green deal Archives - European Industrial Pharmacists Group (EIPG)

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

Environmental sustainability: the EIPG perspective


Piero Iamartino Although the impact of medicines on the environment has been highlighted since the 70s of the last century with the emergence of the first reports of pollution in surface waters, it is only since the beginning of the Read more

Environmental sustainability: the EIPG perspective

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Piero Iamartino

Although the impact of medicines on the environment has been highlighted since the 70s of the last century with the emergence of the first reports of pollution in surface waters, it is only since the beginning of the 2000s that specific regulatory interventions have been designed to promote the identification of the different sources of pollution and the determination of possible actions to be taken.

The obligation to submit the result of an environmental risk assessment of a medicinal product at the same time as the application for marketing authorisation was introduced only after the publication of the Environmental Risk Assessment (ERA) guideline issued by EMA in 2006, which sets out the guidelines and describes a series of standard tests to be performed. However, this first piece of legislation immediately highlighted limitations as it was applied only to the marketing of medicines from that moment on, without considering the contribution of medicines with the same active ingredient and neglecting the evaluation of those already authorised and on the market.

Over the following years, the problem of the environmental impact of medicines was tackled more extensively with the launch of several projects promoted by the European Commission in partnership with the EFPIA (IMI: Chem21, iPiE and Premier) which have deepened the characterisation of environmental risks, with the identification of priority criteria to be assigned to interventions and the development of models and tools to measure the sustainability of the processes of manufacture, in particular of active substances.

These important projects in recent years have been added to the initiatives undertaken at the European level with the publication in 2020 of the new European pharmaceutical strategy which defines some specific objectives for the mitigation of the environmental impact of medicines that will be reflected in the upcoming revision of European pharmaceutical legislation and which are part of the broader regulatory acts for the ecological transition envisaged by the Green Deal European.

In light of the above, a gradual transformation of some processes and operating methods carried out by the European pharmaceutical industry is envisaged, starting from the development of a new medicinal product to its distribution and, similarly, adequate regulatory interventions will have to be envisaged on the management of the correct use and disposal of medicinal products since the environmental impact of this last phase of the life cycle of a medicinal product is predominant.

Although these changes involve all professionals working in the pharmaceutical industry, a key role is played by the industrial pharmacist who, due to his professional profile dictated by his university curriculum, has the fundamental knowledge bases to occupy different positions in the industry, covering the entire path of medicine from its conception and manufacture as an active ingredient, its development as a medicinal product and its distribution on the market.

With this in mind, EIPG has started the preparation of a document that analyses the main critical areas of the entire production process of a medicinal product and sets out its position on the interventions considered a priority in a perspective of changes that will lead to the inclusion of new methods alternative material resources and will require new skills.

The first critical area examined is the manufacture of the active ingredient, both for its impact as such on the environment and for the process applied to its manufacture. The problem is particularly relevant for small molecules, while it is substantially insignificant for large molecules and even less so for products based on the use of cellular tissues or biological structures (ATMPs). The fundamental parameters to be considered are the environmental toxicity and the bio-degradability of the product. The problem is how to reconcile these two parameters with the chemical-physical and biopharmaceutical characteristics that an active ingredient must possess to be administered, absorbed and then carry out the desired pharmacological activity. The effort required in the design and screening phase of a new small molecule is the identification of a structural parameter that makes it more eco-friendly without compromising its purpose. Although this criticality does not arise in the case of large molecules and ATMPs, for these active ingredients the environmental impact due to higher energy consumption attributable to the need for low-temperature storage conditions may prevail.

About the production process of small molecules, which today still represent the largest percentage of active ingredients in development and on the market, it is essential to definitively introduce the application of the principles of Green Chemistry, as highlighted by the most recent studies (IMI Premier Project). The prospect is that of a progressive change in the synthesis processes with the use of reagents and less toxic solvents that are entirely recyclable and reusable, as well as the development of a synthesis route that allows the least number of operations, generating the least amount of waste and maintaining the best possible efficiency. It is desirable to increase biocatalysis processes as well as the introduction of more incisive treatments in the management of industrial wastewater to accentuate chemical degradation before their transfer to eternity.

A second large critical area where important changes are expected is the manufacturing processes of the medicine from the active substance to its availability for distribution on the market. Also in this area, interventions can be identified to optimize the use of the resources used, with particular reference to energy consumption and the use of water. These two parameters are already the subject of numerous studies for the development of new energy containment processes with the introduction of innovative plant solutions, and further improvements are expected considering the benefits that derive from them in terms of efficiency and therefore costs.

Among the parameters closely linked to the medicinal product that shows a significant environmental impact, attention must be paid to the packaging materials used in the pharmaceutical industry. A priority intervention must focus on certain widely used plastic materials that are difficult to dispose of and not recyclable, identifying alternative materials with the consequent need to study their compatibility with the medicinal product, especially if used in direct contact, and their impact on the stability profile of the same, as required by the reference standards. Other objectives should be the choice of secondary packaging materials that can be easily recycled by the end user, as well as the reduction of their volume, also favoured by the digitization of the information materials related to them. The implementation of these interventions will require adjustments both to the packaging lines used in the pharmaceutical industry and to the alternative ways of managing products in the transport and distribution phase, with a marked increase in studies for the reuse of packaging materials in line with the principles of the circular economy.

The prospects of the expected changes in the path from the active substance to the medicine will have to be accompanied by an assessment of the possibilities of intervening in the supply chain used by the pharmaceutical industry involving suppliers of active ingredients, materials and medicines. The regulatory guidelines and commitments on actions to improve environmental sustainability will require a progressive review in the management and evaluation of suppliers according to their ability to apply the ecosustainability criteria of their processes, giving preference to those who take this path.

The above analysis, limited to the areas of greatest environmental criticality, highlights the transformations that are expected in the pharmaceutical industry in the coming years with the implementation of the provisions that will be progressively adopted at the European level. We think there should be good coordination between the impositions for environmental sustainability and the need to adhere to pharmaceutical regulatory requirements to facilitate the implementation of changes. This coordination is essential as innovation will be the guiding criterion for the introduction of the required changes to meet the sustainability objectives.


The debate on the “Do No Significant Harm” principle in R&D

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by Giulianna Miglierini

The “Do No Significant Harm” (DNSH) principle is a widely diffused approach aimed to guarantee the respect of ethical limits while dealing with many kinds of activities. It is the case, for example, of the use of big data to conduct behavioural studies, or of health research aimed to be of help to society without hurting anyone. Available frameworks regulating the ethical approach to research usually focus on the protection of participants against unwanted, potentially harmful effects resulting from the study. Examples of such frameworks are the 1964 Declaration of Helsinki and the 1979 Belmont Re-port, which do not mention the protection of other people and of the environment.

The DNSH and the European Green Deal

The introduction of the Do Not Significant Harm principle within the Taxonomy regulation (EU 2020/825) represents the first example of its extensive application aimed to prevent unintended damages to the environment. According to the regulation, beneficiaries of financial support from EU institutions are expected to assess the possible negative climate and environmental impacts of their projects, and to avoid any activity that may negatively impact the sustainability objectives of the European Green Deal.

These include six main areas of attention, i.e. mitigation of and adaptation to climate change, sustainable use and protection of water and marine resources, control and prevention of pollution, the transition to a circular economy, and the protection and restoration of biodiversity and ecosystems.

The inclusion of the DNSH principle in the Taxonomy regulations means that the above-mentioned objectives would apply to any EU funded activity, including framework research programmes such as Horizon Europe.

Many critics arose from this move of the Commission, as it may greatly affect the effective capacity of researchers to plan and realise their activities. As a part of the debate, MEP member Christian Ehler presented in July 2021 a written question to the Commission aimed to clarify how the DNSH aspects of a project would be evaluated and scored during the assessment of the proposals, and the impact they may have on the final outcome of such assessment.

The written answer provided by EU Commissioner Mariya Gabriel stated that “the application of the ‘Do No Significant Harm’ principle in Horizon Europe is voluntary at project level”, and that its inclusion in the project description will have no impact on the assessment of the proposal. According to the Commission, no declaration of projects compliance with the principle is re-quested, and no undue increase of the administrative burden for applicants is present. Instead, the reference made to the DNSH principle would only aim to raise awareness about the environmental risks linked to research activities and encourage the identification and mitigation of potential measures.

A second written question presented in August 2022 asked the Commission to provide further details, i.e. how many applications under Horizon Europe included the DNSH principle in the project description, the percentage of 2021/2022 budget covered by DNSH and the number of evaluations in which the DNSH principle was used in the assessment of the application.

The written answer by Commissioner Gabriel indicated references to the DNSH principle in proposals vary according to its relevance to the specific thematic area and technology readiness levels. Only 2.6% of proposals referred to parts of the programme that make no explicit reference to DNSH considered the principle; this percentage reached 29.6% for applications referred to parts of the programme making explicit reference to it (data 12 August 2022). Commissioner Gabriel also said almost half of the budget of the work programme for 2021-2022 made explicit reference to the DNSH principle, and that all EU actions and policies have to be consistent with the objectives of the Paris Agreement and the Green Deal oath ‘do no harm’.

The ongoing debate

No matter to say, the position of the European Commission to extend the implementation of the DNSH principle across all research activities activated a reach debate within the R&I community. The initial objections by MEPs were based, according to Mr. Ehler, on the possible absence of “democratically legitimised criteria” (read more on Science|Business).

According to a viewpoint article published in Science|Business, the DNSH approach chosen by the Commission would be not the right way to address the issue of environmental sustainability. “Rather, research and innovation policy should be reconfigured to allow researchers to ‘stay with’ the harms they (might) do”, wrote the authors. The alternative to DNSH sees greater attention towards a better understanding of what really constitutes a “harm”. According to the authors, a definition of “significant harm” should be agreed upon between humans, non-humans, and ecosystems experiencing harm, thus avoiding any technocratically and unilaterally handed down definition. They also discuss the appropriateness of the concept of ‘situatedness’ in order to reach a suitable definition of significant harm.

Key to this vision should be the “understanding that there is no universal, objective viewpoint from which one might determine which research is beneficial or harmful, for whom, and to what degree”. To this instance, elements to be considered in the assessment include the time needed for the harm to manifest, its geographical location or the involvement of marginalised actors. Furthermore, the approach adopted by the EU Commission would not be suited to solve the ambiguities. A possible solution would be represented by the “creation of spaces where ambiguous harms can be appropriately engaged”.

The associations representing the academic and scientific world also took a position against the extension of the DNSH principle to all projects under European R&I framework programmes.

The European University Association (EUA), CESAER (representing universities of Science and Technology) and Science Europe (on behalf of major public organisations funding or performing research in the EU) jointly published a statement to ask support to the Parliament as for the approval of amendment 165, focused on feasibility, appropriateness and proportionality of all programmes and activities, in accordance with the relevant sector-specific rules. The associations also underline that the implementation of the DNSH principle should not be counterproductive and weaken the contribution of the R&I community to sustainability and green objectives.

According to EUA, clear guidelines are missing on how the principle should be implemented in practical terms. Furthermore, the broad application of the DNSH principle might especially undermine the possibility to undertake fundamental research activities. As for now, the principle applies only to European Innovation Council projects, and missions and clusters of Pillar II of particular relevance for their environmental outcomes and impacts.

In a position paper of October 2022, CAESAR asked, among others, for an “ethics by design” approach, based on a ethical checklist to be included in the design phase of projects. Briefings with the proposal evaluator and project reviewer should also be improved in order to clarify when the DNSH principle has to be taken into account.

According to Science Europe, the implementation of the principle should not add an additional administrative burden to researchers and increase the complexity of project proposals and evaluations. The association also asks for the broader application of the DNSH principle to be preceded by a thorough assessment of its current implementation in Horizon Europe.


Some perspectives on green pharmaceuticals

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by Giuliana Miglierini

The central role the green agenda plays within the EU Commission’s transformative policies impacts also on the development and availability of pharmaceutical products characterised by a improved sustainability. The concept of “Pharmaceuticals in the environment” (PiE) is entering the new legislative framework; the undergoing revision of the pharmaceutical legislation, for example, may include among other the request of environmental risk assessment and urban wastewater treatment. But also, the goal of a circular economy at net zero emission and the revision of the chemical legislation.

As explained by Dr Bengt Mattson, Policy Manager at the Swedish research-based pharmaceutical industry association Läkemedelsindustriföreningen (Lif) during a recent EIPG’s webinar, the EU Commission Action plan on environment for years 2021-2023 includes twenty legislative and non-legislative files impacting also the pharma sector.

The theme of the so-called “green pharmaceuticals” is also part of the broader approach to environmental sustainability of the chemical industry. The topic is not new, for example the EU and IMI-funded CHEM21 project in years 2012-2017 focused on the development of new manufacturing processes for the pharmaceutical industry to reduce the use of expensive and toxic materials. Another target of the project included the development of environmentally friendly methods useful to save time and costs, while reducing waste.

Activities focused on the antimicrobial drug flucytosine, with the final goal to use flow chemistry and biocatalyst techniques to make it more easily available also in lower income countries to treat a fungal form of meningitis in HIV/AIDS patients. The new, cleaner and safer method developed under the project allowed to reduce the need for expensive toxic chemicals and other raw materials, with a corresponding decrease both in costs and wastes. As a side activity, the CHEM21 project also explored more efficient screening methods to find new enzymes potentially useful as biocatalysts in industrial chemical reactions.

A Green-by-design future for pharmaceutical processes

At the EIPG’s webinar, Dr Mattson discussed from many different perspectives how R&D initiatives may influence green manufacturing. The attention moved from packaging and energy in the ’90-ies to APIs released in the environment at the beginning of the new millennium. The ’20-ies shows a greater attention to API-related emission and to aspects linked to the efficient use of resources and the resulting carbon footprint. From this point of view, it may result not easy to correctly estimate the expected environmental impact of a pharmaceutical product. Biological substances, for example, may be more easily biodegradable than synthetic small molecules, but they may also require more energy to ensure the correct storage conditions.

The development of green processes represents a great challenge for chemists and pharmacists working in the pharmaceutical industry. A possible approach to Green Drug Design has been explored, for example, by another IMI project, Premier. Results have been recently published in the Environmental Science & Technology Letters.

The “Greneer” approach includes among others, criteria aimed to achieve avoidance of non-target effects and of use of persistent, bioaccumulative, and toxic (PBT) substances, and exposure reduction. The final goal would be the development of “green-by-design” active pharmaceutical ingredients.

Green pharmaceutical processes should also prefer more eco-friendly, renewable raw materials, with a particular attention to the choice of solvents and reagents. Waste water treatment to eliminate residues of pharmaceuticals is a typical example of downstream measures put in place at the industrial level to reduce the environmental impact of manufacturing activities. As noted during the webinar, the main source of this type of pollutants remains excretion by patients, followed by inappropriate disposal.

The pharmaceutical supply chain, and in particular community pharmacists represented by PGEU, is also active to inform patients, develop national and regional collection schemes for expired and unused medicines, and to make available more sustainable packing materials and transports.

A call to action from the UK

In the UK, the request emerging from a report by the Office of Health Economics (OHE), commissioned by the Association of the British Pharmaceutical Industry (ABPI) is for the government and other stakeholders to take immediate action “to secure the era of green pharmaceuticals”.

The report highlights the challenges for the pharmaceutical industry in order to reach the ambitious target of net zero carbon. Among these is the difficulty to quickly change processes to increase sustainability while maintaining product safety, the need to collaborate at all levels along the complex global pharmaceutical supply chain, the high waste-to-product ratio on the supply side of the medicines market, the new environmental impact profile of innovative drug products compared to established small molecule technologies, and the lack of reward for sustainability.

The report also suggests high-priority activities, including investment in decarbonisation and a long-term energy strategy for transition away from fossil fuels. Common regulatory standards and environmental reporting standards should be agreed upon by regulators of different geographic areas, including the EU and US. Financial support for the adoption of greener technologies by both the industry and the NHS is also suggested. Improvements to the NHS’s supply chain may come by the Supplier Roadmap and more sustainable procurement processes and health technology assessment methods. Public-private partnerships may represent the tool to launch proof of concept pilots for sustainability schemes or co-invest on key infrastructure projects.

Standardised metrics to be used to publicly disclose emissions and progress against targets are suggested as a useful tool for the industry, together with the life cycle analysis (LCA) of products, and the development of innovative solutions for waste management and efficiency improvement.

Other insights on green pharmaceuticals

Many other things may be said on green pharmaceuticals, but we are running out of space. We then highlight some useful links readers may refer to deepen the topic.

An outcome of the CHEM21 project is represented by the CHEM21 online learning platform, managed by the ACS Green Chemistry Institute. The platform offers many free educational and training materials in the field of the sustainable synthesis of pharmaceuticals.

The Green Chemistry Working Group of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) has elaborated a Green Aspirational Level (GAL) metrics to assess the green efficiency for a given API’s manufacturing process, based on the complexity of its ideal synthesis route.

The industrial associations also committed to take action in the field of Environment, Health, Safety and Sustainability (EHS&S). The three main European groups representing, respectively, the research-based industry (EFPIA), the auto-cure (AESGP) and the generic and biosimilar sectors (Medicines for Europe) have developed the Eco-Pharmaco-Stewardship (EPS) framework. The initiative takes into consideration the entire life-cycle of a medicinal product, including roles and responsibilities of all parties involved.

The Medicine Maker’s editor Stephanie Sutton interviewed some industrial experts on different aspects of sustainability (here the link to the article). Some other comments from industrial representatives have been reported by Cynthia A. Challener in an article published on PharmTech.com