legislative framework Archives - European Industrial Pharmacists Group (EIPG)

A new member within EIPG


The European Industrial Pharmacists Group (EIPG) is pleased to announce the Romanian Association (AFFI) as its newest member following the annual General Assembly of EIPG in Rome (20th-21st April 2024). Commenting on the continued growth of EIPG’s membership, EIPG President Read more

The EU Parliament voted its position on the Unitary SPC


by Giuliana Miglierini The intersecting pathways of revision of the pharmaceutical and intellectual property legislations recently marked the adoption of the EU Parliament’s position on the new unitary Supplementary Protection Certificate (SPC) system, parallel to the recast of the current Read more

Reform of pharma legislation: the debate on regulatory data protection


by Giuliana Miglierini As the definition of the final contents of many new pieces of the overall revision of the pharmaceutical legislation is approaching, many voices commented the possible impact the new scheme for regulatory data protection (RDP) may have Read more

EMA/EFSA joint report on human dietary exposure to residues of veterinary medicines, pesticides and feed additives

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By Giuliana Miglierini

The presence of residues of veterinary medicines, feed additives and pesticides in food of animal origin may pose exposure risks for human health. The topic has been historically approached under different perspectives according to the specific reference legislative framework and the respective authority involved in regulating and monitoring the products. The European Medicines Agency (EMA) and the European Food Safety Authority (EFSA) are among the main regulators involved in setting and verifying the legally binding maximum residue limits (MRLs) for chemical substances, together with the European Chemicals Agency (ECHA).

EMA and EFSA received in 2020 a mandate by the European Commission to work at the development of a harmonised approach to the assessment of dietary exposure to residues of veterinary medicines in food of animal origin. The comparison of the current situation run by the two agencies included only exposure assessment methods used in the regulatory areas, which are all based on traditional deterministic approaches. The resulting recommendations have recently been published in the form of a joint report.

EMA/EFSA experts focused on key concepts and features in order to provide a general agreement on the basic “building blocks” of a recommendable harmonised methodology, leaving the setting up of more detailed methodological aspects targeted to the different sectorial applications to a further phase of discussion. The document shall now be assessed by the European Commission and, if adopted, may request the implementation of specific action targeted to the different sectors to reach a better harmonisation. The Technical Report to be submitted to the Commission may also contain other elements to be considered.

Meanwhile, on 9 February 2023 the Commission implementing Regulation (EU) 2022/1255 designating antimicrobials or groups of antimicrobials reserved for treatment of certain infections in humans entered into force. The regulation lists a wide range of antibiotic, antiviral and antiprotozoal active substances. Those use is from now on excluded to treat animals, so to preserve their efficacy in humans. The measure is part of the broader approach against antimicrobial resistance, and it aims to promote a more prudent and responsible use of antimicrobial medicinal products in animals, including very strict rules on their veterinary prescription for prophylactic and metaphylactic use.

The main issues examined by the EMA/EFSA report

Sectorial legislations in the field of medicinal products (managed by EMA), food (EFSA) and chemicals (ECHA) may greatly differ from one another in the approach and methodologies chosen to define exposure limits and to run risk assessments referred to residues of veterinary medicinal products, feed additives, pesticides and biocides. This lack in harmonisation may lead to significantly different outcomes in the assessment of the same active substance, especially when it is characterised by a dual use for applications in different sectors.

There are several pieces of legislation in place aimed to guarantee a high level of protection of both human and animal health and the environment [Commission Regulation (EU) 2018/7829, Regulation (EC) No 1107/200910 and Commission Regulation (EC) No 429/2008], as well as sectorial legislations in the pharmaceutical, food, and feed additives fields that may diverge at the level of data requirements, purpose of the required studies, methodologies for exposure assessment, consumption models, etc.

In general terms, exposure studies are usually run using radiolabeling to trace the fate of a substance and to characterise its metabolites and their concentration in edible tissues/food commodities from target animals. The “residue of concern” (RoC) considered in the dietary exposure assessment is most commonly estimated assuming that metabolites have the same pharmacological/ toxicological potential as the parent compound. The difficulty of measuring the concentration of all compounds in residue monitoring often leads to the selection of a marker residue to be traced.

Health Based Guidance Values (HBGVs, or Reference Values) corresponds to the concentration of a chemical that may present hazards for the human, animal or environmental health; they are listed in the EFSA Open Food Tox Database, as well as in similar WHO and US-EPA databases.

HBGV, as well as acceptable daily intake (ADI) in case of chronic risk and the acute reference dose (ARfD) in case of acute risk, can be used in association with the estimated dietary exposure to the RoC to evaluate the risk of exposure.

The report initially discusses the different approaches and models currently in use by EMA, EFSA, the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and the Joint Meeting on Pesticide Residues (JMPR). Reference is made to the alternative definitions for the establishment of residue limits related to veterinary medicinal products charactering the different sectorial legislation, as well as to methods to assess the related hazard.

The Theoretical Maximum Daily Intake model (TMDI, or diet-based approach), for example, is used by EMA to estimate the risk from life-long exposure to residues in food commodities from animals treated with veterinary medicinal products. This model has been already abandoned by JECFA and EFSA, that switched respectively to the Feed Additives Consumer Exposure (FACE) and Pesticide Residue Intake Model (PRIMo 4), as better suited to estimate age-dependent exposure scenarios based on individual food consumption data. The report also discusses the Global Estimated Chronic Dietary Exposure (GECDE) model, and the International Estimated Daily Intakes (IEDI) model. This last one is based on the WHO GEMS Food Cluster diets, estimating average per capita consumption figures based on international trade and production statistics of foods.

A further level of complexity in the assessment has to be considered for substances with dual uses, such as veterinary medicines and pesticides. In such instances, it is important to note that maximum residue limits/levels may vary for the same substance in the same animal commodity, as their concentration may differ in different tissues and/or organs (i.e., muscle, fat, liver, kidney, eggs, or milk). This may result in uncertainties at the level of the enforcement of the appropriate level and residue definition by different authorities.

The recommendations for future harmonization

The analysis and evaluation of the performance of the many available methods led EMA and EFSA to conclude that the observed differences in exposure assessment could be primarily attributed to the type and use of consumption and occurrence data. Other possible elements impacting on the obtained result may include the chosen calculation model and exposure model, the exposure to residues from multiple uses, and the use of commodity definitions and combined exposure from multiple species. Different timelines in the implementation of scientific innovation may have also contributed to the observed divergences.

The final goal of the exercise was to obtain a most realistic exposure assessment possible based on the available methodologies. The so identified “preferred methodology” focuses on data sources and models, includes also alternative proposals on a number of items, and it might represent the “blueprint” for a future harmonised methodology. EMA and EFSA’s recommendations pay particular attention to exposure assessment as the first step of a risk assessment; as for risk characterisation, no specific recommendations have been developed during this round of discussions.


A study on medicines shortages from the European Commission

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by Giuliana Miglierini

The study on medicines shortages commissioned in March 2020 by the European Commission upon request of the European Parliament and Council has been published; the document, prepared by a consortium led by Technopolis, suggests 16 possible policy measures – both legislative and not-legislative – that the Commission may consider while drafting a new legislative proposal to govern the issue, expected to be announced at the end of 2022.

According to the current EU pharmaceutical legislation (Directive 2001/83/EC), marketing authorization holders (MAHs) have to submit – two months before the temporary or permanent interruption of supply of a certain medicinal product – a pre-notification to the relevant national competent authorities (NCAs) (Article 23a, a part in the case of exceptional circumstances).

The mandate to continue supply to cover the needs of patients, and respective responsibilities of MAHs and wholesale distributors are established by Article 81 of the same directive.

The new study will support some of the achievements set forth in the Pharmaceutical Strategy; another action undertaken to reduce the impact of shortages in the EU is represented by the EU Executive Steering Group on Shortages of Medicines Caused by Major Events, an initiative set up in March 2020 with the contribution of the Commission, EMA and member states.

The Commission study on shortages by Technopolis confirms that current market framework conditions for off-patent medicines play against supply resilience – said Rebecca Guntern, President ad-interim of Medicines for Europe, commenting the release of the study –. As long as healthcare systems only focus on the cheapest possible price for off-patent medicines and do not reward investments to ensure robust supply chains, the only option for companies is to be the cheapest or to leave the market.

The main outcomes of the study

The study on shortages focused its attention on medicines for human use marketed in the EU/ EEA in the period 2004-2020. The main objectives of the exercise include the identification of shortages’ root causes and specific characteristics, the assessment of the adequacy of the current framework (at EU and national level) and of possible solutions to address the problem.

Data from the shortages registries kept by national competent authorities (NCAs) of 22 EU’s countries was only available for years 2007-2020. Commercial data on pharmaceutical sales from IQVIA MIDAS was also used, and extensive consultation with stakeholders was run under different formats.

Central to the 16 recommendations highlighted in the study is the establishment of a centralized and harmonised EU-wide definition of medicine shortages, as well as of harmonised reporting criteria. The latter should aim to collect sufficiently detailed information on key parameters (e.g. product details, MAH, details on the shortage and impact).

Different definitions, systems for notifications and type of information requested are currently in use in the various member states; even the definition of “shortage” agreed in 2019 by EMA and HMA was not considered by stakeholders adequate to differentiate between critical and non-critical shortages. According to the report, this fragmented situation doesn’t allow for the sharing of data and comparative analysis between countries, thus resulting in the overall inefficiency of the system.

Attention should be paid also to the creation of a EU-wide list of medicines subject to critical shortages; specific policies and regulations may be developed on this basis to improve their availability. Medicines typically experiencing shortages are older, off-patent and generics drugs with low profit margins; the main therapeutic areas involved include pain, hypertension, infections and oncology.

The creation of dialogue platforms at the national level is also envisaged, where to exchange the point of view of different supply chain stakeholders (including patients and healthcare providers). The study highlights the high burden shortages create on pharmacists and physicians looking for the best possible treatment alternative for their patients. A possible way to address this issue would see the availability of information about alternative medicines in shortage databases. In many cases, this type of occurrence is referred just to some countries within the EU, thus suggesting inequitable distribution and access rather than global supply issues may play a major role in shortages.

Understanding the root causes

Limited reporting is a key point to be solved in order to improve the understanding of root causes of shortages. According to the study, a reductionist approach to reporting is often used; this makes fully evident just acute causes (e.g. a problem at the production site), but leaves unattended more systemic issues (e.g. consolidation of manufacturing, resulting in a very limited number of production sites) and market-related factors (e.g. single-winner procurement practices).

Quality and manufacturing issues account for approx. half of all cases of shortages, suggest the report; among commercial reasons are market withdrawals and unexpected increases in demand. The information available for the analysis was judged insufficient to exactly asses the potential risks linked to outsourcing of manufacturing activities (including the production of APIs) and parallel distribution.

The proposed recommendations ask for greater transparency of industry supply quotas as well as parallel traders’ and wholesalers’ transactions. Suppliers should establish adequate shortage prevention and mitigation plans; legal obligations for MAHs and wholesalers are suggested in order to maintain a safety stock of (unfinished) products for medicines of major therapeutic interest at EU-level.

A new legislation to tackle shortages

The provisions set forth by Articles 23a and 81 of the Directive have been transposed differently into the single national legislations, often well before the establishment of the shortages registries. Several EU’s countries have acted on their own to strengthen the system, for example establishing mandatory reporting on stock levels and export restrictions. Nevertheless, according to the study available data are not sufficient to draw final conclusions on the costs and efficacy of stock keeping obligations on the level of (notified) shortages in the countries where they were introduced.

A more pro-active approach to the management of medicines shortages by MAHs and distributors may be supported by the availability of a EU-wide and uniform legislation governing financial sanctions to be applied if notification requirements and/or supply responsibilities are not met. Other suggestions include the adoption of common principles for the introduction of national restrictions on intra-EU trade, and the availability of greater flexibilities for emergency imports of specific products in case of market withdrawals and other critical shortages. As for procurement, the study indicates the opportunity to address public procurement tenders also considering the incorporation of requirements for more diversified, multiple tenderers and thereby supply sources.

From a regulatory perspective, the document highlights the opportunity to reduce costs and simplify administrative procedures for the submission of post-approval changes. The availability of an accelerated mutual recognition procedure (MRP) within the EU is also suggested, together with a more efficient use of the Repeat Use Procedure. Improved flexibility should be a target also with respect to the EU-wide regulation governing medicines packaging and labelling, so to allow for the use of digital leaflets and multi-country/multi-language packaging and labelling.


Medical Cannabis in Europe

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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.