Periodic Reporting for period 1 - ETERNAL (Boosting the reduction of the environmental impact of pharmaceutical products throughout their entire life cycle.)
Reporting period: 2022-09-01 to 2024-02-29
ETERNAL aims to contribute to the sustainable development of pharmaceutical manufacture, use and disposal, by using and promoting full life cycle approaches covering design, manufacture, usage, and disposal, assessing the environmental risks of not only the API and residues/metabolites but other chemicals and by-products of the production process. This type of approach is essential to take into consideration the types of green manufacturing approaches under consideration by the pharmaceutical industry, as evidenced by the range and scope of case studies being undertaken within ETERNAL. Specific application of our risk and life cycle assessment approaches to the ETERNAL case studies is a key element of the proposed work and will provide industry and policymakers with key examples of how whole life cycle assessment may be used to evaluate the changes in environmental impacts expected due to the introduction of green manufacturing processes.
Given an expected increase in medicine consumption in Europe (and indeed worldwide) due to rising demand from aging populations and a general growing dependence on pharmaceutical drugs, pharmaceuticals are a priority area from an environmental health perspective. One area of growing concern stems from the presence of pharmaceutical residues that can enter the environment at all stages of their life cycle (via effluents from manufacturing, natural excretion, or improper disposal), and can accumulate in fish, vegetables, livestock, and end up in drinking water. Indeed, more than 770 pharmaceuticals and their metabolites have been found in the environment worldwide and there is concern about the potential consequential harm to human health and the environment.
To address such problems and abate these concerns, the ETERNAL project aims to:
a) boost the reduction of the environmental impact of pharmaceutical products by advancing a roadmap of technological innovations in the fields of biocatalysts, carcinogenic impurity capture, substitution of non-recycled solvents, correct treatment of recycled solvents, membrane technology, continuous manufacturing processing and digitalization towards a) green production methods and b) one-step disposal where drugs are fully metabolized in the body and break down immediately and harmlessly in the environment.
b) increase the understanding of the environmental impact and toxicity of pharmaceuticals among industry, the research community and regulators to inform pharmaceutical strategies and policies based on scientific evidence. A key feature will be a holistic full systems approach, considering the full life cycle impact, from manufacture onwards (also considering such aspects as plant cleaning and the entry of cleaning solvents into the environment, and supply chain…).
c) create an opportunity to catalyze behavioural change or social innovation by informing consumers/patients about safe disposal methods for unused or expired medicines. Additionally, change will be pushed by promoting the choosing of the least environmentally-hazardous medicines among healthcare practitioners, as well as sensitizing around the area of improved prescription accuracy.
Given an expected increase in medicine consumption in Europe (and indeed worldwide) due to rising demand from aging populations and a general growing dependence on pharmaceutical drugs, pharmaceuticals are a priority area from an environmental health perspective. One area of growing concern stems from the presence of pharmaceutical residues that can enter the environment at all stages of their life cycle (via effluents from manufacturing, natural excretion, or improper disposal), and can accumulate in fish, vegetables, livestock, and end up in drinking water. Indeed, more than 770 pharmaceuticals and their metabolites have been found in the environment worldwide and there is concern about the potential consequential harm to human health and the environment.
To address such problems and abate these concerns, the ETERNAL project aims to:
a) boost the reduction of the environmental impact of pharmaceutical products by advancing a roadmap of technological innovations in the fields of biocatalysts, carcinogenic impurity capture, substitution of non-recycled solvents, correct treatment of recycled solvents, membrane technology, continuous manufacturing processing and digitalization towards a) green production methods and b) one-step disposal where drugs are fully metabolized in the body and break down immediately and harmlessly in the environment.
b) increase the understanding of the environmental impact and toxicity of pharmaceuticals among industry, the research community and regulators to inform pharmaceutical strategies and policies based on scientific evidence. A key feature will be a holistic full systems approach, considering the full life cycle impact, from manufacture onwards (also considering such aspects as plant cleaning and the entry of cleaning solvents into the environment, and supply chain…).
c) create an opportunity to catalyze behavioural change or social innovation by informing consumers/patients about safe disposal methods for unused or expired medicines. Additionally, change will be pushed by promoting the choosing of the least environmentally-hazardous medicines among healthcare practitioners, as well as sensitizing around the area of improved prescription accuracy.
Since the project is still in its first year and a half of development, the results are still preliminary and on a small scale. It is therefore expected to achieve the completion of the objectives and challenges set by the project as the months progress. By way of summary, the following are the key objectives broken down and what has been achieved to date:
Objective 1: To launch a cocreation lab to ensure the mobilization of an industry-research-compliance partnership that facilitates codesign in an application-industry oriented R&D initiative.
• Scoping sessions between the research-technological development teams and the pharmaceutical industry hosts of the 6 Case Studies to codesign the application-oriented developments.
• Definition of the specifications, industry requirements, business/environmental impact KPIs and regulatory compliance requirements for each of the Case Studies to inform the R&D (TRL3-4) and further scale up (TRL5-6) involved parties.
Objective 2: To reduce the use of solvents and increase of green solvents.
• It is expected a reduction between 20-40% considering each case study. Reduction in solvent use thanks to the inclusion of continuous technologies and new synthetic routes. The reduction of solvent is linked directly to the technology applied and its complexity.
• Application of greener solvents in new synthesis routes applied by pharmaceutical companies.
Objective 3: To optimize solvent recycle/recovery options for processes with potential carcinogenic impurities like nitrosamines. Application of membrane technology and other technologies for solvent swaps, purification and product recovery resulting in lower energy consumption.
Objective 4: To apply mechanochemistry in the production of pharmaceutical products (HME, TSMG).
Application of Hot Melt Extrusion and Twin-Screw Melt Granulation in the obtaining of pharmaceutical formulations for immediate or modified release. The validation of this objectives will be provided after the analysis of the product quality (comparison with batch process).
Objective 5: To develop more eco-efficient purification/capture routes (for solvents and wastewater) with biobased products.
• Enzymatic degradation of molecules at their end-of-life (waste effluents).
• Capture of nitrosamine or other carcinogenic impurities (metals…) and APIs with natural based sorbents (NBS).
• Validated by analysis of intermediate of final products along the process line.
Objective 6: To develop innovative workflow digitalization, Process Analytical Technology (PAT) and Digital Twin solutions to enable Quality by Design and Continuous Manufacturing for competitive and scalable methods of production.
Architect a multi-agent Holonics-based Digital Twin framework for increased process understanding, optimisation, predictive capability, a by-design link between process variables and environmental impact KPIs and dynamic control of continuous manufacturing processes in the pharmaceutical industry, which will be implemented and validated on selected ETERNAL case studies.
Objective 7: To scale up the innovations in 6 industrial pilots hosted in pharmaceutical partners.
Objective 8: To assess the regulatory implications of the adoption of the innovations and to ensure a pathway to compliance.
Objective 9: To generate new scientific knowledge on the environmental fate and eco-toxicological effects of pharmaceuticals:
• Assess the approaches used for the environmental risk assessment (ERA) and life cycle assessment (LCA) of pharmaceuticals studied.
• Provide experimental and modelling support, via comparative ERA & LCA, for the project case studies, including comparative modelling studies to assess the environmental and life effects of modified production processes and new compounds.
• Cooperate with EC’s Joint Research Centre (JRC) in new approach methodologies for ecotoxicity assessment.
Objective 10: To catalyse behavioural change, participation and social innovation for reducing the environmental impacts of pharmaceuticals in terms of safe use and disposal.
Objective 1: To launch a cocreation lab to ensure the mobilization of an industry-research-compliance partnership that facilitates codesign in an application-industry oriented R&D initiative.
• Scoping sessions between the research-technological development teams and the pharmaceutical industry hosts of the 6 Case Studies to codesign the application-oriented developments.
• Definition of the specifications, industry requirements, business/environmental impact KPIs and regulatory compliance requirements for each of the Case Studies to inform the R&D (TRL3-4) and further scale up (TRL5-6) involved parties.
Objective 2: To reduce the use of solvents and increase of green solvents.
• It is expected a reduction between 20-40% considering each case study. Reduction in solvent use thanks to the inclusion of continuous technologies and new synthetic routes. The reduction of solvent is linked directly to the technology applied and its complexity.
• Application of greener solvents in new synthesis routes applied by pharmaceutical companies.
Objective 3: To optimize solvent recycle/recovery options for processes with potential carcinogenic impurities like nitrosamines. Application of membrane technology and other technologies for solvent swaps, purification and product recovery resulting in lower energy consumption.
Objective 4: To apply mechanochemistry in the production of pharmaceutical products (HME, TSMG).
Application of Hot Melt Extrusion and Twin-Screw Melt Granulation in the obtaining of pharmaceutical formulations for immediate or modified release. The validation of this objectives will be provided after the analysis of the product quality (comparison with batch process).
Objective 5: To develop more eco-efficient purification/capture routes (for solvents and wastewater) with biobased products.
• Enzymatic degradation of molecules at their end-of-life (waste effluents).
• Capture of nitrosamine or other carcinogenic impurities (metals…) and APIs with natural based sorbents (NBS).
• Validated by analysis of intermediate of final products along the process line.
Objective 6: To develop innovative workflow digitalization, Process Analytical Technology (PAT) and Digital Twin solutions to enable Quality by Design and Continuous Manufacturing for competitive and scalable methods of production.
Architect a multi-agent Holonics-based Digital Twin framework for increased process understanding, optimisation, predictive capability, a by-design link between process variables and environmental impact KPIs and dynamic control of continuous manufacturing processes in the pharmaceutical industry, which will be implemented and validated on selected ETERNAL case studies.
Objective 7: To scale up the innovations in 6 industrial pilots hosted in pharmaceutical partners.
Objective 8: To assess the regulatory implications of the adoption of the innovations and to ensure a pathway to compliance.
Objective 9: To generate new scientific knowledge on the environmental fate and eco-toxicological effects of pharmaceuticals:
• Assess the approaches used for the environmental risk assessment (ERA) and life cycle assessment (LCA) of pharmaceuticals studied.
• Provide experimental and modelling support, via comparative ERA & LCA, for the project case studies, including comparative modelling studies to assess the environmental and life effects of modified production processes and new compounds.
• Cooperate with EC’s Joint Research Centre (JRC) in new approach methodologies for ecotoxicity assessment.
Objective 10: To catalyse behavioural change, participation and social innovation for reducing the environmental impacts of pharmaceuticals in terms of safe use and disposal.
At this moment of the project, no result have been achieved.