SINO-EUROPE SYMPOSIUM ON TRADITIONAL CHINESE MEDICINE & HERBAL MEDICINE-MARKET OVERVIEW ®ULATION POLICY

Experience and Challenge of European Medicines Registration in China Karin Schleisiek

(Senior Regulatory and Scientific Affairs Manager, Global Strategy and Business Development Division, Dr. Willmar Schwabe GmbH & Co. KG, Germany)

Thanks for the introduction. Good afternoon, ladies and gentleman and chairman. I would like to give you such a presentation of challenges, experiences of herbal medicine registration in China. My experiences are based on herbal medicines. I am responsible for the maintenance of herbal medicinal products. Additionally I am responsible for international regulatory framework. Also I have worked for other companies for 15 years. Working in an international environment means there are big and small challenges in our daily life. So do regulators and CPA.

First of all, it is the language issue. Before I was discussing with my colleague about country of origin,obviously, this word has 2 meanings, which could be species or geographical origin. And in the end we are talking about different things.

We must find out the meaning of the word. Then of course, we have tradition and cultural background.This morning, we have talked about what is the meaning of traditional medicines. It might be the traditional use,traditional production process or several other meaning of tradition. Every time we need to find out what is its specific meaning. Then of course, we have other requirements like legislation guidelines and regulatory framework. Every impressiveness of different presentation this morning is Australian, European and Chinese framework. Different responsibilities of manufacture and authority have different meanings. We have different regulatory systems, frameworks and documents. For example, in Europe we have CTD framework and in China there are many different documents.

So for me this means sometimes the same documents offered in different contexts could make this process more convenient.

Let us start from the quality issue.

I think we have some traditions on this aspect.Quality requirement for a medicinal product parts from its regulatory framework. This means we have a tradition of established use and full application. In any case, we have a requirement that quality should be described properly.I think this requirement also appears in China because of the patients' rights to have good quality of herbal medicines.

If a patient buys a product he would like to have the high quality of herbal medicines. However, there are different definitions of high quality. So we could see that the herbal medicinal products have compound products. In Europe, there are extracts, decoction pieces,Chinese patent medicine. We often do not know the same component and main therapeutic effects. Contribution of single components to the therapeutic activity is not clear in many cases.

We know its main therapeutic fields, but there are always 100 to 200 substances we could not categorize every one. Herbal substances usually are leaves, flowers,roots, etc. Herbal preparations usually are extracts,distillates, pressed juices, etc. Herbal medicinal products have different dosage forms such as tablet, injection,capsule etc. We could see if the nature changes natural plants also change, but our aim is to keep consistent quality of the HMPs. It is the same both in China and Europe.

What is quality?

We have different emphasis on the quality of herbal medicinal products. On one hand, we have raw material.The first is its geographical origin. The second we must define minimum requirements for active components of the definition of species. For purity, we need to ensure there is no pesticide residue. We must always to use the same raw material.

Then we have some knowledge and systematic studies on chemical components, which is an important research field in China. Its aim is to know about chemical components, especially for botanical medicines. The next step is to know about its extracts. So the traditional course in China is to use several compounds, several plants. In China, herbal medicinal products have many mixtures rather than single herbal medicine, which means more or less we need to identify the active substances. It is a broad range. We need to conduct character description and have knowledge of all kinds of mixtures and compounds.

Manufacturing process is also very important. That whether they adopted modern procedures or traditionally established production process is a big range.

For example, decoction pieces or extracts have their own suited procedures. And we are adapting the description of our manufacturing process and procedures to make sure everyone knows the true technologies and procedures. Sometimes it is quite difficult.

There are some concepts of standard quality.European system is different from Chinese system in that we have different categories of extracts. Our standards and quantifies are different. If they are mixed then it would be complicated.

At the end we try to keep updated and consider science and technology, which means our systems are growing and are getting more modern. We have complicated systems in Europe and in China. The variation of Europe and China is very often. If there are any adjustments or update we will also conform to this change.

Time for submitting is varied in different countries.It might take several months or several years to submit application. In any case we try to keep as similar as possible among countries.

Quantified extracts

The content of the active substance is defined on the basis of the content of the extract and additionally on the content of the active marker within a limited, specified range. Our aim is to ensure the content of the extract in finished products is fixed, including these compounds.When finished products are done, the label must conclude the content of active marker as well as the extract.

Standard extracts

The content of the active substance is defined on the basis of the content of an active marker. In this case we really know these active markers contribute to the therapeutic activity, which reveal high levels. That is why this type of standard extracts focus on the active marker only.

Now for natural material, the aspect was produced on the basis of extract and then produces herbal medicinal products. In this case there are two possibilities: on the one hand, you can use quantified concepts to produce finished products; on the other hand, you can adjust its active marker based on its range of excipient, that is to say, the number of extracts could vary in this case. Its therapeutic effects are related to this active marker. That is why the label contains the active marker.

The third category is other extracts.

The content of the active substance is defined batch per batch on the basis of the content of analytical marker. This is very similar to the TCM. The analytical is categorized from the raw material, followed by the whole production process and shape the content of the extract.What does this mean? For example, there is an extract,which has two different contents of extracts on both sides.

This concept is very important especially when you are defining the plant and raw material to guarantee the same quality in our products. Of course we have another type of extracts. The definition of manufacture process and farmer materials is also very important, particularly within this type of extracts.

Let us focus on the aspects of raw material origin.

First of all, the definition of drug species should be clarified. We have to define in any case of drugs. Sometimes raw material has different species. We have to guarantee always using the same. In China, there was the same name for the same species. That is why we need to define the difference between one species and other species.

That is why we must mark its geographical origin.Meanwhile it is easy to define species. The second is to define the geographical origin. For this we can consider the worldwide original availability. For example some drugs we need to consider its grow, because it will cause impacts in harvesting periods.

For stability of raw materials, some drugs have good stability over the year, but some drugs might be sensitive for storage. This is the context and we need to follow this path.

Then we have also to consider the climatic conditions. Under what climatic condition the plant can grow? The raw materials might be from different origins and we need to differentiate.

Marine climate is different from inland climate, thus we need to consider and make clear that the quality is always the same. Then we have economic considerations,cultivation or collection practices. We have to calculate the quality of the raw material. Whether there are big or small raw material producers or some companies can provide such chances, which could be supplied to Chinese market. Very often there might need several suppliers to provide raw materials.

Furthermore, we needs to guarantee a freedom of choose, because sometimes some suppliers might face climate limitation or other limitations which are not suitable for production. Generally, we will overlook these samples and after saying yes, your products can be applied to commercial production. Then we need to order a demand of raw materials and analyze them. After passing analyzing process they are allowed to produce.This needs to negotiate with China and to list suppliers,which leave a freedom of choosing partners, as a result of that quality stability could be ensured.

Challenges

The first challenge between China and EU is regulations. For imported products, a CPP should be provided. The registration documentation of the product in China is related to the product in the country of origin.We need to provide CPP, which means if we register in Germany, obviously we need to conform to EU's regulations, pharmacopeia and guidelines.

On the other hand, the same drug must comply with Chinese requirements, Chinese pharmacopeia, Chinese guidelines and Chinese principles. At the same time, this is very challenge. For example, we have a drug release test and CoA (Certificate and Analysis). That is to say we must be based on European legislation and guidelines as well as manufacturer's specification. When the drug was released and came to China tests would be performed according to Chinese legislation, Chinese guidelines and import specification.

This means they need to do a lot of work. From Germany lab place to China lab place, we must focus the transformation of substances, which is a demanding requirement. Sometimes, this is quite difficult, because we do not have required equipment in our laboratory,which is quite usual in Europe and not available in China.We need to ensure the consistence of the equipment.Sometimes, we might confront some inspections. Chinese customs have already known what Europeans are doing. Then we explain that how we could achieve that requirements. Sometimes this is not that easy.

Then it comes to the challenges regarding to some principles of clinical documents. This is a notice released by State Food and Drug Administration, from which we could see some requirements of natural products, design and evaluation of clinical trials based on the modern medical theory and sufficient testing data to indicate the rationality of the target drug profile, non-clinical and clinical efficacy and safety.

So what is our challenge in this case? Let us have a look at EU's system, which has already such experiment,application, well established use and traditional herbal medicinal product. We have clear requirements, which is to offer clinical and non-clinical efficacy and safety.These requirements sometimes are contradictory. So we hope this process could be simplified to successfully register in China as well as in Europe. Our goal is to have a close cooperation with the authorities to find realistic and product specific solutions in order to enliven the two markets. Thanks for listening!