The Maze Of Regulatory Requirements For Cannabis Medicinal Products In Europe – An Impression Of Scattered Regionalism, Associated With Risks For Patients

By Prof. Dr. Markus Veit, Managing Director, Alphatopics GmbH

IN the absence of existing national or European requirements, the regionally competent authorities in our federally organised drug surveillance system define somewhat arbitrarily which requirements for medicinal cannabis are to be valid in their respective jurisdiction. The resulting requirements are by no means consistent and, in my opinion, they cannot always be deduced from the existing legal provisions.

In the EU concepts have been elaborated for herbal medicinal products as to from when production should be carried out under GMP (in demarcation to GACP) and which processing steps should be carried out under GMP Part II or GMP Part I, respectively. Such a concept for instance exists for the manufacture of medicinal teas; it has been successfully practised in the EU for many years and is recognised by the authorities. Here, the collection of the herbal starting material as well as the initial drying and coarse comminution are conducted under GACP. The production of the actual herbal preparation, the fine cutting and homogenisation are carried out according to GMP Part II and its packaging and labelling according to GMP Part I. Such a concept could easily be transferred to purified cannabis flowers and would look as follows:

The cultivation and the first processing steps of the herbal starting material are carried out under GACP until drying. Starting with the drying process, the production of the active ingredients (preparations, e.g., extracts) is carried out under EU GMP Part II. The third stage of the value chain, the production of a medicinal product, is carried out under EU GMP Part I or – in the case of cannabis prescription and magistral medicinal products – according to the requirements set by the German ApBetrO (Ordinance on the Operation of Pharmacies). There is no reason why such a concept could not be applied to cannabis medicinal product.

Only individual authorities categorise cannabis flowers as active ingredients or starting materials in analogy to the concepts established for medicinal teas. This categorisation requires that the cannabis flowers are intended for use as medically active constituents in the manufacture of medicinal products or which, through their use in the manufacture of medicinal products, are intended to become medically active constituents of the medicinal products (cf. section 4 para. 19 AMG (German Medicinal Products Act)). This is the case, if the cannabis flowers are used as starting material for prescription medicinal products by pharmacies and essential manufacturing steps are carried out in the pharmacy. If the cannabis flowers are dispensed as they are or just packaged or refilled, their categorisation as active ingredient would be rather far-fetched. In the value chain, in the sense of the definitions provided in the European Pharmacopoeia, the harvested inflorescences would need to be defined as herbal drugs, the trimmed or purified flowers as the herbal preparation, i.e. the active ingredient which will then become a prescription or magistral medicinal product by being subjected to essential manufacturing steps in the pharmacy. The manufacturing steps to be carried out would then for instance consist in testing, milling, batch documentation, weighing, packaging, labelling and release. This is very similar to the manufacture of medicinal teas as prescription or magistral medicinal products, with the exception that it seems appropriate in the case of cannabis flowers to already draw the line between GACP and GMP when drying the flowers or inflorescences. In Germany, the Government of Upper Bavaria as well as the LAVG Brandenburg currently take this position that this categorisation is applicable to medicinal cannabis flowers. In the light of the concepts established for medicinal teas, this position is very comprehensible. Most authorities in Germany and also individual EU Member States, however, consider cannabis flowers and in some cases also preparations such as extracts to be an intermediate (bulk) medicinal product for the preparation of prescription and magistral medicinal products in the pharmacy.

In this concept, too, the cultivation and initial processing steps of the herbal starting material are assessed as being subject to GACP. For cannabis flowers the manufacture of the active ingredient then starts with drying. That means that the processing steps taken to purify the flowers, including the trimming of the flowers, are considered to represent the production of the active ingredient and the following packaging and labelling to be the first steps in the manufacture of the (bulk) medicinal product. As far as herbal preparations are concerned, the view on demarcation between the production of the active ingredient and manufacture of the (bulk) medicinal product is not consistent. In any case a prescription or magistral medicinal product results from the manufacturing steps taken in the pharmacy (e.g. testing, storage, milling, batch documentation, weighing, comminution, measuring, filling, packaging, labelling and release). This perception, however, contradicts the categories established in the EU for the manufacture of herbal medicinal products and hence seems disconcerting. For no other herbal medicinal product is the value chain defined in this form. It is understandable that drying represents a critical manufacturing step in the case of cannabis flowers. Only when dried appropriately will the accumulation structures of the plant not be destroyed and the cannabinoids be protected against oxidative degradation as well as a loss of terpenes by evaporation prevented. The drying method also has a substantial impact on microbiological secondary contamination and germ growth and hence on the potential contamination with mycotoxins, too. Therefore it seems appropriate to establish the line between GACP and GMP Part II prior to drying. That authorities consider bulk packaging for transport to the wholesale trade and pharmacies to already be steps for manufacturing a medicinal product and therefore require manufacture under GMP Part I may be attributed to the fact that they have far better control of the value chain this way, since an import permit and a wholesale licence are required for medicinal products, but not for active ingredients in the EU. Finally, medicinal products require a full EU QP release complying with Annex 16. The GMP certificates to be issued to non-MRA States by EU Member States on the basis of inspections are ultimately used by authorities to bring essential manufacturing steps into the European Single Market, for instance by refusing to include the packaging in the third-country certificate. These different GACP/GMP concepts in Germany, depending on the respective inspectorate, are now additionally flanked by different demands on importers and wholesale traders with respect to quality requirements to be applied to the flowers; this concerns the specification of heavy metals, microbiological limits, the applicability of the DAB monograph, (transport) stability data to be presented as well as “permitted” routes of administration and container sizes. There are no legal provisions (within the scope of GMP monitoring) for a number of these requirements, and in individual cases one gains the impression that the acting GMP inspectors or inspectorates are insufficiently familiar with the particularities of herbal medicinal products. This applies to cannabis extracts to an even greater extent.

As shortly mentioned above, the drying of the harvested cannabis flowers is the most critical step after the harvest. It has a great impact on the secondary bioburden and hence also on the secondary formation of mycotoxins. Since cannabis flowers are not homogenised, a sample that is representative of the batch cannot be obtained. Therefore the microbial contamination analysis using individual samples is never representative of the whole batch; this particularly applies to inappropriately dried flowers, because the danger of mould nest formation is implicit here. In this area of conflict preventive hygiene measures during the cultivation of cannabis play a decisive role in reducing the risk of contamination. For this reason, drying must be carried out under strict quality assurance measures. Based on a process validation, controls need to be established that ensure drying to be conducted completely in all plant structures down to a residual water content at which microbial growth is no longer to be feared. This is the case when the activity of water is below 0.6. Drying also has substantial effects on the (stability of) accumulated cannabinoids and terpenoids as well as the integrity of the accumulation structures. The risk of a change in the cannabinoid profile caused by chemical reactions must be assessed during process validation, too. It must therefore be ensured that the drying conditions are suitable to preserve the accumulation structures of the cannabinoids and terpenoids.

In the absence of specific requirements under pharmaceutical law for use by vaporisation, the authorities sometimes demand compliance with the requirements of the category “inhalation use (special requirements for liquid preparations for nebulisation)” according to Ph. Eur. monograph 5.1.4.. These are the strictest requirements that exist for medicinal products – apart from the parenteral medicinal products to be administered under sterile conditions. This is attributed to the fact that the medicinal products or routes of administration covered by this category are based on aerosols or micronised powders. Due to their direct entry into the respiratory tract and the lungs, such administration is associated with a high risk. However, due to the heat-induced germ reduction, this risk does not exist in this form when vaporising cannabis flowers, so that this requirement is not appropriate. This particularly applies because the strict microbiological requirements for medicinal products to be administered by inhalation can usually only be met by germ reduction by means of treatment with ionising radiation during the collection of the cannabis flowers.

According to Section 7 of the German Medicines Act (AMG) and Section 1 of the Ordinance on Medicinal Products Treated with Radioactive or Ionising Radiation (AMRadV), cannabis flowers treated with ionising radiation can only be marketed in Germany with a corresponding marketing authorisation. The BfArM (Federal Institute for Medicinal Products and Medical Devices) has published a fact sheet on its homepage and established an application procedure. Applications must be submitted by the person placing the product on the market. In the view of some authorities, this leads to the paradoxical situation that each importer has to submit an independent application, even if identical varieties are imported that come from the same producer. An interesting constellation arises in the administrative area of the Government of Upper Bavaria, where cannabis flowers are classified as active ingredients to which the prohibition with reservation of authorisation pursuant to Section 7 (1) AMG does not apply. If one takes this view to its logical conclusion, in such cases it is the pharmacies that place the cannabis flowers treated with ionising radiation on the market as medicinal products for the first time. As a rule, however, they will not hold the authorisation actually required according to the AMRadV.

In doing so, apart from the administrative effort associated with irradiation, the authorities accept the risk that the radiation treatment of the flowers may lead to changes that adversely influence the risk-benefit ratio. In a multi-substance mixture such as cannabis, it is impossible to ultimately exclude radiolysis products to have an influence on efficacy and/or safety and to determine with certainty that the data to be generated in the context of a marketing authorisation are actually representative. The monograph “Pharmaceutical Preparations” of the European Pharmacopoeia states: “In the manufacture/preparation of non-sterile pharmaceutical preparations, appropriate measures are taken to ensure their microbiological quality.” Recommendations in this regard are provided in the General Texts 5.1.4 ‘Microbiological Quality of Non-Sterile Pharmaceutical Preparations and of Substances for Pharmaceutical Use’ and 5.1.8 ‘Microbiological Quality of Herbal Medicinal Products for Oral Use and Extracts Used in their Preparation’. Accordingly, these are by no means binding requirements, but recommendations. It is therefore the responsibility of the manufacturer or party placing the product on the market to set an appropriate specification for cannabis flowers that does not require the flowers to be treated with radiation. The limits provided for category B of Ph. Eur. chapter 5.1.8. seem appropriate for this purpose. However, the risk of contamination with Aspergillus spp. should be taken into account. Inhalation of cannabis contaminated with Aspergillus spp. can have serious effects if the germs are not killed, especially in immunocompromised patients [2]. Even though not provided for in the present draft version, it remains to be hoped that the requirements for the microbiological quality will also be adequately defined in the final version of the monograph for cannabis flowers in the European Pharmacopoeia and that hence adequate handling of this quality attribute can be achieved. In this context It must be emphasised once again that the microbiological quality of cannabis flowers can (and should) be optimised by taking appropriate measures during cultivation, processing and storage, as well as by selecting suitable packaging materials and transport conditions. This is also in agreement with the requirements provided in the “Reflection paper on microbiological aspects of herbal medicinal products and traditional herbal medicinal products” (EMA/HMPC/95714/2013), where the following statement is made: “Minimising contamination with micro-organisms and microbial toxins should be ensured ideally by monitoring and limiting both primary and secondary contamination, i.e. by prevention rather than by use of decontamination methods.“

The lower end of the scale regarding regulatory requirements is formed by practices by which, for financial reasons, these requirements are tried to be circumvented with the acceptance of the authorities. In my opinion these practices are, however, not only inappropriate, but illegal and pose a risk for patients. This particularly applies to the practice of only carrying out the last step of the drying process under GMP and transporting and/or importing only partially dried goods. This is exactly what is apparently happening with flowers imported to Germany without a GMP manufacturing authorisation being available for the manufacturing companies. These flowers are evidently also cultivated under non-controlled hygiene conditions outdoors and/or in greenhouses that cannot be fully controlled. In the light of the risks illustrated above it is accepted in doing so that patients are exposed to substantial risks by the possible contamination with Aspergillus spores and mycotoxins – especially in case of inhalative administration via vaping. The obligation to take appropriate quality-assuring measures in the value chain lies with the manufacturers of medicinal products. In the case of magistral medicinal products, this is the manufacturing pharmacy. Hence, to fulfil their duties of care, pharmacies should always demand a written declaration from their suppliers on the compliance with GACP requirements during cultivation of the plants as well as a copy of the GMP manufacturing authorisation for the manufacturing site in the third country where drying processes are carried out.

Altogether this situation is intolerable; it gives the impression of scattered regionalism. Apart from the risks for patients, a distortion of competition takes place, too. It is therefore necessary to demand that consistent standards be created, according to which procedures are carried out at a national or (better) European level and which requirements apply with regard to quality assurance in both, the collection of the herbal starting material as well as the processed cannabis flowers. As a pharmacist, I would even like go one step further and consider the use of cannabis flowers an anachronism in the light of the fact that cannabis extracts have become available in the meantime. When cannabis flowers are processed to extracts, which are then administered in suitable dosage forms as magistral medicinal products or via vaping, the risks illustrated above do not exist. Thus, patients can be protected from the contamination risks described. Any appropriate extract preparation involves homogenisation, which allows representative analysis of microbial contamination and the possible contamination with mycotoxins (and other contaminants) to be validly analysed using representative samples. The bioburden of the herbal starting material is much less critical, since extraction is also associated with a germ reduction. Extracts are homogeneous active ingredients that can be dosed much more precisely and with respect to paediatric use can finally also be formulated in dosage forms suitable for children. Further advantages of extracts will be addressed in a separate publication. I can hence very well understand that the prescription of flowers is intended to play a subordinate role in the current draft of a resolution by the G-BA (Federal Joint Committee).