Pyrrolizidine Alkaloid Contamination in Medicinal Plants: Regulatory Requirements and Their Impact on Production and Quality Control of Herbal Medicinal Products.

Against the background of potential contamination of medicinal plant materials with pyrrolizidine alkaloids caused by weeds, suppliers of herbal drugs and manufacturers of herbal medicinal products have taken action by establishing a Code of Practice by monitoring potential contamination and by collection of data. In August 2020, the Herbal Medicinal Products Committee, in its new draft public statement, proposed a daily intake of 1.0 µg of pyrrolizidine alkaloids per day for adults in general, also including contaminations of herbal medicinal products. Over the past years, the results of data collections showed a remarkable reduction of the pyrrolizidine alkaloid burden in herbal drugs and herbal extracts. Meanwhile, a stable situation has been achieved for herbal drugs, while further improvement can be observed for herbal extracts. The results indicate that the implemented measures have been efficient and contribute to a continuous and sustainable reduction of pyrrolizidine alkaloid contamination. A permanent limit of 1.0 µg of pyrrolizidine alkaloids per day is considered appropriate to guarantee sufficient availability of batches used for the production of herbal medicinal products. The new Ph.Eur. general chapter 2.8.26 describes, as an example, an analytical procedure suitable for the determination of target pyrrolizidine alkaloids.

Novel Insights into Pyrrolizidine Alkaloid Toxicity and Implications for Risk Assessment: Occurrence, Genotoxicity, Toxicokinetics, Risk Assessment-A Workshop Report.

This paper reports on the major contributions and results of the 2nd International Workshop of Pyrrolizidine Alkaloids held in September 2020 in Kaiserslautern, Germany. Pyrrolizidine alkaloids are among the most relevant plant toxins contaminating food, feed, and medicinal products of plant origin. Hundreds of PA congeners with widespread occurrence are known, and thousands of plants are assumed to contain PAs. Due to certain PAs' pronounced liver toxicity and carcinogenicity, their occurrence in food, feed, and phytomedicines has raised serious human health concerns. This is particularly true for herbal teas, certain food supplements, honey, and certain phytomedicinal drugs. Due to the limited availability of animal data, broader use of in vitro data appears warranted to improve the risk assessment of a large number of relevant, 1,2-unsaturated PAs. This is true, for example, for the derivation of both toxicokinetic and toxicodynamic data. These efforts aim to understand better the modes of action, uptake, metabolism, elimination, toxicity, and genotoxicity of PAs to enable a detailed dose-response analysis and ultimately quantify differing toxic potencies between relevant PAs. Accordingly, risk-limiting measures comprising production, marketing, and regulation of food, feed, and medicinal products are discussed.

Challenges in the quality of herbal medicinal products with a specific focus on contaminants.

BACKGROUND: The complex regulatory framework for the quality of herbal medicinal products, in particular with regard to potential contaminants, consists of legal provisions including Pharmacopoeia requirements, relating to limits as well as in most cases to methods for determination. OBJECTIVE: This review intends to provide an overview on the legal requirements for testing potential contaminants in herbal drugs used for the production of herbal medicinal products. METHODOLOGY: The following issues are described and discussed: For the assessment of pesticide residues, Chapter 2.8.13 of the European Pharmacopoeia and Regulation (EC) 396/2005 applies, for heavy metals the general Pharmacopoeia monograph as well as the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q3D guideline on elemental impurities. The Pharmacopoeia also includes limits and acceptance criteria for microbiological purity and aflatoxins, respectively. Polycyclic aromatic hydrocarbons are mentioned in Regulation (EC) 1881/2006 for food as well as in a Reflection Paper on herbal medicinal products. For several years, a potential contamination with pyrrolizidine alkaloids was discussed which led to measures being imposed on industry and health authorities. RESULTS: Various examples demonstrate that the evaluation of data from daily analytical practice is extremely useful to gain an overview on the occurrence of residues and/or contaminants in herbal drugs and herbal preparations. Such evaluations might assist manufacturers in their individual risk assessment and the definition of their testing strategies and contribute to guarantee the quality and safety of the marketed products. CONCLUSION: Annual data evaluations demonstrate that a remarkable decrease of the pyrrolizidine alkaloid content burden in herbal drugs and extracts used for the production of herbal medicinal products has been achieved over the past few years. However, it has also become clear that this issue cannot be completely solved in the near future.

Pyrrolizidine alkaloids in food and phytomedicine: Occurrence, exposure, toxicity, mechanisms, and risk assessment - A review.

Among naturally occurring plant constituents, the 1,2-unsaturated pyrrolizidine alkaloids (in the following termed 'PAs') play a distinct role because of the large number of congeners occurring in nature and the pronounced toxicity of some congeners. Several PAs are hepatotoxic in humans, experimental and farm animals and were shown to be potent hepatocarcinogens in laboratory rodents. Although the general mode of action leading to toxicity has been elucidated, i.e., being mediated by metabolic conversion of the parent molecule into a highly reactive electrophile capable of attacking cellular target molecules, major questions related to the risk assessment of PAs remain unresolved. It was the aim of a workshop held in September 2018 to shed more light on the occurrence, exposure, mode of action, toxicokinetics and -dynamics of PAs to improve the scientific basis for an advanced toxicological risk assessment. The contributions in nine chapters describe the scientific progress using advanced analytical methods, studies in subcellular fractions, cell culture, experimental animals and humans and the use of PBPK modeling and structure-activity relationship considerations aiming at a better understanding of PA toxicity and genotoxicity. Since PAs differ considerably in their toxic potencies and substantial species differences in sensitivity towards PA exposure exist, a special emphasis was placed on these issues.

Review: Quality of herbal medicinal products: State of the art of purity assessment.

BACKGROUND: The European Pharmacopoeia as well as further legal provisions contain rules for the assessment of potential residues and contaminants in herbal substances and preparations used for the production of herbal medicinal products, e.g. for the assessment of pesticide residues, heavy metals and other elemental impurities, mycotoxins and microorganisms. As a potential contamination caused by weeds, the occurrence of pyrrolizidine alkaloids is being discussed for several years which lead to measures of health authorities limiting the PA content in herbal medicinal products and to measures of industry consisting of reducing the probability of PA occurrence in medicinal plants and the respective products. CONCLUSION: In this context and with regard to all kinds of potential residues or contaminants, collection and evaluation of data from daily analytical practice of manufacturers and suppliers is useful for the assessment of the situation and the definition of testing strategies.

Pyrrolizidine alkaloid contamination in herbal medicinal products: Limits and occurrence.

Since 2013, a potential contamination of medicinal plant material with pyrrolizidine alkaloid-containing weeds e.g. Senecio has been discussed. The knowledge about such a risk of contamination induced suppliers of medicinal drugs and manufacturers of medicinal teas to investigate the situation regarding herbal drugs and teas and other medicinal products of plant origin. As due to worldwide cultivation/collection and season-dependent sourcing processes an immediate elimination or even reduction of PA contamination at all sourcing sites was considered impossible, manufacturers have taken action by application of their Code of Practice, by monitoring pyrrolizidine alkaloid contamination and by collection of data, by elimination of peak exposures as well as by participation in research projects. The Herbal Medicinal Products Committee at the European Medicines Agency recommended a transitional limit of 1.0 µg pyrrolizidine alkaloids per day related to the final product for three years which has recently been prolonged by a further two years. Against the background of the assessment of the European Food Safety Authority, the option of establishing a permanent limit of 1.0 µg per day should be taken into consideration during future discussions.

Ethanol in herbal medicinal products for children : Data from pediatric studies and pharmacovigilance programs.

Herbal medicinal products are indispensable in children, e. g., in functional gastrointestinal diseases and coughs and colds, especially when available in liquid dosing forms for which dosing can be adapted ideally to different age groups. Despite being generally accepted as safe, the ethanol content of many of these products, necessary for Galenic reasons, has raised questions regarding their safety. Therefore, safety data from more than 50,000 children in noninterventional pediatric studies with these products, as well as data from routine clinical use in several million children, were assessed. No evidence of the involvement of the ethanol content in any adverse drug reactions was found. This allows us to conclude that these herbal medicinal products are safe in the age groups for which they are authorized or registered and that the present labeling is adequate to allow for their safe use in the pediatric population.

Assessment of genotoxicity of herbal medicinal products: application of the "bracketing and matrixing" concept using the example of Valerianae radix (valerian root).

An assessment of genotoxicity is a precondition for marketing authorization respectively registration of herbal medicinal products (HMPs), as well as for inclusion into the 'Community list of herbal substances, preparations and combinations thereof for use in traditional herbal medicinal products' established by the European Commission in accordance with Directive 2001/83/EC as amended, and based on proposals from the Committee on Herbal Medicinal Products (HMPC). In the 'Guideline on the assessment of genotoxicity of herbal substances/preparations' (EMEA/HMPC/107079/2007) HMPC has described a stepwise approach for genotoxicity testing, according to which the Ames test is a sufficient base for the assessment of genotoxicity in case of an unequivocally negative result. For reducing efforts for testing of individual herbal substances/preparations, HMPC has also developed the 'guideline on selection of test materials for genotoxicity testing for traditional herbal medicinal products/herbal medicinal products' (EMEA/HMPC/67644/2009) with the aim to allow testing of a standard range of test materials which could be considered representative of the commonly used preparations from a specific herbal drug according to a 'bracketing/matrixing' approach. The purpose of this paper is to provide data on the practical application of this bracketing and matrixing concept using the example of Valerianae radix, with the intention of facilitating its inclusion in the "Community list". Five extraction solvents, representing the extremes of the polarity range and including also mid-range extraction solvents, were used, covering the entire spectrum of phytochemical constituents of Valerianae radix, thereby including polar and non-polar constituents. Extracts were tested in the Ames test according to all relevant guidelines. Results were unequivocally negative for all extracts. A review of the literature showed that this result is in accordance with the available data, thus demonstrating the lack of a genotoxic potential. In conclusion the two guidelines on genotoxicity provide a practically applicable concept. Valerianae radix has no genotoxic potential, supporting its use in HMPs and its inclusion in the Community list.

Current perspectives on herb-drug interactions in the European regulatory landscape.

Herb-drug interactions have turned out not to be a major issue in the European regulatory landscape. For a minority of herbal preparations, herb-drug interactions are clinically relevant, e.g., between high-dose St.John's wort extracts and a number of chemical substances. The inclusion of adequate information on such interactions into the package leaflet is important for the safe use of the products. Information on potential interactions is also part of the official HMPC monographs. However, only for some herbal preparations described in these monographs, such a potential is known. Thus, in accordance with the relevant European guidance documents, potential interactions should be assessed critically for their clinical relevance, and a balanced assessment is required when regulatory documents are established or regulatory measures are implemented.

Assessment of genotoxicity of herbal medicinal products: a co-ordinated approach.

The submission of data on genotoxicity is a precondition for marketing authorisation respectively registration of herbal medicinal products (HMPs) with well established or traditional use in some countries. In European regulatory guidelines prepared by the Committee on Herbal Medicinal Products (HMPC) of the European drug regulatory agency EMA, a test strategy is defined giving a pragmatic framework adapted to the assessment of the potential genotoxicity of HMPs. It describes a stepwise approach, including the possibility to reduce the number of extracts of a herbal drug to be tested by the use of a bracketing and matrixing approach. According to this strategy, Kooperation Phytopharmaka, a scientific society in the field of HMPs, has so far coordinated the conduction of genotoxicity tests for 30 herbal drugs within the frame of a joint project of several manufacturers of HMPs. Results are delivered to the cooperation partners for use in regulatory applications.

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