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Regulatory landscape of nanostructured biomaterials for tissue regeneration
Regulatory landscape of nanostructured biomaterials for tissue regeneration
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Marco Morra*, Alice Ravizza†, Silvia Pascale‡ * Nobil Bio Ricerche S.r.l., Portacomaro (AT), Italy, †DIMEAS Politecnico di Torino, Torino, Italy, ‡Sorin Group Italia S.r.l. (LivaNova), Saluggia (VC), Italy
2.1 Identification of the appropriate regulatory landscape In Europe, the so-called New Legislative Framework (adopted in 2008) allows for a comprehensive regulatory framework to operate effectively for the safety and compliance of industrial products that include also products intended to provide medical treatment to human beings, including medicinal products (MPs) and medical devices.
2.1.1 Intended use The New Legislative Framework allows the classification of industrial products into many categories, for example, not only MPs, medical devices, and cosmetics but also machinery, personal protection equipment, toys, lifts, equipment powered by low voltage and many more.1 Any product intended to provide medical treatment to human beings should be able to be classified either as MP or as a medical device. While the complete definitions of “medicinal product”2 and “medical device”3 can be easily found in the appropriate legislative text, a rough distinction can be easily made by focusing on the mechanism that allows obtaining of the clinical benefit. If the product operates through the pharmacological, immunological, or metabolic mechanism of action, then it is a drug; if it does not, then it is a medical device. Most often, the “mechanism of action” can be widely described as metabolic since all stimuli, even those which are nonpharmacological but, for example, mechanical, promote in the patient body a pharmacological, immunological, or metabolic response. For this reason, it is always necessary to define the “intended and aimed clinical benefit,” therefore, the word “action” is used with a meaning of “effect” [1].
1
https://ec.europa.eu/growth/single-market/goods/new-legislative-framework_en. Article 1(2) of Directive 2001/83/EC3. https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/ dir_2001_83_consol_2012/dir_2001_83_cons_2012_en.pdf. 3 Article 2 of Europe Medical Device Regulation (MDR). https://eur-lex.europa.eu/legal-content/EN/TXT/ PDF/?uri=CELEX:32017R0745. 2
Nanostructured Biomaterials for Regenerative Medicine. https://doi.org/10.1016/B978-0-08-102594-9.00002-4 © 2020 Elsevier Ltd. All rights reserved.
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2.1.2 What is a “device containing nanomaterials”? In Europe, a uniform definition for nanomaterials is available: “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 1–100 nm.”4 The European Authorities recommend that in the design and manufacture of devices, manufacturers should take special care when using nanoparticles (NPs) for which there is a high or medium potential for internal exposure [2]. At the state of the art, nanomaterial-containing medical devices are widely widespread, for example, all products that contain pigments or filler materials are affected, such as for example, powdered medical gloves, pigmented compression or antithrombosis stockings, superabsorber-containing dressing materials, tubes for ventilation, plastic syringes and many other products. Moreover, many dental materials are affected: impression materials, adhesives, prostheses, or artificial teeth as these products contain powder, for example, porcelain powder, glass powder, pyrogenic silicas, pigments, or other basic substances that meet the definition of nanomaterials. In many cases, Medical devices may be considered as containing nanomaterials because grinding or other crushing processes were involved in their manufacture [3].
2.1.3 What is an “ancillary” medicinal substance? This case relates to a device that incorporates, as an integral part, a substance which, if used separately, may be considered to be an MP within the meaning of Article 1 of MPs Directive in Europe5 and which is liable to act upon the body with action that is ancillary to that of the device [4]. The substance incorporated in the device must meet the three following conditions: ●
●
●
the substance, if used separately, may be considered to be an MP; the substance is liable to act upon the human body; the action of this substance is ancillary to that of the device.
The “ancillary” clause indicated that the device shall achieve its main function by nonmetabolic means, but that the medicinal substance may help to achieve the clinical benefit. A medical device incorporates a medicinal substance as an integral part, if and only if the device and the substance are physically or chemically combined at the time of administration (i.e., use, implantation, application, etc.) to the patient. Advanced therapy medicinal products (ATMPs) are innovative therapies based on genes (gene therapy), cells (cell therapy), or tissues (tissue engineering); some of them may contain also medical devices (called combined ATMPs—as for example, when cells are embedded in a biodegradable matrix or scaffold). These therapies are expected to bring important health benefits offering revolutionary new opportunities for the treatment of disease and injury. 4 5
http://ec.europa.eu/environment/chemicals/nanotech/faq/definition_en.htm. https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/dir_2001_83_consol_2012/ dir_2001_83_cons_2012_en.pdf.
Regulatory landscape of nanostructured biomaterials for tissue regeneration 31
2.1.4 What is a drug delivery product? This category involves a device that is intended to administer an MP in the case where the device and the MP form a single integral product, which is intended exclusively for use in the given combination and which is not reusable [4]. In Europe, the drug delivery product is governed by the MPs Directive. Moreover, the device part of the product, that is the part involved with the storage and delivery of the drug, should comply with some essential requirements on safety from the Medical Device Regulation. Some examples include prefilled syringes, precharged nebulizers, and patches for dermal delivery, implants containing MPs in a matrix whose primary purpose is to release the MP [4]. For all these examples, safety essential requirements apply on the part of the product that does not have a metabolic effect but that is nonetheless involved in the clinical benefit. For example, the materials of the prefilled syringe shall be compatible with the medicine that is contained, the needle of the syringe shall be in biocompatible steel, and the syringe shall be sterile. Similarly, the implant material that is intended to deliver the MP shall also be biocompatible and sterile. Nanomaterials have achieved incredible importance in medicine because they can be also used as carriers for delivering small molecules such as drugs, nucleic acids, and proteins. In addition, the drug particles itself can be engineered to form nanoscale size materials that can get to unreachable areas. Nowadays, there are numerous nanomaterials that could be effective in drug delivery, for example, in cancer therapy even if there are still many obstacles to overcome.
2.2 Introduction to medical device regulation All devices incorporating or consisting of nanomaterial are classified as: ●
●
●
class III if they present a high or medium potential for internal exposure; class IIb if they present a low potential for internal exposure; class IIa if they present a negligible potential for internal exposure (Table 2.1).
2.3 Main applicable standards The MDR requires providing compliance to essential requirements of safety: proof of compliance can be provided by following appropriate technical standards. There are many available technical standards, from international organizations, such as the ISO, IEC, and ASTM, providing information regarding technical requirements and regarding test methods, test numerosity, and acceptability criteria for a great range of product characteristics.
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Table 2.1 Analysis of some essential requirements (Medical Device Regulation 2017/745 Annex I and VIII rule 19) Applicable ISO standard
RES n.
Extract of text
What is required
10.1 (partial)
Particular attention (note of author “while defining the risk- benefit profile”) shall be paid to: the compatibility between the materials and substances used and biological tissues, cells and body fluids, taking account of the intended purpose of the device and, where relevant, absorption, distribution, metabolism and excretion Particular attention (note of author “while defining the risk- benefit profile”) shall be paid to: the confirmation that the device meets any defined chemical and/or physical specifications
The device shall not trigger an unwanted tissue response when it comes in contact with the human body, for example, when it is implanted
ISO 10993-1
The manufacturer shall be able to verify that the devices actually include the intended materials in the intended proportions The manufacturer shall be able to verify that each residue or contaminant coming from manufacturing or storage is known, measured, and taken into account when assessing biocompatibility and overall risk The manufacturer shall be able to verify the kind and quantity of materials that are released from the device and that this information and taken into account when assessing biocompatibility and overall risk
Test to be performed according to best practices, for example GLP or ISO 10993-18 or ISO/TS 10993-19 Typically Leachables and Extractables tests performed according to ISO 10993-12 followed by toxicological risk assessment according to ISO 10993-1
10.1 (partial)
10.2
10.4.1
Devices shall be designed, manufactured, and packaged in such a way as to minimize the risk posed by contaminants and residues to patients, taking account of the intended purpose of the device, and to the persons involved in the transport, storage, and use of the devices. Particular attention shall be paid to tissues exposed to those contaminants and residues and to the duration and frequency of exposure Devices shall be designed and manufactured in such a way as to reduce as far as possible the risks posed by substances or particles, including wear debris, degradation products and processing residues that may be released from the device. Devices or those parts thereof or those materials used therein that— are invasive and come into direct contact with the human body—(re) administer medicines, body liquids or other substances, including gases, to/from the body, or—transport or store such medicines, body fluids or substances, including gases, to be (re) administered to the body
Typically Leachables and Extractables tests performed according to ISO 10993-12 followed by toxicological risk assessment according to ISO 10993-1; in some cases, additional testing and assessment of in vivo testing according to ISO 10993-6
Regulatory landscape of nanostructured biomaterials for tissue regeneration 33
Table 2.1 Continued RES n.
Extract of text
What is required
10.6
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. Special attention shall be given to nanomaterials
11.1
Devices and their manufacturing processes shall be designed in such a way as to eliminate or to reduce as far as possible the risk of infection to patients, users and, where applicable, other persons. The design shall: (a) reduce as far as possible and appropriate the risks from unintended cuts and pricks, such as needle stick injuries, (b) allow easy and safe handling, (c) reduce as far as possible any microbial leakage from the device and/or microbial exposure during use, and (d) prevent microbial contamination of the device or its content such as specimens or fluids
The manufacturer shall be able to verify the kind and quantity of particles and nanomaterials that are released from the device and that this information is taken into account when assessing biocompatibility and overall risk Devices containing nanomaterials shall be sterile if implanted, and the sterilization process shall be validated to ensure repeatability
Applicable ISO standard Challenge to manufacturers: testing and assessment of in vivo testing according to ISO 10993-6
There are different standards, according to the sterilization method. For example, sterilization by irradiation is described in ISO 11137
Some standards are considered particularly appropriate to regulatory purposes and are, therefore, inserted in a list of “harmonized” (i.e., approved for regulatory purposes) standards by the Commission.6 Compliance to harmonized standards provides a presumption of conformity to the applicable requirements: in practical terms, this means that once the testing according to an appropriate standard is completed, no further testing is required for that particular requirement. A brief example: for a device that is sterilized by irradiation, application of the appropriate ISO 11137 guides the manufacturer through the different steps of sterilization validation. 6
http://ec.europa.eu/growth/single-market/european-standards/harmonised-standards_en
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In the field of nanostructured biomaterials for tissue regeneration, there are two main areas of concern that should be described in detail: the material biocompatibility and the material sterility state.
2.3.1 Biocompatibility Biocompatibility can be defined as “Compatibility with living tissue or a living system by not being toxic, injurious, or physiologically reactive and not causing immunological rejection.”7 Biocompatibility testing ranges from the initial screening of new materials to product release testing, periodic audit testing, and nonclinical or premarket safety evaluations to meet current international standards. Safety evaluation studies (in vitro and in vivo) are conducted on a variety of biomaterials, medical devices, and related products to identify any potentially harmful effects on the living organism. There are many standards related to biocompatibility assessment, the most important are: ●
●
ISO 10993—“Biological Evaluation of Medical Devices Part 1: Evaluation and Testing” ISO 14971 “Medical devices—Application of risk management to medical devices (Annex I)”
Moreover, the FDA released an important guideline on application of these standards.8 Lately, the industry experienced preference to chemical constituent testing (toxicological assessment) and in vitro models, considered acceptable under a regulatory point of view if these methods yield equally relevant information as compared to animal models. It must be noted that within a risk management process, that sees biocompatibility as one source of potential risk, design of each device should choose appropriate materials, assessing biocompatibility data from the review and evaluation of existing data from all sources, including Literature, Toxicological assessment, and the selection and application of additional tests (in vitro and in vivo). For this reason, Biological evaluation is based on material and raw material identification data, Data regarding biocompatibility of materials and composites from literature and from past clinical and preclinical experience and only as a last resource from testing. Moreover, biological testing is firstly based on Toxicological assessment. According to the risk-based approach, test planning is defined by categorization of medical devices by nature of body contact and duration of contact and therefore by characterization for toxicological hazards, informed by testing and measuring the substances that are leachable and extractable from the material in known—standard-based conditions. 7 8
https://www.merriam-webster.com/dictionary/biocompatibility. FDA “Use of International Standard ISO 10993-1, “Biological evaluation of medical devices—Part 1: Evaluation and testing within a risk management process” Guidance for Industry and Food and Drug Administration Staff.
Regulatory landscape of nanostructured biomaterials for tissue regeneration 35
Assessing of hazards from materials, additives, and leachable is based on Toxicology data, evaluation according to criteria of dose-response rate and nature of exposure (time, path, total exposure over the clinical life). Subsequently, it is possible to estimate the risk on patient health. For this reason, it is very important to characterize the biomaterial according to its intended use (location in the human body and duration of contact) in order to assess the “Exposure route” and dose, that are relevant for risk.9 Biocompatibility of medical devices including nanomaterials is in the scope of a dedicated subsection of ISO 10993. ISO 10993-22 is available since 2017 and provides detailed guidance of nanomaterials characterization in terms of: ●
●
●
Chemical composition: (answering to the question: What is it made of?). Physical description: (answering to the question: What does it look like?). Extrinsic properties (answering to the question: How does it interact with the surrounding environment?).
Toxicological risk assessment of nanomaterials is based on their specific characteristics: while dose levels for toxicology studies are conventionally expressed on a mass concentration basis, this information may not be appropriate for nanomaterials. For this reason, ISO 10993-22 recommends that “in addition to mass concentration, other parameters including surface area and particle number concentration should be used to fully characterize the dose of nanomaterials”. Exposure to nanomaterials released by medical devices is related to the intended use and also to some material characteristics, including degradation products (that may consist in particles in the nanoscale), release as a consequence of wear, and generation of nanoscaled particles during some manufacturing or deployment processes such as, for example, grinding performed during medical procedures (e.g., during dental procedures). For all these reasons, there are some biocompatibility endpoints that require special considerations when assessing medical devices containing nanomaterials. The toxicological evaluation provides important information for the following assessment of in vitro cytotoxicity and genotoxicity, carcinogenicity, and reproductive toxicity. For genotoxicity studies of medical devices containing nanomaterials, ISO 1099322 does not recommend the most used genotoxicity test method that is described in ISO 10993-3 (bacterial reverse mutation test) and instead recommends mammalian cell systems because of their potential to take up the nano-objects. Any in vivo test for genotoxicity should be preceded by careful planning and identification of the target organ. ISO 10993-2 indicates several transgenic animal models. For carcinogenicity, ISO 10993-22 indicates that evaluation of the carcinogenic risk should be considered if human exposure is high or chronic but also indicates that a case-by-case approach should be used for the choice of the correct in vivo model. 9
Exposure: Refers to any condition which provides an opportunity for an external environmental agent to enter the body Dose: Refers to the amount of agent actually deposited within the body Response: Refers to the biological effect of the agent
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Assessment of reproductive toxicity of the nanomaterials used should be considered in compliance with the requirement of ISO 10993-3. Testing is considered more appropriate especially in case of prolonged or permanent-contact medical devices likely to come into direct contact with reproductive tissues, embryos, or fetus; energy-depositing medical devices; devices that are absorbable or that are containing leachable nanomaterials/nanoparticles for which complete elimination has not been demonstrated. ISO 10993-22 also contains guidance on Immunotoxicity, irritation, and sensitization, on hemocompatibility, on systemic toxicity, and on implantation.
2.3.1.1 Classification of medical devices Medical devices may be classified: By nature of body contact: (a) Surface (skin, mucosa, breached surface). (b) External path (indirect blood path, ex IV sets, tissue as path ex laparoscopes, blood circuits). (c) Implant devices (tissue or bone and blood).
By duration of contact: A. Limited—24 h or less. B. Prolonged—24 h to 30 days. C. Permanent—30 days plus (even intermittent).
2.3.1.2 Characterization of medical devices As regards of biocompatibility planning, devices are characterized according to the intended use and device characteristics by the following procedure: (a) Define each material/device and its use and its reasonably foreseeable misuse. Intended purpose. Intended population. Intended users. ●
●
●
(b) Physically and chemically characterize each material/device. From supplier information. From testing. ●
●
2.3.2 Sterility As a very broad definition, sterility (as applied to medical devices) means the condition of being free from viable microorganisms. Such a condition is generally obtained through the process of sterilization, whose purpose is to inactivate the microbiological contaminants, transforming the nonsterile products into sterile ones. There are several sterilization methods that can be used in order to obtain the sterility of a medical device: filtration, formaldehyde, autoclaving, ethylene oxide, gamma irradiation, ozone, hydrogen peroxide, plasma, or UV irradiation.
Regulatory landscape of nanostructured biomaterials for tissue regeneration 37
Before mentioning relevant standards, it is important to underline that the process of sterilization, by its own nature, falls into those processes that cannot be fully verified by subsequent complete inspection and testing of the product. For this reason, sterilization requires validation (and relevant standards) that is the action of checking or proving the validity of the process in advance, routine monitor, and equipment maintenance. Shortly, activities involved with sterilization involve development, validation, and routine control of the process, subjected to standards aimed at ensuring that the sterilization process is reliable and reproducible. The overall goal is to assure that the probability of there being a viable microorganism present on the device after sterilization is acceptably low. The Sterility Assurance Level (SAL) defines the probability of survival of a single microorganism; its specification can vary between jurisdictions. Methods involved with the determination of microorganism population are defined by ISO 11737-1, Sterilization of health care products—Microbiological methods Determination of a population of microorganisms on products. Methods involved with the sterilization process are defined by ISO 11737-2, Sterilization of medical devices—Microbiological methods—Part 2: Tests of sterility performed in the definition, validation, and maintenance of a sterilization process. In Europe, the harmonized standard specifying requirements for designating a terminally sterilized device as sterile is EN 556-1. It has also been adopted in a number of countries outside Europe, for example, Australia and China. EN 556-1 specifies that a probability of a viable microorganism on a device of 10−6 or less is required in order to designate a terminally sterilized medical device as sterile. This point raises important implications because certain devices cannot withstand a terminal sterilization process achieving this probability. This is particularly true in devices made up of materials sensitive to traditional sterilization processes, for example, those involving irradiation, or including cellular or biologically based components. Many plastics, for instance, undergo chain scission or crosslinking on irradiation, with significant effects on average chain length and molecular weight. Biological molecules can change conformation and loose biological activity. In this respect, EN 556-1 includes an explanatory note that permits acceptance of a probability >10−6 (e.g., 10−5), considering the individual situation, including the risk assessment undertaken by the manufacturer of the device. Applicability of this clause can be sought through discussion with regulatory bodies. Usually, nanomaterials are not sterile and can be contaminated at any stage of their production with biological species, for example, endotoxins (which is a common contaminant coming from the Gram-negative bacterial cell membrane). For this reason, there are Good Laboratory Practice and protocols to take the necessary precautions in order to avoid/reduce endotoxin contamination, especially for some NPs that had shown high binding properties to endotoxin throughout synthesis and processing [5]. Moreover, nanomaterials could be susceptible to being damaged by sterilization techniques, particularly when biological materials are involved. For example, sterilization by autoclaving could origin chemical and physical changes caused by heating in NPs with “low melting point” or that contain proteins/antibodies. Otherwise, sterilization by gamma irradiation could induce the formation of free radicals that
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Nanostructured Biomaterials for Regenerative Medicine
could cause chemical changes plus impact the stability of the product (especially in polymeric materials). “Aseptic manufacturing” is an option but could be quite complicated in particular for a multiple step process. Consequently, it is essential to test several methods in order to find the specific sterilization to be performed for each particular nanomaterial, and an appropriate series of tests must be utilized during the development phase in order to understand the impact of sterilization on the nanomaterial. Sterilization remains a critical step for the use of nanomaterials in medical devices, and the effects of sterilization on the integrity of the physicochemical properties of nanomaterials (immediately and after a long time) still require to be investigated.
2.4 What is to be demonstrated 2.4.1 Safety In the medical device field, a safe device can be described as a device with a favorable risk-benefit profile. In the Reg. EU 27017/745, this requirement is described as the fact that devices shall not compromise the clinical condition or the safety of patients. Patients are not the only stakeholders that shall be taken into consideration as the Regulation also requires that manufacturers assess the risk-benefit profile as regards of the safety and health of users or, where applicable, other persons. The Regulation also describes what a “favorable” risk-benefit profile is by explaining that any risks which may be associated with the medical device use shall be acceptable when weighed against the benefits to the patient. This also means that any risks are compatible with a high level of protection of health and safety, taking into account the generally acknowledged state of the art. This poses a special concern to manufacturers of medical devices containing nanomaterials, as the potential of exposure of patients and also of users shall be taken into consideration by assessing the state-of-the-art knowledge.
2.4.1.1 Role of the in vitro and in vivo testing Safety is typically demonstrated by compliance to safety standards, such as, for example, standards for biocompatibility and for sterility. Safety is a characteristic that is therefore proven by testing significant samples so that the results can adequately describe the safety profile of the commercial product that is actually placed on the market. The selection of a significant test sample can be especially challenging when testing medical devices based on nanomaterials. The applicable standard ISO 10993-22 provides guidance on the sample preparation and selection, as it requires that nanomaterials should be characterized in the form they will be delivered to the end-user, which is a clear requirement that the final device (or a significant portion) is tested. If only a portion of the final device is tested, the manufacturer shall describe representative samples from the final device in terms of materials processed in the same manner as the final device in order to directly evaluate a nanomaterial component.
Regulatory landscape of nanostructured biomaterials for tissue regeneration 39
The outcome of in vitro and in vivo testing is assessed, according to compliance to standards and to comparison to state of the art, in order to describe the potential device risk.
2.4.2 Clinical performance and clinical benefit According to the Regulation EU 2017/745,10 the term “clinical performance” of a device means the ability of that device, resulting from any direct or indirect medical effects which stem from its technical or functional characteristics, including diagnostic characteristics, to achieve its intended purpose as claimed by the manufacturer, thereby leading to a clinical benefit for patients, when used as intended by the manufacturer; clinical performance is best described by technical, chemical, and physical characteristics of the device itself. On the other hand, the Regulation describes the “clinical benefit” as the positive impact of a device on the health of an individual, expressed in terms of a meaningful, measurable, patient-relevant clinical outcome(s), including outcome(s) related to diagnosis, or a positive impact on patient management or public health. For this reason, there is a measurable and predictable cause-effect relationship between the performance (how the device acts on the human body) and the benefit (how the human body positively responds). Thus, the building up of the data required to show compliance to Regulations follows a sequence of steps of increasing complexity: in vitro data, often obtained by cell culture testing, provide ethical and scientific “green-light” for the preclinical animal, in vivo testing. Feedback from animal testing, evaluated through the requirements of safety, performance, and benefit, as just described, provide in turn green light for clinical evaluation as further described in the next section.
2.4.2.1 Role of the in vivo and clinical testing Clinical performance and clinical benefit are usually described not only by means of compliance with the standard, but also by assessing the device behavior and its impact on a living tissue or organism. Testing is therefore also performed on applicable animal models and, when technically necessary and ethically acceptable, clinical performance and benefit are studied with the involvement of patients. For clinical testing, there is a clear requirement in MDR 2017/745 that the endpoints of the clinical investigation shall address the intended purpose, clinical benefits, performance, and safety of the device. The endpoints shall be determined and assessed using scientifically valid methodologies. The primary endpoint shall be appropriate to the device and clinically relevant. For nanomaterials, the challenge in the assessment of the clinical performance and subsequent clinical benefit is, therefore, linked to the challenge of determining appropriate endpoints.
10
Medical Device Regulation 2017/745 Article 2.
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2.5 From the project to the product Research Institutes, innovative Start-Ups/SMEs and Large Industries have individual plans to convert new “nano ideas” into products… but they have the same challenge: the commercialization of nanostructured devices for tissue regeneration is much more complicated than other products. When new products/processes are developed, a strong effort must be made to ensure that they are healthful and environmentally safe. The toxicity of NPs is mainly given by their physical/chemical characteristics (size, shape, surface charge, etc.) and the presence/ absence of active groups on the surface. Therefore, there are several complex regulatory and approval processes (depending on under which different product categories fall the new “nano idea”) to follow for commercialization, but they have often some “gray area” where neither the notify body nor the manufacturer has a clear idea of what to do. The development and commercialization of a “nano-product” (the term include both product containing NPs and produced using nanotechnologies) require collaboration among many different actors, due to the complexity of the matter and requires a long time (the time to market is often “close” to 20 years). Moreover, costs for translating an idea to a commercial product are extremely high (in part due to the enormous expenses requested for the clinical trials); therefore, a very careful screening of innovative ideas has to be performed as soon as possible (in order to not vast money).
2.5.1 Ensuring a consistent level of quality 2.5.1.1 Manufacturing Essential conditions for the development of an industrial scale “nano-manufacturing” are the capability to preserve nanoscale properties while incorporating into products, an online metrology in order to allow effective measurements/quality control and the availability of high throughput. The challenge is maintaining the properties and quality of “nano-system” during high-rate/volume production as well as during the lifetime of the product after production. Nano-manufacturing consists in a combination of process steps that often need specific tools (like the computer-aided design and manufacturing—CAD/CAM— especially if hybrid 3D printing is involved) and a precise quality control. The latter is a very important point because even small variations in processing of NPs can result in variations of toxicity. Sukhanova et al., in a recent paper, highlighted as the NP toxicity strongly depends on their physical and chemical properties, such as the shape, size, electric charge, and chemical compositions of the core and shell [6]. Moreover, nano-manufacturing must be safe for the workers, so any possible detection and measurement of the type and amount of NPs in the workplace have to be performed.
2.5.1.2 Quality control Nanomaterials possess exceptional unique nanoscale “size-dependent” physical, optical, and chemical properties that are completely different than their bulk counterpart. Therefore, what must be controlled and in which way?
Regulatory landscape of nanostructured biomaterials for tissue regeneration 41
The big challenge is not only the development of new analytical tools that make a possible measurement at nano-to-microscale (including dispersion of NPs within a matrix and at interfaces), but that these tools have to work in real-time embedded in the production line and above all, they must be “nonintrusively” or destructively. In the meantime, new methods of calibration and standardization have to be developed in order to ensure the accurate interpretation of results. A typical flow chart of a generic manufacturing process, with quality control steps, is shown in Fig. 2.1.11 Starting from the raw materials, an acceptance test must be performed in order to inspect materials and verify their conformity. Tests could be different for each material and could include, for example, Physicochemical characterizations (particle size, crystallinity, water solubility, surface characteristics, etc.). Each manufacturing phase must be subject to continuous analysis and during the manufacturing process, a statistical sampling (screening) could be performed in order to supervise the process and the final product. The controls that could be performed are, for example, an “in-process” monitoring of equipment, process parameters, and semifinished products, the control of dispersions, surface roughness measurements (to certify surface treatments), the control of the bonding and nonbonding interactions at the interface of the matrix and the transition region and last but not least the control of the toxicity of NPs. Critical control points (and procedures to monitor them) could be also determined in order to identify hazards, but it is even more important to set up corrective actions to be taken when a deviation is identified. At the end of the process, a final lot acceptance test and life test must be performed in order to confirm the quality of the final product.
2.5.2 Postmarket activities: surveillance and vigilance Postmarket activities involve actions to be performed after a medical device was firstly put on the market. They can be divided into two categories: ●
●
Proactive—Postmarket Surveillance Reactive—Vigilance
Postmarket surveillance is defined as: “the proactive collection of information on quality, safety or performance of medical devices after they have been placed on the market.” (According to the Global Harmonization Task Force.) Vigilance is defined as: reporting of incidents that can occur with medical devices, when they do not perform as intended, thereby leading in the worst case to injury or death. The purpose of medical device vigilance is to protect the health and safety of persons; evaluate incidents to prevent recurrence; determine the effectiveness of corrective actions and preventive actions, and monitor and learn from experience. Activities involved with postmarket surveillance typically involve seeking customer feedback 11
Modified from a Windbond website figure: http://www.winbond.com/hq/about-winbond/quality-policy/ management/management.html?__locale=en.
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relating to whether the organization has met customer requirements. This may be accomplished by some of the following methods: Focus groups Reviewing customer complaint information
●
●
The quality manager will yearly monitor the performance and safety of company products already on the market by observing, collating, and reviewing the following: Vigilance results review Per defect Per product Customer complaints Medical practitioner feedback Independent research Trade journals
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●
●
●
●
●
●
Vigilance has to do with Incidents. Examples of Incidents are: – Device malfunction or deterioration that occurs while the device is used as intended by the manufacturer. – Unanticipated adverse reaction or unanticipated side effect that is not stated in the information provided by the manufacturer. – Interactions with other substances or products. – Degradation/destruction of the device (e.g., fire). – Inappropriate therapy. – An inaccuracy, omission, or deficiency in the labeling, instructions for use and/or promotional materials, except information that is part of the general knowledge of the intended user.
Vigilance results can be defined using criteria such as: – – – –
number of incidents/field corrective actions in the year; number of incidents/field corrective actions per defect; number of incidents/field corrective actions per product; number of incidents/field corrective actions after complaints.
Results are compared with information from previous years. Occurrence of incidents should be notified to the relevant National Competent Authority.
2.6 Roles and responsibilities 2.6.1 Manufacturers According to the MDR 2017/745,3 a manufacturer is defined as: “A natural or legal person who manufactures or fully refurbishes a device or has a device designed, manufactured, or fully refurbished, and markets that device under its name or trademark.” The obligations of the manufacturers of medical devices (including the ones containing NPs) are, therefore, to demonstrate the conformity of their products with the legal requirements.
Regulatory landscape of nanostructured biomaterials for tissue regeneration 43
But it is also of extreme importance for manufacturers to be clearly aware of the supply chain and the impact of manufacturing activities. This is because in the global environment, nowadays, the use of contract manufacturing is often unavoidable in order to reduce costs and supply line issues. There are two documents prepared by the European Association of Notified Bodies for Medical Device that could help understanding the EU regulations on this matter: NB-MED/2.5.2/Rec1 “Subcontracting—QS related” and NB-MED/2.15/Rec1 “Voluntary Certification at an Intermediate Stage of Manufacture.”12 Moreover, manufacturers have to apply a postmarket surveillance system in order to constantly monitor the performance of their products and report every adverse incident (vigilance report) and field safety corrective actions (FSCAs) to EU Competent Authorities. An FSCA is an action taken by a manufacturer to report any technical or medical reason leading to a recall of devices and the new Medical Device Regulation addresses specific timelines for FSCA reports.
2.6.2 Competent authorities In Europe Competent Authorities, nominated by each government, are usually the Ministries of Health of each member State (instead, in the United States there is only one competent authority: the FDA). Therefore, each European country has its own Competent Authority in charge of market surveillance and designating and monitoring the independent Conformity Assessment Bodies (Notified Bodies). European National Competent Authorities for Medical Devices have created a group (CAMD) in order to enhance the level of collaborative work, communication, and surveillance of medical devices across Europe.
2.6.3 Notified bodies A notified body is an organization designated by an EU country to assess the conformity of certain products, including medical devices, before being placed on the market. These bodies carry out tasks related to conformity assessment procedures set out in the current Medical Device Directive and will from 2020 also carry out tasks related to conformity assessment procedures set out in the new upcoming regulation. The conformity assessment procedure for class I devices is being carried out, as a general rule, under the sole responsibility of manufacturers in view of the low level of vulnerability associated with such devices. For class IIa, class IIb, and class III devices, an appropriate level of involvement of a notified body is compulsory. Since devices containing nanomaterials are classified, in the Regulation 2017/745, at least in class IIa but more frequently in classes IIb and III, the intervention of a Notified Body in the marking procedure shall be expected. As part of their involvement in the certification process, notified bodies audit the technical documentation and the manufacturing, control, and distribution processes 12
http://www.team-nb.org/nb-med-documents/.
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Process
Quality control Method Storage
Finished product quality confirmation
Reliability confirmation Life test and environmental test
Sampling inspection Lot acceptance test
Manufacturing
Screening
Equipment, submaterial environment, cleanliness discipline—Monitoring Process parameters, semifinished product inspection—Monitoring
Testing and visual inspection
Appearance and characteristics 100% inspection
Raw materials
Raw materials quality conformance
Inspection on raw materials Acceptance test
Fig. 2.1 Example of a quality control flowchart.
and have the right and duty to carry out both announced and unannounced on-site audits and to conduct physical or laboratory tests on devices to ensure continuous compliance by manufacturers.
2.7 Relationship between regulatory requirements and intellectual property The Intellectual Property of NPs (or of a product containing them) and the relationship between regulatory requirements is a “mine-laden” that will become of strategic importance in the next future owing to the increasing numbers of innovative products/ technologies involving NPs. There are concomitant reasons that brought to these very difficult circumstances… First of all, patent laws usually exclude the possibility to patent methods for the treatment of the human body using surgery and therapy but allow the patenting of products used in these procedures. But this could be subverted by the patenting of NPs because “at the end” the patent could cover also the way of their utilization that could be considered as “a method.” Moreover, NPs, and medical products containing them have to comply with strict regulations in order to enter in a commercial market. In vitro, in vivo tests, and clinical trials must be performed following standardized procedures for a given period of time,
Regulatory landscape of nanostructured biomaterials for tissue regeneration 45
but a medical device could be exempted from regulation if a similar product is already on the market. This allows shortening incredibly the time-to-market and the costs. On the contrary, the same MD is often recognized as “new” from the Intellectual Property Rights viewpoint and therefore it is protected by patent laws. These two “way of seeing the matter” could create several issues, because if there is a patent protecting the MD, this means that it is innovative/new and therefore, it must be validated following regulations and vice versa. Sure enough, if an MD containing NPs is considered “new” this could greatly impact the time and cost required for its commercialization, especially after the entering into force, on May 25, 2017, of two new MD regulations”13 that has led to longer time periods for obtaining marketing approval. As a result, MD manufacturers should seek compensation for their loss of patent protection by requesting a Supplementary Protection Certificate (SPC = extension of the patent term up to 5 years). But the SPC regulation is one of the most controversial areas of European IP law because SPC can be obtained only for products that have been authorized for the first time as medicinal or plant protection products in the European Union. That means in Europe, formulation and MD patents cannot be the subject of SPCs. However, several MDs often include active ingredients (combinations or borderline MD), thus, they may in principle be eligible for SPC protection, but it could generate a lot of problems the fact that a single borderline product may be classified as an MD or an MP depending on the approach of each different Member States. It is, therefore, possible to imagine a scenario where a particular product is not only authorized differently as an MD or an MP throughout Europe but also that the accessibility of asking for an SPC in those States where it has been authorized as an MD may be different among EU members. During the last years, several requests of SPC were evaluated by different EU member’s patent courts but only in The Netherlands and Germany some cases were accepted. Totally different is the situation in the United States where the US law allows obtaining patent term extensions (PTE) for Class III (high-risk) MD and furthermore gives the possibility to extend a patent in case of unreasonable delays during the examination at the US Patent and Trademark Office [the so-called patent term adjustments (PTAs)]. In order to avoid unequal treatments on “this site of the Ocean,” the hope is that also in Europe it could be recognized that MD Cass III are facing similar levels of regulation to pharmaceutical products because nowadays they are subject to high standards in order to obtain the required conformity assessment certificate, and therefore SPC could be requested. Actually, the European Commission is aware of this matter and is looking into potential reform of the SPC system (following the outcomes of consultation done in 2017). 13
https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32017R0745 https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX:32017R0746
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References [1] M. Racchi, S. Govoni, A. Lucchelli, L. Capone, E. Giovagnoni, Insights into the definition of terms in European medical device regulation. Expert Rev. Med. Devices 13 (10) (2016) 907–917, https://doi.org/10.1080/17434440.2016.1224644. [2] Regulation EU 2017/745, whereas (15) and Annex I Essential requirement 10.5 [3] IMDRF Definition and regulation in terms of mechanism of action and intended use IMDRF-3 /20 March 2013/. [4] MEDDEV 2.1/3 rev.3 Borderline products, drug-delivery products and medical devices incorporating, as integral part, an ancillary medicinal substance or an ancillary human blood derivative [5] R. Darkow, T. Groth, W. Albrecht, K. Lutzow, D. Paul, Functionalized nanoparticles for endotoxin binding in aqueous solutions, Biomaterials 20 (1999) 1277–1283. [6] A. Sukhanova, et al., Dependence of nanoparticle toxicity on their physical and chemical properties, Nanoscale Res. Lett. 13 (2018) 44.
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Marco Morra*, Alice Ravizza†, Silvia Pascale‡ * Nobil Bio Ricerche S.r.l., Portacomaro (AT), Italy, †DIMEAS Politecnico di Torino, Torino, Italy, ‡Sorin Group Italia S.r.l. (LivaNova), Saluggia (VC), Italy
2.1 Identification of the appropriate regulatory landscape In Europe, the so-called New Legislative Framework (adopted in 2008) allows for a comprehensive regulatory framework to operate effectively for the safety and compliance of industrial products that include also products intended to provide medical treatment to human beings, including medicinal products (MPs) and medical devices.
2.1.1 Intended use The New Legislative Framework allows the classification of industrial products into many categories, for example, not only MPs, medical devices, and cosmetics but also machinery, personal protection equipment, toys, lifts, equipment powered by low voltage and many more.1 Any product intended to provide medical treatment to human beings should be able to be classified either as MP or as a medical device. While the complete definitions of “medicinal product”2 and “medical device”3 can be easily found in the appropriate legislative text, a rough distinction can be easily made by focusing on the mechanism that allows obtaining of the clinical benefit. If the product operates through the pharmacological, immunological, or metabolic mechanism of action, then it is a drug; if it does not, then it is a medical device. Most often, the “mechanism of action” can be widely described as metabolic since all stimuli, even those which are nonpharmacological but, for example, mechanical, promote in the patient body a pharmacological, immunological, or metabolic response. For this reason, it is always necessary to define the “intended and aimed clinical benefit,” therefore, the word “action” is used with a meaning of “effect” [1].
1
https://ec.europa.eu/growth/single-market/goods/new-legislative-framework_en. Article 1(2) of Directive 2001/83/EC3. https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/ dir_2001_83_consol_2012/dir_2001_83_cons_2012_en.pdf. 3 Article 2 of Europe Medical Device Regulation (MDR). https://eur-lex.europa.eu/legal-content/EN/TXT/ PDF/?uri=CELEX:32017R0745. 2
Nanostructured Biomaterials for Regenerative Medicine. https://doi.org/10.1016/B978-0-08-102594-9.00002-4 © 2020 Elsevier Ltd. All rights reserved.
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2.1.2 What is a “device containing nanomaterials”? In Europe, a uniform definition for nanomaterials is available: “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 1–100 nm.”4 The European Authorities recommend that in the design and manufacture of devices, manufacturers should take special care when using nanoparticles (NPs) for which there is a high or medium potential for internal exposure [2]. At the state of the art, nanomaterial-containing medical devices are widely widespread, for example, all products that contain pigments or filler materials are affected, such as for example, powdered medical gloves, pigmented compression or antithrombosis stockings, superabsorber-containing dressing materials, tubes for ventilation, plastic syringes and many other products. Moreover, many dental materials are affected: impression materials, adhesives, prostheses, or artificial teeth as these products contain powder, for example, porcelain powder, glass powder, pyrogenic silicas, pigments, or other basic substances that meet the definition of nanomaterials. In many cases, Medical devices may be considered as containing nanomaterials because grinding or other crushing processes were involved in their manufacture [3].
2.1.3 What is an “ancillary” medicinal substance? This case relates to a device that incorporates, as an integral part, a substance which, if used separately, may be considered to be an MP within the meaning of Article 1 of MPs Directive in Europe5 and which is liable to act upon the body with action that is ancillary to that of the device [4]. The substance incorporated in the device must meet the three following conditions: ●
●
●
the substance, if used separately, may be considered to be an MP; the substance is liable to act upon the human body; the action of this substance is ancillary to that of the device.
The “ancillary” clause indicated that the device shall achieve its main function by nonmetabolic means, but that the medicinal substance may help to achieve the clinical benefit. A medical device incorporates a medicinal substance as an integral part, if and only if the device and the substance are physically or chemically combined at the time of administration (i.e., use, implantation, application, etc.) to the patient. Advanced therapy medicinal products (ATMPs) are innovative therapies based on genes (gene therapy), cells (cell therapy), or tissues (tissue engineering); some of them may contain also medical devices (called combined ATMPs—as for example, when cells are embedded in a biodegradable matrix or scaffold). These therapies are expected to bring important health benefits offering revolutionary new opportunities for the treatment of disease and injury. 4 5
http://ec.europa.eu/environment/chemicals/nanotech/faq/definition_en.htm. https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/dir_2001_83_consol_2012/ dir_2001_83_cons_2012_en.pdf.
Regulatory landscape of nanostructured biomaterials for tissue regeneration 31
2.1.4 What is a drug delivery product? This category involves a device that is intended to administer an MP in the case where the device and the MP form a single integral product, which is intended exclusively for use in the given combination and which is not reusable [4]. In Europe, the drug delivery product is governed by the MPs Directive. Moreover, the device part of the product, that is the part involved with the storage and delivery of the drug, should comply with some essential requirements on safety from the Medical Device Regulation. Some examples include prefilled syringes, precharged nebulizers, and patches for dermal delivery, implants containing MPs in a matrix whose primary purpose is to release the MP [4]. For all these examples, safety essential requirements apply on the part of the product that does not have a metabolic effect but that is nonetheless involved in the clinical benefit. For example, the materials of the prefilled syringe shall be compatible with the medicine that is contained, the needle of the syringe shall be in biocompatible steel, and the syringe shall be sterile. Similarly, the implant material that is intended to deliver the MP shall also be biocompatible and sterile. Nanomaterials have achieved incredible importance in medicine because they can be also used as carriers for delivering small molecules such as drugs, nucleic acids, and proteins. In addition, the drug particles itself can be engineered to form nanoscale size materials that can get to unreachable areas. Nowadays, there are numerous nanomaterials that could be effective in drug delivery, for example, in cancer therapy even if there are still many obstacles to overcome.
2.2 Introduction to medical device regulation All devices incorporating or consisting of nanomaterial are classified as: ●
●
●
class III if they present a high or medium potential for internal exposure; class IIb if they present a low potential for internal exposure; class IIa if they present a negligible potential for internal exposure (Table 2.1).
2.3 Main applicable standards The MDR requires providing compliance to essential requirements of safety: proof of compliance can be provided by following appropriate technical standards. There are many available technical standards, from international organizations, such as the ISO, IEC, and ASTM, providing information regarding technical requirements and regarding test methods, test numerosity, and acceptability criteria for a great range of product characteristics.
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Table 2.1 Analysis of some essential requirements (Medical Device Regulation 2017/745 Annex I and VIII rule 19) Applicable ISO standard
RES n.
Extract of text
What is required
10.1 (partial)
Particular attention (note of author “while defining the risk- benefit profile”) shall be paid to: the compatibility between the materials and substances used and biological tissues, cells and body fluids, taking account of the intended purpose of the device and, where relevant, absorption, distribution, metabolism and excretion Particular attention (note of author “while defining the risk- benefit profile”) shall be paid to: the confirmation that the device meets any defined chemical and/or physical specifications
The device shall not trigger an unwanted tissue response when it comes in contact with the human body, for example, when it is implanted
ISO 10993-1
The manufacturer shall be able to verify that the devices actually include the intended materials in the intended proportions The manufacturer shall be able to verify that each residue or contaminant coming from manufacturing or storage is known, measured, and taken into account when assessing biocompatibility and overall risk The manufacturer shall be able to verify the kind and quantity of materials that are released from the device and that this information and taken into account when assessing biocompatibility and overall risk
Test to be performed according to best practices, for example GLP or ISO 10993-18 or ISO/TS 10993-19 Typically Leachables and Extractables tests performed according to ISO 10993-12 followed by toxicological risk assessment according to ISO 10993-1
10.1 (partial)
10.2
10.4.1
Devices shall be designed, manufactured, and packaged in such a way as to minimize the risk posed by contaminants and residues to patients, taking account of the intended purpose of the device, and to the persons involved in the transport, storage, and use of the devices. Particular attention shall be paid to tissues exposed to those contaminants and residues and to the duration and frequency of exposure Devices shall be designed and manufactured in such a way as to reduce as far as possible the risks posed by substances or particles, including wear debris, degradation products and processing residues that may be released from the device. Devices or those parts thereof or those materials used therein that— are invasive and come into direct contact with the human body—(re) administer medicines, body liquids or other substances, including gases, to/from the body, or—transport or store such medicines, body fluids or substances, including gases, to be (re) administered to the body
Typically Leachables and Extractables tests performed according to ISO 10993-12 followed by toxicological risk assessment according to ISO 10993-1; in some cases, additional testing and assessment of in vivo testing according to ISO 10993-6
Regulatory landscape of nanostructured biomaterials for tissue regeneration 33
Table 2.1 Continued RES n.
Extract of text
What is required
10.6
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. Special attention shall be given to nanomaterials
11.1
Devices and their manufacturing processes shall be designed in such a way as to eliminate or to reduce as far as possible the risk of infection to patients, users and, where applicable, other persons. The design shall: (a) reduce as far as possible and appropriate the risks from unintended cuts and pricks, such as needle stick injuries, (b) allow easy and safe handling, (c) reduce as far as possible any microbial leakage from the device and/or microbial exposure during use, and (d) prevent microbial contamination of the device or its content such as specimens or fluids
The manufacturer shall be able to verify the kind and quantity of particles and nanomaterials that are released from the device and that this information is taken into account when assessing biocompatibility and overall risk Devices containing nanomaterials shall be sterile if implanted, and the sterilization process shall be validated to ensure repeatability
Applicable ISO standard Challenge to manufacturers: testing and assessment of in vivo testing according to ISO 10993-6
There are different standards, according to the sterilization method. For example, sterilization by irradiation is described in ISO 11137
Some standards are considered particularly appropriate to regulatory purposes and are, therefore, inserted in a list of “harmonized” (i.e., approved for regulatory purposes) standards by the Commission.6 Compliance to harmonized standards provides a presumption of conformity to the applicable requirements: in practical terms, this means that once the testing according to an appropriate standard is completed, no further testing is required for that particular requirement. A brief example: for a device that is sterilized by irradiation, application of the appropriate ISO 11137 guides the manufacturer through the different steps of sterilization validation. 6
http://ec.europa.eu/growth/single-market/european-standards/harmonised-standards_en
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In the field of nanostructured biomaterials for tissue regeneration, there are two main areas of concern that should be described in detail: the material biocompatibility and the material sterility state.
2.3.1 Biocompatibility Biocompatibility can be defined as “Compatibility with living tissue or a living system by not being toxic, injurious, or physiologically reactive and not causing immunological rejection.”7 Biocompatibility testing ranges from the initial screening of new materials to product release testing, periodic audit testing, and nonclinical or premarket safety evaluations to meet current international standards. Safety evaluation studies (in vitro and in vivo) are conducted on a variety of biomaterials, medical devices, and related products to identify any potentially harmful effects on the living organism. There are many standards related to biocompatibility assessment, the most important are: ●
●
ISO 10993—“Biological Evaluation of Medical Devices Part 1: Evaluation and Testing” ISO 14971 “Medical devices—Application of risk management to medical devices (Annex I)”
Moreover, the FDA released an important guideline on application of these standards.8 Lately, the industry experienced preference to chemical constituent testing (toxicological assessment) and in vitro models, considered acceptable under a regulatory point of view if these methods yield equally relevant information as compared to animal models. It must be noted that within a risk management process, that sees biocompatibility as one source of potential risk, design of each device should choose appropriate materials, assessing biocompatibility data from the review and evaluation of existing data from all sources, including Literature, Toxicological assessment, and the selection and application of additional tests (in vitro and in vivo). For this reason, Biological evaluation is based on material and raw material identification data, Data regarding biocompatibility of materials and composites from literature and from past clinical and preclinical experience and only as a last resource from testing. Moreover, biological testing is firstly based on Toxicological assessment. According to the risk-based approach, test planning is defined by categorization of medical devices by nature of body contact and duration of contact and therefore by characterization for toxicological hazards, informed by testing and measuring the substances that are leachable and extractable from the material in known—standard-based conditions. 7 8
https://www.merriam-webster.com/dictionary/biocompatibility. FDA “Use of International Standard ISO 10993-1, “Biological evaluation of medical devices—Part 1: Evaluation and testing within a risk management process” Guidance for Industry and Food and Drug Administration Staff.
Regulatory landscape of nanostructured biomaterials for tissue regeneration 35
Assessing of hazards from materials, additives, and leachable is based on Toxicology data, evaluation according to criteria of dose-response rate and nature of exposure (time, path, total exposure over the clinical life). Subsequently, it is possible to estimate the risk on patient health. For this reason, it is very important to characterize the biomaterial according to its intended use (location in the human body and duration of contact) in order to assess the “Exposure route” and dose, that are relevant for risk.9 Biocompatibility of medical devices including nanomaterials is in the scope of a dedicated subsection of ISO 10993. ISO 10993-22 is available since 2017 and provides detailed guidance of nanomaterials characterization in terms of: ●
●
●
Chemical composition: (answering to the question: What is it made of?). Physical description: (answering to the question: What does it look like?). Extrinsic properties (answering to the question: How does it interact with the surrounding environment?).
Toxicological risk assessment of nanomaterials is based on their specific characteristics: while dose levels for toxicology studies are conventionally expressed on a mass concentration basis, this information may not be appropriate for nanomaterials. For this reason, ISO 10993-22 recommends that “in addition to mass concentration, other parameters including surface area and particle number concentration should be used to fully characterize the dose of nanomaterials”. Exposure to nanomaterials released by medical devices is related to the intended use and also to some material characteristics, including degradation products (that may consist in particles in the nanoscale), release as a consequence of wear, and generation of nanoscaled particles during some manufacturing or deployment processes such as, for example, grinding performed during medical procedures (e.g., during dental procedures). For all these reasons, there are some biocompatibility endpoints that require special considerations when assessing medical devices containing nanomaterials. The toxicological evaluation provides important information for the following assessment of in vitro cytotoxicity and genotoxicity, carcinogenicity, and reproductive toxicity. For genotoxicity studies of medical devices containing nanomaterials, ISO 1099322 does not recommend the most used genotoxicity test method that is described in ISO 10993-3 (bacterial reverse mutation test) and instead recommends mammalian cell systems because of their potential to take up the nano-objects. Any in vivo test for genotoxicity should be preceded by careful planning and identification of the target organ. ISO 10993-2 indicates several transgenic animal models. For carcinogenicity, ISO 10993-22 indicates that evaluation of the carcinogenic risk should be considered if human exposure is high or chronic but also indicates that a case-by-case approach should be used for the choice of the correct in vivo model. 9
Exposure: Refers to any condition which provides an opportunity for an external environmental agent to enter the body Dose: Refers to the amount of agent actually deposited within the body Response: Refers to the biological effect of the agent
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Nanostructured Biomaterials for Regenerative Medicine
Assessment of reproductive toxicity of the nanomaterials used should be considered in compliance with the requirement of ISO 10993-3. Testing is considered more appropriate especially in case of prolonged or permanent-contact medical devices likely to come into direct contact with reproductive tissues, embryos, or fetus; energy-depositing medical devices; devices that are absorbable or that are containing leachable nanomaterials/nanoparticles for which complete elimination has not been demonstrated. ISO 10993-22 also contains guidance on Immunotoxicity, irritation, and sensitization, on hemocompatibility, on systemic toxicity, and on implantation.
2.3.1.1 Classification of medical devices Medical devices may be classified: By nature of body contact: (a) Surface (skin, mucosa, breached surface). (b) External path (indirect blood path, ex IV sets, tissue as path ex laparoscopes, blood circuits). (c) Implant devices (tissue or bone and blood).
By duration of contact: A. Limited—24 h or less. B. Prolonged—24 h to 30 days. C. Permanent—30 days plus (even intermittent).
2.3.1.2 Characterization of medical devices As regards of biocompatibility planning, devices are characterized according to the intended use and device characteristics by the following procedure: (a) Define each material/device and its use and its reasonably foreseeable misuse. Intended purpose. Intended population. Intended users. ●
●
●
(b) Physically and chemically characterize each material/device. From supplier information. From testing. ●
●
2.3.2 Sterility As a very broad definition, sterility (as applied to medical devices) means the condition of being free from viable microorganisms. Such a condition is generally obtained through the process of sterilization, whose purpose is to inactivate the microbiological contaminants, transforming the nonsterile products into sterile ones. There are several sterilization methods that can be used in order to obtain the sterility of a medical device: filtration, formaldehyde, autoclaving, ethylene oxide, gamma irradiation, ozone, hydrogen peroxide, plasma, or UV irradiation.
Regulatory landscape of nanostructured biomaterials for tissue regeneration 37
Before mentioning relevant standards, it is important to underline that the process of sterilization, by its own nature, falls into those processes that cannot be fully verified by subsequent complete inspection and testing of the product. For this reason, sterilization requires validation (and relevant standards) that is the action of checking or proving the validity of the process in advance, routine monitor, and equipment maintenance. Shortly, activities involved with sterilization involve development, validation, and routine control of the process, subjected to standards aimed at ensuring that the sterilization process is reliable and reproducible. The overall goal is to assure that the probability of there being a viable microorganism present on the device after sterilization is acceptably low. The Sterility Assurance Level (SAL) defines the probability of survival of a single microorganism; its specification can vary between jurisdictions. Methods involved with the determination of microorganism population are defined by ISO 11737-1, Sterilization of health care products—Microbiological methods Determination of a population of microorganisms on products. Methods involved with the sterilization process are defined by ISO 11737-2, Sterilization of medical devices—Microbiological methods—Part 2: Tests of sterility performed in the definition, validation, and maintenance of a sterilization process. In Europe, the harmonized standard specifying requirements for designating a terminally sterilized device as sterile is EN 556-1. It has also been adopted in a number of countries outside Europe, for example, Australia and China. EN 556-1 specifies that a probability of a viable microorganism on a device of 10−6 or less is required in order to designate a terminally sterilized medical device as sterile. This point raises important implications because certain devices cannot withstand a terminal sterilization process achieving this probability. This is particularly true in devices made up of materials sensitive to traditional sterilization processes, for example, those involving irradiation, or including cellular or biologically based components. Many plastics, for instance, undergo chain scission or crosslinking on irradiation, with significant effects on average chain length and molecular weight. Biological molecules can change conformation and loose biological activity. In this respect, EN 556-1 includes an explanatory note that permits acceptance of a probability >10−6 (e.g., 10−5), considering the individual situation, including the risk assessment undertaken by the manufacturer of the device. Applicability of this clause can be sought through discussion with regulatory bodies. Usually, nanomaterials are not sterile and can be contaminated at any stage of their production with biological species, for example, endotoxins (which is a common contaminant coming from the Gram-negative bacterial cell membrane). For this reason, there are Good Laboratory Practice and protocols to take the necessary precautions in order to avoid/reduce endotoxin contamination, especially for some NPs that had shown high binding properties to endotoxin throughout synthesis and processing [5]. Moreover, nanomaterials could be susceptible to being damaged by sterilization techniques, particularly when biological materials are involved. For example, sterilization by autoclaving could origin chemical and physical changes caused by heating in NPs with “low melting point” or that contain proteins/antibodies. Otherwise, sterilization by gamma irradiation could induce the formation of free radicals that
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Nanostructured Biomaterials for Regenerative Medicine
could cause chemical changes plus impact the stability of the product (especially in polymeric materials). “Aseptic manufacturing” is an option but could be quite complicated in particular for a multiple step process. Consequently, it is essential to test several methods in order to find the specific sterilization to be performed for each particular nanomaterial, and an appropriate series of tests must be utilized during the development phase in order to understand the impact of sterilization on the nanomaterial. Sterilization remains a critical step for the use of nanomaterials in medical devices, and the effects of sterilization on the integrity of the physicochemical properties of nanomaterials (immediately and after a long time) still require to be investigated.
2.4 What is to be demonstrated 2.4.1 Safety In the medical device field, a safe device can be described as a device with a favorable risk-benefit profile. In the Reg. EU 27017/745, this requirement is described as the fact that devices shall not compromise the clinical condition or the safety of patients. Patients are not the only stakeholders that shall be taken into consideration as the Regulation also requires that manufacturers assess the risk-benefit profile as regards of the safety and health of users or, where applicable, other persons. The Regulation also describes what a “favorable” risk-benefit profile is by explaining that any risks which may be associated with the medical device use shall be acceptable when weighed against the benefits to the patient. This also means that any risks are compatible with a high level of protection of health and safety, taking into account the generally acknowledged state of the art. This poses a special concern to manufacturers of medical devices containing nanomaterials, as the potential of exposure of patients and also of users shall be taken into consideration by assessing the state-of-the-art knowledge.
2.4.1.1 Role of the in vitro and in vivo testing Safety is typically demonstrated by compliance to safety standards, such as, for example, standards for biocompatibility and for sterility. Safety is a characteristic that is therefore proven by testing significant samples so that the results can adequately describe the safety profile of the commercial product that is actually placed on the market. The selection of a significant test sample can be especially challenging when testing medical devices based on nanomaterials. The applicable standard ISO 10993-22 provides guidance on the sample preparation and selection, as it requires that nanomaterials should be characterized in the form they will be delivered to the end-user, which is a clear requirement that the final device (or a significant portion) is tested. If only a portion of the final device is tested, the manufacturer shall describe representative samples from the final device in terms of materials processed in the same manner as the final device in order to directly evaluate a nanomaterial component.
Regulatory landscape of nanostructured biomaterials for tissue regeneration 39
The outcome of in vitro and in vivo testing is assessed, according to compliance to standards and to comparison to state of the art, in order to describe the potential device risk.
2.4.2 Clinical performance and clinical benefit According to the Regulation EU 2017/745,10 the term “clinical performance” of a device means the ability of that device, resulting from any direct or indirect medical effects which stem from its technical or functional characteristics, including diagnostic characteristics, to achieve its intended purpose as claimed by the manufacturer, thereby leading to a clinical benefit for patients, when used as intended by the manufacturer; clinical performance is best described by technical, chemical, and physical characteristics of the device itself. On the other hand, the Regulation describes the “clinical benefit” as the positive impact of a device on the health of an individual, expressed in terms of a meaningful, measurable, patient-relevant clinical outcome(s), including outcome(s) related to diagnosis, or a positive impact on patient management or public health. For this reason, there is a measurable and predictable cause-effect relationship between the performance (how the device acts on the human body) and the benefit (how the human body positively responds). Thus, the building up of the data required to show compliance to Regulations follows a sequence of steps of increasing complexity: in vitro data, often obtained by cell culture testing, provide ethical and scientific “green-light” for the preclinical animal, in vivo testing. Feedback from animal testing, evaluated through the requirements of safety, performance, and benefit, as just described, provide in turn green light for clinical evaluation as further described in the next section.
2.4.2.1 Role of the in vivo and clinical testing Clinical performance and clinical benefit are usually described not only by means of compliance with the standard, but also by assessing the device behavior and its impact on a living tissue or organism. Testing is therefore also performed on applicable animal models and, when technically necessary and ethically acceptable, clinical performance and benefit are studied with the involvement of patients. For clinical testing, there is a clear requirement in MDR 2017/745 that the endpoints of the clinical investigation shall address the intended purpose, clinical benefits, performance, and safety of the device. The endpoints shall be determined and assessed using scientifically valid methodologies. The primary endpoint shall be appropriate to the device and clinically relevant. For nanomaterials, the challenge in the assessment of the clinical performance and subsequent clinical benefit is, therefore, linked to the challenge of determining appropriate endpoints.
10
Medical Device Regulation 2017/745 Article 2.
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2.5 From the project to the product Research Institutes, innovative Start-Ups/SMEs and Large Industries have individual plans to convert new “nano ideas” into products… but they have the same challenge: the commercialization of nanostructured devices for tissue regeneration is much more complicated than other products. When new products/processes are developed, a strong effort must be made to ensure that they are healthful and environmentally safe. The toxicity of NPs is mainly given by their physical/chemical characteristics (size, shape, surface charge, etc.) and the presence/ absence of active groups on the surface. Therefore, there are several complex regulatory and approval processes (depending on under which different product categories fall the new “nano idea”) to follow for commercialization, but they have often some “gray area” where neither the notify body nor the manufacturer has a clear idea of what to do. The development and commercialization of a “nano-product” (the term include both product containing NPs and produced using nanotechnologies) require collaboration among many different actors, due to the complexity of the matter and requires a long time (the time to market is often “close” to 20 years). Moreover, costs for translating an idea to a commercial product are extremely high (in part due to the enormous expenses requested for the clinical trials); therefore, a very careful screening of innovative ideas has to be performed as soon as possible (in order to not vast money).
2.5.1 Ensuring a consistent level of quality 2.5.1.1 Manufacturing Essential conditions for the development of an industrial scale “nano-manufacturing” are the capability to preserve nanoscale properties while incorporating into products, an online metrology in order to allow effective measurements/quality control and the availability of high throughput. The challenge is maintaining the properties and quality of “nano-system” during high-rate/volume production as well as during the lifetime of the product after production. Nano-manufacturing consists in a combination of process steps that often need specific tools (like the computer-aided design and manufacturing—CAD/CAM— especially if hybrid 3D printing is involved) and a precise quality control. The latter is a very important point because even small variations in processing of NPs can result in variations of toxicity. Sukhanova et al., in a recent paper, highlighted as the NP toxicity strongly depends on their physical and chemical properties, such as the shape, size, electric charge, and chemical compositions of the core and shell [6]. Moreover, nano-manufacturing must be safe for the workers, so any possible detection and measurement of the type and amount of NPs in the workplace have to be performed.
2.5.1.2 Quality control Nanomaterials possess exceptional unique nanoscale “size-dependent” physical, optical, and chemical properties that are completely different than their bulk counterpart. Therefore, what must be controlled and in which way?
Regulatory landscape of nanostructured biomaterials for tissue regeneration 41
The big challenge is not only the development of new analytical tools that make a possible measurement at nano-to-microscale (including dispersion of NPs within a matrix and at interfaces), but that these tools have to work in real-time embedded in the production line and above all, they must be “nonintrusively” or destructively. In the meantime, new methods of calibration and standardization have to be developed in order to ensure the accurate interpretation of results. A typical flow chart of a generic manufacturing process, with quality control steps, is shown in Fig. 2.1.11 Starting from the raw materials, an acceptance test must be performed in order to inspect materials and verify their conformity. Tests could be different for each material and could include, for example, Physicochemical characterizations (particle size, crystallinity, water solubility, surface characteristics, etc.). Each manufacturing phase must be subject to continuous analysis and during the manufacturing process, a statistical sampling (screening) could be performed in order to supervise the process and the final product. The controls that could be performed are, for example, an “in-process” monitoring of equipment, process parameters, and semifinished products, the control of dispersions, surface roughness measurements (to certify surface treatments), the control of the bonding and nonbonding interactions at the interface of the matrix and the transition region and last but not least the control of the toxicity of NPs. Critical control points (and procedures to monitor them) could be also determined in order to identify hazards, but it is even more important to set up corrective actions to be taken when a deviation is identified. At the end of the process, a final lot acceptance test and life test must be performed in order to confirm the quality of the final product.
2.5.2 Postmarket activities: surveillance and vigilance Postmarket activities involve actions to be performed after a medical device was firstly put on the market. They can be divided into two categories: ●
●
Proactive—Postmarket Surveillance Reactive—Vigilance
Postmarket surveillance is defined as: “the proactive collection of information on quality, safety or performance of medical devices after they have been placed on the market.” (According to the Global Harmonization Task Force.) Vigilance is defined as: reporting of incidents that can occur with medical devices, when they do not perform as intended, thereby leading in the worst case to injury or death. The purpose of medical device vigilance is to protect the health and safety of persons; evaluate incidents to prevent recurrence; determine the effectiveness of corrective actions and preventive actions, and monitor and learn from experience. Activities involved with postmarket surveillance typically involve seeking customer feedback 11
Modified from a Windbond website figure: http://www.winbond.com/hq/about-winbond/quality-policy/ management/management.html?__locale=en.
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relating to whether the organization has met customer requirements. This may be accomplished by some of the following methods: Focus groups Reviewing customer complaint information
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●
The quality manager will yearly monitor the performance and safety of company products already on the market by observing, collating, and reviewing the following: Vigilance results review Per defect Per product Customer complaints Medical practitioner feedback Independent research Trade journals
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●
●
●
●
●
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Vigilance has to do with Incidents. Examples of Incidents are: – Device malfunction or deterioration that occurs while the device is used as intended by the manufacturer. – Unanticipated adverse reaction or unanticipated side effect that is not stated in the information provided by the manufacturer. – Interactions with other substances or products. – Degradation/destruction of the device (e.g., fire). – Inappropriate therapy. – An inaccuracy, omission, or deficiency in the labeling, instructions for use and/or promotional materials, except information that is part of the general knowledge of the intended user.
Vigilance results can be defined using criteria such as: – – – –
number of incidents/field corrective actions in the year; number of incidents/field corrective actions per defect; number of incidents/field corrective actions per product; number of incidents/field corrective actions after complaints.
Results are compared with information from previous years. Occurrence of incidents should be notified to the relevant National Competent Authority.
2.6 Roles and responsibilities 2.6.1 Manufacturers According to the MDR 2017/745,3 a manufacturer is defined as: “A natural or legal person who manufactures or fully refurbishes a device or has a device designed, manufactured, or fully refurbished, and markets that device under its name or trademark.” The obligations of the manufacturers of medical devices (including the ones containing NPs) are, therefore, to demonstrate the conformity of their products with the legal requirements.
Regulatory landscape of nanostructured biomaterials for tissue regeneration 43
But it is also of extreme importance for manufacturers to be clearly aware of the supply chain and the impact of manufacturing activities. This is because in the global environment, nowadays, the use of contract manufacturing is often unavoidable in order to reduce costs and supply line issues. There are two documents prepared by the European Association of Notified Bodies for Medical Device that could help understanding the EU regulations on this matter: NB-MED/2.5.2/Rec1 “Subcontracting—QS related” and NB-MED/2.15/Rec1 “Voluntary Certification at an Intermediate Stage of Manufacture.”12 Moreover, manufacturers have to apply a postmarket surveillance system in order to constantly monitor the performance of their products and report every adverse incident (vigilance report) and field safety corrective actions (FSCAs) to EU Competent Authorities. An FSCA is an action taken by a manufacturer to report any technical or medical reason leading to a recall of devices and the new Medical Device Regulation addresses specific timelines for FSCA reports.
2.6.2 Competent authorities In Europe Competent Authorities, nominated by each government, are usually the Ministries of Health of each member State (instead, in the United States there is only one competent authority: the FDA). Therefore, each European country has its own Competent Authority in charge of market surveillance and designating and monitoring the independent Conformity Assessment Bodies (Notified Bodies). European National Competent Authorities for Medical Devices have created a group (CAMD) in order to enhance the level of collaborative work, communication, and surveillance of medical devices across Europe.
2.6.3 Notified bodies A notified body is an organization designated by an EU country to assess the conformity of certain products, including medical devices, before being placed on the market. These bodies carry out tasks related to conformity assessment procedures set out in the current Medical Device Directive and will from 2020 also carry out tasks related to conformity assessment procedures set out in the new upcoming regulation. The conformity assessment procedure for class I devices is being carried out, as a general rule, under the sole responsibility of manufacturers in view of the low level of vulnerability associated with such devices. For class IIa, class IIb, and class III devices, an appropriate level of involvement of a notified body is compulsory. Since devices containing nanomaterials are classified, in the Regulation 2017/745, at least in class IIa but more frequently in classes IIb and III, the intervention of a Notified Body in the marking procedure shall be expected. As part of their involvement in the certification process, notified bodies audit the technical documentation and the manufacturing, control, and distribution processes 12
http://www.team-nb.org/nb-med-documents/.
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Process
Quality control Method Storage
Finished product quality confirmation
Reliability confirmation Life test and environmental test
Sampling inspection Lot acceptance test
Manufacturing
Screening
Equipment, submaterial environment, cleanliness discipline—Monitoring Process parameters, semifinished product inspection—Monitoring
Testing and visual inspection
Appearance and characteristics 100% inspection
Raw materials
Raw materials quality conformance
Inspection on raw materials Acceptance test
Fig. 2.1 Example of a quality control flowchart.
and have the right and duty to carry out both announced and unannounced on-site audits and to conduct physical or laboratory tests on devices to ensure continuous compliance by manufacturers.
2.7 Relationship between regulatory requirements and intellectual property The Intellectual Property of NPs (or of a product containing them) and the relationship between regulatory requirements is a “mine-laden” that will become of strategic importance in the next future owing to the increasing numbers of innovative products/ technologies involving NPs. There are concomitant reasons that brought to these very difficult circumstances… First of all, patent laws usually exclude the possibility to patent methods for the treatment of the human body using surgery and therapy but allow the patenting of products used in these procedures. But this could be subverted by the patenting of NPs because “at the end” the patent could cover also the way of their utilization that could be considered as “a method.” Moreover, NPs, and medical products containing them have to comply with strict regulations in order to enter in a commercial market. In vitro, in vivo tests, and clinical trials must be performed following standardized procedures for a given period of time,
Regulatory landscape of nanostructured biomaterials for tissue regeneration 45
but a medical device could be exempted from regulation if a similar product is already on the market. This allows shortening incredibly the time-to-market and the costs. On the contrary, the same MD is often recognized as “new” from the Intellectual Property Rights viewpoint and therefore it is protected by patent laws. These two “way of seeing the matter” could create several issues, because if there is a patent protecting the MD, this means that it is innovative/new and therefore, it must be validated following regulations and vice versa. Sure enough, if an MD containing NPs is considered “new” this could greatly impact the time and cost required for its commercialization, especially after the entering into force, on May 25, 2017, of two new MD regulations”13 that has led to longer time periods for obtaining marketing approval. As a result, MD manufacturers should seek compensation for their loss of patent protection by requesting a Supplementary Protection Certificate (SPC = extension of the patent term up to 5 years). But the SPC regulation is one of the most controversial areas of European IP law because SPC can be obtained only for products that have been authorized for the first time as medicinal or plant protection products in the European Union. That means in Europe, formulation and MD patents cannot be the subject of SPCs. However, several MDs often include active ingredients (combinations or borderline MD), thus, they may in principle be eligible for SPC protection, but it could generate a lot of problems the fact that a single borderline product may be classified as an MD or an MP depending on the approach of each different Member States. It is, therefore, possible to imagine a scenario where a particular product is not only authorized differently as an MD or an MP throughout Europe but also that the accessibility of asking for an SPC in those States where it has been authorized as an MD may be different among EU members. During the last years, several requests of SPC were evaluated by different EU member’s patent courts but only in The Netherlands and Germany some cases were accepted. Totally different is the situation in the United States where the US law allows obtaining patent term extensions (PTE) for Class III (high-risk) MD and furthermore gives the possibility to extend a patent in case of unreasonable delays during the examination at the US Patent and Trademark Office [the so-called patent term adjustments (PTAs)]. In order to avoid unequal treatments on “this site of the Ocean,” the hope is that also in Europe it could be recognized that MD Cass III are facing similar levels of regulation to pharmaceutical products because nowadays they are subject to high standards in order to obtain the required conformity assessment certificate, and therefore SPC could be requested. Actually, the European Commission is aware of this matter and is looking into potential reform of the SPC system (following the outcomes of consultation done in 2017). 13
https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32017R0745 https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX:32017R0746
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References [1] M. Racchi, S. Govoni, A. Lucchelli, L. Capone, E. Giovagnoni, Insights into the definition of terms in European medical device regulation. Expert Rev. Med. Devices 13 (10) (2016) 907–917, https://doi.org/10.1080/17434440.2016.1224644. [2] Regulation EU 2017/745, whereas (15) and Annex I Essential requirement 10.5 [3] IMDRF Definition and regulation in terms of mechanism of action and intended use IMDRF-3 /20 March 2013/. [4] MEDDEV 2.1/3 rev.3 Borderline products, drug-delivery products and medical devices incorporating, as integral part, an ancillary medicinal substance or an ancillary human blood derivative [5] R. Darkow, T. Groth, W. Albrecht, K. Lutzow, D. Paul, Functionalized nanoparticles for endotoxin binding in aqueous solutions, Biomaterials 20 (1999) 1277–1283. [6] A. Sukhanova, et al., Dependence of nanoparticle toxicity on their physical and chemical properties, Nanoscale Res. Lett. 13 (2018) 44.