Study and Countermeasures on Safety Control of Traditional Chinese Medicines Industry Chain

Ji Shen (季 申)

(Director, Traditional Chinese Medicines/Health Food Department; Chief Expert, Shanghai Institute for Food and Drug Control, China)

I'm very grateful to Chinese Pharmaceutical Association and DIA for their elaborate organization, so that we are able to participate in the Sino-Europe Symposium. Yesterday and today, several professors have talked about various aspects. It is true that the effectiveness of traditional Chinese medicine is important, and safety is equally important. For this reason, our laboratory works on the effective test, and at the same time, since 2001, we have been focusing on the safety of traditional Chinese medicines, especially the research on exogenous pollution. Today, I would like to share with you some of the quality control of the whole industry chain of traditional Chinese medicine and some of our thoughts.

NECESSITY OF SAFETY CONTROL

I'm going to share these things in several aspects today. I mainly want to talk about why we have to carry out the safety control of traditional Chinese medicine. Today, Professor Tu talked about some ideas. So did I. Why is it necessary to carry out the safety control? As research discovers more, as you have just said that our herbs depend on cultivation, Chinese patent medicines rely on production. Every aspect of the whole industry chain is related to its quality and safety, from seeds, seedlings and planting, to timely processing of medicinal materials, roguing, production and circulation. In this process, herbs are planted by us, while they were cultivated by herbal peasants in the past. Today, many companies are here, such as Tasly. Big companies are all here, they have many bases. I'm thinking about that after so many years, how many bases, even Tasly, their lands, fertilization, pesticides and atmospheric pollution are now under your unified control? This issue has brought some problems. We GAP and others, employing herbal peasants to cultivate herbs. However, research may show that some are not planted by herbal peasants. They have experience in food and planting crops like rice and wheat. But without herbal peasants and scientific guidance, there are some problems, which are abuses and lack of guidance. Especially in the past 5 years, it has been paid closed attention to the problem of toxins in its processing and storage due to their own stromata. We found that the toxins may not be put in the first place 5 years ago. Now I think that the trace toxicity of mycotoxins will bring a lot of harm and is included in some scope.

In terms of the problems of the whole industry, if we don't take the source, guide the farmers, and regulate the entire processing, what is the use of our supervision? We feel that we must control it from the source, in order to achieve real results.

SAFETY SYSTEM OF CHINESE PHARMACOPOEIA

I want to share with you the current safety system of Chinese Pharmacopoeia. It should say that there is much content we can refer to in these editions (from 2000 to 2005) of Chinese Pharmacopoeias. Aspects like no matter the standard methods, or the limited varieties have gradually been improved. In addition, there are corresponding methods for aspects such as pesticide residues and heavy metal toxins. How to control them in these methods? Through my explanation, we can come together to reach a consensus.

At present, I want to share with you some of our related research and development. Within nearly 20 years of research and development, we have gradually improved in terms of pesticide residues, heavy metals, toxins, and illegal additions, including pigments. We have not only included some methods in the appendix of the 4thChinese Pharmacopoeia. In addition, we are constantly researching, accumulating methods, providing services for supervision, and playing a better role in guiding the first-line planting process control.

About pesticides

The problem of pesticides is very complicated, because traditional Chinese medicines are so complicated, plus we have some external problems due to the fertilization and farming, which are limitation and measurement, so there are challenges. In the whole research process, after deciding what kind we want to monitor, what method system we want to build, and how to study Chinese medicine, we carry out various researches on them, so that we can form a norm. On one hand, I think that we still want to guide the farmers for the cultivation. We must know what fertilization can be chosen during the cultivation. But if we don't know which pesticide that farmers have applied and we couldn't monitor them, the problem will come. What we have done are complementary to each other, for better helping of planting, better choice of reasonable pesticides, as well as the harvest time, use of dosage and product control, formed the comprehensive control.

At present, after many efforts for editions of our Chinese Pharmacopoeia, we have divided it into mass spectrography, chromatography and other aspects. Today, we have many European friends here. I went to Europe about 8 years ago, where I visited a Spanish institute for the control of food and agrochemicals. Every day in Spain, vegetables and fruits ready for marketing need to be tested qualified through the tests of 300 listed pesticides during the whole night before they are able to be introduced to the market at 6 o'clock. This is very impressive for me. I think that the first is the high consciousness in Europe, and the second is the strength of powerful government supervision. How is our Chinese medicine? In fact, I feel that if we are in an orderly situation, this supervision is much easier when we are well aware of it. Is it reasonable? In this case, I personally think that it is necessary to force it, in order to help and guide our medicinal herbs cultivation and some effective regulation in the process.

We are now using this method, chromatography. And I just responded to the opinion of Professor Tu. As we study the chromatography, if we do so, I personally believe that there is no way to do multi-residue testing in chromatography, whose false positive and false recessive may lead to some problems. Now in turn, internationally, whether it is the European Union, or the United States, they both use the mass spectrometry. We also use the mass spectrometry when taking the Chinese medicine as the material basis, so that a few hundred components are identified in one shot. As we do research, relevant supports will come, that agricultural products for pesticide reference have already been supplied in China, which greatly reduces the cost. This research method and reference products are time-saving. We now have 227 methods in Chinese Pharmacopoeia, and I don't think the method is the problem. The key is the combination of pre-processing and the method, so as to overcome false positives and false recessive. How long does the analysis take? It is only 15 minutes for 153 kinds, 40 minutes for volatile ones, and 1 hour for pre-processing, except some special handling. By using the establishment of this matrix for interference, in 1 or 2 hours, we can find out what kind of pesticide residue it contains from hundreds of kinds, perhaps accomplishing both the qualitative and the quantitative.

Is it expensive? I don't think so. Firstly, reference products are easy to commercialize now, and they are very cheap, except for the solid ones, which are pricy. Secondly, it is about the analysis time. If there are hundreds of component chromatograms, you can only identify several pesticide residues per day, with high cost. However, we can quickly and accurately find the target and get the results accurately. If we say that based on the thousands of sample data we have accumulated in the past few years, we have found some indications. In the future, we must use the mass spectrometry for measurements, as the output grows sharply. For example, just like in the past TV sets we bought were pricy, while they are cheap today due to mass production. Similarly, the cost for research on the effectiveness of traditional Chinese medicine will be definitely reduced, and it will effectively play a regulatory role, that you can't leave it, and can't operate without this method.

Over the years, we've continuously developed. As we do research, special pesticides have been found. The study of special pesticides such as acidic pesticides should be individualized. In addition, we found that the Chinese medicine matrix is too complicated, which needs us to carry out individualized research. In our laboratory, we add some special requirements to the pre-processing for the pigmentary, greasy, flavonoid and other kinds of matrix of each plant. Our lab constantly accumulates blank matrices, and each time we use matrix interference deduction similar to food, we can more accurately find our targets. In these aspects, we believe that from the technical point of view, we need to continue our research, and the purpose is being able to control the safety quickly, accurately and economically.

In the past 2 years, we have also started to develop high-throughput techniques, in which we can identify 508 kinds of pesticides in one shot and have developed more than 600 methods. There are 4 people in our team who returned from the CFSM laboratory and the US Department of Agriculture. At the CFSM, the work was also the identification of pesticide residues in herbal medicines. Recently, we have just helped the CFSM to carry out global re-certification of 400 pesticides. I think this work, for either the EU or the United States, will definitely reach a consensus in the future. During the past 2 months, an American expert from Ministry of Agriculture, who specializes in pesticide residues, came to our laboratory for communication. In the future, the method must be fast and economical with supervision. We don't rely on testing. When the situation is in disorder, we need to cast our net widely. In orderly circumstances, what we do can be targeted, which means do not waste our energy.

About toxins

Five years ago, because there were relevant methods noted in the Chinese Pharmacopoeia, so that I thought there was nothing else we need to do. Later, I arrived in Germany a few years ago. I went there for an international conference and immediately realized that in Germany, they had already been working on more than 400 kinds of mycotoxins. However, they were still in their infancy, no matter in food or other aspects. Therefore, such teratogenic, poisonous and severe circumstances, I think, should also be paid attention to in the field of our Chinese medicines. Why should we pay attention to it in Chinese medicines? Because Chinese medicines infected with fungi are different from pesticide residues. The pesticide residues are externally added, which are different from the toxins. In any part of the cultivation and storage process, due to the presence of endophytic bacteria or external bacteria, the toxins will erupt, and different toxins are produced by different matrices. Therefore, the individualized research is even more important, we think it is necessary for us to be concerned about this aspect of research.

At present, we look at our domestic toxins. Currently, the concern of toxins that related to food is gradually increasing. Guidelines and methods for one circumstance of our Chinese medicines were included in Chinese Pharmacopoeia in 2015. How can it be reasonably balanced? We are working hard on it.

During the construction of the whole system, the system of Chinese medicines mycotoxins, we must pay attention to the mycotoxins of clear toxicity, high international attention and covering toxin concealment. At the beginning, some toxins we studied were not poisonous, but once they broke down in the human body, they became toxins with harmful toxicity, that were the hidden toxins. For this reason, we paid attention to them and studied them. We made a single-component, a multi-component and a high-throughput for this situation. I thought that some kind of matrix would produce some kind of toxin. Later, I found that certain kinds of matrix may produce many types of toxins, which was one of our research results.

I think we have been developing these toxin methods for so many years. At present, we have developed 75 kinds of LC-QTOF, starting with 62 kinds, and then 75 kinds. Our main problem is how to do the largest matrix interference, different methods for different matrices. Each matrix interference leads to false positive or false recessive, so it must be very accurate to do this work.

Therefore, in Chinese Pharmacopoeia, we plan to establish a high-throughput or series of mycotoxins in Chinese medicine in the future, and carry out some rapid early warnings on high-risk varieties to provide a basis for setting standards. Of course, everything is on the way, and we are working on it.

Chinese Pharmacopoeia's version of 2015, I personally feel that we have taken a big step on 1P, which means that we now have 3 methods in aflatoxins, and we have 11 methods classified into 7 categories related to the guiding principles in it. Moreover, 14 Chinese herbal medicines have been tested for Aspergillus flavus, and our Chinese Pharmacopoeia has made great progress in safety. A new version will be handed over next year. At present, the toxins in the new version have been approved by the expert committee. The methods in the guiding principles has been extracted and put into the general rule of method inclusion, and new methods are continuously developed. It is worth noting that for example, zearalenone, its methods and requirements are included in the coix seed.

I would like to report that how we studied it for so many years. Firstly, we worked on Chinese medicines, which are largely used in both food and medicine. Like the coix seed, it may be eaten as food and consumed in large quantities. Secondly, we carried out research on Chinese medicines full of fat and protein, as well as some animal and rhizome medicines. I am also very grateful to our National Bureau and our Shanghai Bureau for a lot of exploratory research on us, and they discovered the issue. We then did research on these aspects and found some problems, in which we strive to have good control of them in the future.

These are 75 kinds of mycotoxins we have established. The whole test with weighting process is no more than 2 hours, and we can quickly find out which one among these 75 kinds of mycotoxins contaminates Chinese medicines. This is because we may encounter unexpected events which often need to be controlled, so that the sensitivity is high.

We also find out how the mycotoxins come to exist, and the prevention and control measures have been carried out to this end. I think that mycotoxins, including safety, are preventable and controllable. The key is to find out how to prevent it. How to prevent and control it? We have studied on the aspects of the internal and external factors in the whole process, its pollution level, and the strains that produce toxins, trying to control from the source to the products.

For example, we did research on a snakegourd peel and found how it contained corn gibberellins, and its content was very high. Because it is also a high-risk variety, from its systematic situation of the discovery, we returned to the base to investigate it. As soon as we saw the medicinal materials, planting and processing, we found a problem: if not pay attention to any of the links of soil, young fruits, unripe fruits and processing, the medicine will produce high content of corn gibberellins. How to avoid it? That is what we need to do. To this end, we searched for the strains that produce toxins, as well as its sensitive factors to propose prevention and control measures for its strains. We controlled the key sensitive factors like moisture. After research, we effectively found its key points and helped the company to effectively control them from planting and harvesting. So now their snakegourd peel and preparations are very good.

We have also studied a series of mycotoxins, which we recommend that everyone here could pay attention to. In the normal and reasonable planting, harvesting and processing condition, everything is good. However, if unreasonable, the corresponding result is easy to generate toxins, not only aflatoxins, but also other toxins, which is something we need to pay attention to. If we attach importance to it, we can control it safely.

About heavy metals

It has formed a consensus. Chinese medicine is indeed special, which also includes mineral medicines with some elements in them, such as cinnabar. I remember that in a report I specifically mentioned how to conduct reasonable research on cinnabar. It cannot be expressed in its total volume, but in a reasonable way. For this reason, we did systematically study the mineral medicines in Chinese Pharmacopoeia for many years, and provided relevant methods. In recent years, we have paid attention to the problems of reasonably solving the valence state of toxicity in it by applying the methods including HPL-CICP-MS. For example, some problems of trivalent, pentavalent, and divalent mercury, they cannot be expressed in terms of their total volumes. Reasonable expression can help people better understand Chinese medicinal materials and understand our Chinese medicines, rather than using the expression of total volume, which we feel may induce the public panic.

COUNTERMEASURES AND PROSPECTS

Personally, I have some ideas and countermeasures. What are the problems with Chinese medicines pesticide residues? In fact, we are still not sound in the registration of pesticides in the Chinese medicinal materials. Chinese medicines are crops, and the attention on them is not enough.

In the past few years, large companies have attached great importance to this issue, and they started from the source. Only when we strengthen the guidance on pesticides and herbal peasants, can we own great staying power. We need be able to guide them to use pesticides reasonably, but there are also basic research shortcomings of limiting the dosage during the process. For example, limiting the dosage, we have a lot of European friends all over the world today, how many ADRs (adverse drug reaction) we have to do to set it? How much data we need? A lot. Then again, based on the present global farming limitation related to aspects like food, set by federal countries, how to make a reasonable general rule?

I personally feel that we have to be more in line with the international community and learn more from them. In addition, in terms of analyzing problems, as we screen more and more, we find more and more problems. And I think it's not a bad thing to find the problem right now, because it is better than you don't know. Yesterday, many experts said that in the future we will have a massive health industry. Now if we want to be healthy, taking medicine is not enough. Chinese medicines includes a kind of formula, which contains more than 10 or 20 kinds of medicinal materials, and there are dose stacking and food stacking. In addition, some people take it for a month, 2 months or half a year. All these problems, including the dietary consumption, need to be considered.

How to be reasonable is a problem we have to think about. What are the problems with toxins? We found that the infective toxins are related to different matrices of Chinese medicinal materials, and they have serious inhomogeneity once infected. As aflatoxins multiply quickly, when sampling, we may find there is no aflatoxin in one of the samples, while its content of another one is very high. This situation is also worth noticing. Throughout the planting process, some Chinese medicines include mycotoxins themselves if they suffer from bad weather this year. How to avoid this problem? Like food, I learned it from people in the food system.

In this way, we can avoid the situation within the whole processing and storage. For example, be aware of the moisture of the Chinese medicinal material and the moisture of the decoction pieces. Some people think that we maybe too strict on moisture. Moisture is a key factor, that if under high moisture, improper storage, and certain temperature and humidity, it is easy to produce mycotoxins. We control the quality in all aspects rather than isolated, so that we can do it. If we fail to control the quality of Chinese medicinal materials, there will be the transmission of infection to the Chinese medicine.

Heavy metal problem, everyone thinks that it is more likely to derive from the soil environment. Heavy metal is related to fertilization, including soil and environment. In fact, if the fertilizer is mixed with unreasonable ingredients, corresponding heavy metals are also introduced in it. Of course, illegal cultivation is another case. As we fight against fake products, I personally think that there are fewer and fewer cases of illegal cultivation. This is the power of our supervision, which is effective. We must pay attention to heavy metals as well as fertilization.

The difficulty in controlling the safety of traditional Chinese medicine is its complicated dosage forms, which can produce too much interference. It requires high personnel quality and experienced staff. For example, there are methods recorded in the pharmacopoeia. The previous person did according to the pharmacopoeia and succeeded. However, I say no. We must understand the nature of pesticides and the matrices. We need to be well trained, and after we have feelings about them gradually, we can tell this is interference, that is a false positive. Thus we can effectively make an accurate judgment. I think in the aspect of accumulation of technology, professionals are very important. I used to feel that this could be achieved by training. However, it cannot be said that if there is no training, we will never make a progress. We must keep improving by all means, such as our food and other aspects. Owing to our institute also works on pesticides for food, we realize that there are still gaps in the talents of different systems, and we need to accelerate the training of our talent team.

In addition, there are some special personalized pesticides and toxins with special properties, needing individualized research. We feel that we should apply the high-throughput. Fast, targeted and progressive methods are the future methods, due to lack of time. What's more, to reduce the cost, mass spectrometry is definitely a direction in the future, but it must be fast and accurate, be done by the way of comparison, and by cheap ways. And why say so? The solid is too expensive, and we use to buy it. It is so pricy to buy from Europe that a dozen milligrams of it costs several thousand yuan. What's really used in the experiment is a dilute solution. If it is tested stable, the cost will be greatly reduced. The test cost should also be considered, and we study this issue.

LIMITING THE QUANTITIES

Professor Tu was very worried just now. Indeed, if the Chinese medicinal materials are dead, we will have no medicines to take. We cannot let this happen. What to do? We should not only control the safety, but also ensure everyone having access to medicine, as a European friend just said. I'm very confident now, and many large enterprises in China have come to me to do European and American registration testing, letting them go out to report. At the beginning, the samples were not qualified. After constantly looking for the cause, at last, it was very successful, which is still keeping them in a very safe situation now, and this is a great progress.

What I think need to do? Well, there are 2 ways for limiting the dosage. One is based on the transformation. According to our daily consumption and dosage, in which we consider the comprehensive quantity, as well as compounds like 10 flavors or 20 flavors, we transform the food. The other one is to set the maximum residue limit, which is a big deal. Japan, Europe and America, they all do so. Few countries are over the maximum residue limit.

I often attend this kind of meetings, that everyone has to vote by raising hands for something like what is the limit of wheat to be controlled, or how about Chinese medicinal materials? How to make it reasonable? I'm sure that it is also necessary to establish it under an international general rule. But only if it is based on the dosage of traditional Chinese medicine, it is a reasonable evaluation method. We believe that we'd better keep working on the transformation and research to solve our future problems.

Regarding the establishment of the limit, I think there are several points need to be clarified. Based on the registration, the risk list and so on, we feel that we must also make some rules on the forbidden and limited use, the unregistered and commonly use, so that we can continue to develop. Therefore, weather some forbidden and limited uses, which are unregistered, mean they can be used? Take it slowly, because if they are not registered in Chinese medicinal materials, we have to coordinate and negotiate with Ministry of Agriculture. In principle, it belongs to A-type regulations internationally. As for our commonly used pesticides, they should be regulated according to the regulations, and gradually be promoted according to the similarly slack limit based on transformation of dosage, so as to ensure the sustainable development of Chinese medicines industry.

Toxin is also a concept. No matter toxins, pesticide residues, or heavy metals, their limits are also consistent with the international concept of establishing standards. I went to the Netherlandish Research Institute for Food Safety last year to discuss with them. Very well, we are now very good friends. Due to the same international concept, I also consulted them about the food, and listened to their good advice on Chinese medicinal materials. We are currently working together. The security issue is world-wide, without national boundaries. But under the circumstances that the characteristics of Chinese medicinal materials are in line with the international rules, how to establish the standard is a question we have to think about. How to do? What is the method in the future? Here is my viewpoint: I divide it into short-term goals and long-term goals. In the near future, we must have methods first. If there are no methods, others won't know. If we throw up our hands, we'll never know.

For example, the EU just mentioned 70 limits, and they have removed methods. So does the USP. They have 110 pesticides, but the methods have also been removed. Why? In general, each experimental method of the EU and the United States is quite advanced in the detection technology of pesticide residues. For example, during an international comparison, they do method comparisons. In the data comparison, it is not only about what method must be used for each experiment, but also that you should get accurate data. That's the most significant.

At the moment, why do we promote methods? Indeed, there is still a long way to go in the aspect of Chines medicines, compared with that of food. And we need to recognize the status quo. We teach everyone how to do it. Once you have the method experience, each laboratory can guarantee the data accuracy. There is no compulsive method in the long term.

In the near future, we still have to teach everyone. At present, the method system should be transformed. In the long term, it should be established in accordance with international standards. Risk assessment can also be conducted for representative varieties. In the long run, we will establish a long-term monitoring mechanism. With the continuous efforts of us and the efforts of different systems to work together, we will synchronize and systematize the limiting methods of Chinese medicines. It is our goal. And this is my report. Thank you. Please give us your valuable comments. Thank you.