19 October 2020 - Authored by:Adrian Dykes
Today, the French National Agency for Medicines and Health Products Safety (ANSM) has officially launched the call for applications (“appel à candidatures”) for medical cannabis suppliers to participate in the pilot programme that will be started by 31 March at the latest. The call for applications follows the publication of the ministerial order providing the statement of works (“cahier des charges”) in the Official Journal yesterday. This order had been expected eagerly since the publication of the long-awaited implementing decree last week (see our previous blog post “French medical cannabis pilot programme to start by 31 March 2021 at the latest, confirms long-awaited decree”). Finally, medical cannabis suppliers should now have all requirements and documents available to start preparing their applications for the pilot programme.
Medical cannabis suppliers which seek to participate in the pilot programme must submit their applications (by registered mail with return receipt or in person at the ANSM) by 24 November 2020, 4:30pm CET at the latest (i.e., 35 days from today). Importantly, the application must be made in French and comply with the detailed requirements and specifications described in the statement of works (which have been determined in consultation with the experts of the Specialised Scientific Committee (CST). Any questions regarding the application can be addressed to firstname.lastname@example.org until 18 November 2020.
- The statement of works specifies the characteristics of medical cannabis products that will be provided in the context of the pilot programme, in particular their qualitative and quantitative composition (THC and CBD content), pharmaceutical form (inhalation, oral and sublingual forms), product quality, package leaflet and labelling. Please find a detailed summary of the statement of works below. To be noted: the ANSM has reserved the right to modify certain (minor/complementary) requirements in the coming weeks so suppliers should monitor the ANSM website.
- In addition to verifying the content of the application dossiers, the ANSM also requires that candidates provide medical cannabis product samples, the conformity and quality of which will be tested as well (in its laboratories). Samples must be sent by 24 November as well. Importantly, suppliers will need to obtain both an import authorisation for narcotic substances from the ANSM and an export authorisation for narcotic substances from the country of origin before shipment of such samples is possible, so they should timely apply for such authorisations.
- In addition to complying with the detailed specifications in the statement of works, suppliers will have to choose a pharmaceutical establishment located in France for the distribution of medical cannabis to pharmacies and hospital pharmacies that will participate in the pilot programme. The relevant forms required in this respect (e.g. partnership agreement, authorisation of the opening of a pharmaceutical establishment – downloadable here – French language) can be submitted until 15 December.
The ANSM indicates on its website that the candidates will be selected according to the following procedure/conditions (“conditions d’attribution”):
- First, the ANSM will analyse the application files in light of the various compliance criteria that are detailed in the technical response framework (“cadre de réponse technique“) (downloadable here – French language) for the following three aspects:
- Requirements related to the characteristics of the parties involved (eg. supplier, distributor)
- Requirements related to the manufacturing method of raw materials and finished products
- Requirements related to finished products (eg labelling, dosage, controls)
- Second, subject to compliance with the aforementioned compliance criteria, the files will be assessed according to the following weighting (for a total of 100 points):
- Criteria related to finished products: 50 points
- Criteria related to the manufacturing method of raw materials and finished products: 30 points
- Criteria related to the proper execution of the supply of medical cannabis: 20 points
Key requirements of the Ministerial Order and statement of works (“Cahier des charges”) published on 19 October 2020
- For each form (3) of medical cannabis, two providers will be selected: the first will be chosen to be the primary provider and the second to be the secondary provider in case of failure of the first. The organisation of the distribution of medical cannabis to hospital pharmacies and pharmacies will be carried out by a pharmaceutical establishment with the status of operator (“exploitant”) and importer if applicable (in case the cannabis products have to be imported in the EU) chosen by the supplier.
- In the context of the pilot programme, the supply of medical cannabis, which includes import where necessary and distribution by an operator, must be carried out free of charge. Any supplier selected to provide medical cannabis free of charge as part of the pilot programme may not claim or expect at the end of the programme any guaranteed right or direct or indirect benefit linked to its participation in the programme, particularly in the event of the possible generalisation of the use of cannabis for medical use by the French authorities.
Characteristics of medical cannabis
- Applications, to be submitted in French, must comply with the technical specifications as described in the appendix to the Order. The supplier may submit an application for one or more lots as described below. However, the same supplier may not be selected as the holder of all the lots. If the supplier submits an application for several lots, he must indicate the order of priority and must submit them separately.
- Medical cannabis must be supplied as a finished product and in its final packaging ready to be delivered to the patient. At least two package sizes per form are desired. However, these sizes should not exceed the equivalent of one month’s treatment. In addition, it is recommended that the supplier include in his offer a package corresponding to 7 days of treatment. All packaging must be airtight and guarantee the product’s good conservation.
- The forms of medical cannabis are expected to be the following:
- A form for inhalation by vaporisation such as dried flowering tops or granules, containing delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD);
- An oral form based on extracts solubilised in an oily matrix in capsule form or equivalent pharmaceutical form containing THC and CBD;
- An oral or sublingual form based on extracts solubilised in an oily matrix containing THC and CBD.
- The supplier may submit a tender for one or more of the following lots:
- Dominant THC ratio “as an indication THC 20 : CBD 1”.
- Batch 1.1: Flower THC > 8 %, CBD < 1 %;
- Batch 1.2: THC oil > 5 mg/ml, CBD < 1 mg/ml;
- Batch 1.3: Oral form to be ingested THC > 5 mg/ml, CBD < 1 mg/ml.
- Balanced ratio “as an indication THC 1 : CBD 1”.
- Batch 2.1: Flower THC and CBD > 5 %;
- Batch 2.2: THC and CBD oil > 5 mg/ml ;
- Batch 2.3: Oral form to be ingested THC and CBD > 5 mg/ml.
- Dominant CBD ratio “as an indication THC 1 : CBD 20”.
- Batch 3.1: Flower THC< 1 % CBD > 5 %;
- Batch 3.2: THC oil < 1 mg/ml, CBD > 5 mg/ml ;
- Batch 3.3: Oral form to be ingested THC < 1 mg/ml, CBD > 5 mg/ml ;
- Batch 3.4: Flower THC < 5 %, CBD > 5 %;
- Batch 3.5: THC oil < 5 mg/ml, CBD > 5 mg/ml;
- Batch 3.6: Oral form to be ingested THC < 5 mg/ml, CBD > 5 mg/ml.
- A “patient” leaflet in French must be attached to each package and made available electronically (QR code). It must include in particular the following information: labelling information, dosage, administration instructions, contraindications, adverse effects, drug interactions, warnings (symptoms and instructions in case of overdose, etc.) and precautions for use (e.g. ability to drive vehicles or use machines), pharmacovigilance contact, manufacturer’s address. The contents of the package leaflet will be validated beforehand by the ANSM. The products delivered must have an expiry date of at least 6 months after the delivery date.
- It should be noted that once the suppliers and the forms of medical cannabis have been selected, no modification may be made throughout the period of the pilot programme without the agreement of the ANSM, whether the modifications concern the composition of the product, its manufacturing method, its packaging or the methods of cultivation and production as specified in the suppliers’ offers.
Estimated quantity of medical cannabis
- The French pilot programme will involve the monitoring of 3,000 patients, divided between therapeutic indications or clinical situations, the list of which is set by order of the Minister of Health, for a period of 18 to 24 months. The number of patients treated for each therapeutic indication or clinical situation selected for the experiment is defined by decision of the Director General of ANSM. On the basis of these indicative figures as defined by the aforementioned decision, suppliers are invited to submit an offer mentioning the proposed quantity for one year (12 months). The actual quantities to be supplied will depend solely on the orders placed by the operator.
- The supplier will have to specify in his offer the total quantity he recommends for the whole duration of the pilot programme as well as the quantity per month (in kilograms and litres according to the form for which he is making an offer).
- For dried or granulated flowering tops, the supplier must indicate the quantity in grams (g) per bottle.
- For capsules, the supplier must specify the quantity of product per capsule in millilitres (mL) and the number of capsules per bottle.
- For the oral or sublingual form based on extracts solubilized in an oily matrix, the supplier shall specify the quantity in millilitres (mL) per bottle.
- The supplier’s offer must mention its stock, its quarterly production and manufacturing capacities for the form(s) for which it is making an offer and its storage methods. It should also indicate the supply chain management and monitoring systems that can be implemented to ensure the continuous supply of medical cannabis.
Characteristics of the vaporisation device
- For flower batches, the applicant will have to indicate whether he is able to provide a vaporisation device for the entire duration of the pilot programme, since the only possible and authorised mode of administration of cannabis in the form of dried flowering tops or granules will be the inhalation route, after vaporisation with an adapted system (dedicated medical device). It is therefore recommended that the supplier can offer such a device for each patient with a prescription.
- As this equipment has by definition the status of a medical device, the manufacturer will have to indicate its status with regard to the conformity for placing it on the market. In the event that the medical device does not have the CE marking, the manufacturer will have to justify and indicate, where appropriate, the evaluation procedure in progress or indicate whether the device is placed on the market outside the territory of the European Union.
Characteristics of the supplier and operator
- The supplier must be incorporated as a legal entity whose corporate purpose is, in particular, to cultivate cannabis for medical purposes and/or to manufacture medical cannabis.
- The supplier shall indicate in its offer the various sites for the cultivation of cannabis and the manufacture of medical cannabis as well as provide samples of medical cannabis, together with their certificates of analysis of the raw material and the finished products.
- The supplier must indicate in its offer whether it is or has been the holder of a contract or an authorisation to supply medical cannabis in a country authorising the use of medical cannabis. If this is the case, the offer must specify the name of the customer if it is a legal entity, the country concerned and include a summary of the distribution methods and volumes supplied.
- The supplier must specify in his offer the human and material resources made available for the execution of all services.
- For the distribution of medical cannabis, the supplier must, in its offer, present a partnership which has been entered into or is under negotiation with an authorised pharmaceutical establishment located in France. The latter must have the status of operator and importer if applicable. It is the supplier’s responsibility to verify the veracity of such status.
- As medical cannabis has the status of a narcotic, the operator must also have a narcotics authorisation relating to medical cannabis in the context of the pilot programme. This authorisation will be issued to successful operators after the selection of applicants.
Supply to the chosen operator
- The supplier is obliged to deliver the medical cannabis according to the actual needs within the scope of the pilot programme. The risks relating to the transport and delivery of the medical cannabis are managed between the supplier and its operator.
- Under no circumstances may the medical cannabis to be supplied be delivered before the final notification of the supplier selection decision by the ANSM. It is only after this notification that the supplier must build up a stock of medical cannabis with its operator in order to guarantee the supply of the first order 30 days after the selection of the supplier. After this period, the supplier must guarantee delivery within a maximum of 28 working days after the order, at the place, day and time defined by the operator at the time of the order. The supplier may propose in his offer a delivery time of less than 28 days.
- The operator will be obliged to always have a stock equivalent to one month’s treatment for all patients affected by the form of medical cannabis for which the supplier is selected. However, in the month before the end of the experiment, the operator must have a maximum stock equivalent to one month’s treatment per form.
Correspondence with the ANSM
- The ANSM will provide the supplier with the name of an “agency correspondent” and an alternate who will generally constitute the contact point for the supplier. The person in charge for the supplier will be the person authorised to represent the supplier to the agency correspondent for any question relating to the performance of the services. This person must be able to express himself fluently in French (both in writing and orally).
Obligations of the supplier
- The supplier is subject to a so-called “obligation of result” according to the conditions provided for in the specifications and undertakes, for the execution of the services, to comply with the specifications and terms and conditions described in the Order.
- Obligation to provide information, advice and warnings: the supplier shall be deemed to have taken note of all the elements relating to the performance of the services. He may not point out errors, omissions or inconsistencies in order to perform only an incomplete or improper service. His duty to inform, advise and warn consists in fully informing ANSM of the consequences of the various decisions that he may have to make, to draw its attention when he detects risks of any kind, and to suggest all useful steps or solutions. The supplier is bound by an obligation to provide advice, in particular with regard to the content of the orders placed with him.
Failure to fulfil obligations and consequences
- In the event of non-compliance of medical cannabis, delay, negligence, total or partial non-performance, poor execution of the specifications or purchase orders, the ANSM may take two types of measures: (i) temporary or definitive recourse to the substitute supplier and/or (ii) termination of the specifications with regard to the supplier at the origin of the breach. In this respect, the ANSM may, as the case may be, launch a contradictory procedure with the supplier in order to determine the causes of the breach, demand corrective measures and prevent their recurrence.
Specification and controls to guarantee the quality of the products
- The document aims to establish guidelines and requirements for the setting of specifications and for the application of a documentation and traceability system for the supply of products meeting pharmaceutical standards containing cannabis from commercial suppliers. These requirements apply exclusively within the framework of the pilot programme.
- Suppliers must transmit one dossier per product proposed. The documents sent by suppliers to the ANSM may be confidential: in this case, they must be clearly identified as such. However, some of them may be communicated by ANSM in application of the Code of relations between the public and the administration.
- The specifications include the critical requirements of Module 3 of the pharmaceutical dossier that must be provided for the registration of herbal medicinal products. The objectives are to guarantee the quality and ensure the traceability of the plant and products and to guarantee the reproducibility of treatments and user safety, with the same cannabinoid chemical profile from one batch to another, for both the plant and the finished products.
- Monographs exist in the European Pharmacopoeia for most testing and dosing operations. Monographs for the plant “Fleur de Cannabis” (Cannabis Flower) exist in the national pharmacopoeias of at least two European Union Member States (Germany and the Netherlands) as well as in Switzerland. If other monographs exist for the control of the plant, as a raw material or finished product, as well as for finished products, alternative control methods may be taken, if appropriately justified.
- The following guidelines serve as recommendations to suppliers:
- Guidelines on Quality of HMPs/THMPs” (CPMP/QWP/2819/00 Rev. 2) ;
- Guidelines on Specifications: test procedures and acceptance criteria for HS, HP, HMPs/THMPs (CPMP/QWP/2820/00 Rev. 2);
- Q&A on Quality of HMPs/THMPs” (EMA/HMPC/41500/2010 Rev. 6) Contaminants ;
- RP on Microbiological aspects of HMPs and THMPs (EMA/HMPC/95714/2013);
- ICH Q2 guidelines for validation ;
- Recommendation for regulators – Cannabis Operations. American Herbal Products Association, 2016.
- As part of the evaluation of the responses to the call for applications, the ANSM will carry out laboratory analysis of samples representative of the products intended to be used during the pilot. In order to do so, suppliers will have to send the following samples:
- for forms intended for vaporisation (flowers, powders or granules): 3g of product ready for use, packaged as intended for patients. The delivery device must also be made available to the authorities (1 unit);
- for forms intended for oral and sublingual routes: one or more ready-to-use multi-dose packs, as intended for patients, corresponding to a minimum of 20 doses.
In addition, suppliers must be prepared to transmit, at any time, at the request of the ANSM, samples for analysis in the context of the pilot programme.
Requirements concerning the manufacturing method of raw materials and finished products
- Compliance with good agricultural practices is required, following the guidelines “Good agricultural and collection practices” (GACP) for starting materials of herbal origin (EMEA/HMPC/246816/2005). The supplier commits to a set of specifications to be included in his file and the related documentation. Any use of fumigation must be justified by the supplier.
- The following guidelines serve as recommendations to suppliers:
- “Specifications: test procedures and acceptance criteria for herbal substances, herbal preparations and HMPs/THMPs” (CPMP/QWP/2820/00 Rev. 2 – Draft Rev. 3)
- Reflection paper on fumigants (EMEA/HMPC/125562/2006).
- The storage conditions of the raw material must be documented. The usual stability of cannabis flowers stored under correct storage conditions is 1 year. Stability data shall be provided as appropriate.
- Manufacturing and control extracts:
- The manufacturing processes and controls in progress to obtain the extract, the solvents used, the batch size and the adjuvants used for titer adjustment.
- The addition of inert excipients and technological excipients, preservatives and antioxidants is possible. These are mentioned (name, purity), as well as their content (fixed or variable within a range justified by the supplier).
The method of obtaining the extracts is described (degree of division of the plant drug, type of extraction, solvent/mass ratio of the processed plant drug, duration, temperature, pressure). The use of recycled solvents is specifically mentioned and must be justified. Recycling procedures are described and/or are subject to control and monitoring measures. The quality of the recycled solvents is subject to specifications. These specifications can be provided in the file made available to the ANSM.
Characteristics of the plant
- The plant is used for the production of extracts or is delivered directly to the patient, after appropriate division has been carried out beforehand. The plant meets the specifications of the monograph “Plant Drugs” (1433) of the European Pharmacopoeia. In the absence of a European monograph defining cannabis flowers, the supplier may, for example, comply with the specifications of the monograph of the German Pharmacopoeia. The supplier may set his own specifications.
- The labelling of the plant specifies the cannabinoid content, the batch number and the expiry date.
Characterisation and control of extracts
- The general monograph “Plant Drug Extracts”, European Pharmacopoeia. no. 765, serves as a recommendation.
Finished product requirements
Elements to be provided in the application:
- The pharmaceutical form, the formulation, the qualitative and quantitative composition (excipients with details of their qualities and functions, active ingredients) and the type of packaging must be described. The nature and frequency of the controls carried out on the excipients shall be specified. The batch size must be indicated;
- Dosage of cannabinoids: the method used for the determination of cannabinoids must be precisely described, indicating in particular the method of sampling, sample preparation, the technique and controls used, and the methods of calculation of the contents of molecules of interest.
- For forms intended for spraying (in particular plant drugs (inflorescences) fragmented (granules), divided, pulverised): imperatively, total THC (corresponding to THC + THCA without it being necessary to dose each one separately), total CBD (corresponding to CBD + CBDA without it being necessary to dose each one separately), CBN (considered as a control of THC degradation);
- For forms intended for the oral and sublingual routes: imperatively, THC, THCA, CBD, CBDA, CBN (considered as a control of THC degradation).
- Characterisation of mono- and sesquiterpenes: profiling of mono- and sesquiterpenes is recommended, particularly for products intended for vaporization. Any suitable method can be used to determine the relative profile of mono- and sesquiterpenes.
- Batch data: at least two certificates of analysis of batches already produced, including at least the elements listed in 5.2. of the Order are provided.
- Conservation: storage conditions are described;
- Stability: a summary of the stability characteristics is provided, justifying the expiry date;
- Control of the pharmaceutical form/pharmacotechnical tests: depending on the pharmaceutical form of the finished product, the following tests are carried out:
- level of division into dosage units: for inflorescences;
- uniformity of mass: for soft capsules and drinkable or sublingual drops;
- water content: for the drinkable or sublingual drops;
- any other specification proposed by the supplier.
The control method can be in accordance with the European Pharmacopoeia or failing this must be described in detail, indicating in particular the sampling method ;
- The labelling (in French) is described. It includes :
- the name of the plant drug, with, where appropriate, the variety ;
- the pharmaceutical form ;
- the composition (in particular the excipients with a known effect);
- the cannabinoid content; possibly the total THC / total CBD ratio;
- the quantities of THC (and THCA where applicable) and CBD (and CBDA where applicable) delivered per unit of mass or volume, respectively, for solid or liquid forms offered in bulk;
- the batch number;
- the indication of the route of administration ;
- storage and handling recommendations;
- indication of the expiry date.
Elements to be provided with each batch of finished product
- For forms intended for vaporisation (in particular plant drugs (flowers) fragmented (granules), divided, pulverised), a certificate of analysis including :
- foreign elements;
- degree of division: according to supplier’s specifications;
- loss on drying;
- microbiological control;
- aflatoxin and ochratoxin contents;
- levels of pesticides;
- contents of heavy metals;
- total ash;
- results of the quantitative analysis of cannabinoids. The result of the determination must be between 90% and 110% of the content indicated on the label;
- where applicable, results of the analysis of essential oil content and mono- and sesquiterpene profile.
- For forms intended for the oral and sublingual route, a certificate of analysis including:
- microbiological control according to paragraph 5.1.4 of the European Pharmacopoeia;
- aflatoxin and ochratoxin contents;
- levels of pesticides;
- contents of heavy metals;
- results of the quantitative analysis of cannabinoids. The result of the determination must be between 90 % and 110 % of the content indicated on the label;
- where applicable, results of the analysis of the profile in mono- and sesquiterpenes.
This post was written by Eveline Van Keymeulen and Alexis Vaujany.