by Giuliana Miglierini
Business based on medicinal products containing cannabis-derived substances has greatly developed in Europe in recent years, due to the many beneficial pharmacological properties offered by the plant Cannabis sativa. The global medical cannabis market is rapidly expanding (36% compound annual growth rate/CAGR 2017-2024), with Germany as the leading country (49,5% CAGR).
The medical use of cannabis in Europe refers to the EU Parliament’s resolution 2018/2775 of 13 February 2019, aimed to clearly and unambiguously distinguish between “medical cannabis” and “cannabis-based medicines”. The second ones have undergone clinical trials as all medicinal products and have been assessed by competent regulatory authorities to achieve approval. Only cannabis-based medicinal products should be considered for a safe and controlled medical use, suggests the Parliament resolution.
According to an article by Lipnik-Štangelj and Razinger (Arh Hig Rada Toksikol 2020;71:12-18), just one medicine characterised by a 10% concentration of cannabidiol (CBD, one of the main active components of cannabis) was centrally approved in 2019 by EMA for the therapy of intractable childhood epilepsy. Other medicinal products containing other types of cannabinoids have received approval through mutual recognition procedure or at the national level.
EU’s member states have not yet adopted a uniform approach on how to regulate the cultivation, manufacturing and use of medical cannabis; there is also a lack of uniform indications as for the modalities and contents of the labelling of cannabis-derived medicinal products. An extensive discussion of different legislative and regulatory frameworks relevant to the medical use of cannabis and cannabinoids have been addressed by a report published in 2018 by the European Monitoring Centre for Drugs and Drug Addiction.
The German approach
One of the first European countries to invest in medical cannabis has been Germany, where cultivation is allowed exclusively for medical purposes. A targeted Cannabis Agency (Cannabisagentur) was created in 2017 as a part of the local regulatory agency German Federal Institute for Drugs and Medical Devices (BfArM), in parallel with the coming into force of the Cannabis as Medicine Act.
The Agency has selected by a tender procedure three companies allowed to cultivate cannabis in Germany (Aphria RX GmbH, Aurora Produktions GmbH and Demecan GmbH), for a total production of approx. 2600 kg per year. BfArM started in July 2021 the state sale of medical cannabis from German cultivation, maintaining also open the possibility to import the plant for medical use.
The characteristics of the standardised cannabis extracts are described in a dedicated monograph of the German Pharmacopeia; the cultivation of the plant and the manufacturing of medical cannabis, which is a prescription drug, is also subject to the German narcotics law regulations (BtMG), to Good Agricultural and Collection Practices (GACP) and to Good Manufacturing Practices (GMP). German pharmacies can buy medical cannabis directly from the dedicated portal of the Cannabis Agency; a GMP/GDP-certified company is in charg of distribution. The price established by BfArM for pharmacies is 4,30 €/g.
The case in Greece
Greece also approved in 2018 a specific legislation on cannabis for medical use (Law 4523/2018, amending Law 4139/2013), providing the full reference framework for the cultivation, manufacturing, regulatory approval and distribution of cannabis-based medicinal products.
According to data by the Greek Ministries of Development and Investments and Rural Development and Food published in April 2020 by the Medical Cannabis Network, estimates of investments in the sector are reaching €1,68 billion and more than 8.000 employees.
The government aims to improve the attractiveness of Greece for cannabis cultivation and instalment of manufacturing plants – thanks to the favourable climatological and working conditions – as a way to support the expansion of the national economy. To this regard, possible competitors are Portugal, Malta or Cyprus, all countries characterised by similar favourable conditions.
Greece currently allows for the cultivation of cannabis with a THC content not exceeding 0,2%. A new law has passed in the Greek Parliament to regulate the production, export and distribution of final medical cannabis products with a THC content of more than 0,2%.
The new law is expected to create a special framework for cannabis businesses based in Greece and devoted to export only; their activities may be also subject to laws, regulations and GMP/GDP guidelines of the importing country.
Companies interested in establishing this sort of productions currently need to fulfil a wide set of conditions in order to receive permits for cultivation and authorisation by the Greek National Organisation for Medicines (EOF) to produce and market their products, which are classified as medicines. Criteria for authorisation are listed in the joint Ministerial Decision released in connection to the 2018 Law. The issuing of the permit by Greek authorities usually needs about three months time.
The common licence level allows for the initial establishment of a new manufacturing facility; the majority of companies which applied so far have received this type of licence (57/100). The second level of the licence refers to the authorisation to operation.
According to the experts interviewed by Medical Cannabis Network, current issues still to be solved include “establishing a clear definition of the type of greenhouses needed for a particular crop and the specific type of finished medicinal products that will eventually be allowed to circulate commercially”.
Malta, the QP for cannabis medicine production needs to be a pharmacist
Malta has issued in 2018 the Production of Cannabis for Medicinal and Research Purposes Act, the law governing the sector of medical cannabis for prescription.
The document provides detailed information on Quality & Stability of cannabis-based medical products (Appendix I), Security & Transportation (Appendix II) and Cultivation, Harvesting & Packaging (Appendix III).
Malta’s Medicines Authority is responsible for the evaluation of the technical and scientific documentation submitted by the applying companies, and for the issuing of the authorisations for import and wholesale distribution of cannabis-based products for medicinal use. Only finished products are allowed, they must also comply to the relevant legislation of the destination country.
The Maltese framework for the production of medical cannabis is characterised by the fact the Qualified Person (QP) responsible for the manufacturing plant has to be engaged by the license holder and must be a pharmacist registered with the Maltese Pharmacy Council and resident in Malta. This provision differs from the requirements outlined in Directive 2001/83/EC governing the manufacture and import of medicinal products for human use, transposed into the local Medicines Act and subsidiary legislation, where many other types of degrees (Pharmacy, Medicine, Veterinary, Chemistry, Pharmaceutical Chemistry and Technology, or Biology) are also considered.
Medical cannabis products licensed under the Medicines Act (Chapter 458 of the Laws of Malta) or manufactured under GMP can be sourced by licensed importers or wholesale distributors, provided the possession of the necessary approvals and permits. A Letter of Intent (LOI) from a Malta Enterprise is also needed to run operations related to medicinal cannabis production, analysis and research. The local regulatory agency can run inspections of the manufacturing facilities to verify their compliance to GxP; EU-GMP certification is needed prior to the starting of the manufacturing activities.
Research activities on medical cannabis is also supported through the Advanced Scientific Initiatives Directorate, in particular in the case of established organisations for scientific collaboration.
A pool of beneficial active ingredients
The plant Cannabis sativa contains a very rich pool of more than 480 compounds, among which are more than 100 cannabinoids. D9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the main cannabinoid substances present in cannabis, the first one representing the main psychoactive and addictive constituent of the plant. On the other hand, CBD has no intoxicating or addictive properties. Many other cannabinoids possess an interesting pharmacological and therapeutic profile, and have been studied for possible use as neuroprotective agents (e.g. in case of anxiety disorders, depression, post-traumatic stress disorder), and for their effects as anti-emetics or on chronic pain (e.g. in cancer disease), inflammation, bacterial infections, etc.