Herbal Medicinal Products: HMPC's Statement on Pyrrolizidine Alkaloids

The Herbal Medicinal Products Committee (HMPC) of the EMA has published the draft of the updated public statement on pyrrolizidine alkaloids (PAs). The statement contains, among other things, the limit values for the daily maximum intake of PAs and can be commented until 15 November 2020.

Maximum daily intake of PAs recommended by the HMPC

The document is an update of the public statement published in 2014, which contained 0.35 µg PAs per day as maximum intake level. This limit is also specified in the Ph. Eur. draft for the new chapter 2.8.26. Contaminant pyrrolizidine alkaloids. At the same time, the USP is currently developing a new chapter on <1567> Pyrrolizidine Alkaloids.

In 2016, the German Federal Institute for Drugs and Medical Devices (BfArM) had asked pharmaceutical companies to check the risk of contamination in a product-specific way, to determine the content of pyrrolizidine alkaloids and to take measures if necessary. The aim of this BfArM measure was to avoid an exposure to PAs above 1 µg per day.

The revised HMPC document now comes to the following limit values:

Oral use of medicinal products (with PA-containing herbal starting materials/herbal preparations):

  • Based on a 50 kg person, a daily intake of max. 1.0 µg PAs per day is recommended for adults.
  • Sensitive groups (children): The maximum permissible intake of PAs must be converted accordingly (according to the document, for example, a body weight of 20 kg would result in a maximum daily intake of 0.5 µg PAs per day)

Topical application of medicinal products (with PA-containing herbal starting materials/herbal preparations):

  • It must be ensured that the recommended daily intake of max. 1.0 µg PAs for adults is maintained when using the medicinal product. The administration is restricted to intact skin. 
  • Sensitive groups (children): see oral use.

Contaminations:

  • For contamination of medicinal products with PAs (e.g. by APIs and / or excipients) the limit of max. 1.0 µg per day for adults also applies. For children and adolescents, the limit value must be converted accordingly in relation to the body weight.
  • The following applies to medicinal products with PA-containing herbal starting materials / herbal preparations: The sum of PAs of the API and possible PA contamination (e.g. by excipients) must not exceed the limit values.

Recommended strategy for the risk management of possible PA contamination
The basic procedure for risk management of PA contamination in herbal medicinal products should be based on the ALARA concept ("As Low As Reasonably Achievable", i.e. the risk should be as low as possible). According to the HMPC, contamination of herbal source materials with PA-containing herbs should not occur at all due to pharmaceutical product quality requirements and compliance with GACP and GMP.

With regard to the quality of herbal medicinal products, two main aspects should be considered:

  • Implementation of a suitable test procedure to ensure and control that PA values meet the requirements for limit values,
  • Implementation of measures to avoid or reduce possible PA contamination in herbal medicinal products.

The "HMPC Public Statement on the use of herbal medicinal products containing toxic, unsaturated pyrrolizidine alkaloids (PAs) including recommendations regarding contamination of herbal medicinal products with pyrrolizidine alkaloids" can be viewed on the EMA website.

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