1. In which form should the documents be submitted?
Applications for the registration of a traditional herbal medicinal product should be submitted in accordance with the Austrian Medicines Act (Arzneimittelgesetz, AMG) as amended. The documents to be submitted as part of the application for registration are specified in Article 12a AMG, and they should be submitted in CTD format, preferably electronically.
2. Which application form should be used for the registration of a traditional herbal medicinal product?
Information about the transmission of documents see guide L_Z45_Leitfaden_zur_Elektronischen_Einreichverordnung_EEVO.
3. Under which conditions can a medicinal product be registered in accordance with Article 12 AMG?
The applicant has to demonstrate the following: The indications are exclusively appropriate to traditional herbal medicinal products. The medicinal product is, by virtue of its composition and purpose, designed for use without prescription. The medicinal product is exclusively designed for administration in accordance with a specified strength and posology. A corresponding product has been in medicinal use throughout a period of at least 30 years, including at least 15 years within the European Economic Area. The data on the traditional use, including safety and plausibility of efficacy, are sufficient. The traditional use can be demonstrated either by bibliographical data or by means of an expert report. No additional demonstration of the traditional use is required when a reference is made to a Community Monograph according to Article 16(h)3 of Directive 2001/83.
For combinations with vitamins or minerals and for medicinal product containing more than one active ingredient, data on the combination should be provided. In case traditional use has been demonstrated for the combination, but not for the single active substances, data on the single active substances should be provided.
Evidence of a person responsible for pharmacovigilance; description of the pharmacovigilance system and (if appropriate) the risk management system.
Details are given in Articles 12 and 12a AMG.
4. What is a ‘corresponding’ herbal medicinal product in accordance with Article 12a AMG?
A corresponding herbal medicinal product has the same active ingredient, the same or similar indications, an equivalent strength and posology, and the same or a similar route of administration, as the herbal medicinal product which is submitted for registration.
The phrase ‘same active ingredient’ is somewhat difficult to interpret, especially with respect to extracts from herbal drugs. However, what is clear is that ‘same active ingredient’ means the same plant, plant part, and extraction solvent; moreover, a similar concentration of the extraction solvent (especially with water-alcohol mixtures) and a similar drug-extract ratio are required. Overall, therefore, the traditional herbal medicinal product must be closely related to published data or to other medicinal products.
If the active substance deviates with regard to the mentioned parameters a comprehensive comparison using different analytical methods would be necessary to demonstrate the chemical equivalence to the corresponding product.
5. Can an extract whose efficacy and safety has previously been demonstrated in clinical studies performed according to GCP be registered with the same indications as a traditional herbal medicinal product?
No. In this case, either a bibliographic application (“well–established use”) or a full application will have to be submitted.
6. How can the evidence of traditional use be demonstrated?
Evidence of traditional use can be demonstrated through any form of scientific documentation. Also, it is important to document that the medicinal use of the product has not been just sporadic, but that the product has been used continuously over longer periods within the requested 30 years.
If the product submitted for registration is in line with a community monograph of the HMPC the contents of modules 2.4 and 2.5 (evidence for traditional use) can be replaced by a cross reference to the monograph and the respective assessment report.
If reference is made to a corresponding authorized or registered medicinal product the evidence for the long-standing use should be supported by marketing authorization data as well as evidence for the authorized indication and posology.
The ‚Guideline on the assessment of clinical safety and efficacy in the preparation of community herbal monographs …‘ (Doc. Ref. EMEA/HMPC/104613/2005) should be applied in case that the evidence on the traditional use is justified by standard references for phytotherapy.
7. What are the requirements with respect to the quality of traditional herbal medicinal products?
The quality aspect of a medicinal product is independent from its traditional use. Therefore, no exemptions can be made with respect to the physicochemical, biological, and microbiological data to be submitted.
Traditional herbal medicinal products may contain herbal drugs which are not the subject of a pharmacopoeia monograph and for which only limited analytical procedures have been published. Therefore, the quality of traditional herbal medicinal products must be determined on a case-by-case basis, taking into consideration its composition and the analytical procedures available to document its quality.
The following guidelines should be considered:
‚Guideline on quality of herbal medicinal products1/traditional herbal medicinal products‘ (Doc. Ref. EMA/CPMP/QWP/2819/00 Rev. 2)
‘Guideline on specifications: test procedures and acceptance criteria for herbal substances, herbal preparations and herbal medicinal products/ traditional herbal medicinal products’ (Doc. Ref. EMA/CPMP/QWP/2820/00 Rev. 2)
‘Guideline on quality of combination herbal medicinal products / traditional herbal medicinal products’ (Doc. Ref. EMEA/HMPC/CHMP/CVMP/214869/2006)
8. Are stability tests necessary for traditional herbal medicinal products?
Yes, stability tests are necessary both for the active substance(s) and for the finished product. The data have to be submitted as part of the registration dossier. When adequate instructions for storage are foreseen, stress tests at higher temperatures may be waived.
The selection of adequate analytical markers may be difficult, especially for preparations containing several herbal drugs. The applicant should try to document that the extracts in their totality are sufficiently stable.
9. After the end of the shelf-life, do herbal drugs containing essential oil in tea preparations have to correspond to the stability guidelines (i.e., a maximum deviation of + 10 per cent versus the initial value), or is it sufficient that the requirement
Herbal drugs contained in a monograph must, throughout their entire shelf-life, fulfil the requirements of the pharmacopoeia.
For herbal drugs not contained in a monograph, the content of essential oil at the end of the shelf-life must be within the standard limits given in the scientific literature.
10. Are MRP/DCP possible for the registration of traditional herbal medicinal products?
If the traditional herbal medicinal product submitted for registration is in line with a community monograph of the HMPC or it consists of herbal substances, preparations or combinations thereof contained in the Community list MRP/DCP shall apply.
If the THMP deviates from the HMPC monograph or the list entry MRP/DCP is possible on a voluntary basis. Discussion with Member States intended to be included in any procedure is recommended before submission of an application. See also the Q&A on traditional herbal medicinal products of the CMDh.
11. How is an herbal preparation defined?
Herbal preparations are obtained by subjecting herbal substances to treatments such as extraction, distillation, expression, fractionation, purification, concentration or fermentation. These include comminuted or powdered herbal substances, tinctures, extracts, essential oils, expressed juices and processed exudates.
The degree of purification, fractionation or concentration is neither defined nor limited in the legislation. Therefore also purified substances of herbal origin (like D-Camphor) are acceptable as active ingredient in traditional herbal medicinal products. See also the regulatory Q&As of the HMPC.
12. In traditional herbal medicinal products the herbal preparations may be combined with vitamins and minerals. What kind of data is necessary in order to substantiate the 30 years of traditional medicinal use?
Evidence of at least 30 years of medicinal use has to be provided for the herbal active substance or the combination of the herbal active substances. For additional vitamins and minerals data have to be submitted for the substantiation of the ancillary action in the proposed indication and posology.
13. What is the meaning of “well-established use” with regard to herbal medicinal products? What kind of data have to be submitted?
The term "well-established use" corresponds with the bibliographic application according to §10a AMG.
For herbal medicinal products in the dossier particular importance should be paid to the comparability of the product submitted for marketing authorisation and the reference products which were used in the published non-clinical and clinical investigations. A formal equivalence regarding the plant source, the plant part used, the extraction solvent and the drug-extract-ratio is essential. Analytical data demonstrating the similarity between the product submitted and the reference product may be asked for.
The non-clinical and clinical data have to comply with the current scientific standards.
If the product submitted for marketing authorization is in line with a community monograph for well-established use of the HMPC the contents of modules 2.4 and 2.5, 4 and 5 can be replaced by a cross reference to the monograph and the respective assessment report. Relevant scientific data which has been published since the publication date of the HMPC monograph should be presented in the dossier and discussed taking into account the HMPC assessment report.
14. What is the correct application form for an application according to "well-established use"?
Information about the transmission of documents see guide L_Z45_Leitfaden_zur_Elektronischen_Einreichverordnung_EEVO.
15. Pyrrolizidine alkaloids (PA): What limits do apply for PA if a medicinal product contains a plant which biosynthesises PA?
Following the national decree according to §5 of the Austrian Medicines Law from 1.8.1994 medicinal products which contain parts or constituents of plants of the genus Cynoglossum, Petasites, Senecio, Symphytum or the species Eupatorium cannabinum or Tussilago farfara must not be placed on the market unless it can be demonstrated by means of a state-of-the-art analytical method that the finished product does not contain PA.
From this ban homoeopathic medicinal products are exempted if they contain potency ≥ D6 for oral use or potency ≥ D4 for cutaneous use. The potency refers to the final concentration in the finished product.
In the light of the fact that pyrrolizidine alkaloids have been detected in herbal substances and preparations from plants, which do not typically biosynthesize these compounds a revision of the national decree according to §5 of the Austrian Medicines Law is considered.
16. Pyrrolizidine alkaloids (PA): Is it necessary to determine the content of PA in all kind of herbal preparations (herbal substances, herbal extracts)?
Current reports have shown that pyrrolizidine alkaloids have been detected in herbal substances, which do not typically biosynthesize these compounds. Data regarding the actual content are necessary in order to assess the risk and to set measures for the safety of the patients. Investigations led to the conclusion, that the occurrence of pyrrolizidine alkaloids is probably due to contamination with other plants, which are co-collected during harvesting. Because the content of pyrrolizidine alkaloids may result from contamination with very few plants (e.g. species of the genus Senecio, ragwort), appropriate control cannot be assured with measurements based on “Good Agricultural and Collection Practice” only.
Based on the experience gained so far it can be assumed that
- Hyperici herba,
- Passiflorae herba,
- Matricariae flos,
- Alchemillae herba,
- Liquiritiae radix,
- Melissae folium,
- Menthae piperitae folium,
- Salviae folium,
- Taraxaci herba cum radice,
- Thymi herba,
- Equiseti herba (NEW),
- Urticae radix (NEW),
- Urticae herba, Urticae folium (NEW)
- and preparations thereof
contain PA in considerable amounts. Therefore, with immediate effect, marketing authorization holders or registration holders of herbal medicinal products, traditional herbal medicinal products, as well as of pharmacy-proprietary medicinal products and of homoeopathic medicinal products with active substances of the above mentioned herbal substances or herbal preparations thereof have to collect data on the content of toxic pyrrolizidine alkaloids. Essential oils are currently not in the scope of this obligation.
The BASG reserves the right to modify the list of plants which have to be analysed depending on the results obtained from now.
17. Pyrrolizidine alkaloids (PA): What limits for PA are acceptable for preparations of plants which do not biosynthesise PA?
Generally a limit of 1 µg PA with respect to the maximum daily dose of the finished product is applicable. A justified limit has to be set in the release specification of the finished product. Depending on the results of the analyses the following test scheme is applicable:
- No or very low contamination
90% of the investigated samples of a certain source of the herbal substance contain ≤ 0.1 µg of toxic PA with respect to the maximum daily dose of the finished product according to the approved SmPC. No sample contains more than 0.35 µg PA with respect to the maximum daily dose of the finished product. Skip testing is acceptable. The testing scheme must be derived from the data.
- Low contamination
90% of the investigated samples of a certain source of the herbal substance contain ≤ 0.35 µg of toxic PA with respect to the maximum daily dose of the finished product according to the approved SmPC. No sample contains more than 1.0 µg PA with respect to the maximum daily dose of the finished product. Skip testing with shorter intervals is acceptable. The testing scheme must be derived from the data.
- Relevant contamination
If categories A and B are not applicable a routine testing on PA content in the release specification has to be implemented. The content must not exceed 1.0 µg PA with respect to the maximum daily dose of the finished product.
Changes of the specification have to be submitted as variation (marketing authorisations, registrations in MRP/DCP) or national variation according to §24 (national registrations) until 1.7.2017 to the BASG. In case of applications for new marketing authorisations / registrations the risk of a contamination with PA has to be fully addressed.
18. How should the analysis of PA be performed?
The actual testing should be performed on the extract. Only in justified cases testing is acceptable at the stage of the herbal starting material (e.g. herbal teas). In this case special care should be exercised on the sampling plan (risk of spot contamination). The results can be extrapolated to the finished product. In the case of combination medicinal products the impact of all herbal ingredients has to be considered.
The applicant is advised to use the SPE-LC-MS/MS method published by the German Federal Institute for Risk Assessment (BfR-PA-Tea-2.0/2014). Other methods are acceptable provided they are fully validated in accordance with ICH Q2 (R1).
Created: 15.04.2009 | Page last modified: 21.02.2017