Medical Cannabis - How to get GMP-ready?
An increasing number of countries legalize cannabis for medicinal purposes. New Zealand1, Belgium2 and France, for example, are currently discussing to follow Germany, where cannabis for medicinal use was legalized in 2017.3
Marihuana has been legalized in 34 states of the USA for medical and / or recreational use (11 states), but not by federal law. In addition to the previously legalized Marihuana (for medical and recreational use), Canada proposed a new "Edibles" regulation for edible cannabis products and topicals.
France recently published a proposed framework together with a dossier for implementing a French medical cannabis pilot programme which is based on the recommendations of the French Comité scientifique spécialisé temporaire (CSST).4 The main objective of this programme is to evaluate cannabis prescription and dosage and to assess its acceptance among health care professionals and patients. In addition, safety and efficacy data for medical cannabis will be collected. The two-year pilot programme is expected to start in the second half of 2020. Thus, medical cannabis will not be legalized in France prior to the end of 2022.
In addition, Health Canada (HC) published a proposed regulatory approach for a new class of cannabis products referred to as Cannabis Health Products (CHPs) which would not require practitioner oversight.5 According to HC, there is a growing interest in potential therapeutic use of cannabis for minor ailments. Moreover, cannabis products with unauthorized health claims are emerging on the Canadian market illegally. Examples are cannabidiol (CBD) products, i.e. products containing no more than 10 ppm tetrahydrocannabinol (THC). Interest in these CBD products has also increased in the Unites States since the U.S. Congress passed the Agriculture Improvement Act of 2018 (the 2018 Farm Bill) in December 20186. Among other things, this law established a new category of legal cannabis classified as "hemp" - defined as cannabis and cannabis derivatives with no more than 0.3 percent of THC (on a dry weight basis concentration). In France, it is prohibited to distribute CBD-Products if they contain any traces of THC and/or if they derived from not-authorized varieties and/or parts of plants7. Manufacturers and distributers of CBD-Products are not allowed to claim any therapeutic use/eff ect.
Heidelberg, Germany18/19 June 2024
GMP and Quality Requirements for Radiopharmaceuticals
However, the FDA approved the medicinal cannabis product Epidyolex and the EMA followed last year and authorized Epidyolex for the treatment of rare forms of childhood epilepsy. Epidyolex contains high-purity cannabidiol (CBD) as the active ingredient. It is the fi rst CBD product to receive a positive decision in the centralized EU approval procedure.
Following these global developments, there will be a growing need for producers to supply chemists, physicians and patients with the newly legalized drug.
What qualifies as "medical grade Cannabis"?
Several European countries published pharmacopoeial Monographs for Cannabis flowers (e.g. the German DAB Monograph8, the DK Monograph9) and extracts (the German Draft DAB Monograph10). In addition, other countries like, for example, New Zealand (NZ) and the U.S., have their own quality standards (NZ Product Quality Standards Monograph1; American Herbal Pharmacopoeia: Cannabis Inflorescence and Leaf (2013)). However, these standards are currently not harmonized - neither between the EU member states nor between the EU and/or Canada, the U.S., NZ, etc.
In Europe, these products must comply with the relevant requirements laid down under Medicinal Law (including Pharmacopoeias, EU-GMP/GDP and GACP) and the Narcotics Law. In Germany, for example, the BfArM (the Federal Institute for Drugs and Medical Devices) has taken over new responsibilities by establishing the Cannabis Agency. The goal of this agency is to contribute to ensuring the supply of medical-quality cannabis. Cannabis is not meant to be stored directly at BfArM during any stage of the purchasing, harvesting or distribution process. These steps will be carried out by relevant producers or other commissioned companies (i.e. suppliers, importers). Hence, the agency will only manage and monitor the cultivation, harvest, processing, quality assurance, storage, packaging and distribution of cannabis to wholesalers, chemists or manufacturers.
The EU GMP inspectorates are responsible for issuing manufacturing and import licenses or EU GMP Certificates. Thus, they will perform inspections at the production sites of manufacturers who apply for these certificates and licenses. For example, the starting point for any German GMP certification is a German-based company that applies for such certificate at their local responsible authority.11
Many questions remain
Some of the questions which are currently intensely discussed in relation to medical cannabis are:
- When does GACP (Good Agricultural and Collection Practice12) end and EU GMP (Good Manufacturing Practice13) start?
- Growing: What are the requirements regarding soil, light, irrigation, facilities etc.?
- Harvest: Which steps fall under "harvest" - e.g. cutting, trimming, and washing?
- Post Harvest: Is the EU/GMP certificate required only for "drying to packaging" operations, or for the full production cycle ("growth to packaging")?
- What are the requirements relating to physical security measures?
- What has to be considered in regard of EU-GDP (Good Distribution Practice14)?
- How to get a MA-(Manufacturing Authorization), Import License? How to get an EU-GMP Certificate?
- What are the requirements of the (German) Narcotics Law and/or the Single Narcotic Convention15?
- What are the quality requirements for Cannabis Flowers and Extracts? Are there any special requirements for extraction solvents used in the production of cannabis extracts?
- What are the differences between the various pharmacopoeial monographs and quality standards (e.g. regarding Pesticides, Heavy Metals, Microbial Contamination and Mycotoxins)?
- Equipment / Manufacturing: What has to be considered in relation to qualification and validation?
- Which type of Decontamination method could be used/is allowed? In contrast to the US situation, the use of ethylenoxide for herbal drugs is prohibited in the EU, for example.
- What are the stability requirements? Which aspects have to be considered for analytical labs?
- What are the gaps between GPP (Good Production Practices1,16) and EU-GMP?
- What will be checked during EU-GMP-inspections?
EU-GMP vs. GPP
Since there is currently no harmonized legislation globally and/or in the EU (e.g. regarding pharmacopoeias etc.), some of the topics listed above are very relevant for EU as well as non-EU growers/ suppliers and ex -/importers.
For example, the EU-GMP guidelines include principal requirements for
- The Pharmaceutical Quality System (PQS),
- Premises and Equipment (including Qualification),
- Documentation (including Records and Data Integrity),
- Validation (including Manufacturing, Computer System, and Analytical Validation),
- Quality Control (including Stability Programme),
- QP Batch Release,
- Outsourced Activities (including Audits),
- Complaints and Product Recall, and
- Self Inspection.
In addition, the EU-GMP of Annex 7 - Manufacture of Herbal Medicinal Products provides guidance for the application of GACP.
GACP gives appropriate guidance and defines basic rules which can be adapted to specific conditions. The Principle of GACP is different to highly regulated GMP; levels and requirements for GACP need to be defined on a case-by-case basis. According to Annex 7 for primary steps that take place in the field the standards of GACP is applicable. GMP is applicable to further cutting and drying steps. In Canada, for example, GPP (Good Production Practices) for cultivation of medicinal cannabis have to be applied.16, 17 So far, the GPP framework regulates the cultivation and processing of all cannabis products for both medicinal and recreational use. The major components of GPP concern facilities and equipment, sanitation, quality assurance, quality control, record keeping, and security requirements.18
According to reference 1, there are a number of areas where the two standards EU-GMP and GPP do not align. The EU-GMP guidelines "are more detailed, providing principles and interpretation" on what must be included in a PQS to comply, "while the GPP standard provides less detail and is therefore more open to interpretation. This difference makes it difficult to directly compare the two standards". For example, stability testing is not required under GPP. Under EUGMP, the stability programme designed in accordance with the ICH Q1 Guidelines is required to establish the shelf life of a product. In addition, EU-GMP requires full validation as part of the PQS, while this is currently not required under GPP1.
Since there are some substantial differences (which still have to be identified in detail) between GPP and EU-GMP, non-EU suppliers will have to implement EU-GMP standards if they want to supply medical cannabis to the EU market. However, since there is currently no harmonized EU standard for medical cannabis (e.g. Ph. Eur. monograph), national legislations, guidelines and monographs will have to be followed and applied in addition to EU-GMP.
ECA Cannabis Working GroupTo move forward in developing a harmonized "GMP" standard for medical cannabis, the ECA (European Compliance Academy) is currently establishing a working group which will start to work on an overview of currently available Guidelines etc. from all around the world. The group will then further work on a "white paper" or some kind of framework to support the development of a harmonized standard on a global level to show and work on closing the gaps currently existing between the different regional approaches and regulations.
Dr Andrea Kuehn-Hebecker
... is Operations Director and organises and conducts courses and conferences on behalf of the ECA Academy in the area packaging, development and Lifecycle Management.
4 Cannabis à visée thérapeutique: Projet d'expérimentation (https://ansm.sante.fr/S-informer/Points-d-information-Points-d-information/Cannabis-a-visee-therapeutique-en-France-LANSM-publie-la-proposition-du-Comite-d-experts-sur-le-cadre-de-la-phase-experimentale-de-mise-a-disposition-Point-d-Information).
5 Consultation on Potential Market for Cannabis Health Products that would not Require Practitioner Oversight (https://www.canada.ca/en/health-canada/programs/consultationpotential-market-cannabis/document.html)
7 Mildeca: https://www.drogues.gouv.fr/actualites/cannabidiol-cbd-point-legislation
8 DAB (Deutsches Arzneibuch, German Pharmacopoeia) Monograph "Cannabisblüten (Cannabis flos)", BAnz AT 12.05.2017 B7 / BAnz AT 24.04.2018 B5
9 Monograph (Danish Pharmacopoeia), Dansk monografi "Cannabisblomst (Cannabis flos)", Produktformer for medicinsk cannabis, Journalnummer: Sundheds- og Ældremin., Lægemiddelstyrelsen, j.nr. 2019021125.
10 Draft DAB (Deutsches Arzneibuch, German Pharmacopoeia) Monograph "Eingestellter Cannabis-Extrakt (Cannabis extractum normatum)", BAnz AT 06.05.2019 B6
11 GMP certification and GMP certificate in Europe - an overview (https://www.concept-heidelberg.com/service/gmp-certification-europe.html)
12 Good agricultural and collection practice for starting materials of herbal origin (https://www.ema.europa.eu/en/good-agricultural-collection-practice-starting-materials-herbal-origin)
13 EudraLex - Volume 4 - Good Manufacturing Practice (GMP) guidelines (https://ec.europa.eu/health/documents/eudralex/vol-4_en)
14 Good Distribution Practice of medicinal products & active substances for medicinal products for human use (https://ec.europa.eu/health/documents/eudralex/vol-4_en)
15 United Nations Single Convention on Narcotic Drugs of 1961
16 Good Production Practices Guide for Cannabis - Requirements under Part 5 of the Cannabis Regulations (ISBN: 978-0-660-25850-8), 2019