Quality Control for Traditional Medicines - Chinese Patent Medicines

Ma Shuangcheng (马双成)

(Researcher, Chairmen Member of Professional Committee of Pharmaceutical Analysis, China Pharmaceutical Association

Director of Institutes for Control of Chinese Traditional Medicines and Ethnic Medicines, National Institutes for Food and Drug Control)

Ji Shen: Dr. Ma Shuangcheng, Director of Institutes for Control of Chinese Traditional Medicines and Ethnic Medicine, National Institutes for Food and Drug Control, is a long-term researcher on the quality standards of Chinese materia medica, Chairman Member of the Risk Assessment of the Pharmacopoeia of People's Republic of China, and is also the Director Member of the Professional Committee of Drug Risk, China Pharmaceutical Association, and the Director Member of the Directors Committee of Chinese Materia Medica Quality and Safety. He has long been engaged in the control of the quality and safety of Chinese materia medica, and has also been included in the National 10000 Talent Plan. Let's invite Dr. Ma to give a report. Thank you.

Ma Shuangcheng: I am responsible for drug identification. I am very grateful to the organizer for giving me such an opportunity. I am much honored to be able to speak here today. Knoess is a good friend of mine. We met in Hong Kong and discussed Hong Kong standards together. Later we held a teleconference. Knoess is also the co-chairman of our association. He is a member of our executive committee. We have been communicating the quality control of Chinese materia medica. Today, I finally have an opportunity to exchange face-to-face quality control issues, as well as with professors and experts to discuss. Because our translation is very good, I am going to use my own language.

My report includes 3 parts: the first part is general introduction, the second part is the quality control of Chinese patent medicines, and the third part is the quality control standard and future development of Chinese patent medicines.

GENERAL lNTRODUCTlON

What are Chinese patent medicines? Chinese patent medicines should be based on traditional Chinese medicine decoction pieces. They must conform to the theoretical guidance of Chinese medicine and produce certain dosage forms according to certain prescriptions and preparation techniques. It must be approved by National Medical Products Administration, and then it can be treated as Chinese patent medicines. Chinese patent medicines must have a name, a process, a standard, and a test method, including action and indications, its scope of application, and contraindications. This is a complete Chinese patent medicine.

The prescription consists of botanical drugs, animal drugs, mineral drugs, Radix Ginseng, Flos Carthami, Cinnabaris, Gypsum Fibrosum, etc.

Characteristic

Chinese patent medicines can be compound medicines and single prescription, which is composed of a single herb, but fewer in quantity. Guanxin Danshen Tablet is composed of 3 decoction pieces, including Radix Salviae Miltiorrhizae, Radix Notoginseng and Lignum Dalbergiae Odoriferae oil, which are all decoction pieces. Some decoction pieces are processed, so the prescription must indicate what kind of processed products. For example, Qiju Dihuang Pills should clearly indicate Fructus Corni that processed with wine.

There has been in the history of application of Chinese patent medicines since Shang Dynasty. China approved the application of Chinese patent medicines since 1985. In the past, all provinces have approved, with more than 3,000 years of application history, including pills, tablets, capsules, and traditional Chinese medicine injections. Nowadays, about 8,000 Chinese patent medicines are now in use.

The production process of some products is very simple, for example the pieces may be crushed into powder and add some excipients. Another one is the drug is extracted through a complicated process to make an intermediate of the extract, and after various treatments, it is made into a corresponding dosage form.

QUALlTY CONTROL FOR CHlNESE PATENT MEDlClNES

Process control

The process control of Chinese patent medicines is emphasized in China. The process must be strictly controlled from raw materials to the decoction pieces, then to the extraction, to deep processing, etc., even to the final administration for patients, and intermediate storage. If any of these things go wrong, any Chinese patent medicines will have problems. In Europe, it is necessary to standardize planting.

Quality standard control

The approval of Chinese patent medicines must have a standard, a test method, an approval standard, and a statutory standard. Now China implements the standard in Pharmacopoeia of People's Republic of China. From the 10thedition, the 15thedition, it is now being developed for 2020 next year. The Pharmacopoeia is now available in English.

In addition, the approval of these standards included the standards of National Bureau, and some provincial standards. There are no Chinese patent medicines standards in the province, mainly the processing standards, and the standard of decoction pieces. Some Chinese patent medicine decoction pieces have provincial standards. Chinese patent medicines only have national standards, including national approvals of the Pharmacopoeia, and some standards approved by Ministry of Health in the past.

A complete Chinese patent medicines standard item includes component and processing method. The processing method is simple and basic, not a detailed one. There may be core things. This is the basic method. Specifically, how much temperature can be raised. Some places can be adjusted.

Description of characteristics, identification and inspection

Different dosage forms of medicines have different inspection items. Some need P value, while some need relative density, including the basic requirements of each preparation, harmful elements, abnormal toxicity, and microbial limit inspection. In addition, the fingerprint and feature map, content determination, functional indication, dose, precautions, specifications, storage, are a complete quality standard content.

Identification is to identify the composition of the prescription, which can use microscopic methods, as well as some general physical and chemical detection methods, and also use chromatographic methods, including thin layers. The modern technology of biomolecular also can be used.

For example, microscopic technology is actually very economical and easy to use. For example, the big honey bolus are made by crushing the herbs and adding honey to the powder. It can be identified by using microscopic technology instead of high-end mass spectrometry, because a mass spectrometer is worth several billion yuan. In order to control the cost, it is necessary to adopt some economically practical and feasible methods. This microscopic method is a very practical method especially for powder medicines. Of course, there are also some X-ray diffraction methods, especially for powder medicines, and metal. The most important method is the thin layer method, in which almost all Chinese patent medicines are subjected to thin layer chromatography. There are also methods of molecular biology, mainly for animal drugs, and raw powders.

The liquid method can identify many ingredients, which is very complicated for single Chinese materia medica, and more complicated for a compound, but we still get a lot of information from that. Although some ingredients are contained in different herbs, there may be exclusive and unique, and the proper use of ingredients in Chinese patent medicines can be derived from its special ingredients.

Another inspection is to check for heavy metals and harmful elements. The appendix of Pharmacopoeia introduced some methods. We also have limits, such as lead 5 pdm, cadmium 0.3, arsenic 2, mercury 0.2, and copper 20.

There is also some toxic ingredients inspection. There are 28 kinds of toxic drugs in the State Council list in China, including Radix Aconiti, Radix Aconiti Kusnezoffii, Radix Aconiti Lateralis Preparata, Cinnabaris, etc. In the prescription, aconite, aconitine, mesaconine and hypaconitine are highly toxic. They will perform a project on the inspection item to check that not exceed the quantity, which may be toxic.

The most important is microbiological test. All oral preparations must be microbiologically examined.

Fingerprints and feature maps, especially traditional Chinese medicine injections must be tested by fingerprints or feature maps. For Danshen Injection, there is a standard map for different batches, and the similarity is compared by software. There are also some orally administrated preparations, such as Guizhi Fuling Capsule, which is tested by feature map. The sample should be compared with this feature map, and its similarity should reach 0.85, which is not easy for oral preparation.

The determination of the content is to determine the active ingredient toxic components, and even some of the indicator components. We can use the volume method, including some methods of chromatography, and now the most commonly used chromatographic methods, especially liquid phase methods. For example, Gegensu Qinlian Tablet is determined for puerarin by a liquid phase method. The one we measured is puerarin, which is measured with the liquid phase chromatography method. This is a silver yellow capsule, 4 components, the main component of Astragalus, and the right side is a sample map. We measure these 4 main components and determine the content. For Danshen Tablets, 3 components were tested.

QUALlTY CONTROL STANDARD AND FUTURE DEVELOPMENT OF CHlNESE PATENT MEDlClNES

Re-evaluation of post-marketing products

After the approval of the Chinese patent medicines, it will be checked again. Before 2008, we basically checked according to the standard. Since 2008, we will perform some exploratory testing, or research-based testing. Chinese patent medicines may have 10 herbs. In our standards, we may only test 3 of them, and the others will not be tested. So we did some research-based testing to find some of these problems.

Standard test

Before 2008, testing is basically the standard test. From 2008 to now, the pass rate of our standard test is very high. That is to say, the factory has no problem with Chinese patent medicines products, at least meeting the statutory standards. So the overall control is still better. However, from the perspective of expansion and researchbased testing, there are still some problems. The researchbased testing includes safety test, consistency test and validity test.

Safety examination

For example, the safety inspection section will focus on heavy metals and harmful elements, pesticides and flatoxins, including some chemical dyeing. For the sake of good look, some medicines are dyed with some pigments in China. Then the pigments in the original powder or extracted drugs will be transferred to the herbal medicines, since some pigments are toxic. We have such screening platforms, including heavy metals, pesticides, aflatoxins, and pigment.

Effectiveness

The validity focuses on the target ingredients, whether the quality is good, and the amount of ingredients is not enough. Although according to the standard test, such as doing a TLC, the TLC spots may appear. It is possible to add this prescription amount to 100%, and the amount of spots will also appear, indicating the quality is not good.

For example, some Chinese patent medicines contain too many non-medicinal parts, due to processed from decoction pieces. For example, Radix Bupleuri should use the flower part, but the ground parts, stems and leaves are added. Another problem is that unclear ingredients are added. There are a lot of sand in Gypsum Fibrosum. And also chemical staining is found. It is because of the test after listing, these problems can be found through research-based test.

From the post-marketing quality re-evaluation, our standard inspection is still relatively good. Some problems have been discovered through the extended test, and we should consider how the future Chinese medicine standard should be constructed.

There are 3 aspects: safety, effectiveness, and consistency. In terms of safety, these ingredients must be brought out. Its toxic components can be found by chemical methods, and these toxic components must be included into the standards. Of course, the biological methods could be used to evaluate its toxicity. What is the method? If it is mature, it should be included in the standard.

What are the active ingredients? What is the effective fraction? The chromatographic methods and biological methods can be used to evaluate its effectiveness. The ingredients and methods of Chinese patent medicines will be included in the standard. For the consistency of the whole prescription inspection, National Center for Drug Evaluation together with us drafted how to build quality control standards, hoping the control of the whole prescription, which has long been fully controlled in Japan. Of course, as far as possible, if there are 10 kinds of medicines in the prescription, and 10 kinds of medicines are to be tested.

In addition, some feature maps, fingerprints, including examination with multi-indicator components, the most importantly, Chinese patent medicines check items cannot be missed, including microbiological testing. The content is still these, and we should try to consider comprehensively and try to control the whole prescription.

Attention should be paid to safety, including harmful elements of heavy metals, microbes, chemical staining and other indicators.

Not only the traditional methods, but we can also use modern technology. For example, Colla Corii Asini is used in many Chinese patent medicines. A combination of liquid chromatography mass spectrometry was used to find the characteristic state inside. Because Colla Corii Asini is made from donkey skin, and the things that made from other skins are not called Colla Corii Asini. In the past, Colla Corii Asini is managed as Chinese patent medicines, but now it can be included into decoction pieces. We have adopted modern technology for identification and quantitative determination.

In addition, the effectiveness is determined by cell membrane chromatography, etc. These technologies can be adopted, of course. Through a large number of research, they can be included into the standard after getting mature. The purpose of building a new Chinese patent medicines quality control system is to comprehensively evaluate the quality of Chinese patent medicines, and to improve the quality control of Chinese patent medicines. Thank you all.