What are the GMP Requirements for Medical Cannabis?

Medical cannabis, like all other medicinal products, is subject to strict pharmaceutical regulations, and thereby to GMP (Good Manufacturing Practice) requirements. In Germany, the application of GMP is laid down in the Medicinal Products and Active Substances Manufacturing Ordinance (AMWHV), while the EU GMP Guidelines set specifications at a European level. Annex 7 of the EU GMP Guidelines (Manufacture of Herbal Medicinal Products) offers detailed information on GMP requirements for herbal medicinal products. In addition, there are the GACP guidelines on good agricultural and collection practices.

The EU GMP inspectorates, in turn, are responsible for issuing manufacturing and import authorisations (MIA) or EU GMP certificates. They carry out inspections at the sites of manufacturers who apply for these certificates and authorisations. The starting point for a German GMP certificate, for example, is a company based in Germany that applies for such a certificate with the relevant local authority.

What is "Medical-grade Cannabis"?

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. In the case of cannabis, trimming and curing also play an important role.

The GACP rules already place high standards on seed quality, cultivation, collection and harvesting, and in some cases on the initial processing steps such as sorting and cutting. Drying and further manufacturing steps usually fall under GMP.

The latest revision of the GACP guidelines also includes clearer specifications on when activities fall under GACP, GMP Part II (active ingredients) or GMP Part I (finished medicinal products). In general, the closer the preparation is to the final product, the stricter the requirements. For indoor cultivation, for example, critical quality characteristics and process parameters must be defined, with a standardised cultivation process and qualified equipment. In addition, all actors in the supply chain (e.g. growers, harvesters, collectors, producers, wholesalers, processors of medicinal plants and herbal substances) must maintain proper batch documentation and quality systems and require the same from their partners.

Detailed information on which manufacturing steps fall under GACP or GMP is provided in EU GMP Annex 7 (Manufacture of Herbal Medicinal Products). Additionally, the EMA has published a document with questions and answers on GMP for herbal extracts used as active pharmaceutical ingredients (APIs) (see Questions and answers on GMP requirements applicable to the early manufacturing steps for comminuted plants and herbal extracts used as active substances).

According to the EU GMP guidelines (Chapter 6, Quality Control), the manufacturer must also have an ongoing stability program in place to ensure the shelf-life of a product. The program must comply with the requirements of ICH Q1 (Stability) (see also Stability testing for medical cannabis - what needs to be considered?).

Decontamination

There are various methods for reducing microorganisms in plant materials, such as fumigation with ethylene oxide, treatment with ozone or irradiation. However, the treatment of plant material with ethylene oxide is prohibited in the European Union (EU) due to genotoxicity, risks to workers and the formation of toxic reaction products. The European Medicines Agency (EMA) "Reflection Paper on Microbiological Aspects of Herbal Medicinal Products and Traditional Herbal Medicinal Products" also emphasises that decontamination treatment must not be used as a substitute for GACP or GMP.

Cannabis flowers are often irradiated to meet the high microbial quality requirements for inhalation use. In Germany, for example, an application for irradiation approval must be submitted in accordance with AMRadV (Verordnung über radioaktive oder mit ionisierenden Strahlen behandelte Arzneimittel - "Regulation on Radioactive or Ionising Radiation-Treated Medicinal Products"). The irradiating company must have a valid GMP certificate. The microbial load ('bioburden') at which irradiation is carried out should be specified and the irradiation process must be validated. In addition, it must be demonstrated that the components of the plant material are not adversely affected by the treatment, and that no harmful residues remain.

Pharmacopoeias and Monographs

Monographs for cannabis flowers and cannabidiol (CBD) have now been published and implemented in the European Pharmacopoeia (Ph. Eur.). The Ph. Eur. CBD monograph applies to the substance isolated from the Cannabis sativa L. plant. In Germany, there is also a monograph for cannabis extracts (Deutsches Arzneibuch (DAB) monograph) and the CBD monograph of the German Drug Codex (DAC - Deutscher Arzneimittel Codex) for synthetic CBD. In addition, other countries such as the USA have their own quality standards for cannabis flowers and CBD (USP CBD monograph (currently still in draft form) and the USP Herbal Medicines Compendium (HMC) monograph on inflorescences of cannabis species ('Cannabis Species Inflorescence Monograph'). However, these standards are often not harmonised, particularly between the EU and the USA, for example with regard to specifications for impurities.

The pharmacopoeia monographs usually contain requirements regarding identity, purity (e.g. foreign matter, loss on drying (LOD), ash) and active ingredient content. Particular 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 (specifications depending on the dosage form / route of administration, e.g. stricter requirements for inhalation use). The pharmacopoeias (e.g. European Pharmacopoeia (Ph. Eur.), United States Pharmacopeia (USP)) also contain general monographs on 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 dosage forms (e.g. tablets, ointments, syrups) and packaging materials (e.g. glass, plastics, etc.).

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
• Medical Cannabis - How to get GMP-ready? GMP Journal, Issue 27