Pyrrolizidine alkaloids in medicinal products

Risk evaluation and assays required to ensure quality and safety

Responsibility lies with the marketing authorization holders for herbal and complementary medicinal products as well as outlets that dispense magistral formulations and specialities of the house made from medicinal plants or preparations derived from such plants.

Pyrrolizidine alkaloids (PAs) are chemical compounds that occur naturally in numerous plants. PAs have been shown to have harmful effects on the liver.


Hundreds of structurally different PAs occurring in several thousand different plant species have been identified. These include known medicinal plants (e.g. comfrey [Symphytum officinale L.], borage [Borago officinalis] or coltsfoot [Tussilago farfara] and common weeds (e.g. groundsel [Senecio vulgaris] or South African ragwort [Senecio inaequidens]).


The toxic effect of PAs has been known for a long time. Back in 1992, the then German Federal Health Office (Bundesgesundheitsamt, BGA) stipulated the maximum concentrations permissible in Germany in finished medicinal products made with plant drugs containing PA in a publication in the German Federal Gazette [1]. The then Intercantonal Office for the Control of Medicines in Switzerland (IOCM) adopted these maximum concentrations in the course of a reexamination procedure.


A publication issued in 2013 by the German Federal Institute for Risk Assessment (Bundesinstitut für Risikobewertung, BfR) revealed that food teas or herbal teas can contain PA even if the plants from which the teas are made do not include any PA-containing plant species [2]. The PAs enter these products via weeds that are harvested with the plants for the teas.


It has since been shown that many plant-based foods and medicinal plants are affected by the PA weed problem. Since contamination with individual specimens of these weeds is sufficient to produce toxicologically relevant concentrations in medicinal products, measures that go beyond the existing Good Agricultural and Collection Practice (GACP) are needed to ensure their quality and safety.


Accordingly, on 31 May 2016, the European Medicines Agency (EMA) published a statement on the PA-containing weed problem with recommendations for risk management and quality control [3].

Current data show that substantial quantities of PA may be detected in the following medicinal plants and derived preparations even though they do not contain PA themselves.

St. John's Wort (Hyperici herba)
Passionflower herb (Passiflorae herba)
Camomile (Matricariae flos)
Lady's Mantle (Alchemillae herba)
Liquorice root (Liquiritiae radix)
Balm leaf (Melissae folium)
Peppermint (Menthae piperitae folium)
Sage (Salviae folium)
Dandelion with root (Taraxaci herba cum radice)
Thyme (Thymi herba)

 

In its publication, the EMA recommends tolerating a maximum PA limit of 1 µg per day relative to the maximum daily dose for a three-year transitional period. After this period, the limit will be reduced to 0.35 µg PA.


During the transition phase, manufacturers of plant-based active substances and finished herbal medicinal products will be required not only to comply with current GACP, but also to implement measures to mitigate the PA weed problem.

 

Until further notice, Swissmedic will adopt the EMA’s recommended limit of a maximum of 1 µg PA relative to the maximum daily dose.

 

In light of the above, the Agency requires holders of authorisation for herbal and complementary medicinal products and outlets that dispense magistral formulations and pharmacy preparations made from medicinal plants or preparations derived from such plants

 

  • to conduct a risk evaluation – particularly for the medicinal plants mentioned above – with immediate effect
  • if necessary, to collate and record data on the content of toxic pyrrolizidine alkaloids.

A worst-case scenario should be assumed for calculations conducted in the course of a risk evaluation with no in-house PA residue analyses (highest value in tea drugs published to date: 3430 µg/kg, assuming complete extraction).


Medicinal products that exceed the maximum limit of 1 µg PA relative to the maximum daily dose may not be placed on the market in Switzerland.


Pharmaceutical companies and outlets that dispense magistral formulations and pharmacy preparations should implement these measures as soon as possible as part of the process of exercising their responsibility.


Starting in mid-2017, Swissmedic will be carrying out random checks of risk evaluations and compliance with the limit.


The following test schedule will be adopted, depending on the risk evaluation and data already determined:


A) No or very low contamination
90% of the tested samples have a PA content of ≤ 0.1 µg, no sample contains more than 0.35 µg PA relative to the maximum daily dose stated in the Information for healthcare professionals or Patient information: Skip testing is acceptable.


B) Low contamination
90% of the tested samples have a PA content of ≤ 0.35 µg, no sample contains more than 1.0 µg PA relative to the maximum daily dose stated in the Information for healthcare professionals or Patient information: More frequent skip testing is acceptable.


C) Relevant contamination
If categories A and B do not apply, routine testing for PA should be specified in the release specification. The content may not exceed 1.0 µg PA relative to the maximum daily dose.

 



[1] Bekanntmachung über die Zulassung und Registrierung von Arzneimitteln vom 5. Juni 1992; Abwehr von Arzneimittelrisiken – Stufe II, here: medicinal products containing pyrrolizidine alkaloids with an 1,2-unsaturated necin structure. Bundesanzeiger no. 111, 17 June 1992.


[2] Pyrrolizidinalkaloide in Kräutertees und Tees. Statement 018/2013 issued by the Federal Institute for Risk Assessment on 5 July 2013. http://www.bfr.bund.de/cm/343/pyrrolizidinalkaloide-in-kraeutertees-und-tees.pdf


[3] Public statement on contamination of herbal medicinal products/traditional herbal medicinal products with pyrrolizidine alkaloids; Transitional recommendations for risk management and quality control, EMA 31 May 2016. http://www.ema.europa.eu/docs/en_GB/document_library/Public_statement/2016/06/WC500208195.pdf