Pyrrolizidine alkaloids in medicinal products
Recently, pyrrolizidine alkaloids have also been detected in herbal preparations made from plants that do not biosynthesize pyrrolizidine alkaloids. Studies suggest that contamination with weeds may be responsible. Since even very few individuals of weeds (such as species of the genus Senecio, greiseweed) can lead to toxicologically relevant concentrations in medicinal products, measures according to Good Agricultural and Collection Practice GACP are not sufficient to ensure quality.
From data available so far, it is evident that above all:
- St. John's wort (Hyperici herba),
- Passionflower herb (Passiflorae herba),
- chamomile (Matricariae flos),
- Lady's mantle herb (Alchemillae herba),
- licorice root (Liquiritiae radix),
- lemon balm (Melissae folium),
- peppermint (Menthae piperitae folium),
- sage (Salviae folium),
- dandelion herb with root (Taraxaci herba cum radice) and
- thyme (Thymi herba)
- and preparations thereof
PA in partly considerable quantities. Therefore, with immediate effect, data on the content of toxic pyrrolizidine alkaloids must be collected from marketing authorization holders / holders of registration of herbal medicinal specialties, traditional herbal medicinal specialties, pharmacy-own and homeopathic medicinal specialties with herbal active ingredients from the above-mentioned medicinal plants or preparations made from them.
In principle, the limit of 1 µg PA related to the maximum daily dose should not be exceeded.
Depending on the analytical results, the following test scheme is to be applied:
A) No or very low contamination
90% of the tested samples of a herbal preparation have a PA content of ≤ 0.1 µg related to the maximum daily dose according to the approved SmPC, no sample contains more than 0.35 µg PA related to the maximum daily dose: skip testing is acceptable. The test plan is to be determined based on the data.
B) Low contamination
90% of the tested samples of a herbal preparation have a PA content of ≤ 0.35 µg related to the maximum daily dose according to the approved SmPC, no sample contains more than 1.0 µg PA related to the maximum daily dose: skip testing at shorter intervals is acceptable. The testing schedule is to be determined based on the data.
C) Relevant contamination
If Categories A or B are not applicable, routine testing for PA shall be specified in the release specification. The level shall not exceed 1.0 µg PA based on the maximum daily dose.
Herbal active ingredients in homeopathic medicinal specialties for internal use from a dilution of D6 and for external use from a dilution of D4 are exempt from the mandatory analyses. For active ingredients in lower potencies, a calculated risk assessment may also be sufficient if the dosage is correspondingly low. A worst-case scenario is to be applied for the calculations (maximum value published to date in tea drugs: 3430 µg/kg, assumption of complete extraction).
The implementation of these measures is the responsibility of the pharmaceutical companies within the scope of their responsibility.
As of now, BASG will review the implementation as part of the next regulatory activities. Changes of specifications have to be submitted as variation (approvals) or national change according to §24 (registrations).
BASG reserves the right to change the list of plants and preparations to be tested depending on the data collected.
The §5 regulation of 1.8.1994 concerning medicinal products containing plants of the genera Cynoglossum, Petasites, Senecio, Symphytum or the species Eupatorium cannabinum or Tussilago farfara is exclusively applicable to medicinal products containing one or more of the mentioned plants as active ingredients or excipients.
In light of the fact that pyrrolizidine alkaloids have been detected in herbal preparations prepared from plants that do not biosynthesize pyrrolizidine alkaloids, a revision of the regulation underlying this requirement is contemplated.
Further information is available under FAQ.
Queries (technical): Department of Herbal, Homeopathic and Veterinary Medicinal Specialties Tel.: +43 (0)50 555-36528 E-mail: firstname.lastname@example.org
Queries (for media): Communications Management E-mail: email@example.com