What are the GMP Requirements for Herbal Medicinal Products?

Like all other medicinal products, herbal medicinal products (HMPs) are subject to strict pharmaceutical regulations and therefore to GMP (Good Manufacturing Practice) requirements. In Germany, for example, the application of GMP is laid down in the Medicinal Products and Active Substances Manufacturing Ordinance (Arzneimittel- und Wirkstoffherstellungsverordnung - AMWHV). At European level, requirements are defined in the EU GMP guidelines (EudraLex Volume 4). Annex 7 of the EU GMP guidelines (Manufacture of Herbal Medicinal Products) provides detailed explanations of the GMP requirements for HMPs. These are supplemented by the GACP guidelines on good agricultural and collection practices.

Quality of Herbal Medicinal Products (HMPs)

The quality of a herbal medicinal product depends on numerous factors, such as cultivation, extraction process, and manufacture of the finished medicinal product including packaging, storage, and transport. These processes (as well as analytical and cleaning procedures) must be validated to ensure consistent product quality. The GACP rules therefore already place high standards on the seed quality, cultivation, collection, and harvesting, as well as, where applicable, the initial processing steps, such as sorting / cutting. Drying and further manufacturing steps usually fall under GMP. More detailed information on which manufacturing steps fall under GACP or GMP can be found in EU GMP Annex 7 (Manufacture of herbal medicinal products). In addition, the EMA has published a document with questions and answers on GMP for herbal extracts used as active pharmaceutical ingredients (APIs). According to this document, reference should be made to the table in Annex 7 of the EU GMP guidelines, which outlines the application of GACP and GMP. Amongst others, it states that the initial extraction steps in the manufacture of plant extracts used as active substances should be carried out in accordance with the requirements of EU GMP Part II (GMP for active substances) (see Questions and answers on GMP requirements applicable to the early manufacturing steps for comminuted plants and herbal extracts used as active substances).

Specifications for ensuring quality across all stages of manufacture, i.e., from the herbal substance and the extract (active pharmaceutical ingredient, API) to the finished product, must be available and complied with (see also Guideline on specifications: test procedures and acceptance criteria for herbal substances, herbal preparations, and herbal medicinal products). These usually include requirements for identity, purity (e.g., foreign matter, loss on drying, ash), and active ingredient content. Special attention is paid to contaminants such as heavy metals ("elemental impurities"), pesticide residues, mycotoxins (e.g., aflatoxins and ochratoxins), pyrrolizidine alkaloids (PAs), and microbial contaminants (see also Reflection paper on microbiological aspects of herbal medicinal products and traditional herbal medicinal products and the draft USP Chapter <1120> Ensuring Microbiological Quality of Articles of Botanical Origin). In addition, dosage form-specific tests, stability studies, and in-use studies are performed. According to the EU GMP guidelines (Chapter 6, Quality Control), the manufacturer must have an ongoing stability testing program to ensure the shelf-life of a product. The program must comply with the requirements of ICH Q1 (Stability) (see also Reflection paper on stability testing of herbal medicinal products and traditional herbal medicinal products).

Decontamination

There are various methods for reducing microorganisms in plant materials, such as fumigation with ethylene oxide, treatment with ozone, or irradiation. However, the European Medicines Agency (EMA) "Reflection Paper on Microbiological Aspects of Herbal Medicinal Products and Traditional Herbal Medicinal Products" emphasizes that decontamination treatment must not be used as a substitute for GACP or GMP. Furthermore, it must be demonstrated that the components of the herbal material are not adversely affected by the treatment and that no harmful residues remain.

The use of ethylene oxide, for example, leads to a significant reduction in microbial contamination ("bioburden"). However, the treatment of plant material with ethylene oxide is prohibited in the European Union (EU) due to genotoxicity, hazards to workers, and the formation of toxic reaction products.

In the US, the use of ethylene oxide, methyl bromide, or propylene oxide as fumigants for herbal dietary supplements is not permitted. Under certain conditions, however, the use of such fumigants is permitted for selected herbs and spices. The U.S. Environmental Protection Agency (EPA) has therefore established tolerance levels for residues of ethylene oxide and the reaction product 2-chloroethanol for certain herbs and spices.

Pharmacopoeias and Monographs

The competent national and international authorities (e.g., the European Medicines Agency (EMA) or the U.S. Food and Drug Administration (FDA)) base their approval and registration of herbal medicinal products on compendial monographs, among other things. A pharmacopoeia is an official set of rules. It specifies the binding quality standards that medicinal products must meet in order to be considered safe and effective.

The monographs of the pharmacopoeias (e.g., German Pharmacopoeia (DAB), Swiss Pharmacopoeia (Ph. Helv.), European Pharmacopoeia (Ph. Eur.), United States Pharmacopeia (USP)) contain general specifications for the quality of herbal drugs (Ph. Eur.: "Herbal Drugs"; USP: "Articles of Botanical Origin") and preparations made from herbal drugs ("Herbal Drug Preparations," e.g., extracts), as well as for dosage forms (e.g., tablets, ointments, syrups) and packaging materials (e.g., glass, plastics, etc.). Also, there are individual monographs for specific herbal drugs (e.g., Cannabis flower, St. John's wort, etc.) and preparations made from herbal drugs (e.g., Chamomile fluid extract).

Pharmacopoeias often contain information on reference substances (Herbal Reference Standards - HRS), as well. In 2008, the EMA's Committee on Herbal Medicinal Products (HMPC) published a Reflection paper on markers used for quantitative and qualitative analysis of Herbal Medicinal Products and traditional Herbal Medicinal Products, and in 2012 a Concept paper on non-pharmacopoeial reference standards for herbal substances, herbal preparations and herbal medicinal products / traditional herbal medicinal products.

Useful Links

• Quality of Herbal Drugs - What's new? - GMP Journal, issue 44
• EudraLex Volume 4 (EU GMP)
• Good agricultural and collection practice (GACP) for starting materials of herbal origin
• The European Medicines Agency's scientific guidelines on herbal medicinal products.
• EMA's Questions and answers on quality of herbal medicinal products/traditional herbal medicinal products.
• US Food and Drug Administration. 21 CFR §111: Current good manufacturing practice in manufacturing, packaging, labeling, or holding operations for dietary supplements; final rule. Federal Register. 2007;72(121):34752-34958.