Homeopathic Medicinal Products
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.
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.
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.
Information about the transmission of documents see Guideline: electronic Release Regulation EEVO (L_Z45).
On the website of the HMA-HMPWG the following documents are available:
- “Points to consider on non-clinical safety of homeopathic medicinal products of botanical, mineral and chemical origin”
- “Points to consider on safety of homeopathic Medicinal Products from Biological origin”
The content of the dossier has to follow the Annex I of Dir 2001/83/EC as amended and the note for guidance of the HMPWG “Guidance on module 3”.
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.
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.
Please see the Nr. 15 FAQs on Herbal Medicinal Products for the list of plants and herbal preparations for which a testing is mandatory and the testing scheme. Irrespective of the above mentioned list all herbal preparations (herbal drugs, herbal preparations) of plants, which biosynthesise PA (e.g., species of the genera Cynoglossum, Petasites, Senecio, Jacobaea symphytum, Eupatorium, Tussilago), have to be tested on the 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).
Generally a limit of 1.0 µg PA with respect to the maximum daily dose of the finished product is applicable (by analogy with the requirements for herbal medicinal products). 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.
The risk of a contamination with PA has to be fully addressed in the dossier.
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). 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).
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.
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-Monohydrat (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.