Questions and answers about the production of cannabis bulk and cannabis primary products

The company must maintain a system to ensure that security risks are dealt with. A security risk assessment must be performed and documented. If security situations arise, the company must consider if there is cause for taking further security measures. This risk assessment must consider the risks associated with the company’s production, including site access, staff, camera surveillance, alarm system, keys/codes, etc.

The company must ensure that access is restricted. Unauthorised persons are only permitted to enter the premises where cultivation, processing, production or handling of cannabis take place if duly escorted. See further information in our Recommendations for security of companies that manufacture medicinal cannabis (PDF) (in Danish only).

The person responsible for security is a key figure, and the company must ensure that this person has the needed resources to complete their tasks adequately. This person must have thorough knowledge of the company’s security procedures. To be authorised by the Danish Medicines Agency as a person responsible for security, you must pass the assessment of good conduct by the Danish National Police.

The company must provide documentary evidence of the origin of the seeds or other propagating material collected. It must be clear from which material the produced plants originate. The company must ensure that the propagating material used is homogeneous, e.g. by using clones (cuttings) from the same mother plant or seeds from inbred lines.

For the line used by the company, the plant’s chemical profile, morphological description and name of variety, if relevant, must be documented. If varieties containing less than 0.2% THC are used, certified seeds can be used. For information about certified seeds, see the website of the TystofteFoundation: www.tystofte.dk.

Yes, the selected or developed clone/genotype (mother plant) can be used for production in the pilot programme provided there is documentary evidence that the rules governing cultivation, including use of the primary material for cultivation, have been observed also in the development scheme. This means that it may be necessary to establish a new mother plant if this cannot be documented.

The company must ensure uniform and standardised cultivation conditions to produce a homogeneous product. This involves the control of light intensity, light spectrum, day length, humidity, watering, fertilizer application, temperature, air change, cultivation medium, age of the harvested plant and the time of day when harvested.

Cannabis cultivation intended for the production of products for the medicinal cannabis pilot programme must fulfil the requirements in EMEA/HMPC/246816/2005 Good Agricultural and Collection Practice for starting materials of herbal origin (GACP).

A batch means a defined quantity of cannabis bulk or cannabis primary product processed in one process or series of processes so that it could be expected to be homogeneous. A batch must be confirmed and documented as expected to be homogenous. This is done by validating the manufacturing process. Before a validation can begin, the company’s quality assurance systems must first be implemented and approved, and the premises for production must be appropriately qualified. Manufacturing directions must also have been established.

The validation of a manufacturing process is expected to verify that three independently processed batches will deliver a product expected to be homogenous in a standardised cultivation and production environment.

Medicinal cannabis is outside the scope of the European organic regulation. This means that medicinal cannabis cannot be certified or marketed as an organic product.

It is not possible to use hemp grown pursuant to the rules governing industrial hemp in the pilot programme. You cannot cultivate industrial hemp with the purpose of producing products for the pilot programme. But there is nothing to prevent companies authorised under the pilot programme from using cannabis varieties that are also authorised for industrial hemp.

Pesticides are not allowed in the cultivation and production of cannabis products based on Danish-grown cannabis in the pilot programme.

Pesticides may not be used in the cultivation of medicinal cannabis in Denmark. This follows from the executive order on the cultivation, production and distribution of cannabis bulk and production of cannabis primary products (Danish title Bekendtgørelse om dyrkning, fremstilling og distribution af cannabisbulk og fremstilling af cannabisudgangsprodukter).

A pesticide is also called a plant protection product or a herbicide. Pesticides are used to protect plants or plant products from pests such as fungi or insects or to prevent infestation from such pests. It can also be used to control weeds or prevent the growth of unwanted plants.

Pesticides can be both chemical substances and microorganisms. So, whether a substance is a pesticide depends on what it is going to be used for. It is not a question of whether the substance is chemical or of natural origin – or if it can otherwise be used in food products.

The use of natural predators is not considered as pesticide use

The Pesticide Regulation 1107/2009 belongs under the Ministry of Environment and Food of Denmark. If you are not sure whether a substance is a pesticide, the Ministry of Environment and Food of Denmark can help you clarify the matter. If the ministry assesses it not to be a pesticide, the substance is not subject to the ban on pesticides imposed on Danish cultivators in the Act on a Medicinal Cannabis Pilot Programme (Danish title: Lov om forsøgsordning med medicinsk cannabis).

Read more about pesticides on the website of the Danish Environmental Protection Agency.

The Danish Environmental Protection Agency assesses if a substance classifies as a pesticide under the Pesticide Regulation as this falls under the agency’s remit. It is also this agency that authorises pesticides prior to their use on crops in Denmark.

The Danish Medicines Agency administers the rules on the cultivation of cannabis in Denmark, including the ban on pesticides.

The Danish Agricultural Agency offers professional assessment and advice about cultivation.

You should only consider irradiating herbal substances if absolutely necessary to ensure sufficient microbial purity, and if there is no other way to achieve this purity. So, it depends on the level of microbial purity required for the product in question. For example: A herbal substance for tea is not required to have the same microbial purity as a product used for inhalation. Strict thresholds apply to inhalation products because these products (microorganisms) are absorbed through the lungs directly. This means the company must look for other ways to reduce the microbial count. This should primarily be ensured by means of preventive measures, and only if necessary additionally by decontamination. Using irradiation as a means to prevent contamination will only be accepted if other methods (e.g. short heat treatment) are unsuitable for the product in question.

If you plan to carry out irradiation yourself, you must pay attention to the rules on ionising radiation. These can be found on the website of the Danish Health Authority, Radiation Protection.

Some countries require medicinal cannabis to be irradiated before accepting any import.

Since pesticides are not allowed to manage pests of plants, measures should be taken to prevent the risk of infection. The following may be considered:

• Filtration of ventilation air to prevent the entry of flying insects and fungal spores, etc.
• Isolation of cultivation units to prevent pests from spreading to the entire cultivation area
• Hygiene measures to prevent pests from spreading via plants that are moved in production
• Sufficiently high quality of water and cultivation medium used
• Sorting and possibly cleaning after harvesting
• Efficient drying process after harvesting

Cannabis must be grown without the use of pesticides. Natural predators could therefore be used as an alternative means of prevention and in some cases management of pests in cannabis production, however provided that it does not affect the quality and consistency of the product.

Any use of natural predators must take place under controlled conditions, which means that you are expected to have ensured:

• a scientifically reasoned choice of natural predator;
• a regular assessment of how the population of natural predators is developing in the production of medicinal cannabis;
• a regular assessment of whether the use of natural predators is affecting the production and the content of the cultivated cannabis;
• a health-scientific risk assessment of any potential contamination with natural predators in the finished product; and
• that there are no residues of natural predators in the finished product.

You will need to obtain an import certificate for euphoriant substances from the Danish Medicines Agency before you can import euphoriant substances (including cannabis cuttings) to Denmark. The application form and guidelines on import of euphoriant substances are available on the website of the Danish Medicines Agency (some only in Danish). Be aware that it is punishable to import cannabis cuttings without valid certificates.

Additional rules for companies buying cuttings from non-EU countries:

• Cannabis cuttings intended for planting coming from non-EU countries are subject to phytosanitary import requirements. The import requirements imply that the plants must be accompanied by a phytosanitary certificate and that the plants will be subject to import control when they are introduced into Denmark. In addition, the import must in advance be notified to the Danish Agricultural Agency, which will subject the plants to import control according to the usual import procedures. The importer pays a user charge for the import control. See the website of the Danish Agricultural Agency for more information.
• Companies importing plants subject to control must also be registered with the Danish Agricultural Agency as importers and will in this connection also be charged an annual registration fee. You can find more information in the Danish Agricultural Agency’s executive order on the import of plants and plant products, etc. (Danish title: Bekendtgørelse om import af planter og planteprodukter m.m.)

Additional rules for companies buying cuttings from EU countries:

• Plants must be free from quarantine pests, but otherwise there are no other phytosanitary requirements.

Seeds from the cannabis plant are not a controlled euphoriant substance. An import certificate issued by the Danish Medicines Agency is therefore not required to import seeds.

Additional rules for companies buying seeds from non-EU countries:

• Seeds must be free from quarantine pests (Schedule 2 of the Danish Agricultural Agency’s executive order on import of plants and plant products, etc. (Danish title: Bekendtgørelse om import af planter og planteprodukter m.m.)) No further phytosanitary requirements are imposed on the import of cannabis seeds from non-EU countries (third countries).

Additional rules for companies buying cannabis seeds from EU countries:

• Seeds must be free from quarantine pests, but otherwise there are no other phytosanitary requirements.

The requirements appear from the Danish Drug Standards.

A separate contract for each individual analysis is not required. However, the contract must detail all the analysis tasks being subcontracted to a contract acceptor.

Companies holding an authorisation are permitted to carry out the required product analyses themselves. If so, reference standards must be used for validation and application of the company's analytical methods.

The analyses of the herbal substance (for products to be admitted to the Danish Medicines Agency's lists) must follow the standard described in the specification which the company had approved by to the Danish Medicines Agency, i.e. the monograph for cannabis flower in the Danish Drug Standards or similar monograph.

The requirement for a competent person is very much like the qualified person (QP) that pharmaceutical companies are required to employ pursuant to the rules of good manufacturing practice for medicinal products (GMP). The competent person must be present to safeguard patient safety by vouching for the quality of the products and ensure that all requirements and rules have been complied with for every batch released to the market.

The competent person should be separated organisationally from the company's management and sales division as it will ensure that the competent person releases only products fulfilling the qualitative requirements. The requirement for a competent person is essential to ensure patient safety and quality, which is why this person's qualifications and independence are of utmost importance.

The competent person must be at the company regularly, and not only when products are to be released. The company determines the hours needed based on the activities of the company, but the Danish Medicines Agency considers that at least 10 hours are needed to justify that the person is at the company regularly.

If during an inspection the Danish Medicines Agency finds that the competent person’s presence is inadequate, this may be reported as a deviation that the company must correct.

A competent person cannot be approved before a new application or an application to vary an existing authorisation is submitted. Thus, the approval of a competent person takes place in connection with the review of applications. If the person fulfils the competent person requirements provided in the executive order and the guide ‘Requirements for and expectations of the competent person in a company authorised to produce cannabis products’ (in Danish only), approval of this person should not be a problem.

A person who does not fulfil these requirements will generally not be approved as a competent person by the Danish Medicines Agency.

The requirements for export of cannabis bulk and cannabis primary products appear from the executive order on cannabis bulk and cannabis primary products (Danish title: Bekendtgørelse om cannabisbulk og cannabisudgangsprodukter.

A company wanting to export cannabis bulk and cannabis primary products must hold an authorisation to manufacture cannabis bulk and cannabis primary products covering the activity “export of cannabis bulk” and/or “export of cannabis primary products”. If the company already holds an authorisation to manufacture cannabis bulk and cannabis primary products but the activity is missing on the authorisation, the company will need to submit a variation application to the Danish Medicines Agency to have the activity comprised by the authorisation. In addition, the company must hold a relevant authorisation to handle euphoriant substances with the activity “export”.

The export of cannabis is also subject to the executive order on euphoriant substances (Danish title: Bekendtgørelse om euforiserende stoffer). This executive order regulates cross-border import and export and contains provisions on import and export certificates for each consignment. For exports, the application is to be sent to the import country, which issues an import certificate. This certificate is then sent to the Danish Medicines Agency for issuance of an export certificate. The administration time for issuance of import and export certificates in Denmark is five business days from receipt by the Danish Medicines Agency. However, the administration time in other countries may be considerably longer.

Find out more abouthow to apply for authorisation and certificates under the rules governing euphoriant substances.

The executive order on cannabis bulk and cannabis primary products does not specify any labelling requirements for cannabis primary products to be exported. However, there is a requirement for traceability of the products, which the manufacturer must observe. This means the packages will need to be labelled with e.g. batch number and company details. 

The authorities of the import country may impose specific requirements on the labelling of the exported cannabis primary products, which the Danish companies must comply with. We refer to the competent authorities in the import country. 

Please note that the cannabis primary products to be exported must neither be admitted to the Danish Medicines Agency's list nor bear the same name as a cannabis product admitted to the list.

Cannabis that is packaged in consumer-ready containers where only a label is missing does not qualify as bulk; this is a primary product. By definition cannabis bulk is to be further processed or packaged in consumer-ready packages; in other words, this is the step before packaging in a container.

Cannabis in a blister pack can qualify as bulk, since the blister packs are to be further processed by packaging into boxes.

It must be ensured that the cannabis primary product cultivated in Denmark meets the established specifications, before it is used to produce a cannabis intermediate product.

The shelf life (storage time and conditions) is usually determined based on stability studies conducted by the company itself. In determining the shelf life, analogies may be drawn with similar products or possibly with any excipients used. It is determined from product to product based on its formulation. If no data on shelf life are available, the company must set a preliminary shelf life and storage conditions, following which the company will initiate stability studies to document a more accurate shelf life and storage conditions. Stability data obtained in the development scheme can be used for determining shelf life. However, these data must be confirmed once the company has been granted an authorisation under the pilot programme.

The studies must be completed in compliance with relevant ICH guidelines. See, for example, CHMP/QWP/122/02 rev. guideline on stability testing: Stability testing of existing active substances and related finished products.

The requirement that the names of the two cannabis primary products cannot be identical is to avoid confusion between exported cannabis primary products and cannabis primary products intended for Danish patients.

Yes, cannabis primary products with the same specification can be produced for Danish patients and export, respectively, as long as the products do not bear the same name.

It is only possible to export cannabis bulk and cannabis primary products – and thus not finished cannabis intermediate products with Danish labelling for patient use. 

Likewise, cannabis bulk and cannabis primary products may only be exported to countries whose authorities permit the import of cannabis products for medicinal use. To find out if it is possible to export to a specific country, we advise you to contact the authorities in the country concerned.

A site is a geographical location. The authorisation is site specific, which means that all geographical locations must appear on the authorisation with addresses and descriptions of the activities carried out at each individual site.

The GACP rules and GMP rules overlap. In some areas, e.g. drying and trimming of the flower, both GACP and GMP apply.

Yes, the relevant requirements appear from the executive order on the cultivation, production and distribution of cannabis bulk and production of cannabis primary products. Further information about these rules is provided in the guide to applying for an authorisation for cannabis bulk and cannabis primary products.

The activities that may be subcontracted are production, analysis, receipt, storage and/or delivery. Please note that release cannot be subcontracted. Analysis is the only activity that may be subcontracted to companies in other EU/EEA countries.

According to the rules, only cannabis bulk and cannabis primary products may be legally exported, so exporting cannabis cuttings is not permitted within the pilot programme. However, it is possible to obtain an authorisation for activities with euphoriant substances covering cultivation intended for propagation and distribution of cuttings.

Analysis can be subcontracted to laboratories in EU/EEA countries as long as they have a Manufacturing and Importation Authorisation (MIA). This can be checked in the EudraGMDP database. The related requirements appear from the executive order on cannabis bulk and cannabis primary products.

The laboratory needs either of the following authorisations to analyse medicinal cannabis in the pilot programme.

1. An authorisation to manufacture cannabis bulk and cannabis primary products
2. A manufacturer's authorisation pursuant to section 39(1) or (2) of the Danish Medicines Act.

The authorisation must include the concerned analysis-related activities, and the laboratory must also hold a relevant authorisation pursuant to the executive order on euphoriant substances.

The related requirements appear from the executive order on cannabis bulk and cannabis primary products (Danish title: bekendtgørelse om cannabisbulk og cannabisudgangsprodukter). A manufacturer of cannabis bulk and cannabis primary products must ensure that the cannabis products follow the same manufacturing processes and comply with the specifications of the product and meet the requirements therein.

This means that the requirements for analysis of content, etc. regarding cannabis bulk must follow the same requirements specified for primary products. Companies wishing to produce cannabis bulk must draw up a specification that also provides a framework detailing the relevant benchmarks for the analysis.

The Danish Drug Standards contains a monograph of cannabis flower with indication of the analysis parameters.

You can read more about this in Destruction and record-keeping for companies authorised to cultivate cannabis for medicinal use (PDF) – in Danish only

Process validation is usually a three-step process:

1. The company prepares a protocol for process validation.
2. The company is granted a manufacturing authorisation under the pilot programme after an inspection.
3. The company can carry out process validation with cannabis material cultivated in the pilot programme.

The company will find it useful to prepare a protocol for process validation based on experience from cannabis material cultivated in the development scheme.

A manufacturer of cannabis bulk may distribute its own manufactured cannabis bulk to companies holding an authorisation to manufacture cannabis bulk and/or an authorisation to manufacture cannabis primary products and holding a relevant authorisation for activities with euphoriant substances. If the manufacturer intends to use a carrier, they must enter into a contract with that carrier.

Transportation of cannabis bulk must comply with good distribution practice for active pharmaceutical ingredients (APIs) and the executive order on euphoriant substances.

The manufacturer of cannabis bulk can sell its own manufactured cannabis bulk to companies holding an authorisation to manufacture cannabis bulk or an authorisation to manufacture cannabis primary products and holding a relevant authorisation for activities with euphoriant substances (see question on export).

Two companies may enter into detailed quality agreements describing the division of responsibilities in relation to batch release. These are not the same as the QP-QP agreements appearing from annex 16 of EU-GMP, but the principles from annex 16 can be applied.

This means that it is acceptable for a competent person to base the release on partial deliveries from a competent person from another company as long as the standard EU-GMP requirements, e.g. for conclusion of a formal quality agreement and audits are, fulfilled.