Nanomedicine – new EU Commission guidance on the risks of nanomaterials in medical devices

Background – Nanomedicine and the legal nature of the guidance document

Nanomedicine is a technically innovative field that already has a wide range of applications, such as carbon nanotubes (CNTs), nanosilver in bone cement, nanosilver coatings for implants and catheters, nanosilver wound compresses or drug delivery systems. Aside from the opportunities and potential of nanomedicine, however, nanoparticles in medical devices pose great challenges for manufacturers. The use of nanomaterials in medical devices now requires manufacturers to consider risks that used to be largely ignored.

The general definition (European Commission Recommendations 2011/696/EU, EC 2011), describes nanomaterial as materials containing particles essentially in the size range 1 nm to 100 nm.

The publication of the Commission guidance document was preceded by a public consultation procedure in which a total of 110 reports and opinions were submitted by eleven organizations and companies.

Guidance documents are published by the European Commission and are not legally binding. They do, however, reflect the positions of the Commission, competent authorities, notified bodies and industry (for instance, where the interpretation of particular legal concepts is concerned) and concretize certain obligations in order to ensure harmonization within the European Economic Area. They may therefore also be relevant in product liability proceedings, for example, since by adhering to guidance documents the manufacturer may be able to prove that it has complied with its obligation to exercise due care.

The guidance documents on nanomaterials described here also set out in detail the obligations that medical device manufacturers must meet within the conformity assessment procedure for products containing nanomaterials.

The guidance document in detail

• The guidance document contains information on risks to consider (as part of conformity assessment procedures) when a nanomaterial is used in a medical device, since nanoparticles have specific characteristics that distinguish them from larger particles with the same chemical composition.
  
  The use of nanomaterials in medical devices may take various forms. Examples are the targeted use of free nanomaterials (e.g. iron oxide or gold nanomaterials in oncology), free nanomaterials in a paste-like form (e.g. dental fillings), free nanomaterials added to a medical device (e.g. nanosilver as an antibacterial agent in wound dressings), and the use of fixed nanomaterials as a coating on implants to increase biocompatibility (e.g. nano-hydroxyapatite), to prevent infection (e.g. nanosilver) or to strengthen any biomaterials used (e.g. carbon nanotubes in catheter wall).
  
  It is also acknowledged that nanometre-sized particles can be generated as a result of the wear and tear of medical devices, even if the medical device did not originally contain nanomaterials.
   
• The guidance document aims to ensure that the safety of medical devices using nanomaterials is assessed in line with the International Standards ISO 10993-1: 2009 “Biological evaluation of medical devices”. SCENIHR recommends a step-by-step approach that takes account of the particular characteristics and possible release of nanoparticles.
  
  
• The risk assessment of nanomaterials in medical devices described in the document is based on a physicochemical characterization of these materials. The assessment should be performed taking account of the type of medicinal device, the type of tissue contact involved and the duration of this contact. The safety assessment of nanomaterials should be performed with the scope of the general biological assessment of medical devices, as described in ISO 10993-1: 2009.
  
  The guidance document stresses the need to give special consideration to possible different characteristics, drug interactions and/or special effects when assessing the safety of nanomaterials. Manufacturers’ existing evaluation procedures may need to be modified as a result.
  
  
• For the risk assessment of medical devices with nanomaterials, the guidance document recommends a phased approach. These phases cover the assessment of:
  
  Particle release (phase 1), particle distribution and persistence (phase 2), toxicological hazard assessment (phase 3), risk characterization/risk assessment (phase 4).
  
  In phase 1, an evaluation of the device’s potential to release nanoparticles either directly or due to wear of the device during use should be performed. Phase 2 aims to determine the distribution and persistence potential of the particles released. Then, in phase 3 appropriate toxicity tests are used to assess the risk of damage to specific organs whilst taking account of risk characteristics and potential for persistence. These results are intended to form the basis for the final risk characterization in phase 4.
  
  The risk assessed after completion of these phases should finally be compared to the risk of using comparable medical devices without nanomaterials.

Conclusion and outlook

The field of nanomedicine holds promise for the future and will be increasingly relevant both in research and in business. For this reason, the European Commission’s guidance document is to be welcomed, as well as its approach to considering specific characteristics of nanomaterials as part of a risk assessment of medical devices. Only experience of using the guidance in practice, however, will reveal the extent of any regulative deficits.

The guidance presented here is intended to clearly set out the legal requirements to be met by medical device manufacturers at EU level within the conformity assessment procedure in line with the Medical Devices Directive (and at national level in Germany in line with the German Act on Medical Devices (Medizinproduktegesetz)). As these requirements are becoming more wide-ranging and are accompanied by individual Commission measures to ensure that overriding objectives of patient safety are achieved, it is crucial for manufacturers to be fully informed before the marketing authorization stage and the distribution of a potentially hazardous product.