Periodic Reporting for period 3 - BIORIMA (BIOmaterial RIsk MAnagement)
Période du rapport: 2020-11-01 au 2022-01-31
BIORIMA focused on biomaterials in the nano range in accordance with the call on "Support for good governance in biomaterials research following the safe, integrated and responsible approach as laid down in "Nanosciences and Nanotechnologies: An action plan for Europe". BIORIMA had the following objectives:
1: Generate and store a bank of relevant reference and/or certified, well-characterised reference NBM – covering the classes: metal/metal oxide, ceramics, organics and hypbrids (see Table 1) - for use in BIORIMA and for future projects which produce NBM and need to have access to the reference BIORIMA NBM for comparative purpose. Support the standardisation of the production methods (e.g. large sample preparation/assessment) of the proposed NBM, including methods that will reflect their eventual deployment as part of ATMP and MD. Undertake a Life Cycle Analysis of the proposed NBM and perform an assessment of their potential exposure to humans and the environment.
2: Develop exposure assessment/monitoring systems, on the field detection systems as well as methods for their performance assessment; assess accidental risks including explosion and massive release of NBM. 3: Compare and validate current (and/or to develop including validation of new) test methods, including in vitro, in vivo methods, to detect adverse effects from NBM to:
• human health including acute and chronic toxicity (including oral, inhalation, dermal and intravenous injection);
• environment; ecotoxicity tests, persistence, bioaccumulation, toxicity and life cycle impacts on all forms of biota;
• integrate the Exposure and Hazard assessment into an overarching Intelligent Testing Strategy (ITS) compatible with the current evaluation/test guidance for biomaterials ISO-10993-1;
4: Develop (web-based) predictive models of the toxic behaviour of engineered NBM; To adapt, extend and validate a reliable thorough overarching methodology for tiered risk assessment for engineered NBM; generate different risk reduction strategies and systems and the BIORIMA IRM framework for evaluating and implementing them; develop a rationale for selecting the tools in objectives 1, 2 and 3 and use them to evaluate the risk profile of NBM – as demonstrated through case studies; integrate the BIORIMA tools into a web-based Decision Support System (DSS) available to all stakeholders (Academia, Industry, Patient organisation, regulatory bodies and Standardisation authorities).
1: Generate and store a bank of relevant reference and/or certified, well-characterised reference NBM – covering the classes: metal/metal oxide, ceramics, organics and hypbrids (see Table 1) - for use in BIORIMA and for future projects which produce NBM and need to have access to the reference BIORIMA NBM for comparative purpose. Support the standardisation of the production methods (e.g. large sample preparation/assessment) of the proposed NBM, including methods that will reflect their eventual deployment as part of ATMP and MD. Undertake a Life Cycle Analysis of the proposed NBM and perform an assessment of their potential exposure to humans and the environment.
2: Develop exposure assessment/monitoring systems, on the field detection systems as well as methods for their performance assessment; assess accidental risks including explosion and massive release of NBM. 3: Compare and validate current (and/or to develop including validation of new) test methods, including in vitro, in vivo methods, to detect adverse effects from NBM to:
• human health including acute and chronic toxicity (including oral, inhalation, dermal and intravenous injection);
• environment; ecotoxicity tests, persistence, bioaccumulation, toxicity and life cycle impacts on all forms of biota;
• integrate the Exposure and Hazard assessment into an overarching Intelligent Testing Strategy (ITS) compatible with the current evaluation/test guidance for biomaterials ISO-10993-1;
4: Develop (web-based) predictive models of the toxic behaviour of engineered NBM; To adapt, extend and validate a reliable thorough overarching methodology for tiered risk assessment for engineered NBM; generate different risk reduction strategies and systems and the BIORIMA IRM framework for evaluating and implementing them; develop a rationale for selecting the tools in objectives 1, 2 and 3 and use them to evaluate the risk profile of NBM – as demonstrated through case studies; integrate the BIORIMA tools into a web-based Decision Support System (DSS) available to all stakeholders (Academia, Industry, Patient organisation, regulatory bodies and Standardisation authorities).
In Period 1 we produced a Project Data Inventory, identified existing/new requirements regarding data collection. Selection of NBM was devoted to maximize the impact of BIORIMA by selecting a set that represent real-world needs of industry, regulators and other stakeholders working with biomaterials for biomedical applications. We demonstrated that there are several activities in the life cycle where a potential release of particles in the nanometre range is likely to occur. WP4 is developed robust, inter-laboratory validated test methods for identification of potential adverse health effects of NBM containing medical products and devices and testing schemes to assess possible environmental effects of such materials. We developed a conceptual integrated Risk Assessment (RA) strategy for NBM used in MD and ATMP. This strategy includes IATA. A conceptual strategy for Risk Management (RM) of NBM's was developed. Developments were integrated into the BIORIMA RMF, presented, discussed and reported in a White Paper. The development of the BIORIMA DSS started, basic communication channels were set, internal/external training was carried out. Transfer of pre-normative research results to regulatory bodies focused to preliminary contacts.
In Period 2 the BIORIMA database is updated as data became available and distribution of NBM was ensured by re-organizing sessions; wide-ranging characterization action in support to risk assessment was provided. A comprehensive characterization framework in support to risk assessment was further developed and advanced for all the NBM. BIORIMA partners formed a COVID-19 task force. Strategies for human health and environmental risk assessment were further refined. Furthermore, the BIORIMA Risk Management Framework (RMF) was finalised. A first round of surveys and on-site visits were evaluated, showing that the DSS and the RMF support the implementation of risk mitigation strategies.
In the last period, BIORIMA concentrated to complete outstanding remaining tasks across the work packages. The database now includes the planned tests/experiments performed by all partners, as part of the BIORIMA Data Inventory, existing and new requirements regarding data collection templates, SOPs, the overall data curation system and the timetables for data generation and curation. We deployed the BIORIMA eNanoMapper database and promptly curated and upload datasets as the project progressed. The DSS is now fully functional, and it is publicly accessible via this link: https://sunds.gd.
In Period 2 the BIORIMA database is updated as data became available and distribution of NBM was ensured by re-organizing sessions; wide-ranging characterization action in support to risk assessment was provided. A comprehensive characterization framework in support to risk assessment was further developed and advanced for all the NBM. BIORIMA partners formed a COVID-19 task force. Strategies for human health and environmental risk assessment were further refined. Furthermore, the BIORIMA Risk Management Framework (RMF) was finalised. A first round of surveys and on-site visits were evaluated, showing that the DSS and the RMF support the implementation of risk mitigation strategies.
In the last period, BIORIMA concentrated to complete outstanding remaining tasks across the work packages. The database now includes the planned tests/experiments performed by all partners, as part of the BIORIMA Data Inventory, existing and new requirements regarding data collection templates, SOPs, the overall data curation system and the timetables for data generation and curation. We deployed the BIORIMA eNanoMapper database and promptly curated and upload datasets as the project progressed. The DSS is now fully functional, and it is publicly accessible via this link: https://sunds.gd.
A key work was promoting the NBM selection, production and distribution. This allowed the partner to have the target NBM and to start the experimental activity. The widespread characterization action supported provided new and extensive physicochemical descriptors to be used in WP 3-5 to promote the correlation and get information on real in vitro dose and fate, in complex biological system. Participation of the companies to production and distribution of NBM offered a key tool to the project, in terms of availability of NBM at high TRL with a clear regulation pathway and of robust information ready to be exploited. Work on hazard assessment was comprehensive and deals with human health and environmental impacts. We addressed acute and chronic or long-term effects and this is something that we will continue to work on in WP4 in order to develop robust test methods for both acute and chronic effects.
Many experimental results developed in BIORIMA show high innovative potential regarding (1) the development of reliable methods and potential reference test materials for NBM characterization and measurement, for (bio-)monitoring and in vitro/in vivo testing, and (2) the new knowledge and know-how produced that go beyond our present understanding on basic mechanisms and factors that control the complex interaction between key material properties and biological organisms or components at the molecular, cellular and tissue level in terms of exposure, dose-response, hazard and risk/safety
These new innovations could trigger and lead to new research in designing, developing, and using safe and sustainable NBMs in a variety of medical applications (e.g. drug and vaccine delivery and innovations, cancer diagnosis and treatment, use as biosensors etc.)
Especially the newly established Risk Management Framework (RMF) that is integrating the most relevant methods, tools and models produced in BIORIMA have a high potential to support and contribute to the current regulation of new smart materials and their application, such as NBMs used in MD and ATMP (within the new EU MDR Regulation 2017/745, or the EU chemicals regulation REACH 2018/1881 (especially to Annexe I, III and VI-XII), but also to initiate and support the standardisation of the tested biomaterials and methods within ongoing standardization efforts (within ISO/TC 229 or CEN/TC 352 on Nanotechnologies, or relevant OECD test guidelines, e.g. on the eco-toxicity of chemicals).
Many experimental results developed in BIORIMA show high innovative potential regarding (1) the development of reliable methods and potential reference test materials for NBM characterization and measurement, for (bio-)monitoring and in vitro/in vivo testing, and (2) the new knowledge and know-how produced that go beyond our present understanding on basic mechanisms and factors that control the complex interaction between key material properties and biological organisms or components at the molecular, cellular and tissue level in terms of exposure, dose-response, hazard and risk/safety
These new innovations could trigger and lead to new research in designing, developing, and using safe and sustainable NBMs in a variety of medical applications (e.g. drug and vaccine delivery and innovations, cancer diagnosis and treatment, use as biosensors etc.)
Especially the newly established Risk Management Framework (RMF) that is integrating the most relevant methods, tools and models produced in BIORIMA have a high potential to support and contribute to the current regulation of new smart materials and their application, such as NBMs used in MD and ATMP (within the new EU MDR Regulation 2017/745, or the EU chemicals regulation REACH 2018/1881 (especially to Annexe I, III and VI-XII), but also to initiate and support the standardisation of the tested biomaterials and methods within ongoing standardization efforts (within ISO/TC 229 or CEN/TC 352 on Nanotechnologies, or relevant OECD test guidelines, e.g. on the eco-toxicity of chemicals).