Silvia Deckena
Senior Consultant
[Update 27.09.2016] The "Code of practice to prevent and reduce pyrrolizidine alkaloid contaminations of medicinal products of plant origin", jointly prepared by the German industry associations BAH and BPI, now is available from the Journal of Applied Research on Medicinal and Aromatic Plants (JARMAP). A German version "Code of Practice zur Vermeidung und Verringerung von Kontaminationen pflanzlicher Arzneimittel mit Pyrrolizidinalkaloiden" (article subject to a fee) was published in pharmind 2016, No. 6, p 836. [Update]
Pyrrolizidine alkaloids are produced by a number of plant species as secondary metabolites against herbivores. The class of compounds comprises about 600 compounds, including a specific subgroup, i.e. 1,2-unsaturated pyrrolizidine alkaloids (PAs) with potentially (hepato-)toxic effects. Therefore, their uptake should be minimized. Apart from few exceptions, such as comfrey (Symphytum), PAs are not contained in the medicinal plant itself but in co-harvested weeds.
In a public statement of 31 May 2016, the European Medicines Agency (EMA) wrote (EMA/HMPC/328782/2016): “In principle, contamination of herbal substances with PA containing weeds should not occur at all for reasons of requirements on pharmaceutical product quality and compliance with GACP/GMP”. Nevertheless, safety concerns would be only low with respect to medicinal products with a 1,2-unsaturated pyrrolizidine alkaloid content up to 0.35 µg in the daily dose for individuals with a body weight of 50 kg under lifelong exposure conditions. For a transition period of 3 years the EMA considers a maximum uptake of 1.0 µg of PAs per day by herbal medicinal products as acceptable. However, the manufacturers of medicinal products are expected to use this transition period to reduce the PA contents to a maximum of 0.35 µg related to the daily dose.
Also foods such as honey and herbal teas can contain PAs. Currently, no regulatory limits have been fixed for these products.
Anyway, a reliable determination method for PA levels below 1000 µg/kg has been developed only a few years ago and involves most current analytical methods such as coupled liquid chromatography / mass spectometry (LC-MS/MS).
Already in spring 2016, first national drug regulatory authorities, including the BfArM (Germany), the AGES (Austria) and the MHRA (UK) notified registration and marketing authorisation holders that medicinal products with herbal ingredients are subject to risk assessment regarding their PA load and that the maximum load should be 1.0 µg of PAs related to the daily dose of the medicinal product and should be reduced even more in the medium term.
The BfArM reserves itself to evaluate in pending proceedings whether the submitted documents comply with the requirements. Failure to submit an according release test for PAs will result in a notice by the BfArM that no batch release will be issued without testing for pyrrolizidine alkaloids. Therefore, registration and marketing authorisation holders of medicinal products with herbal ingredients and homeopathic products need to act as soon as possible.
Diapharm currently supports approvals and registrations in more than 20 EU countries. At the time being, the requirements of the national drug regulatory authorities regarding PAs differ from country to country. For example, the German BfArM demands PA data for all herbal medicinal products, while the Austrian AGES (Bundesamt für Sicherheit im Gesundheitswesen in Österreich) initially only asks for PA levels of medicinal products containing one or more of ten specific medicinal plants or (a) preparation(s) thereof including St John's wort (Hyperici herba), balm (Melissae folium) and dandelion with roots (Taraxaci herba cum radice).
No European-wide standard for PA level content determinations has been established so far. A long-term objective is to include a PA determination method in the European Pharmacopeia, but this has not been implemented yet. The HMPC recommends analyses involving assays of at least 28 toxic PAs. A commonly used method is the LC-MS/MS method (BfR-PA-Tea-2.0/2014) developed by the German Bundesinstitut für Risikobewertung (BfR = Federal Institute for Risk Assessment).
In its public statement, the EMA has defined risk categories for PAs. Depending on the assignment of the medicinal product to one of these categories, routine testing can be required for every batch (risk category C: 1.0 µg to >0.35 µg of PAs related to the daily dose or no data available, respectively) or sample evaluations of individual batches can be considered sufficient (risk category A: ≤0.1 µg of PAs related to the daily dose).
Further effort will be needed to achieve the middle-term reduction in PA levels demanded for medicinal products, in particular for medicinal products currently assigned to risk category C (1,0 µg to >0,35 µg) covering for example aspects such as seed selection, weed management and harvesting techniques. Therefore, the transition period of three years demanded by the EMA is a quite ambitious objective.
The production of each herbal medicinal product has to undergo an acute individual risk management with respect to PAs for marketing authorisation/registration. This will also be reflected in the approval documents such as the release specification. Currently, the requirements specified by individual EU countries are not (yet) completely harmonized. Therefore, individual solutions tailored to the specific risk potentials are needed.
We will be happy to advise you in issues such as the individual assessment and minimization of pyrrolizidine alkaloid risks related to your herbal medicinal products and will be able to support you with knowledge gained in the support of herbal drug marketing authorisations and registrations in by far more than 20 EU countries. Contact us!