2021 USP Open Forum: Pyrrolizidine Alkaloid Contaminants

Overview

An Open Forum about Pyrrolizidine Alkaloid Contaminants was hosted by the U.S. Pharmacopeia (USP) on January 29, 2021. This virtual event had more than 150 attendees, including stakeholders from industry, academia, and regulatory agencies such as the U.S. Food and Drug Administration.

Pyrrolizidine alkaloid (PA) contaminants are potentially toxic compounds that can pose a serious threat to human health. At the Open Forum, subject matter experts presented the latest information on PA contaminants in agricultural crops and foods. They also discussed methods of analysis and the current regulations in different countries. USP sought input and feedback from attendees regarding the USP General Chapters related to PAs that are in development.

Background

PAs are organic compounds that are naturally present in various plant species. These PA-containing plants, usually considered weeds, grow among the target crops and contaminate the harvest. Although farmers try to remove PA-containing plants by following Good Agricultural Collection Practices (GACPs), this is difficult to accomplish, and some PA-containing plants remain mixed in with the desirable crop.

Scientists have identified more than 660 PAs and related compounds called PA N-oxides (PANOs). Many of these compounds are potentially toxic, mutagenic, and carcinogenic to humans if consumed for long periods of time or in large enough amounts to be harmful. PAs are mostly likely to occur in herbal supplements, herbal teas, pollen products, honey, milk, and eggs.

USP strives to provide information and quality standards to assist industry stakeholders in the development and production of safe, high-quality products. To this end, USP is developing two General Chapters related to PA contaminants: <567> Analysis of Contaminant Pyrrolizidine Alkaloids (PAs) and <1567> Pyrrolizidine Alkaloids as Contaminants. These chapters address test methods, reference standards, validation requirements, PA chemistry, dietary exposure to PAs, toxicology, analytical methods and challenges, and regulatory status of PAs in Europe, including the proposed tolerable daily intake levels.

Main topics discussed at the Open Forum

USP convened the Open Forum to encourage discussion and collaboration among stakeholders. A top priority for USP is to ensure that the concerns of all stakeholders are heard. Some of the main points discussed were as follows.

• Testing and analysis of samples for PAs
  • For sample analysis, there is a wide range of techniques. Selective and sensitive methods are needed to meet the regulatory requirements. There is no official analytical method for PAs at this time.
  • LC-MS/MS appears to be a promising method, but multiple methods may be needed for accurate quantification of isomeric PAs.
  • Reference standards will need to be developed. A reference standard that is a mix of many PAs would reduce costs for labs and encourage them to perform this testing.
• Agricultural control of PAs
  • PA-containing weeds can be removed in the field or separated out from the crop after harvesting.
  • New evidence suggests that PA residue can accumulate in the soil and can enter food crops directly from the soil. A validated method is needed for testing soil for PAs.
  • GACPs may not ensure lack of PA contamination and are difficult with herbs that are planted using broadcast seeding.
  • The goal is to minimize PA contaminants in crops because they cannot be eliminated completely.
  • Sampling procedures are very important because a representative sample is needed to test for PAs accurately. Sampling the crop is very cumbersome and requires a large amount of raw material, but sampling the powdered material or extract (such as an herbal product or tea) is less difficult.
  • PA contamination may be sporadic and unpredictable. With herbal extracts that are prepared once per year, some extracts have PA contamination every year, whereas other extracts have no PAs for several years and then show contamination.
• Dietary intake and health effects of PA exposure
  • The European Commission has recommended monitoring food samples for 28 specific PAs.
  • Life-long exposure to PAs in foods is very difficult to estimate.
  • Many published PA values are spot measurements, and it is not known whether they represent any kind of long-term, potential exposure.
  • Some PAs are more potent, and therefore more toxic, than others. This raises the question, should all PAs be treated equally when setting limits in foods?
  • Data are emerging on "relative potency factors" of the various PAs in context with proposed limits, which were based on the most toxic PA.
  • The toxicity of PAs mainly affects the lungs and liver. Long-term exposure has been linked to cancer, particularly cancer of the liver.
  • In the U.S., there are no limits for PAs in honey, but honey producers have published reports on this topic.

Next steps

In response to the discussion at the Open Forum, USP plans to take the following steps with regard to PA contaminants:

• Reach out to U.S. FDA to determine if PAs are on their agenda.
• Communicate to USP’s working group to consider relative potency factors and equivalency studies, while evaluating the feasibility of accepting the European Medicines Agency limits.
• Explore the option of harmonizing USP’s General Chapter <567> Analysis of Contaminant PAs with the European Pharmacopoeia’s new General Chapter Contaminant Pyrrolizidine Alkaloids (2.8.26).
• Investigate developing a mixture of reference standards.

USP welcomes input, comments, and questions from stakeholders and looks forward to ongoing discussions with industry, regulators, academia, and other interested groups and individuals.

Please contact Sandeep Putty, Associate Scientific Liaison, USP, with any questions or comments. Email: sandeep.putty@usp.org

The United States Pharmacopeia (USP) is an independent, nonprofit, scientific organization based in Rockville, Maryland. USP convenes and engages a broad range of stakeholders at its Open Forum events. The main objective is to gather stakeholder input so that USP can better understand their concerns, priorities, and questions about the topic at hand. Specifically, USP seeks feedback from stakeholders to improve the quality and relevance of USP’s General Chapters before they are posted in Pharmacopeial Forum (PF) for public comment.