The laws surrounding the use of nanomaterials in the EU are changing and will definitely affect medical device manufacturers. In April 2017, the European Parliament approved a regulation on medical devices, as well as a regulation on in-vitro diagnostic medical devices. But what does it mean?

Nanomaterials and in vitro

Nanomaterials are an increasingly common product of nanotechnologies. They usually contain nanoparticles, which are defined as smaller than 100 nanometres in at least one dimension. In-vitro is scientifically defined as any process performed or taking place in a test tube, culture dish or elsewhere outside a living organism.

According to the EU’s own advisory stipulations and definitions, nanomaterials are coming into use in healthcare, electronics and cosmetics, and therefore require more oversight. “Their physical and chemical properties often differ from those of bulk materials, so they call for specialised risk assessment. This needs to cover health risks to workers and consumers, and potential risks to the environment,” says the publicised material from the decision.

The EU and other regulatory bodies currently do this on a case-by-case basis, but risk assessment methods need to be kept up to date as the use of nanomaterials grows, especially as the materials find their way into consumer products. Ranging from contact lenses and sticking plasters to pacemakers and hip replacements, in vitro and other diagnostic medical devices are an important aspect of the wider medical world.

Nanomaterials have several advantages in detecting several biomaterials, and in enhancing signals and their inherent effects, says Jin-Ha Choi, in his 2016 paper, ‘Nanomaterial-based in vitro analytical system for diagnosis and therapy in microfluidic device’. Choi is a researcher at the department of chemical and biomolecular engineering at Sogang University of Seoul.

“[Nanomaterials] have been widely applied in the biomedical fields such as biosensor and cancer therapeutics,” he says. “Recently, the development of microfluidic technology has led to superior biological analysis systems to detect biomarkers related to diseases or serve as in vitro drug screening platforms.”

Choi explains that in a microfluidic device, samples can be analysed more accurately, rapidly and simply. In addition, it is possible to culture the cells in these microfluidic devices, therefore making in-situ analysis of secretomes easy.

“Nanomaterials can be easily applied in the microfluidic channels as capturing and signalling materials in order to improve the sensing or therapeutic property,” he writes. “In particular, nanomaterialintegrated microfluidic cell culture model can replace in-vivo disease models for nanotherapeutics screening. In this review, nanomaterial-based sensing systems, which include diverse organic and inorganic nanoparticles, are introduced with specific examples, including microfluidics integrated systems.”

Moreover, microfluidics-derived nanomaterial analytic systems as in vitro 2D or 3D cell culture platform will be presented. This means their uses are only just beginning to be discovered and they will be making a much bigger splash in our lives in the coming years.

European rules

The EU has brought in new rules, as it believes that stricter guidelines are key to ensuring that medical devices such as breast or hip implants are traceable and comply with EU patient safety requirements. These new rules also include laws to tighten information and ethical requirements for diagnostic medical devices; for example, for pregnancy or DNA testing.

But why were the new regulations on these medical devices needed? The EU believes that a diverging interpretation of the existing rules – as well as incidents such as the breast implants scandals of the past few years that led to numerous lawsuits and recalls, and problems involving metal hips – have highlighted the weaknesses of the current legal system and the rules that govern them. According to the EU, there was evidence that the lack of regulation had “damaged the confidence of patients, consumers and healthcare professionals in the safety of medical devices”.

To address this, the European Commission proposed two new regulations on medical devices and in-vitro diagnostic medical devices in 2012. The two regulations will replace three existing directives on medical devices. These new rules will, apparently, significantly tighten the controls to ensure that medical devices “are safe and effective, and at the same time foster innovation and improve the competitiveness of the medical device sector”.

The EU is also hoping that the new rules better reflect the most recent scientific and technological progress, setting the gold standard for medical device regulation globally. The revised rules also provide the conditions needed to consolidate the role of the EU in the long term as a global leader in the sector.

Regulation and report

Medical Device Developments made overtures towards the EU’s in-house growth agency, GROW D4, for comment. The agency specialises in helping businesses in the internal market, particularly SMEs, achieve success. The EU is keenly aware that it needs to look positive and proactive on this matter, and that it is on the side of the customers and public, as well as the wealth and jobcreating medical device manufacturers.

In response to Medical Device Developments’ request for an interview, a spokesperson from GROW D4 said, “The report collects and analyses the Quantitative Structure-Activity Relationships (QSARs) that could be used in a regulatory context, such as the REACH Directive, and tests the application of the workflow for read-across of nanomaterials proposed by European Chemicals Agency.”

The report, the spokesperson is eager to say, does not provide any news regarding the toxicity of nanomaterials. “But [it] shows how alternative methods like read-across may be used to determine toxic properties of nanomaterials,” the spokeperson says. “It also shows that QSARs, and other computational and in-vitro approaches, could potentially play a role in assessing the safety of nanomaterials used in medical devices.”

This, GROW D4 says, does not affect or change the safety specifications of medical devices at all. The agency continues, “One of the main shortcomings of nanomaterials is the lack of knowledge regarding their toxicological mode of action. The current report shows, as an example, the genotoxicity of titanium dioxide as determined by the in-vitro comet assay. There are three possible mechanisms of genotoxicity – direct, indirect, and secondary.”

There are different works in the literature that the EU says point to different mechanisms of toxicity for TiO2, such as ‘Mechanisms of genotoxicity: A review of in-vitro and in-vivo studies with engineered nanoparticles’, a 2014 paper from Zuzana Magdolenova, a researcher at the NILU-Norwegian Institute for Air Research. The second paper is from Azadi Golbamaki from the Laboratory of Environmental Chemistry and Toxicology at the Istituto di Ricerche Farmacologiche Mario Negri, in Milan. His 2013 paper is ‘Genotoxicity of metal oxide nanomaterials: review of recent data and discussion of possible mechanisms’.

“The current report tries to shed some light in the issue by collecting a large dataset consisting of six nanomaterials with more than 50 physico-chemical properties for each,” the EU spokesperson says. “The analysis of this data, which was complemented with the use of chemo-informatic techniques, indicates that coating plays a very important role in the genotoxicity of TiO2 as determined by in-vitro comet assay. It is shown that coated nanomaterials tend to be negative in the test, while uncoated TiO2 tend to be positive.

“Regarding the mechanism, it seems that coating can have two functions: it can firstly behave as a bumper that avoids the contact between DNA or cell components and the reactive part of TiO2; secondly, it can favour the dispersion of TiO2, which reduces the agglomeration and precipitation of TiO2 and therefore reduces the exposure of TiO2 to the cells in the in vitro plates.”

Effect on manufacturers

So how does this all affect medical devices manufacturers and distributors operating under EU law? With regard to medical devices, the new EU regulation contains specific considerations and legal provisions on nanomaterials contained in medical devices:

  • A new essential safety requirement for medical devices, requiring that “devices shall be designed and manufactured in such a way as to reduce, as far as possible, the risks linked to the size and the properties of particles which are, or can be, released into the patient’s or user’s body, unless they come into contact with intact skin only. In this context special attention shall be given to nanomaterials.”
  • A dedicated classification rule for medical devices incorporating, or consisting of, nanomaterials. The critical factor for the classification is the potential for internal exposure. Those devices presenting a high or medium potential for internal exposure will fall under the highest risk class and thus will be subject to the most stringent conformity assessment procedures.

The regulations have some gaps: in vitro diagnostic medical devices (IVDs), in contrast to other medical devices, do not entail direct contact with the body of the patient and no specific provisions on nanomaterials have been included in the new IVD regulation.

“The expert groups to be established under the new Medical Devices Regulation will discuss the application in practice of the provisions of this legislation,” the EU spokesperson states. “With respect to IVDs, the expert group on IVD, to be established under the new IVD legislation, will be in a position to look at the issue of nanomaterials and monitor any market developments and/or emerging risks in this field, regardless of the fact that the new regulation on IVDs does not lay down any dedicated provision on the use of nanomaterials.”

Future rules

With technology moving so rapidly, the legal guidelines surrounding these matters is often outdated before the ink has dried on the paper. The EU says that the “final regulations contain important changes to the current system to enable the sector to produce safer and more innovative devices, and help address future challenges”.

It also states that the new regulations contain many provisions to increase security and regulatory certainty, such as harmonised rules on drug-device combination products, tissue engineering, nanoscience, personalised medicine, substance-based devices and genetic testing. And the EU spokesman says the organisation takes into account the latest developments in the sector, such as medical software, apps and cybersecurity.

The EU hopes that this will boost innovation. “By producing more innovative devices, medical device manufacturers will also be able to offer solutions for disease prevention or early diagnosis that will, in turn, make the healthcare sector more affordable; for example, by helping to prevent or reduce hospitalisation,” the spokesperson says.

Impact of Brexit

Love it or loathe it, there’s no escaping that the UK’s much-discussed exit from the EU will mean a huge change in the way manufacturers buy, sell and even make their products in the continent. Questions on this topic to the Commission were not answered, but it’s plain to see that the current political wrangling in the UK means that while the government hopes it will be able to cut and paste all EU regulation into new UK-specific laws, it could be subject to change. However, nothing is known except that, if planned, these laws would then become UK legislation in 2019.

To allow manufacturers and authorities time to implement the regulations, the regulation on medical devices includes a three-year transition period, and the regulation on in-vitro diagnostic medical devices includes a five-year transition period.

While this is great for manufacturers and gives them time to adjust, it also means that by the time this has all settled – and all parties are aware and in compliance with the law – a whole new issue will have cropped up from the world of technology that will require the process to start all over again.