Legal Aspects of Nanotechnology vs. COVID-19

Summary

Despite the lack of specific regulatory guidelines, many nanomedicines are on the market and their number is growing steadily. These are mainly used in cancer therapy because they require persistent toxic compounds and the tumor landscape is very difficult, which hinders effective drug treatment. The lack of formal regulation of nanomedicines and the manufacture of nanomaterials for health-related applications is a worldwide problem. Inconsistency among different government agencies results in some nanomedicines being classified as medical devices and others as drugs.
Therefore, a global consortium for nanomaterials regulation should be formed to advance these agendas and issue formal guidance to the research communities. Currently, in 2 the context of nanomaterials in the European Union, we are dealing with both binding legal acts and non-binding legal acts, such as recommendations on the fair conduct of scientific research or on the application of a uniform definition of nanomaterials.

Key words/phrases: Legal regulation, safety of nanomaterials, European Union: REACH, precautionary principle, international developments.

1. Introduction

The COVID-19 pandemic has become one of the greatest global health threats in modern history. Advances in nanotechnology development have provided relief in the form of rapid diagnostic tests and rapidly developed vaccines against SARS-CoV-2 [43]. But legal considerations must be factored into the development of nanotechnology solutions to global health problems [43, 23]. In the European Union (EU), this has been recognized as a key technology that can provide new and innovative medical solutions to unmet medical needs [44]. There are an increasing number of applications and products that contain nanomaterials or at least nanotechnology-based claims. The use of nanotechnology in the development of new drugs is now a part for pharmaceutical research [2, 35, 37, 47].

The application of nanotechnology for medical purposes is called nanomedicine. It is defined as the use of nanomaterials for the diagnosis, monitoring, control, prevention, and treatment of disease [47]. However, more research with specific relevance to regulatory issues is needed, particularly with respect to implementation of the definition of nanomaterials, enforcement of product labeling, development of methods for safety testing and risk assessment, and improved availability of quality data on nanomaterials for regulatory purposes [39]. While the definition of nanomaterials is controversial among various scientific and international regulatory agencies, some efforts have been made to find a consensus definition.

Due to their small size, nanomaterials possess novel physicochemical properties that differ from those of their conventional chemical equivalents. These physicochemical properties open up a number of opportunities for drug development. Some examples regarding the application of nanomaterials include.

• The physicochemical properties of the nanoformulation, which can lead to changes in pharmacokinetics, i.e., absorption, distribution, elimination and metabolism,
• the potential to more easily overcome biological barriers,
• toxic properties, and
• their persistence in the environment, and
• pathways in the human body [2, 47].

As the research community continues to explore nanomedicine, its efficacy, and related safety issues, it will be critical to address the scientific and regulatory gaps to ensure that nanomedicine can reach the next generation of biomedical innovation.

First, it is appropriate to establish a clear definition for the presence of nanomaterials. The European Commission (EC) has established a definition based on the Joint Research Centre of the European Commission and the Scientific Committee on Emerging and Newly Identified Health Risks. This definition is used only as a reference to determine whether or not a material is considered a nanomaterial. The European Commission maintains that it should be used as a reference for additional regulatory and policy frameworks related to quality, safety, efficacy, and risk assessment [4]. The EMA Working Group introduces nanomedicines as purposefully designed systems for clinical applications that have at least one component at the nanoscale and have reproducible properties and characteristics related to the specific nanotechnology application and characteristics for the intended use (route of administration, dose) associated with the expected clinical benefits of nanotechnology (e.g., preferential organ/tissue distribution) [35]. According to the former definition, there are three basic aspects to determine the presence of a nanomaterial, namely.

• Size,
• Particle size distribution (PSD), and
• Surface Area [10].

Ideally, characterization of a nanomaterial should be performed at different stages of its life cycle, from design to evaluation of its in vitro and in vivo performance. Interaction with the biological system or even sample preparation or extraction procedures may alter some properties and affect some measurements. In addition, the determination of in vivo and in vitro physicochemical properties is important for understanding the potential risk of nanomaterials [7].

2. Overall legal regulations

Nanotechnology is thus a very broad field that encompasses a number of nanoscale technologies, including pharmaceuticals, biotechnology, genomics, neuroscience, robotics, and information technologies [1]. Regulators have therefore started to address the potential risks of nanoparticles since 2000 [41]. Since 2004, the EU has been developing a regulatory policy to tighten control and improve regulatory adequacy and knowledge of nanotechnology risks [30].

Currently, there are specific regulations on nanomaterials for biocides, cosmetics, food additives, food labelling, and food contact materials [1]. The observation is that nanotechnologies inevitably raise questions, such as.

• public confidence,
• potential risks,
• environmental impact issues,
• transparency of information,
• responsible nanoscience and
• nanotechnology research.

Nanotechnology is defined as a dual-use technology, as it brings opportunities for human progress and development, but it can also pose a serious threat to human health and life and to the environment [1, 13, 30]. It is a very young field, and the effects of nanomaterials on the human body and the environment, especially in the long term, are not always known [38]. Nanomaterials may have increased biological activity as they readily penetrate biological membranes and they may therefore have toxic properties and pose a hazard to humans and animals.

Relevant legal regulations in the European Union do not directly address nanotechnology, so new instruments should be created to prevent the possible harmful effects of nanomaterial use [38]. The possibility of creating a collective legal order in the future is usually not considered, as it can be done only under the condition of obtaining complete knowledge about the properties of nanomaterials. Thus, it is a matter of application of a unified definition of nanomaterial, development of measurement tools related to nanomaterials, development of safety tests and methods of risk assessment.

The aim of the EU legislation is to,

• to provide the public with access to innovative applications of nanotechnology, and

at the same time ensure safety and the protection of health and the environment.

3. COVID-19 impact on food packaging

The European Union (EU) regulatory framework, which consists of several horizontal and sector-specific pieces of legislation, covers nanomaterials explicitly or implicitly. Thus, nanomaterials, and in particular the potential risks associated with them, are in principle covered by existing legislation, even if nanomaterials are not explicitly mentioned [39]. In addition, recently updated product-specific EU legislation, as well as newly proposed legislation, explicitly addresses nanomaterials, including specific nanomaterial information requirements, authorization of nanomaterials for specific uses, and safety assessment that takes into account nanospecific characteristics [39]. The European Commission’s review of nanomaterials legislation concluded that nanomaterials are similar to normal chemicals/substances in that some may be toxic while others are not. Potential risks are related to specific nanomaterials and specific uses. Risk assessment of nanomaterials should be conducted on a case-by-case basis using relevant information. Current risk assessment methods are applicable, although further research is needed from certain aspects of the risk assessment [39].

Although the European Commission has adopted a recommendation for a definition of nanomaterial, this term is currently not clearly defined in a legally binding way, but its definition and implementation depend on the specific legal context.

• First, the question arises whether “it will probably be necessary to base future law concerning [nanotechnology] on prior law concerning analogous prior products or processes,” that is, whether they are compatible with biotechnology, for example [6, 33].
• Some authors see the possibility of increasing the safety of nanomaterial use through non-judicial means [29].
• Because of the dynamics of change in this area, others see an urgent need for the use of soft law [29]. The main question raised in the international literature is whether nanotechnology should be included in the legal framework or whether the so-called soft law mechanisms can be used.
• Currently, in the context of nanomaterials in the European Union, we are dealing with both binding legal acts (regulations, directives) and non-binding legal acts, such as recommendations on the fair conduct of scientific research or the application of a uniform definition of nanomaterials [45]¹ .

Soft law includes:

• Resolutions,
• Guidelines,
• Declarations,
• Messages,
• Programs,
• Plans, usually issued by the authorities involved in the legislative procedures, the result of which is a generally applicable legal act.

The construction of soft law instruments is intended to provide a basis for the future hard legal regulations.

• The literature also points to the need to regulate the intellectual property aspects related to nanotechnology. Also, in the context of patent law, the question arises whether nanotechnology inventions should be excluded from patenting because of the unknown potential risks to human health or the environment, just as in the case of biotechnology inventions [6, 33]. Later, if it is a technology, some of the problems facing nanotechnology will be specific and therefore “can only be addressed by creating entirely new rules.” [18, 50].
• Incidentally, the voluntary programs aimed at gathering information useful for the design of legal instruments are also important.
• In line with the position of the EU bodies, some authors suggest strengthening existing forms of cooperation in the field of nanotechnology and encouraging states to create internal legal regulations [16, 17].
• A difficult issue is the ability to regulate nanotechnology at the international level under future framework agreements [28]. Some authors agree that regulating nanotechnology at the international level is a major challenge because nanomaterials are used in different ways.  However, it seems that comprehensive regulations in the field of nanotechnology will be created in the future. The creation of best practices for handling nanomaterials to be applied at the international level could significantly influence this. Nanotechnologies are an interdisciplinary subject, which is reflected in a very wide range of possible applications. Nowadays, nanotechnologies encompass most areas of technology [28].

The concept of nano-ethics, defined as moral reflection on the development and application of nanotechnology or the manipulation of matter at the molecular level, is emerging in the literature. In this context, there are beginning to be dilemmas regarding the potential harmfulness of nanoparticles. In the case of nanotechnology, there is the question of its availability and its impact on the welfare of humanity. There is a well-founded fear that nanotechnology will become another element that reinforces the division of the world into developed and backward countries or controlled and controlled countries [43]² .

4. Legal regulations in the field of nanotechnology

4.1. Precautionary principle as the basis for nanotechnology regulation

According to Principle 15 of the Rio Declaration, the lack of complete scientific certainty should not be a reason for postponing cost-effective measures to prevent environmental damage [42]. In short, the precautionary principle reflects a “better safe than sorry” approach to potential environmental risks [36]. That is, based on current knowledge, nanomaterials are similar to natural substances in that some may be toxic while others are not [21]. The potential risk is related to specific nanomaterials and specific applications. Therefore, in the case of nanomaterials, a risk assessment is required and should be conducted on a case-by-case basis using relevant information. Currently, the main challenge is to develop validated methods and tools for the detection, characterization and analysis of nanomaterials, to obtain complete information on the risks associated with nanomaterials and to develop methods for assessing exposure to nanomaterials.

Despite the studies conducted to date, we are not able to quantitatively assess the associated risks. The toxicity of individual nanoparticles varies widely, making it difficult to establish a common criterion. Nanoparticle toxicity is evaluated in relation to individual organisms: mammals, protozoa, crustaceans, algae, and plants.  Toxicity to mammals is tested in rodents.  There have been few attempts to evaluate the health status of humans who are occupationally exposed. Sparse studies on human cell lines showed significant DNA damage [27].

Since the risks posed by nanomaterials are not yet fully understood, they should be covered by multi-layered and diverse legislation.  The new regulations need to be drafted based on the precautionary principle and the producer responsibility principle to ensure the safe manufacture, use and disposal of nanomaterials before they are placed on the market.  The precautionary principle allows for a rapid response to potential risks to human, animal or plant health or to the protection of the environment. According to the Commission, the precautionary principle can be invoked when the phenomenon, product or activity poses potential safety risks identified through a scientific and objective assessment, if such an assessment makes it possible to identify such a threat with reasonable certainty [24].

In the case of nanomaterials, we certainly have to deal with the situation where there is no complete knowledge of the risks arising from their use. This principle is enshrined in the legal systems of many countries.  The European Union has included it in Article 191(2) of the Treaty on the Functioning of the European Union (TFEU), resulting in the obligation of Member States to apply this principle in their legislation.  The implementation of this provision helps in assessing the potential risk. It is explicitly stated that even if the presence of nanoparticles in the elements of the environment or waste can be detected, it would be technically difficult to eliminate them. Therefore, the measures taken at the end of the contamination chain, so as to prevent the possible negative consequences for the environment and human health, cannot be effective [21].

As early as 2009, the European Parliament recommended that Member States invest in adequate assessment of the risks arising from the use of nanomaterials in order to fill the knowledge gaps and rapidly develop and implement assessment methods and appropriate and harmonized metrology and nomenclature. There are no methods to assess the risks associated with nanomaterials, making it impossible to develop effective regulatory mechanisms in this area [40].

Only with more detailed and comprehensive scientific research can scientists evaluate the potential risks of nanomaterials and conduct an appropriate risk assessment, as required by the precautionary principle [36]. Consequently, the precautionary principle supports the improvement of new technologies and only prevents the use of new technologies that are harmful to the environment. The precautionary principle does not hinder new technologies. Rather, it strikes a more prudent balance between technological advancement and environmental safety, giving the environment the benefit of the doubt.

Legally non-binding regulations, however, have many advantages that binding regulations do not. First, it may be easier to reach consensus on a particular issue, as the inhibition threshold is reached because of the lower inhibition threshold for parties to agree to nonbinding regulations [3]. This lower inhibition threshold can be very helpful in initiating a joint discourse on possible regulations. Second, soft laws are less costly and more flexible in terms of their negotiation and implementation [46]. Third, the coercive nature of a law is no guarantee that affected individuals will abide by it. Rather, there are are many reasons why individuals adhere to legally non-binding rules, how their socialization, their self-interest, the moral codes of their society prevent them from doing so.

The international community should not only keep in mind the importance of protecting the environment from the negative from the negative effects of nanomaterials, but also think about future regulations for other new technologies. Since the risks posed by new technologies will be one of the greatest environmental challenges of the future, the international community must demonstrate its ability to successfully address the challenges posed by these new technologies. Therefore, effective international regulation of nanomaterial risks must take an important step into a new era of environmental law.

4.2. Treatment in the European Union

In the European Commission (EC) Communication “Nanosciences and nanotechnologies: an action plan for Europe for 2005-2009. Second implementation report for 2007-2009”, it was stated that nanotechnology offers significant potential to improve the quality of life and industrial competitiveness in Europe [26]. Its development and use should not be delayed, unbalanced or left to chance [25]. At that time, a first review of the regulatory framework in the field of nanotechnology was carried out to investigate whether new regulatory measures were needed to cover the risks associated with nanomaterials.

Preliminary results showed that existing regulations in principle cover health issues and environmental impacts. Member State regulators were tasked with assessing national legislation and identifying gaps therein.  Even then, a preventive approach to nanotechnology was recommended. In the absence of complete knowledge on nanomaterials, it was recommended to use existing legal mechanisms related to thresholds, authorization of substances and ingredients, classification of hazardous waste, strengthening of conformity assessment procedures, restriction of the marketing of chemical substances and preparations and their use. However, given limited resources and rapidly evolving technology, it is more likely that a self-regulatory approach will be taken, “perhaps supported by strong incentives in the form of tort liability or criminal laws.” [18].

In 2009, the European Parliament (EP) adopted a report on the regulatory aspects of nanomaterials, which also took into account the Commission Communication of 17 June 2008 entitled “Regulatory aspects of nanomaterials” (COM (2008) 366). The report shows that the European Commission sees the benefits of nanotechnological development, but at the same time is aware of the risks that this development poses to humans and the environment. The European Commission confirmed that knowledge about the potential risks of nanomaterials is incomplete. There is no evidence of the risks posed by specific nanomaterials, and there is an overall lack of methods for adequately assessing the risks associated with concerns about nanomaterials. Given the many doubts about the use of nanomaterials, it seems urgent to include this area in the regulatory framework.

For this reason, since 2008, the European Commission has been reviewing the existing regulations on the use of nanomaterials and identifying the actions that should be taken in the future.  In the second review of nanomaterials legislation, the European Commission highlights the need to improve EU legislation to ensure the safe use of nanomaterials.  The Communication highlights the diverse nature and types of nanomaterials, ranging from everyday materials,as they have been used for decades (e.g., in tires or as anticoagulants in food), to advanced materials used in industry and cancer therapies. More and more is becoming known about the hazardous properties of nanomaterials.

They cannot be categorized, which justifies the need to assess the risk associated with specific applications.  The European Commission emphasizes that an individualized approach should be taken to risk assessment, using strategies based on information about the potential risks in terms of exposure or hazard.  In recent years, the majority of member states have been working on legislation to regulate the use of nanomaterials. The current regulations on the use of nanomaterials consist mainly of two regulations,

• the so-called REACH Regulation (Registration, Evaluation and Authorization of Chemicals) ((EC) No. 1907/2006) and
• the CLP Regulation (Classification, Labelling and Packaging) ((EC) No. 1272/2008).

Nanomaterials are already used in numerous products of everyday use, but the risks have not yet been sufficiently researched, because for many nanomaterials there are hardly any reliable data to assess their potential risks. Closing this knowledge gap is actually the task of European chemicals legislation. However, most of the laws regulating chemicals and products have so far contained no, or only limited, specifications on the handling of nanomaterials.

REACH, the abbreviation for Registration, Evaluation and Authorization of Chemicals, is a milestone in the protection of people and the environment from substances that are harmful to health. The EU regulation required industry to submit data on the environmental and health impacts of its chemicals for the first time starting in June 2007 – as a prerequisite for them to be marketed at all [21]. Until then, harmful effects had to be proven by the legislator before a chemical could be banned. REACH has now reversed the burden of proof. The principle applies: no data, no market.

REACH has also strengthened consumers’ rights to information. Consumers have the right to ask the manufacturer or distributor of a product whether it contains a particularly hazardous substance. Companies are obliged to respond.

REACH lays down strict rules for the use of particularly hazardous substances. They may only continue to be used if a special authorization is granted for this purpose or if there are no safe alternatives. Chemicals are considered “substances of very high concern” if they:

• Cause cancer and damage genetic material or reproductive ability,
• do not degrade in the environment, accumulate in humans and animals, and are toxic,
• are practically not degraded in the environment and accumulate very strongly in the body, but for which no toxic effect has yet been proven,
• have similar hazardous effects, e.g. hormonal effects.

In addition, the ECHA Nanomaterials Working Group (NMWG), composed of experts from EU Member States, the European Commission, ECHA and recognized stakeholder organizations, informally advises on scientific and technical issues related to the implementation of REACH and the Classification, Labeling and Packaging (CLP) legislation with respect to nanomaterials. In addition, ECHA organized a Working Group on the Assessment of Already Registered Nanomaterials (GAARN) to address best practices for assessing and managing the safety of nanomaterials under REACH. ECHA takes into account the findings of these expert groups when developing new or updated guidance. The work of the scientific committees also feeds into the work of other EU bodies such as EFSA, the European Medicines Agency (EMA) and ECHA. All scientific opinions of the Scientific Committees are published on the Internet.

Together with the Center for International Environmental Law (CIEL) and the advocacy organization ClientEarth, BUND in Germany submitted its own proposal for the regulation of nanomaterials [5]. This proposal provides for a new, horizontal EU regulation. On the one hand, it contains general principles for the regulation of nanomaterials and, on the other hand, concrete adaptations of individual EU regulations, in particular the European chemicals regulation REACH.

This is what BUND demands with regard to the provisions of REACH:

• Adoption of the definition for nanomaterials already proposed by the EU Commission in 2011 in all relevant laws. However, these have so far been non-binding.
• A general obligation to report all nanomaterials and nanoproducts. These are to be kept in an EU-wide nano register.
• Labeling of nanomaterials on products in the list of ingredients.
• Closing the gaps for nanomaterials in REACH.

A nano-register [5].

4.3. Regulations

Provisions on nanomaterials can also be found in regulations.  Since nanotechnologies are also used in medicine, a directive on the Community code relating to medicinal products for human use appeared in 2001 (Directive 2001/83/EC) [41]. Procedures for the authorization of medicinal products were also established ((EC) No. 726/2004) [8]. To ensure safety, it is advisable to establish a register of nanomaterials and products containing nanomaterials. Such a register facilitates the monitoring of companies placing nanomaterials on the market and ensures transparency of product data for purchasers. It should be recognized that the European Union is working consistently to regulate nanotechnology.

Individual EU member states have begun implementing initiatives aimed at better informing the public about nanotechnology developments. In the United Kingdom, the DEEPEN (Deepening Ethical Engagement and Participation with Emerging Nanotechnologies) project was launched to provide a basis for social acceptance of nanotechnology development [11]. In the Netherlands, it was the Nanopodium program, one of the most important social dialogue programs in the European Union [49]. Belgium launched the Nanosoc program, which aimed to create a common platform for discussion on nanotechnology for researchers, companies and society. Although nanotechnology does not generate the kind of controversy that biotechnology does, and societies tend to be more positive about the diagnostic and therapeutic possibilities of nanotechnology, they are increasingly demanding detailed information about the long-term effects of nanoparticles on the body.

In Germany, the Nanologue project was launched to highlight the benefits and consequences of nanotechnology, explain the ethical, social and legal issues associated with its use, and promote dialogue between the public and other interested parties [48]. Social acceptance and the elimination of concerns about nanomaterials will have a positive impact on the future and development of nanotechnology. Social dialogue should include civil society representatives and scientists, as well as other stakeholders.

The EU4Health program is the EU’s most ambitious health policy response to the COVID-19 pandemic, which is having a significant impact on patients, medical and healthcare professionals, and healthcare systems in Europe [15]. EU4Health will go beyond a mere crisis response to make health systems more resilient to crises, according to Regulation (EU) 2021/522. The established program will provide funding to eligible institutions, health organizations and NGOs from EU countries or non-EU countries associated with the program. EU4Health paves the way to a European Health Union and focuses on urgent health priorities [15].

The ten specific objectives formulated under the four general objectives are: Improving and promoting health in the Union; Disease prevention and health promotion; Health initiatives and cooperation at international level; Combating cross-border health threats; Prevention, preparedness and rapid response with regard to cross-border health threats; Supplementing national stockpiles with essential crisis-related products, Establishing a reserve of medical, health and support staff, Improvements in medicines, medical devices and crisis-related products, Available and affordable medicines, medical devices and crisis-related products, Strengthening health systems, their resilience and resource efficiency, Strengthening health data, digital tools and services; Digitizing health systems, improving access to care, developing and enforcing EU health law, and evidence-based decision-making and alignment between national health systems [15].

EU countries are consulted on the program’s priorities and strategic orientations and, together with the Commission, ensure the coherence and complementarity of national health policies through the “EU4Health Steering Group.” Before the adoption of the annual work programs, they give their opinion in the EU4Health Program Committee.

The European Commission prepares, adopts and implements the annual work programs. It also monitors and reports on progress toward program objectives. It may seek the opinions of the relevant decentralized agencies and independent health professionals on technical or scientific issues relevant to the implementation of the program. The Health and Digital Executive Agency (HaDEA) will implement the program [15].

Finally, in 2018, the European Commission made changes to REACH Annexes I, III, VI, VII, VIII, IX, X, XI, and XII that took effect on January 1, 2020 [9]. Under the revised REACH requirements, all nanoforms must be registered, with a focus on chemical safety assessment. Nanoforms of substances must additionally be identified and characterized as part of the registration process. Most importantly, risks to the environment and human health must be assessed using OECD-mandated guidelines that are either in place or being developed. Further refinement of the guidelines may be required as industry and its knowledge base continue to grow, but the EU has, as always, set high standards when it comes to maintaining the quality of human health and the environment.

5. International developments

Activities to regulate nanotechnology have also been undertaken in the international arena, as the potential risks arising from developments in this area are seen by many countries [23].

According to the OECD definition, “regulatory frameworks consist of the norms and rules that govern a particular group of persons, actions, or objects and that are enacted by governmental bodies pursuant to statutory authorization.” [34]. At the global level, the Organisation for Economic Co-operation and Development (OECD) launched a strategic program in 2006 within its Framework for Chemical Safety to provide a global forum for discussion of manufactured nanomaterials, particularly their safety assessment and risk evaluation, and to promote the responsible development of these technologies. The OECD Working Party on Manufactured Nanomaterials (WPMN) promotes international cooperation on human health and environmental safety aspects of manufactured nanomaterials and focuses on developing appropriate methods and strategies to ensure safe use of nanotechnology [12]. Under the WPMN program for testing manufactured nanomaterials, OECD WPMN members, together with non-OECD countries and industry, have tested a selected list of manufactured nanomaterials for endpoints relevant to physicochemical properties, environmental fate and toxicology, mammalian toxicology, and material safety [12]. Data obtained under these guidelines are covered by the OECD Mutual Acceptance of Data (MAD) agreement in the evaluation of chemicals. MAD is an essential component of the international harmonization of approaches to chemical safety through regulatory acceptance of these testing guidelines. Therefore, data on nanomaterials obtained under the OECD testing guidelines applicable to nanomaterials are equally covered by MAD.

5.1. The USA

In the United States, the U.S. National Research Council published a report in 2008 that also called for greater regulation of nanotechnology.

The wide range of devices and products produced by nanotechnology companies can send many agencies on their way, such as the Food and Drug Administration, the Environmental Protection Agency, the National Institute of Health, or the Department of Health and Human Services Health and Human Services, either taking their own regulatory approach or developing a coordinated regulatory approach [50].

As part of its leadership in this area, the federal government has authorized the 21st Century Nanotechnology Research and Development Act (“Act”), 15 U.S.C.A. §7501- §7509, authorized $4.7 billion between 2004 and 2008 for the National Nanotechnology Initiative, a nanotechnology initiative composed of nine agencies: the National Science Foundation, the Department of Energy, the National Aeronautics and Space Administration, the National Institutes of Heath, the National Institute of Standards and Technology, the Environmental Protection Agency, the Department of Justice, the Department of Homeland Security, and the Department of Agriculture. The programs of these agencies are overseen by external and intergovernmental committees, while the Office of Science and Technology Policy is responsible for coordinating and managing the National Nanotechnology Initiative (see www.nano.gov for more information). One of the main goals of the Act is to create a collaborative effort between government and industry to develop and commercialize nanotechnology in a coordinated and efficient manner.

Another organization currently addressing the impact of nanotechnology is the American Bar Association. The Section’s Standing Committee on Nanotechnology is currently organizing fora to try to identify the potential risks and hazards associated with nanotechnology and where scientists, advocates, and legislators can discuss the ethical and social implications of nanotechnology [12]. In the medium term, the best approach is to discuss regulation or changes in protections in a more temperate manner and based on the experience gained from addressing problems. In the long term, as nanotechnology matures and becomes established as an industry, it is likely that circumstances will be so different from those in the world today that any current “proposals are bound to overshoot the mark by a wide margin.”

The overview of the major legislation that has been passed related to nanotechnology shows that the priority of the U.S. government to date has been to promote and fund nanotechnology research and development.

Arguably, the biggest problem with regulating nanomedicines is the fact that regulatory agencies such as the FDA use safety data based on bulk materials that do not have the same pharmacodynamic and pharmacokinetic activity as nanomedicines [22]. This means that the safety and efficacy data collected are not representative of what might actually happen if the nanomedicine is used in clinical situations once they receive approval. This leads to problems in establishing regulations for the safety and efficacy parameters of nanomedicines, as a non-nanoversion may meet regulatory standards, but a nanomedicine may not. This means that a nanomedicine may be classified as a drug in one country and a medical device in another, so the regulations that must be met change depending on the classification. Thus, the specific safety and efficacy standards that the product must meet in order to be marketed vary, so a nanomedicine may be used in some countries that may not meet regulatory standards in another [29]. Because of their highly complex structures and properties, it is difficult to establish a sound and consistent manufacturing process that defines the quality, efficacy, stability, and safety of nanomedicines.

Nanomedicine products would be evaluated on a product-specific basis. Manufacturers are advised to coordinate with FDA in the development of their nanotechnology products to establish a mutual understanding of regulatory issues.

This inaction in the changing landscape has led to much criticism of the FDA. As a result, nanoformulations consisting of already approved building blocks appear to be fast-tracked through the system without new drug approval or full premarket review. This strategy is extremely risky and only time will tell if it is appropriate [19].

There have been very few legislative efforts to regulate nanotechnology. In fact, no laws have been passed that directly address the regulation of nanotechnology. Perhaps this is the right approach to take for an emerging technology; however, it leaves room to question whether this is an approach that has allowed nanotechnology to develop in a blind spot. The reason for this blind spot is the lack of accumulated research to determine the safety of these nanomaterials.

Despite these concerns, regulation through legislation is not recommended as a solution for a regulatory framework. This means that regulation by legislation is taken in response to the discovery of a major risk or after a disaster. Thus, it is easy to see the failures of oversight and regulation in the asbestos industry, but it was not easy to see this deficiency when companies were using asbestos in almost all new construction. Because regulatory laws are typically enacted only in response to a reaction to a catastrophic event or overwhelming evidence, they are not considered a viable element of the regulatory framework recommended in this paper [14]³ .

5.2. Australia, Canada and other countries

Australia and Canada are also quite active in nanoregulation.  Both countries have major Environmental Health and Safety (EHS) research programs and have published in-depth reviews of their regulations to identify any limits in the use of nanotechnology.  Although no specific legislation has been enacted, both countries provide for the application of the precautionary principle in the use of nanotechnology.

Japan, China, Korea, and Taiwan, which are heavily involved in nanotechnology, also have important research initiatives at various levels that address EHS issues such as risk assessment and risk management of nanomaterials and nanoproducts. While they participate in the global debate on nanoregulation, no specific initiatives on this topic have been undertaken in these countries [14]. Currently, nanotechnology regulation activities are focused at the national level, and initiatives in the nature of joint research programs can be observed at the international level.

Health Canada has established a working definition of nanomaterials, which states that “any manufactured product, material, substance, ingredient, device, system, or structure is considered a nanomaterial if it is at the nanoscale (1-100 nm) in at least one spatial dimension or is smaller or larger than the nanoscale in all spatial dimensions and exhibits one or more nanoscale phenomena.” [20]. Regarding the approval of nanotechnology products, Canada relies on the existing regulatory framework. Health Canada advises manufacturers to consult with the appropriate regulatory authority early in the development phase to identify and assess the risks and characteristics of the product. In Canada, the Health Portfolio Nanotechnology Working Group was established to gather and discuss issues related to nanotechnology. It consists of representatives from regulatory agencies such as Health Canada and the Canadian Institutes of Health Research (CIHR). A general guidance document on the review of nanotechnology-based biomaterials for health products and foods has also been issued by Health Canada [20].

In Japan, pharmaceuticals are regulated by the Ministry of Health, Labour and Welfare (MHLW)/Pharmaceuticals and Medical Devices Agency (PMDA) [31]. Japanese regulators have yet to develop a definition and nanomedicine-specific regulations for nanomedicines. In 2016, a guide for liposome drug development was published. Nanomedicines are regulated under the Pharmaceutical Affairs Law, a general drug legislation, on a case-by-case basis. It should be noted that regulatory agencies and reviewers are collecting and analyzing data on nanomedicines. The MHLW/PMDA has also collaborated with the EMA in issuing reflection papers, particularly on the development of block copolymer micelle-based drugs and nucleic acid (siRNA)-loaded nanotechnology-based drugs.

Although there is little regulation in this area in Asia, countries such as India, Japan, China, and Thailand are currently establishing government and regulatory policies to address the growing issues in nanotechnology. In India, the Ministry of Science and Technology and the Indian government have set up a group to regulate nanotechnology and have drafted a set of guidelines that have created a three-tiered regulatory framework to help policymakers develop a pathway to regulate nanomedicine. This will ensure the continued growth of this technology while addressing the risks associated with nanomedicine.

6. Conclusions and future prospects

Despite the lack of specific regulatory guidelines, many nanomedicines are on the market and their number is growing steadily. These are mainly used in cancer therapy because they require persistent toxic compounds and the tumor landscape is very difficult, which hinders effective drug treatment. Among the best known are the liposomal preparations Doxil®, AmBisome® and the more recent successes with albumin drug nanoparticles such as Abraxane® and polymeric micelles such as Eligard®, to name a few.
The lack of formal regulation of nanomedicines and the manufacture of nanomaterials for health-related applications is a worldwide problem. Inconsistency among different government agencies results in some nanomedicines being classified as medical devices and others as drugs. What is considered appropriate in one jurisdiction does not translate to other countries, and while small molecules are often not approved globally for this reason, the nanomedicine community is in dire need of a unified approach so that development can continue in line with expectations. The formation of clusters and working groups has not yet made a difference because nanomaterials are not new, and the need and urgency for treatments for specific diseases or conditions cannot be met with the current regulatory structure.
While there have been some efforts by academic communities and government agencies to establish national characterization laboratories, more explicit and stringent guidance is needed from key agencies such as the FDA and MHRA.
Therefore, a global consortium for nanomaterials regulation should be formed to advance these agendas and issue formal guidance to the research communities. Billions of dollars have been poured into nanomedicine development over the past two decades. Without clear leadership and guidance from regulators, these efforts will not lead to product launches, and future investments may be made elsewhere.
Currently, in the context of nanomaterials in the European Union, we are dealing with both binding legal acts and non-binding legal acts, such as recommendations on the fair conduct of scientific research or on the application of a uniform definition of nanomaterials.
An important measure is the regulation of activities in the field of nanotechnology, which is unfortunately not easy due to the application of nanotechnology in various economic sectors. In particular, a unified definition of the term “nanomaterial” should be sought, which will facilitate the identification of materials for the application of the relevant regulatory provisions. Important challenges mainly concern the introduction of validated methods and tools for detection, characterization, and analysis, the completion of information on nanomaterial hazards, and the development of methods for assessing exposure to nanomaterials. The importance of public debate on nanotechnology has been highlighted by several bodies in the EU. The European Commission states that Member States should increase public debate on the benefits, risks, and uncertainties associated with nanotechnology. Individual EU Member States have begun to implement initiatives aimed at better informing the public about nanotechnology developments. The societal dialogue should involve representatives of civil society and scientists.

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¹ This also applies to the liability, see [45]: “This has changed with the new EU regulation on medical devices. In the legislative proposal of the European Commission (autumn 2012) 78 includes, in addition to a specific definition for nanomaterials, regulations for labeling, and a classification for Products containing nanomaterials are envisaged. Accordingly, all products that contain or consist of nanomaterials will be assigned to Class III (highest hazard category), unless the nanomaterial is unless the nanomaterial is encapsulated or fixed in such a way that it cannot be released during the is not released when the product is used as intended.”

² Nanojustice and the E3LSC challenges: However, this is not just about identifying technical problems and developing technological solutions to overcome them. One of the most serious moral failures in addressing global health problems and implementing measures to combat the current pandemic has been the lack of equity in the distribution and use of COVID-19 nanovaccines, i.e., a patent issue: not only have wealthy populations and countries been favored in the introduction of the vaccines, but developed countries have hoarded the pre-ordered doses of vaccine to the detriment of the vast majority of people in developing countries. Dr. Tedros Adhanom Ghebreyesus, Director General of the World Health Organization (WHO), stated, “The world is on the brink of a catastrophic moral failure, and the price for that failure will be paid in lives and livelihoods in the world’s poorest countries. ”
Sociopolitical issues may also raise concerns about class differences between wealthier societies and countries that develop or access the benefits of nanotechnology and those that cannot [50].

³ Despite the lack of a specific legal tool for accessing information about new technologies and products in development . . companies facing [drug approval or biologics approval requirements] have a significant incentive to provide the FDA with the information the agency needs to understand and efficiently review new products, because the products are also weighted very differently later.

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Test LO 6.2

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