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Nanotechnology regulation in the EU
Nanomaterials are considered substances as defined in the existing regulatory framework for chemical substances. Hence, Regulation (EC) No 1907/2006 concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) is the main act that regulates nanomaterials as stated in the 2008 Communication1: “There are no provisions in REACH referring explicitly to nanomaterials. However, nanomaterials are covered by the ‘substance’ definition in REACH”. In 2011, the European Commission released a recommendation for a definition of a nanomaterial:
‘Nanomaterial’ means a natural, incidental or manufactured material containing particles, in an unbound state or as an aggregate or as an agglomerate and where, for 50 % or more of the particles in the number size distribution, one or more external dimensions is in the size range 1 nm-100 nm.
In specific cases and where warranted by concerns for the environment, health, safety or competitiveness the number size distribution threshold of 50 % may be replaced by a threshold between 1 and 50 %.2
It is used in different European regulations to harmonise how nanomaterials are defined across legal frameworks. In June 2022, the European Commission issued another recommendation on the definition of nanomaterials:
'Nanomaterial' means a natural, incidental or manufactured material consisting of solid particles that are present, either on their own or as identifiable constituent particles in aggregates or agglomerates, and where 50 % or more of these particles in the number-based size distribution fulfil at least one of the following conditions:
(a) one or more external dimensions of the particle are in the size range 1 nm to 100 nm;
(b) the particle has an elongated shape, such as a rod, fibre or tube, where two external dimensions are smaller than 1 nm and the other dimension is larger than 100 nm;
(c) the particle has a plate-like shape, where one external dimension is smaller than 1 nm and the other dimensions are larger than 100 nm. In the determination of the particle number-based size distribution, particles with at least two orthogonal external dimensions larger than 100 µm need not be considered.
However, a material with a specific surface area by volume of < 6 m2/cm3 shall not be considered a nanomaterial.3
Since the summer of 2013, there has been an ongoing work to adapt the Annexes of REACH to specifically cover nanomaterials. An impact assessment and a large consultation on this issue have been undertaken by the European Commission. From the 1st of January 2020, explicit legal requirements under REACH apply for companies that manufacture or import nanoforms.4 These reporting obligations are outlined in revised annexes to the REACH regulation:
- characterisation of nanoforms or sets of nanoforms covered by the registration (Annex VI);
- chemical safety assessment (Annex I);
- registration information requirements (Annexes III and VII-XI); and
- downstream user obligations (Annex XII).5
Since 2017, ECHA has also prepared a number of guidance documents to support registrants of nanomaterials. The overview of the key legislation concerning nanomaterials in the European Union is listed in the table below.
|Table AVI-9: Overview of legislation for nanomaterial use in the EU|
|Status||Document title||Country/ Region||Scope||Nano-specific|
|Implemented||Regulation (EC) 1907/2006 concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH)||EU||Chemicals and raw materials||No|
|Implemented||European Commission Recommendation on the Definition of a Nanomaterial (2011/696/EU)||EU||Substances at the nanoscale||Yes|
|Implemented||Commission Regulation (EU) 2018/1881 amending Regulation (EC) No 1907/2006 on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) as regards Annexes I, III, VI, VII, VIII, IX, X, XI, and XII to address nanoforms of substances||EU||Registration duties and obligations for nanomaterials||Yes|
|Implemented||Regulation (EC) on classification, labelling and packaging of substances and mixtures (CLP)||EU||Chemicals and raw materials||No|
Nanotechnology regulation in health sector in the EU
The European Medicines Agency (EMA)6 applies legal framework for general medicinal products to regulate nanomedicines for human use in the European Union.7 The EU legal framework for human medicines lays out standards to ensure a high-level protection of public health and the safety, quality, and efficacy of authorised medicines. A medicinal product requires a marketing authorisation by the competent authorities before being placed on the market. The requirements and procedures for marketing authorisation, as well as the rules for monitoring authorised products, are set out in Directive (2001/83/EC) on medicinal products for human use and in Regulation (EC) No 726/2004 for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency. They also include harmonised provisions for the manufacture, wholesale or advertising of medicinal products for human use.8 All EU legislation in the area of medicinal products for human use is listed in Volume 1 of "The Rules Governing Medicinal Products in the European Union".9
The Medical Devices Regulation, which repealed Directives on medical devices and active implantable medical devices, applies since 2021 after a four-year transition period and covers nanomaterials used in such devices.
The list of main European directives and regulations for health products, including nano-related medicinal products (although not specifically mentioned), is presented in the table below.
|Table AVI-10: Overview of legislation for health products and nanomaterial use in the EU|
|Status||Document title||Country/ Region||Scope||Nano-specific|
|Implemented||Directive 2001/83/EC on medicinal products for human use||EU||Medicinal products||No|
|Implemented||Regulation (EC) No 726/2004 for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency||EU||Medicinal products||No|
|Implemented||Directive 2001/20/EC on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use||EU||Clinical trials||No|
|Implemented||Regulation (EU) No 536/2014 on clinical trials on medicinal products for human use||EU||Clinical trials||No|
|Implemented||Regulation (EC) No 141/2000 on orphan medicinal products||EU||Medicinal products||No|
|Implemented||Regulation (EC) No 1394/2007 on advanced therapy medicinal products||EU||Medicinal products||No|
|Implemented||Regulation (EC) No 1901/2006 on medicinal products for paediatric use||EU||Medicinal products||No|
|Implemented||Regulation (EU) 2017/745 on medical devices||EU||Medical devices||Yes|
The EMA have published a range of specific preliminary guidelines for a range of nanomedicine preparation standards. But these are only at the public consultation stage and no formal regulatory guidance is currently available. The European Nanomedicine Characterisation Laboratory (EU-NCL) works closely with the regulatory bodies to inform and influence decision making on the regulation and potential danger of such products.10
Nanotechnology regulation in the rest of the world
The Medicines and Healthcare products Regulatory Authority (MHRA) regulates medicines within the UK. No clear guidance has been published in relation to nanomedicine approval and these are treated on case-by-case basis. In Canada, existing regulatory framework is used for the approval of nanotechnology products. Health Portfolio Nanotechnology Working Group has been established for the gathering and discussion of issues in relation to nanotechnology, and the general guidance on nanotechnology-based health products and food has been issued by the Health Canada. In Japan, the nanomedicine-specific regulation is yet to be developed and nanomedicine is currently regulated under the Pharmaceutical Affairs Law framework on case-by-case basis.
In the United States, the Food and Drug Agency (FDA) is regulating nanotechnology products, including nanomedicines. It applies the current statutory and regulatory authorities and product-specific standards under its jurisdiction. The Nanotechnology Characterisation Laboratory of the National Cancer Institute has also been contributing to the regulation of nanomedicines for more than 10 years. In April 2022, the FDA issued a guidance document on drug products, including biological products, that contain nanomaterials for the industry. The FDA formed the Nanotechnology Task Force and Nanotechnology Interest Group comprised of representatives from many regulatory centres in order to tackle the issue of regulating nanotechnology worldwide.
There is little regulation regarding nanomedicines in Asian countries, but India, China, Japan and Thailand are currently in the process of determining governance and regulatory policies to address issues on the nanotechnology field.11
In Australia, the government is undertaking reform to the regulation of therapeutic goods to continue to improve the safety, performance and quality of medical devices and improve health outcomes for patients, who require medical devices. In 2015, the Report of the Expert Panel Review of Medicines and Medical Devices Regulation (MMDR) made 58 recommendations for reform of the regulatory framework for medicines and medical devices. The Government accepted 56 MMDR recommendations in 2016, including Recommendation Twenty, which proposed that the regulation of medical devices, wherever possible and appropriate, align with the European Union framework including the classification of medical devices. The Australian Government Department of Health, the Therapeutic Goods Administration (TGA) issued the consultation paper as part of the reform program. This paper examines whether the Australian medical device regulatory framework should be aligned to the EU framework for medical devices containing nanomaterials, and how this could occur. The consultation was closed in 2021.12
1 Commission of the European Communities. (2008). Communication from The Commission to The European Parliament, The Council and The European Economic and Social Committee regulatory aspects of nanomaterials. Available at: https://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=COM:2008:0366:FIN:EN:PDF
2 European Commission. (2011). Commission Recommendation of 18 October 2011 on the definition of nanomaterial Text with EEA relevance. Official Journal of the European Union, 275, 38-40. Available at: https://eur-lex.europa.eu/eli/reco/2011/696/oj
3 European Commission. (2022). Commission Recommendation of 10.6.2022 on the definition of nanomaterial. Official Journal of the European Union, 229, 1-5. Available at: https://ec.europa.eu/environment/chemicals/nanotech/pdf/C_2022_3689_1_EN_ACT_part1_v6.pdf
4 European Commission. (2018). Commission Regulation (EU) 2018/1881 of 3 December 2018 amending Regulation (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) as regards Annexes I, III, VI, VII, VIII, IX, X, XI, and XII to address nanoforms of substances (Text with EEA relevance). Official Journal of the European Union, 308, 1-20. Available at https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=uriserv:OJ.L_.2018.308.01.0001.01.ENG&toc=OJ:L:2018:308:TOC
5 ECHA. (n.d.) Nanomaterials. Available at: https://echa.europa.eu/regulations/nanomaterials
6 European Medicines Agency. (2022). Available at: https://www.ema.europa.eu/en
7 Foulkes, R., Man, E., Thind, J., Yeung, S., Joy, A., & Hoskins, C. (2020). The regulation of nanomaterials and nanomedicines for clinical application: Current and future perspectives. Biomaterials science, 8(17), 4653-4664.
8 European Commission. (n.d.). Legal framework governing medicinal products for human use in the EU. Available at: https://health.ec.europa.eu/medicinal-products/legal-framework-governing-medicinal-products-human-use-eu_en
9 European Commission. (n.d.). EudraLex - Volume 1 - Pharmaceutical legislation for medicinal products for human use. Available at: https://health.ec.europa.eu/medicinal-products/eudralex/eudralex-volume-1_en
10 European Commission. (n.d.). EudraLex - Volume 1 - Pharmaceutical legislation for medicinal products for human use. Available at: https://health.ec.europa.eu/medicinal-products/eudralex/eudralex-volume-1_en
11 Center for Drug Evaluation and Research. (2022). Drug products, including biological products, that contain nanomaterials – Guidance for industry. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/drug-products-including-biological-products-contain-nanomaterials-guidance-industry
12 Australian Government Department of Health. (2021). Consultation: Proposed regulatory options for medical devices containing nanomaterials. Available at: https://www.tga.gov.au/consultation/consultation-proposed-regulatory-options-medical-devices-containing-nanomaterials