Homeopathic Medicinal Products
1. How is a homeopathic medicinal product defined?
Homeopathic medicinal products are prepared from homeopathic stocks according to specific homeopathic manufacturing procedures. These procedures are defined in the European Pharmacopoeia or, in the absence thereof, by the pharmacopoeias currently used officially in a member state of the European Economic Area.
2. Where is the difference between an authorised and a registered homeopathic medicinal product?
In case of a national marketing authorisation evidence on the specific homeopathic efficacy has to be provided either by clinical trials or generally accepted bibliographic data (e.g. Monographs of the Commission D of the former BGA in Germany). The therapeutic indication for a homeopathic medicinal product is granted in accordance with the above mentioned submitted documentation.
In case of a registered homeopathic medicinal product no specific therapeutic indication appears in the name, on the labelling or in the package leaflet. The homeopathic use of the stock must be justified on the basis of adequate bibliographic data (see HMPWG document “Points to consider on the justification of homeopathic use of the stock”). The safety of the medicinal product has to be guaranteed by a sufficient degree of dilution of the active substance(s). Registered homeopathic medicinal products are only administered orally or externally.
3. What application form has to be used for a (national) application for marketing authorisation of a homeopathic medicinal product?
Information about the transmission of documents see Guideline: electronic Release Regulation EEVO (L_Z45).
If you intend to authorise your homeopathic medicinal product according to AMG §10a in conjunction with §9b, the corresponding sections of the dossier must be filled in, e.g. Module 1.5 (Reason why the application type 'bibliographic approval' is applicable: the active substance(s) has/have been in general medical use for more than 10 years; all preclinical and clinical aspects defined in §9b are covered by literature), detailed discussion of preclinical and clinical literature in modules 2.4 and 2.5, detailed presentation of data on general medical use for at least 10 years in module 2.5, as well as the literature references used in modules 4 and 5.
4. What application form has to be used for a (national) application for registration of a homeopathic medicinal product?
Information about the transmission of documents see Guideline: electronic Release Regulation EEVO (L_Z45).
6. What guidance is available with regard to safety of homeopathic medicinal products?
Guidance documents regarding safety of homeopathic medicinal products are available on the HMPWG website.
7. What are the requirements on the quality of homeopathic medicinal products?
The content of the dossier has to follow Annex I of Dir 2001/83/EC as amended; further guidance documents regarding quality of homeopathic medicinal products are available on the HMPWG website.
8. Are data from stability testing necessary for homeopathic medicinal products?
According to the "Points to consider on Stability Testing of HMPs" of the HMPWG two options are acceptable:
a) stability testing of the homeopathic stock according to the guideline on stability testing CPMP/QWP/122/02; or
b) testing of the homeopathic stock for compliance with the specification immediately before further processing. According to the Annex I of Dir. 2001/83/EC as amended stability data obtained from homeopathic stocks are generally transferable to dilutions/triturations obtained thereof. The shelf life of the dilutions/triturations must not exceed the shelf life of the homeopathic stock.
Stability tests should generally include all tests defined in the European Pharmacopoeia for the respective dosage form. Additionally physical parameters (e.g. content of ethanol, relative density) should be tested.
Substance-related stability tests (e.g. as chromatographic fingerprint) may be omitted only if it can be demonstrated that due to the high degree of dilution the concentration of the active substance is below the limit of detection of the analytical method.
9. Are MRP/DCP possible for homeopathic medicinal products?
European procedures may be used in case of registered homeopathic medicinal products.
For authorised homeopathic medicinal products the same criteria apply as for other authorised medicinal products. When planning MRP/DCP attention should be paid to possible special national provisions for the marketing authorisation of homeopathic medicinal products. If the application refers to such special national provision European procedures cannot be used.
10. Pyrrolizidine alkaloids (PA): Is it necessary to determine the content of PA in all homoeopathic medicinal products containing active substances of herbal origin?
Please see the Nr. 15 FAQs on Herbal Medicinal Products for the list of plants and herbal preparations for which a testing is mandatory, as well as generally required measures related to possible PA contamination. This list applies also for homoeopathic medicinal products. Irrespective of the above mentioned list, all homoeopathic preparations made of plants, which biosynthesise PA (e.g., species of the genera Cynoglossum, Petasites, Senecio, Jacobaea, Symphytum, Eupatorium, Tussilago), have to be tested for PA content.
However, herbal preparations in homoeopathic medicinal products are exempted if they contain a potency ≥ D6 for oral use or a potency ≥ D4 for cutaneous use.
Testing of preparations in lower potencies may be waived in case of low posology. A calculated assessment of the risk may be sufficient. For such calculations a worst-case scenario has to be applied (highest published contamination in herbal drugs: 3430 µg/kg, assumption of a complete extraction).
11. Pyrrolizidine alkaloids (PA): What limits for PA are acceptable for homoeopathic medicinal products?
Generally, the same limits as for herbal medicinal products apply.
The limit of 1.0 µg PA with respect to the maximum daily dose of the finished product must not be exceeded for adults. For children and adolescents the limit has to be calculated on the basis of a maximum daily exposure of 0.0237 µg/kg BW. The body weight should be taken from recognised sources, using such growth tables where an adult is given with 50 kg. In the case that the drug product is foreseen for different age groups with different posologies, the lowest limit has to be set in the release specification.
In case of registered homoeopathic medicinal products without specified posology, as a ‘worst-case-scenario’, above mentioned limits refer to the content of the entire container.
A reduced testing scheme is in principle acceptable. The testing frequency has to be established related to the actual contamination and the limit set in the release specification. Based on the testing scheme with a maximum daily exposure of 1.0 µg for adults the following testing scheme is applicable considering the posology for children and adolescents and available batch data:
- No or very low contamination. 90% of the investigated samples of a homoeopathic preparation of herbal origin result in a contamination of ≤ 10.0% of the limit set in the release specification of the drug product. No sample leads to more than 35.0% of this limit. Skip testing is acceptable. The testing scheme must be justified on the basis of batch data and has to be authorised in a procedure (marketing authorisation, registration, variation).
- Low contamination. 90% of the investigated samples of a homoeopathic preparation of herbal origin results in a contamination of ≤ 35.0% of the limit set in the release specification of the drug product. No sample leads to more than the limit set in the release specification. Skip testing with shorter intervals is acceptable. For dossier requirements see category 1.
- Relevant contamination. If categories 1 and 2 are not applicable a routine testing on PA content in the release specification has to be implemented.
In the case of a change of the supplier of the herbal raw material the reduced testing scheme has to be re-evaluated within a variation procedure.
The risk of a contamination with PA has to be fully addressed in the dossier.
12. How should the analysis of PA be performed?
The actual testing should be performed on the stock. Only in justified cases testing is acceptable at the stage of the herbal raw material (plant material). In this case special care should be exercised on the sampling plan (risk of spot contamination, chapter 2.8.20 of Ph. Eur. is applicable). 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 method according to Ph. Eur. chapter 2.8.26. (Contaminant pyrrolizidine alkaloids) considering the requirements for validation and verification. The data from validation / verification as well as data of all reference standards have to be contained in the dossier. If the method is used for analysis of stocks of plants which biosynthesise PA (e.g. species of the genera Cynoglossum, Petasites, Senecio, Jacobaea, Symphytum, Eupatorium, Tussilago) the suitability has to be demonstrated on a product-specific basis.
13. How should the risk assessment related to elemental impurities in excipients and in the finished homeopathic medicinal product be performed considering the new chapter 5.20 in the European Pharmacopoeia?
Homeopathic medicinal products are not excluded from chapter 5.20. Therefore the requirements of the ICH guideline Q3D have to be applied.
Additionally the risk assessment should follow the Guideline on the formalised risk assessment for ascertaining the appropriate good manufacturing practice for excipients of medicinal products for human use (2015/C 95/02).
These guidelines should be applied taking the criticality of the homeopathic medicinal product into account. If applicable same dosage forms (provided they contain the identical excipients) could be grouped and assessed in a worst case scenario. Active substances should also be included in the risk assessment in an appropriate way considering the source and the dilution of the active substance.
Applications for marketing authorisation / registration submitted after implementation of the Ph. Eur. edition 9.3 in German language have to contain a summary of the risk assessment in chapter 3.2.P.5.5.
Variations for already authorised / registered homeopathic medicinal products have to be submitted only in case that the risk assessment triggers changes in the control of impurities, changes or replacement of materials or changes in the manufacturing process.
14. Is it necessary to list in the product information of a homeopathic medicinal product all excipients used in the manufacture of the active substance?
No. In accordance with the Guideline on `Excipients in the labelling and package leaflet of medicinal products for human use´, excipients used in the manufacture of the active substance (for example lactose, whey, sucrose, honey, ethanol, glycerol) and potentially present in trace amounts in the final medicinal product, essentially correspond to residues arising from the active substance manufacturing process. Such residues only need to be listed in the product information along with corresponding warning statements in case their amounts in the final medicinal product represent a potential risk for the patient. For nationally authorised or registered homeopathic medicinal products, thresholds were specified as follows:
- Lactose: not more than 1 mg per maximum daily dose
- Sucrose: not more than 1 mg per maximum daily dose
- Invert sugar (honey): not more than 1 mg per maximum daily dose
- Ethanol: not more than 50 mg per maximum daily dose
- Glycerol: not more than 10 mg per maximum daily dose
In case of registered homeopathic medicinal products without any specified posology, a `worst-case scenario´ is assumed meaning that the amount of excipient used in the manufacture of the active substance is referred to the entire content of final medicinal product within one primary container.
In case the amount in the final medicinal product is below these thresholds, neither listing nor inclusion of warning statements from the Guideline on Excipients is required.
In case the amount is above these thresholds, listing in the product information is required, along with warning statements as foreseen in the Guideline on Excipients.
In case lactose is used as excipient in the manufacture of the active substance and present in the orally applied final medicinal product with more than 1 mg and less than 10 mg per maximum daily dose, the warning statement from the Guideline on Excipients may be amended in the product information of authorised medicinal products with the following statement:
„Dieses Arzneimittel enthält Lactose (weniger als 10 mg pro maximale Tagesdosis). Diese Menge stellt kein Risiko für Patienten mit Lactoseintoleranz dar.“
By analogy, this statement may be added in case of registered homeopathic medicinal products for oral application when the amount of lactose is `less than 10 mg per primary container´.
Affected applicants are encouraged to update the product information accordingly in the frame of the first upcoming variation submission.