Skip to main content

BIOmaterial RIsk MAnagement

Periodic Reporting for period 2 - BIORIMA (BIOmaterial RIsk MAnagement)

Reporting period: 2019-05-01 to 2020-10-31

"BIORIMA is focusing on biomaterials in the nano range in accordance with the call’s emphasis 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"". However, it is clear from Nanosafety research that the material size is a continuous spectrum and the BIORIMA approach is also applicable to larger-sized biomaterials. Specifically, BIORIMA has the following objectives:
Objective 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.
Objective 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.
Objective 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;
Objective 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 developing robust, inter-laboratory validated test methods for identification of potential adverse health effects of NBM containing medical products and devices as well as testing schemes to assess possible environmental effects of such materials. We develop a conceptual integrated human health and environmental 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 has started. Basic communication channels were set, internal/external training was carried out. The transfer of the pre-normative research results to regulatory bodies was focused to preliminary contacts.
In Period 2 the BIORIMA database is updated as data become 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.
A key work during this first period 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. Strong 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 is comprehensive and deals both with human health and environmental impacts. We have addressed both 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. Some of the work is already being utilized towards the development of new test standards and this is something will continue to emphasize as we move forward; it is not sufficient to generate data sets across multiple different model systems, but we also need to ensure contributing to the development or validation of robust test methods for nanobiomaterials that are manufactured for medical products or devices. The BIORIMA IRM framework validation strategy reflects the commitment to bring the achieved results to the NBMs value chain, from production and use, to end-of-life treatments in both industrial facilities and hospitals. Our dissemination strategy reflects the commitment to bring the achieved results to the global community in general and to interested stakeholder groups. Public Training Schools open to everyone support this strategy.

Experimental results achieved so far show a high innovative potential regarding both (1) the development of reliable methods and reference materials for NBM characterization, measurement and in vitro/in vivo testing, and (2) the understanding of basic mechanisms and factors that rule the intrinsic interaction between key material properties and biological organisms at the molecular, cellular and tissue level in terms of exposure, hazard and risk/safety.
The newly established approaches will have a strong impact on the regulation of NBM and their use in MD and ATMP (such as the EU MDR – Regulation 2017/745, or the REACH Regulation 2018/1881 including Annexes I, III and VI-XII), and on method and material standardization (e.g. ISO/TC 229 on Nanotechnologies or OECD test guidelines).
The project coordinator has continuously interacted with other ongoing and upcoming projects and participated in international meetings, promoting the progress of BIORIMA.
Concept IRM Framwork
Progression IRM Framework
BIORIMA Training School
Project Consortium