USP Proposal for Contaminant Pyrrolizidine Alkaloids

As previously announced, a new USP informational general chapter on pyrrolizidine alkaloids (PAs) is being developed. The chapter has now been proposed in the current issue of Pharmacopeial Forum (PF) 48(1), January 2022. The deadline for comments is March 31, 2022.

Proposed USP chapter <1567> Pyrrolizidine Alkaloids as Contaminants

According to the USP, PAs of concern have been detected in dietary supplements, teas / herbal infusions, honey / pollen, wheat, cereals, and vegetables, predominantly due to the presence of PA-containing plants growing near plants of interest and being accidentally co-harvested with plants used in these products. Therefore, the draft chapter includes

• an introduction to PAs;
• structural requirements for toxicity;
• stability;
• dietary exposure;
• acute, subchronic, and chronic toxicity.

The chapter also contains a list of PAs currently recommended for monitoring by the European Commission (EC) together with tolerable daily intake levels set forth by regulatory agencies globally. Furthermore, it discusses analytical methods and existing challenges to measure PA contaminants in herbal medicinal products (HMPs).

European Pharmacopoeia (Ph. Eur.)

The Ph. Eur. already contains a general chapter on Contaminant pyrrolizidine alkaloids (2.8.26). The chapter highlights the predominant use of LC–MS / MS or high-resolution MS that meets the validation requirements given in the Ph. Eur. chapter for analysis of 28 target PAs. According to the USP, however, LC–MS / MS has its limitations. For example, a baseline chromatographic separation is not always achieved for some PA isomers, as well as their respective N-oxides. Furthermore, these isomers have the same molecular weight, thus it is not possible to distinguish them by mass spectrometry (MS). Therefore the USP concludes that there is a need for highly sensitive and selective analytical methods to provide the level of quantification required to control contaminant PAs in HMPs (therefore, the USP previously announced to work in addition on the elaboration of a new general chapter entitled <567> Analysis of Contaminant Pyrrolizidine Alkaloids).

Recommendations & Next steps

The USP encourages manufacturers of HMPs and suppliers of herbal substances to work on minimizing potential PA contamination risk in their supply chain as required by good manufacturing practices (GMP). Manufacturers should

• educate cultivators on the risk of PA contamination,
• ensure the safety of their products,
• evaluate the levels of PAs in their product considering their potential presence arising from the plant itself, from contamination with external PAs (e.g., due to co-harvesting, absorbed from soil), and / or from supply chains,
• use a risk-based approach for determining appropriate limits and testing requirements.

The draft chapter <1567> Pyrrolizidine Alkaloids as Contaminants is available after registration for the Pharmacopeial Forum.