Quality Considerations of Traditional Medicines

Rudolf Bauer

(Professor, Director, Pharmaceutical College, University of Graz, Austria)

Thank you very much for inviting me to this event. It is a good discussion among different fields from Europe, Australian and China on the issue of herbal medicines. For a lot of issues have been discussed by experts and today is the 2ndday of this symposium, there is a little disadvantage for me to give this speech. So I will try to reduce what have been said as far as possible and try to provide different ideas and perspectives.

My theme is still about considerations for herbal quality. I think it is really true, when we discuss about safety and efficacy, that we must be aware of the quality as the base of safety and efficacy. Quality control is essential both for medicinal products and complementary supplements. This means that we must take quality control seriously.

I just give you one example that what must be avoided. This is a paper from years ago, about Echinacea used for preventing rhinovirus colds. This was a study undertaken in the United States and it found that this product was ineffective. We need to realize that it is the extract rather than this plant that leads to ineffectiveness. We must do some clinical studies to find if there are some tests unsuitable for this product. I can not find any compound to show that it is a very bad quality product. If they had contacted me earlier, I would have told them it was unreasonable to do this study because they should use a proper product.

I think this shows how important the quality is. Quality control really should be the starting point for any regulations. So quality, as its definition, is the suitability of either a herbal preparation or a herbal product between its application and expectation. This item includes attributes such as specification and purity. This slide shows some factors which can influence the quality of final products. Because the variety of nature, we have more choices. Nature is not standardized, so we have to accept that the variety may lead to inability, and it need to be controlled. For example, you can control time of harvesting at an early stage.

The second step is to control the processing, including technology, identity, extract, ion exchanger or precipitate. The last stage is manufacture, which involves storage, dry process, its form et al. All these aspects I mentioned should be considered.

In the European Union (EU), there are a lot of very detailed guidelines, but I feel sorry that I cannot introduce them one by one today. However, I have listed all the guidelines here. You can download these guidelines to follow if you want to go for registration in Europe. Also European companies should obey these guidelines, which means products produced in Europe must follow these guidelines.

With regards to agricultural conduct, it is also an issue in China. We have the guidelines on test procedures, accept criteria, and stability. All the guidelines need to be followed.

Quality in Europe is defined by European Pharmacopeia and I think this is an important aspect. European Pharmacopeia is valid in 37 member states of the EU, which have signed agreements and should obey the specific requirements of European Pharmacopeia. You can see that not only European member states but also other states like Turkey have signed to follow European Pharmacopeia. By the way, as observer, China can give some suggestions on European Pharmacopeia during the period of discussion.

We have a lot of monographs about herbal medicines. Here you can see how it developed these years. There are 184 monographs in which 85 represents herbal preparations.

Here is a pharmacopeia for Chinese patent medicine on quality control during processing. Firstly, on the aspects of impurities, if there are adulteration, contaminants and fumigants. In Australia, fumigants are strictly forbidden to avoid this issue.

As for microbiological contamination, it is something relevant. We have several guidelines and limits on it.

At last extract tests are also needed, which focus on active markers. As long as we know its real active marker, we can determine what kind of markers should be adopted to ensure the final quality.

Starting from identification, there are several methods dealing with this aspect. What European Pharmacopeia has been using do not include mass spectrometry and DNA analysis. The Pharmacopeia methods are macroscopic features and microscopic features, especially for finger identification, which is used heavily. But for the future, I think we will follow the methods recommended by Chinese Pharmacopeia like DNA sequence.

Here are some examples to tell you that identification is essential. This side is Siberian Ginseng, which is popular in both Europe and China. In China, one similar plant called Periplocae Radix is toxic. So for similar Ginseng products, we need to identify such products.

If you look on the TLC finger print, you see here that on the one side it lists several different products. Through this kind of identification process, we could easily identify different products, which is a very efficient identification method.

Another example is Herba Leonuri. It has been introduced in the European Pharmacopeia now. Since many years ago, there has been Leonurus Cardiaca L., which is a different species. They are similar in color spectrum. We have done DNA analysis, through which we could see the difference between the 2 species. Moreover, we could use TLC to identify the 2 plants, as a result of which they are different on chemical components.

Tests for contaminants in European Pharmacopeia have been mentioned yesterday. We have many monographs for heavy metals, microbe tests, pesticide overuse and mould residue. Pyrrolizidine alkaloid (PA) is an important issue in preparation.

Here are heavy mental issues. The limitations in European Pharmacopeia are 5 ppm for lead, 1 ppm for cadmium and 0.1 ppm for mercury. And you see that regularly there are some tests for Chinese herbs. There are some unusual situations which are illegal with regard to heavy metals, but it is not so often. If we take care of that, through better planting and soil analysis, heavy metals may be avoided.

Pesticide residue is a more important issue. There are 70 limits listed on monographs of European Pharmacopeia. Maybe there are more than 1,000 kinds of pesticides using in the world. It is impossible to test all the pesticides listed on European Pharmacopeia, but there is also some regulation. For example the food regulation must be respected. If a pesticide is not listed on the European Pharmacopeia or other European contexts, according to the limits of intake and the toxic dose, such course should be avoided.

For microbial quality, we have limits which are based on the use of some processes like processing drugs. We have 3 categories, which limit the microbes. You see there are some bad situations as the conditions of some microbe are severe. Candida albicus, aspergillus niger, salmonella and escherichia coli are also limited. So we should use hot water to process drugs. Overall, the condition of infecting microbe is still very low, and products should obey these different criteria.

It is still an issue that some toxins are produced by fungus, especially for aspergillus flavones. And in European Pharmacopeia, the limits for aflatoxin B1 is 2 μg. Also we have some toxins like aflatoxin B1, B2, G1 and G2. In Germany, there is a regulation on ochratoxin, which is an issue for some specific products.

PA is considered to be a liver toxin. The EU has set a definition based on daily external exposure. Herbal medicinal products are allowed to be sold in Europe only if the daily external exposure is not more than 100 μg, the internal exposure is not more than 1 μg per day and no more than 6 weeks a year, which may be lower in the future.

Before calculating the dose, you need to do analysis, through which you can see the amount of active components in medicinal materials. The determined content is 1.6 mg/kg of Flos Farfarae. According to Herb Medicinal Products Committee (HMPC), 0.2 g of these flowers will be allowed per day.

This is a public statement of European Medicines Agency (EMA). For dust and soil, the EU also has a broad testing procedure, which has been established at the moment.

1. Here is a public statement on contamination of herbal medicinal products (HMPs) with PA - transitional recommendations for risk management and quality control. The HMPC's view is that a patient's exposure to PA from HMPs should be as low as possible, and should not exceed a daily intake of 0.35 μg. However, for a limited transitional period, an intake up to 1.0 μg per day can be accepted. With regard to actions to be undertaken by member states and the concerns relating to the quality of HMPs, 2 main aspects need to be addressed: implementation of suitable testing procedures to ensure PA level being controlled in line with limits agreed, and implementation of measures to avoid or reduce PA contamination of HMPs.

Here is a risk-based test scenario adopted by Germany and Austria:

Class μg PA/day in the HMP Test frequency Acceptance limit: with respect to maximum daily dose of HMP A 0.1 skip testing 90% of samp lelbelow 0.1 microgram/day;none contain ＞ 0.35 microgram/day B 0.35 more frequent skip testing 90% of samp lelbelow 0.35 microgram/day;none contain over 1.0 microgram/day C 1.0 routine testing required no result over 1.0 microgram/day

Here are considerations to assays. If you are talking about assay, we must define its marker compound, which should be reasonable and relevant. And this has been questioned whether we chose the right marker compounds. When developing new monographs we need to think about the marker compound very thoroughly. Nevertheless we have to aware that the marker compound is one compound.

But maybe after testing thousands of components, we are not sure whether the compound is relevant to the overall quality. Finger printing may be a more proper approach. So selecting one marker compound means you are testing the quality in a way, which is the base of a test, but this may be not relevant. Nevertheless we have to find some ways to have a proper assay.

We have also been questioned about the costs. I want to show you one example and maybe we can have a discussion. For example, there is a limit of 0.05% transferulic acid (calculated with reference to the dried drug) in Radix Angelicae Sinensis, and if the content is lower than that percent, it is a bad one.

If we need to compare its constituents, actually there is a peak value, which is a marker defining the quality of Radix Angelicae Sinensis. At this time we need to question that if the marker is the right one.

So for this reason, we must think more about the relevance or therapeutic effects of the marker. And should it be seen as a marker? However, this has achieved an agreement between the HMPC and the EDHM. These compounds have been proven relevant to the therapeutic effects. Unfortunately, we do not have many examples without therapeutic effects.

Chemically defined substances or groups of substances can generally be accepted to contribute substantially to the therapeutic activity of a herbal substance, a herbal preparation or a herbal medicinal product.

Evidence shows that clinical efficacy of a standardized extract is equal to the efficacy of isolated substances or groups of substances (e.g. hydroxyanthracene derivatives and tropane alkaloids)

Such compound or atropine, which is relevant to the therapeutic effects, but the majority of herbal products are lacking clear analysis of components. For that reason, I think we should find some different approaches. Now we have 3 different kinds of extracts considered as standardized herbal components, and they are really assigned to mark the therapeutic relevance. Meanwhile, the herbal components need to be quantified. Some of them are not the only components to cause therapeutic effects, but other herbal components or herbal preparations are lacking relevant data.

We do not know exactly why these components being included and what specific functions do they have. We can only modify these quantified herbal components and mix different batches without excipients. Herbal preparations without these compounds or active ingredients should not be modified.

For the future, we need to figure out how to produce standardized chemical products from different compounds. Here is a good example of gingko extract: a standardized ratio of ginkolide A, B and C. We found that the composition of different batches of gingkoes varied. When we mix them, we consider to choose bathes with stable quality to ensure the quality and extracts of the final product being consistent. Compounds can be analyzed via MCS, metabonomics or other methods in the future. If you get some basic situations of the composition, you can better understand how to standardize them.

Basically, what you need to do is component analysis for different batches through LCMS or some pharmaceutical tests. You will find whether an ingredient is active or not, which can be used to effectively describe the situation of the extract and different batches. I believe this statistical method should be more frequently adopted in quality control.

Now there are some application cases, such as the evaluation of different classes of ginseng. The roots of ginseng are very pricy due to their old ages. After we did spectrometry, we found that their differences started with planting. It means the 2D spectrometry will play a leading role in the future.

Therefore, quality control should be started with planting, which can reduce many problems in the future. The better we control the quality during planting, the higher quality we may get, and to ensure the sustainable supply. When it comes to the extinction of some species, paying attention to the planting should be encouraged.

In summary, quality is a basic requirement which is a premise of safety and efficacy. Comprehensive methods of quality control are needed. What's more, quality ensurance is never opportunistic, and it is the result of quality control for our final products. Therefore, we need good quality control, and it starts with the materials. Finally, to understand different components, we definitely need more evidence and fact, such as mechanisms and principles. Knowledge accumulation is very instrumental to our research. Thank you.