Błażej Włodarczyk
The dynamic development of nanotechnology is contributing to the emergence of increasingly advanced medical devices, whose functional properties result from the use of materials with nanometric dimensions. Nanomaterials make it possible to obtain new biological, mechanical and physicochemical properties, which translates into improved effectiveness of diagnostics, therapy and tissue regeneration. At the same time, their use presents manufacturers and notified bodies with a number of regulatory challenges related to safety assessment, material characterization, biological evaluation and device classification. Regulation (EU) 2017/745 of the European Parliament and of the Council (MDR) introduced, for the first time, detailed requirements relating to devices using nanomaterials, establishing separate classification rules and extended requirements regarding conformity assessment.
Nanotechnology is currently one of the fastest-developing fields of contemporary biomedical engineering. Materials with dimensions below 100 nm exhibit properties significantly different from their macroscopic counterparts. Reducing particle size leads to an increase in specific surface area, and changes in chemical activity, electrical, magnetic and biological properties. As a result, nanomaterials have found wide application in implantology, orthopedics, dentistry, ophthalmology, in vitro diagnostics and controlled drug release systems.
Examples include silver nanoparticles used in antimicrobial dressings, hydroxyapatite nanoparticles used in bone implants, titanium oxide coatings that increase implant biocompatibility, and nanofibers used as scaffolds for tissue engineering.
The benefits arising from the use of nanomaterials are, however, associated with certain risks. Due to the small size of the particles, they may penetrate biological barriers, exhibit increased surface reactivity and different toxicokinetics than conventional materials. In many cases, classical safety assessment methods prove insufficient, which has necessitated the development of new regulatory requirements.
In response to the development of nanotechnology, the European Union addressed the issue of nanomaterials in Regulation (EU) 2017/745 on medical devices (MDR),
1. Definition of a nanomaterial under European Union law
For many years, one of the fundamental regulatory problems was the unambiguous definition of the concept of a nanomaterial. Individual industry sectors and various legal acts applied different definitions, which hindered the conducting of consistent safety assessments.
The basis is currently the European Commission Recommendation of 2022 on the definition of nanomaterial, according to which a nanomaterial means a natural, incidental or manufactured material containing particles in an unbound state, as an aggregate or as an agglomerate, where at least 50% of the particles in the number size distribution have one or more external dimensions in the range of 1 to 100 nm.
The MDR uses its own definition, contained in Article 2(18), which refers to materials containing free, bound or agglomerated particles with nanometric dimensions, while also taking into account their physical and biological properties.
It is important that the classification of a device does not depend solely on particle size, but also on the possibility of contact of the nanomaterial with the body and the potential level of patient exposure
2. Why do nanomaterials require a separate regulatory approach?
The safety assessment of classical biomaterials is based mainly on knowledge of their chemical composition, mechanical properties and the results of biological tests. In the case of nanomaterials, such an approach proves insufficient.
Reducing particle size causes a significant increase in the surface-to-volume ratio. The active surface may be even several hundred times larger than in the case of macroscopic materials, which increases chemical reactivity and the possibility of interaction with the cells of the body.
Nanoparticles can cross biological barriers and accumulate in organs, which may lead to the induction of oxidative stress, the induction of inflammatory reactions, interaction with genetic material, and changes in the activity of the immune system.
An additional difficulty is the fact that the toxicity of nanomaterials depends not only on their chemical composition, but also on particle size, size distribution, shape, porosity, surface charge, degree of aggregation, solubility and surface functionalization.
This means that two materials made of the same chemical substance may exhibit completely different biological properties solely due to differences in their nanometric structure.
From the manufacturer's point of view, this means the need for a much more detailed material characterization than in the case of classical biomaterials.
3. MDR 2017/745 – a new approach to nanomaterials
The most important change introduced by the MDR was the inclusion of nanomaterials as a separate group of materials requiring special safety assessment.
The Regulation emphasizes the need to apply a risk-based approach, according to which the manufacturer should demonstrate that the potential clinical benefits outweigh the risk associated with the presence of the nanomaterial.
The most important requirements concerning nanomaterials are found in:
- Article 2(18) MDR – definition of nanomaterial,
- Annex I MDR – General Safety and Performance Requirements (GSPR),
- Annex VIII MDR – classification rules,
- Annex II MDR – technical documentation,
- Annex XIV MDR – clinical evaluation and PMCF.
Additionally, the following are of significant importance:
- ISO 14971:2019 – risk management,
- EN ISO 10993-1:2018+A11:2021 – biological evaluation,
- ISO 10993-18 – chemical characterization of materials,
- ISO/TR 10993-22 – guidance on nanomaterials,
- MDCG guidance on classification and clinical evaluation.
Of particular importance is Annex I MDR, which sets out the General Safety and Performance Requirements (GSPR). The manufacturer should demonstrate, among other things:
- full identification of the nanomaterial used,
- the stability of the material throughout the entire life cycle of the device,
- the possibility of nanoparticle release,
- potential migration into the body,
- an assessment of user exposure,
- the impact of sterilization processes on the structure of the nanomaterial,
- the impact of material ageing on the safety of the device.
In practice, this means the need to perform a series of additional laboratory tests, the scope of which often exceeds the classical requirements of the ISO 10993 series of standards.
The manufacturer should also demonstrate that the test methods used are appropriate for the assessment of nanostructured materials, since many traditional analytical methods do not provide sufficient sensitivity in the nanometric size range.
4. Classification of devices containing nanomaterials in accordance with the MDR – the significance of Rule 19
One of the most significant changes introduced by Regulation (EU) 2017/745 (MDR) was the establishment of a separate classification rule for devices using nanomaterials. Unlike Directive 93/42/EEC (MDD), which did not directly address this group of materials, the MDR takes into account the potential hazards arising from their specific biological and physicochemical properties.
Rule 19, contained in Annex VIII MDR, classifies medical devices containing or consisting of nanomaterials depending on the potential degree of exposure of the body to nanoparticles. This approach reflects the contemporary understanding of the toxicology of nanomaterials, according to which the mere presence of nanoparticles does not determine the level of risk. Of key importance is the possibility of their release and contact with the body.
The rule provides for the following classification:
- Class III – devices presenting a high or medium potential for internal exposure
internally.
- Class IIb – devices with a low potential for exposure.
- Class IIa – devices in which the possibility of exposure is considered insignificant.
This approach means that the manufacturer must, already at the design stage, carry out a detailed analysis of the possibility of nanoparticle release throughout the entire life cycle of the device, including transport, storage, sterilization, use and disposal.
In practice, notified bodies expect the presentation of a classification justification supported by the results of laboratory tests, an analysis of material degradation, and an assessment of clinical scenarios.
5. Manufacturer's technical documentation
One of the greatest challenges for manufacturers of devices containing nanomaterials is the preparation of complete technical documentation in accordance with Annexes II and III MDR.
In the case of classical biomaterials, the material documentation is usually limited to a description of the chemical composition, the manufacturing process and the results of biological tests. With regard to nanomaterials, the scope of required information is much broader.
The manufacturer should characterize, among other things:
- the average particle size,
- the size distribution,
- the shape of the particles,
- the specific surface area,
- the porosity,
- the degree of agglomeration,
- the chemical composition of the surface,
- the chemical stability,
- the possibility of degradation,
- the release kinetics.
Increasingly, the use of advanced analytical methods is also expected, such as:
- transmission electron microscopy (TEM),
- scanning electron microscopy (SEM),
- dynamic light scattering (DLS),
- zeta potential analysis,
- ICP-MS,
- AFM,
- BET specific surface area analysis.
These studies make it possible to demonstrate that the material retains its properties throughout the entire declared period of use of the device.
6. Biological evaluation in accordance with ISO 10993
Biological evaluation is one of the key elements of the conformity assessment process.
ISO 10993-1 emphasizes that the scope of testing should result from the risk management process, and not from the automatic performance of all possible tests.
In the case of nanomaterials, classical biological tests often prove insufficient.
Depending on the type of medical device, particular analysis is applied to cytotoxicity, local irritation, sensitization potential, systemic toxicity, genotoxicity, assessment of local effects after contact with tissue (formerly the implantation effect), hemocompatibility, chronic toxicity and biodegradation.
Notified bodies increasingly also require the presentation of a justification as to why certain tests were not performed.
For example, a manufacturer may demonstrate that the nanoparticles remain completely bound within the polymer matrix and cannot be released during use. However, such justification should be supported by the results of ageing studies and a mechanical analysis of the material.
In practice, the assessment of the characteristics of degradation products in accordance with the relevant parts of the ISO 10993 series is also playing an increasingly important role.
7. Risk management in accordance with ISO 14971
ISO 14971 remains the fundamental standard concerning risk management for all medical devices.
With regard to nanomaterials, however, this process requires an extended approach.
Typical hazards associated with the use of nanomaterials include the migration of nanoparticles, their accumulation in organs, inflammatory reactions, oxidative stress, material degradation, changes in surface properties and unpredictable bioavailability. The manufacturer should demonstrate that all identified hazards have been properly identified and estimated, mitigated by means of appropriate risk control measures, verified on the basis of test results, and assessed in terms of residual risk. Increasingly, an approach that takes into account the entire life cycle of the device (lifecycle approach) is also used, analyzing changes in the properties of the nanomaterial during many years of use.
8. Requirements of notified bodies – practical aspects
Experience in recent years shows that notified bodies attach particular importance to the consistency of documentation concerning nanomaterials. It is not sufficient merely to indicate the presence of nanoparticles in the material composition – it is necessary to demonstrate their impact on the safety and performance of the device throughout its entire life cycle.
The areas most frequently analyzed include:
- justification for the use of a nanomaterial instead of a conventional material,
- a full physicochemical characterization,
- an assessment of the potential release of nanoparticles,
- the results of degradation and ageing studies,
- a biological evaluation based on risk analysis,
- consistency between the design documentation, the biological evaluation, the clinical evaluation and the instructions for use.
In the practice of conformity audits, a frequent problem is inconsistency between the risk management report and the biological evaluation report.
For example, the risk analysis may indicate the possibility of nanoparticle release during use, while the biological documentation does not include the corresponding tests or justifications.
In the practice of conformity assessment, the following problems occur most frequently:
Problem 1 – lack of unambiguous identification of the nanomaterial
The manufacturer describes the material in marketing terms, but does not present a full technical characterization.
Expectation of the notified body:
Full identification of the material and justification of the impact of its properties on safety.
Problem 2 – lack of assessment of nanoparticle release
A common error is the assumption:
“the nanoparticles are bound within the material, so they do not pose a risk”.
Such a claim requires confirmation by testing.
Problem 3 – insufficient biological evaluation
Tests conducted in accordance with the classical ISO 10993 approach may not cover risks specific to the nanomaterial.
An assessment is necessary of:
- migration,
- degradation,
- breakdown products,
- potential bioaccumulation.
This type of discrepancy is often classified as a nonconformity requiring corrective action before the certificate is issued.
9. Post-market surveillance of the device (PMS and PMCF)
In the case of medical devices using nanomaterials, post-market surveillance (PMS) becomes particularly important. Due to the limited amount of long-term clinical data on the safety of many nanomaterials, the MDR requires continuous monitoring of their performance even after CE marking has been obtained.
The PMS system should enable the manufacturer to systematically collect, analyze and evaluate information concerning the safety and performance of the device under actual conditions of use. Such data may come from user complaints, incident reports, scientific publications, clinical registries, observational studies, and information obtained from distributors and medical personnel.
In the case of Class III devices containing nanomaterials, Post-Market Clinical Follow-up (PMCF) is of particular importance. PMCF studies make it possible to verify whether the safety profile determined at the conformity assessment stage is maintained during many years of use of the device. The data obtained may lead to updates of the clinical evaluation, the risk management documentation and the instructions for use.
From the point of view of supervisory authorities, PMS is not merely a formal obligation, but an element of the continuous process of managing the safety of the device. In the case of nanomaterials, it may constitute a fundamental source of information about rare adverse effects that were not detected during preclinical or clinical studies.
10. Current directions in regulatory development
Despite the introduction of detailed requirements in the MDR, European regulations concerning nanomaterials remain an area of intensive development. One of the main challenges is the lack of fully harmonized test methods enabling the safety assessment of all types of nanomaterials.
The European Commission, the Medical Device Coordination Group (MDCG), the Scientific Committee on Health, Environmental and Emerging Risks (SCHEER), and standardization organizations such as CEN and ISO are currently working on further clarification of the requirements concerning the physicochemical characterization of nanomaterials, methods for assessing nanoparticle release, validation of analytical methods, toxicological models adapted to the specific nature of nanomaterials, the use of alternative methods, including in vitro studies and in silico methods, as well as the assessment of long-term bioavailability and potential bioaccumulation.
An important direction of development is also the harmonization of requirements between regulated sectors. Nanomaterials are used not only in medical devices, but also in medicinal products, cosmetics, food and chemicals. In the longer term, greater consistency can be expected between the requirements arising from the MDR, the REACH Regulation and other legal acts of the European Union.
11. Summary
Nanomaterials constitute one of the most promising groups of materials used in contemporary medical devices. Their use makes it possible to design products with new functional properties that improve the effectiveness of diagnostics and therapy. At the same time, the specific nature of nanostructured materials means that their safety assessment requires a different approach than in the case of traditional biomaterials.
Regulation (EU) 2017/745 introduced the first comprehensive requirements relating to devices containing nanomaterials. Of particular importance are Rule 19 concerning the classification of devices, the obligation of an extended biological evaluation, risk management in accordance with ISO 14971, and the need to conduct effective post-market surveillance of the device.
In practice, the conformity assessment process requires manufacturers to provide a much more detailed material characterization and comprehensive technical documentation as well as an appropriate justification of clinical safety. Notified bodies pay attention not only to compliance with MDR requirements, but also to the consistency of all elements of the documentation – from the design of the device, through biological and clinical evaluation, to the risk management system and the actions carried out after the device is placed on the market.
In the coming years, further development of guidelines concerning the assessment of nanomaterials should be expected, as well as the emergence of new test methods enabling a more precise determination of their safety profile. For manufacturers, this means the need for continuous monitoring of regulatory changes and close cooperation between specialists in the fields of materials engineering, toxicology, clinical evaluation and regulatory affairs.
Bibliography
Błażej Włodarczyk specializes in the conformity assessment of medical devices, with particular expertise in biocompatibility, non-active wound care and skin care devices, soft tissue implants, and devices containing nanomaterials.
His work also includes the assessment of non-active medical devices with a measuring function, devices manufactured using plastics, chemical processes, and non-metallic mineral and non-mineral processing, as well as devices manufactured in cleanrooms and associated controlled environments.
His experience also covers medical device packaging and labelling, enabling him to take a comprehensive approach to device requirements at different stages of the product life cycle.
Błażej is a graduate of Lodz University of Technology, Faculty of Chemistry, where he specialized in Chemistry and Polymer Technology. He further developed his expertise during doctoral studies in Chemical Technology, where he participated in research projects focused on polymers.
He gained professional experience, among other areas, in the research and development department of a medical device manufacturer, where he worked as an R&D Specialist. The combination of his scientific background, materials expertise, and practical experience in the medical device sector enables him to approach conformity assessment from both the perspective of regulatory requirements and the technologies used in the design and manufacturing of medical devices.