Christiane Halbsguth

(Director, Regulatory Affairs, Max Zeller Sohne AG, Switzerland)

I'm glad to introduce safety policies of traditional medicines in both the EU and Switzerland, focusing on heavy metals and impurities. Here is my outline for safety related laws and regulatory policies with several documents, which are necessary steps for marketing authorization before application.

Since there are some monographs playing important roles in safety, especially for the application of marketing authorization, I will talk about cases of some products on the market, including aspects like adverse reactions, processing, data evidence of pharmacovigilance, safety related data evaluation (e.g. frequency), some reports, impurities in herbal medicines, and extracts.

We have mentioned that there are some regulations for medical safety in Europe, where different requirements in different countries. For example in Germany, there is a progressive plan of alkaloid PA, which was discussed in the EU years ago: how much PA is acceptable in a product. At that time there was a specification of PA which was then added to the progressive plan, and they came up with an approach needed to control the amount of PA, which also existed in Switzerland. This is the so called coming into the market under supervision.

If there is an incident or server incident, the authorized manufacturer should provide data evidence of liver toxicity or teratogenicity if asked, or put more data on the label, or conduct post-marketing research.

There are various types of traditional medicines with application history, and there are ways of market access and registration, as well as food supplements in Europe. However, food supplements are not medicines. We can see that the amount of these medicines is rising and safety requirements in the documents for them are stricter, among which the highest requirement is about active components in new herbal medicines. The documents point out that quality safety and efficacy of the active components need to be proved.

Simultaneously, research should be conducted according to ICH guide, and KPI can be performed based on HMPC (Committee of Herbal Medicinal Products monographs and literature. A 10-year application history in Europe and a controlled clinical trial are necessary. For traditional medicines, the HMPC monographs and registration literature can be the reference, and a 15-year application history in the EU and a 15-year application history outside the EU are needed. Legally, Switzerland is not a part of the EU, so my company faces the same difficulty as China in entering Europe.

Let's talk about importance of HMPC monographs. The HMPC will update its monographs, and Germany is in the lead. This is the home page of the EMA (European Medicines Agency), we can find REFERENCES provided in monograph evaluation reports and comments provided by the EU. I've also summarized main information in some drop downs.

All the information is about clinical research, safety research, and evaluation reports, among which, liver toxicity need to be clarified. Rhizoma Cimicifugae is widely used over the world, with few reports of adverse reaction. Therefore, when there is a right label, its usage is safe. Furthermore, the results in its evaluation report of advantages and risks are positive.

After marketing authorization, there may be a report of adverse reaction - AE report. Such a report from medical area, consumers or literature will be reported to the department of pharmacovigilance, in which a person in charge or a qualified person answers a 24-hour hotline for this. After he receives the report, he writes a security report of single event. In Switzerland, it is submitted to the database of pharmacovigilance, while in Europe, it is submitted to the EU one. These 2 databases can be searched. If the AE report attracts the attention of healthy departments, they can also refer to the data and monitoring programs suitable for the adverse reaction. If they know the cause, they can exchange the information by uploading a new report to follow up. You can see the number of electronic pharmacovigilance reports and specific information (e.g. a report of the day, from a pharmaceuticals company, a female, her age and diagnosis number).

The EU database contains more information. As long as you obtain the marketing authorization, you can click on it to find its detailed explanation. Last case is a case in my company, which is spontaneous from a female of non-healthy profession. We can also find other information partly quoted from an Excel table whose information is more than what I've presented. Pharmaceuticals companies can submit information like this, which is submitted by a pharmacist in the EU.

We have discussed the liver toxicity of Rhizoma Cimicifugae and the reference data in the EU (active components and chemical components). The liver toxicity is also mentioned in this table, which must be provided regularly. Each obtainer of marketing authorization in the EU must provide a security report every 5 years. Last report was submitted in January, including summarized information and a conclusion. There is an evaluation report on the home page of EMA, whose safety description and product information remain the same. If the committee saw this, they would ask you to change the label of this product.

Why are impurities in medicines important? We've heard that several impurities in the plants may be toxic. It means if there are impurities in the plant or it is contaminated, the plant may have toxicity. Heavy metals and PA can cause the liver toxicity.

The supervision department in Europe is responsible for testing impurities. Even though cadmium, mercury and other heavy metals are required to be tested according to European Pharmacopoeia, we also test other impurities if necessary. For instance, Korea requires us to detect arsenic, so we take measures to ensure the product is not polluted.

Here is a list of pesticide residues and impurities. Indeed, the cost of tests is pricy that includes lab tests involving 500 reference mechanisms. We cannot afford to do this alone. However, we don't do blank tests neither. Sometimes there are unexpected circumstances. For example, the matrix is clean, so we have to consider other factors like whether there are impurities before harvest, or the impurities are brought by wind, etc to deny the problem in the matrix itself.

For preparations, we also test other things on top of residual solvents, like aflatoxin and microorganism. Our standards for residual solvents, microorganism and pesticide residues are quoted from European Pharmacopoeia.

Here are 2 examples of PA in plants, whose situations are serious. The first is about Hypericum Perforatum L., whose harvest time is flowering period. If one plant is contaminated by impurities, the whole field will get involved, which need to be paid to attention to.

The other case is about Flos Farfarae. We have some public statements like the amount of PA for a patient's intake should be less than 0.35 μg per day, and 1μg per day during the transitional period. Here are some extracts needed to be tested their maximum doses per day. We also analyze our samples to calculate their medians. However, we have to admit that the variables are large. Several batches are impurity-free. But there may be impurities in a batch, or even 2,000 U of impurities in one batch, indicating that there is significant difference between batches.

What's more, we found that the amount of PA intake must be less than the set quantified standard. Because initially we have known that there are impurities in Flos Farfarae itself. So, corresponding solvent was applied in the first stage. Fortunately, until now we haven't found any impurity in batches we tested.

Taking Flos Farfarae as the example, let's have a look at other issues. A German product that was launched in 2001 or 2002 was also listed in Switzerland. This product produced a bad drug reaction. It was an extract of Flos Farfarae. At that time, there was a very serious situation. One of the cases was that the patient accepted the liver transplantation. After that, he also had some serious liver diseases. I will explain to you the case of the health authorities at that time in response to this adverse event. First of all, this product was an extract of plant roots, containing carbon dioxide. In 2004, the product was later withdrawn from the market. There were also other extracts available in the European market, which were from ethanol, so the Swiss authorities decided to control the risk. They decided not to completely revoke their marketing approval, but instead demanded a regulated release. So now we have to do some specific targeted monitoring. We need to include some special warnings and precautions in the description of the information. For example, there are some rare cases of kidney injury. Severe cases must take preparations under the corresponding supervision. These liver injuries generally refer to very serious cases. If it is a rare case, it must be supervised.

Here is another product, which is an extract from herbal leaves. When there was a problem with this product, it was also Switzerland that tested it in time. Its focus was also on whether or not to produce such a liver injury after taking it, and if so, to introduce such a regulatory mechanism, and to require relevant parties to provide new data on liver toxicity, which had become a mandatory requirement. There were no serious cases after this measure was taken.

Due to the regulated release in 2009, situations were improved much better that in 2017, we approved the sale of class B Rx (prescription) to class C Rx. But the sale was only allowed in doctor's prescriptions and some pharmacies. Our clinical trial was also passed in 2017.

Now let's move on to policies and commercialization in Switzerland. Our government wanted to save money and had political considerations. At that time, the government intended to list more products and reduce the number of their sales categories, so they wanted to cancel the sales category C, which had an impact on our products. What Swiss military doctors did was to follow the advice of some experts. They finally decided to eliminate Class C and then classify the corresponding products into Class D. At present, the drug can be obtained from doctors, pharmacies, and pharmacists. So at this stage we want to make sure that security comes first.

In summary, there are specific standards for these herbal products in the EU and Switzerland. Furthermore, we have very clear and detailed regulations for marketing tests, and we also have mandatory monographs under European Pharmacopoeia to better control the quality of herbal medicines and their extracts. In a word, we must ensure sustainable safety and high quality of herbal products. Thank you.