindly use irradiation sterilization, nor to ignore the actual situation and continue to use the traditional sterilization process (irradiation sterilization is widely used for drugs in the market, and more heat sensitive ingredients are retained) It is recommended not to sterilize temporarily , the samples are packed and frozen 3.3 calibration of traditional Chinese medicine reference preparation: the calibration of traditional Chinese medicine reference preparation shall be carried out after it is packaged into final product First, it shall meet the requirements of national drug standards for corresponding varieties (not required for the hygiene of unsterilized varieties) The uniformity, stability and characteristic value range shall be suitable for the specific use of the reference material In order to ensure the stability and traceability of the quality of traditional Chinese medicine reference preparation, fingerprint / characteristic map technology can be introduced to calibrate the corresponding product standards The calibration items mainly include: (1) character The color and shape of the candidate control preparation were observed and its properties were described (2) identification Generally, chromatography and TLC are used for identification For the varieties with poor TLC separation effect, HPLC or GC can be used for identification (3) check The water content, weight difference, loading difference, etc shall conform to the provisions of the corresponding product executive standard Other inspection items can be carried out if necessary (4) A characteristic or fingerprint Generally, HPLC or GC is used to establish the fingerprint, and the main peaks with clear structure are identified and assigned In the process of batch preparation, the similarity between the fingerprint of candidate control extract and that of standard or previous batch should be greater than 0.90 (5) Content determination The content of main components determined by chromatographic method shall not be lower than the provisions of corresponding variety standards The purpose of uniformity assessment is to determine whether the variability between units is statistically significant When sampling, we should take full account of the potential shortcomings of the preparation method of traditional Chinese medicine reference preparation, adopt the appropriate sampling method, or take samples from the parts where there may be differences in the undetermined characteristic values In principle, it shall be gradually extracted at a constant speed during the subpackage process, numbered, marked and recorded according to the time sequence Generally, the number of samples shall not be less than 10 small packaging units Each extraction unit shall be sampled and tested at least twice independently The method and index specified in the content determination item of the corresponding variety executive standard (if there are multiple indexes, select the index with high content) can be selected for Uniformity Inspection If there is no content determination item specified in the standard, the research and development unit shall develop the corresponding content determination method, and take the content determination of raw materials that are not easy to mix as priority (such as precious and fine drugs and mineral drugs in raw powder preparation