Regulation (EU) 2017/745 on medical devices aims to raise the quality and safety standards of products. Among the most emphasized aspects in the Regulation are biocompatibility and the chemical and physical characterization of materials. These elements are also found in Annex I of the document, relating to the general safety and performance requirements (GSPR). This annex is fundamental because, to demonstrate that a device complies with the Regulation, it is necessary to verify that all requirements have been met (for those not applicable, a clear justification of non-applicability is required). Consequently, the choice of materials and substances used in a medical device becomes central, particularly from a toxicity perspective.
Toxicological assessments are the foundation of the entire European regulatory framework on chemical substances, including the REACH and CLP Regulations; the regulation of biocides, plant protection products, cosmetics, food; legislation regarding good manufacturing practices for cleaning validation and impurity control in the pharmaceutical field, as well as in the regulation of medical devices. Hence their importance.
Compliance of Medical Devices
To demonstrate compliance with the Regulation of medical devices, the manufacturer can refer to certain standards. These are technical specifications, which in many cases serve as a useful guide to design and evaluate their product, but they are applicable voluntarily. Some of these same standards are harmonized, meaning adopted at the European level. This implies that the use of such standards provides presumption of conformity with the Regulation’s requirements. At the same time, the generally recognized state of the art must not be underestimated, defined as the body of all the latest scientific updates available. This safeguards those standards that are periodically updated due to increasingly strict safety aspects introduced by the Regulation and which have not yet been harmonized. In any case, it is important to emphasize that what must legally be complied with is the Regulation: the decision to use or not use a standard lies with the manufacturer and cannot be imposed.
Biological Evaluation
Manufacturers of medical devices must ensure the safety of their devices and minimize potential risks (including biological ones). The biological safety evaluation of medical devices is carried out to determine the potential toxicity resulting from the contact of device materials with the body. These must not produce local or systemic adverse effects, be carcinogenic, or reprotoxic. A biological evaluation must be conducted exclusively in line with a risk management process. It is a continuous process through which a manufacturer can identify the biological hazards associated with the medical device, estimate and evaluate the risks, control them, and monitor the effectiveness of the control.
Risk management is intended as an iterative and continuous process, covering the entire lifecycle of a device, which requires constant and systematic updating. Just a few days ago came the news of the publication of the final draft update of ISO 10993-1 (https://www.linkedin.com/feed/update/urn:li:activity:7334196972028841984).
Chemical Characterization
The current version of the standard on biological evaluation (ISO 10993-1) highlights chemical characterization as the first necessary step for proper biological evaluation. Chemical characterization refers to the process of identifying, characterizing, and understanding the compounds that may migrate from the medical device and be bioavailable to the patient. These chemical compounds are often referred to as extractables (substances that can potentially migrate when the material is exposed to exaggerated or aggressive conditions) and leachables (compounds that can potentially migrate from the device under normal use conditions). Extractables and leachables studies are used to examine the chemical components potentially released by the medical device, followed by a toxicological risk assessment to support the conformity evaluation for that specific clinical use.
Toxicological Risk
There is a specific standard for the toxicological risk assessment of these chemical components, ISO 10993-17, whose very recent update was published on September 13, 2023, more than 20 years after the previous version. The first difference from the previous version is already noticeable in the title: “Toxicological risk assessment of medical device constituents,” instead of the well-known “Establishment of allowable limits for leachable substances.” This change highlights the fact that previously, risk assessment only referred to components potentially released from the device (leachables), whereas now it emphasizes the need for toxicological risk assessment of the device’s own constituents as well. The standard includes schematic flow diagrams to show how toxicological risk assessment fits into the risk management process of medical devices and the activities involved in preparing toxicological risk assessment reports.
During the hazard identification process, toxicological information on the chemical constituents must be gathered using multiple sources, and values must be identified as points of departure (PoD)—for example, No Observed Adverse Effect Level (NOAEL), Lowest Observed Adverse Effect Level (LOAEL), or benchmark dose (BMD)—derived from a toxicological study relevant to the endpoint being analyzed. The selection and search criteria must be documented and justified. The reliability and quality of the data must be evaluated and established. When toxicity information on the chemical substance is not available, a structurally similar chemical substance (i.e., an analogue) with adequate toxicity data may be used for a read-across assessment.
What’s New in the New Standard
The revised standard presents a new section on the use of a Toxicological Screening Limit (TSL) for chemical constituents, which helps risk assessors narrow down the range of constituents requiring assessment, saving time and effort. Furthermore, the new standard provides risk acceptance criteria to evaluate the Margin of Safety (MoS) for each component. The standard also clarifies the risk scenarios in which a toxicological risk assessment is recommended and outlines alternative methods for mitigating potential harm.
After careful chemical characterization and toxicological risk assessment, the evaluation of endpoints (e.g., irritation; sensitization; acute toxicity) follows to examine the device’s biocompatibility. The biological evaluation of the medical device, in a manner aligned with what is defined in the reference standard for risk analysis (ISO 14971), indicates that testing should only be performed if the available data and literature on the device are insufficient to cover the endpoints required by the standard.
The standard introduces the Biological Evaluation Plan (BEP), a set of activities that define the biocompatibility profile of a device in relation to the biological risk it poses to the end user, taking into account all available data and conducting appropriate literature searches. If the available information on the device, along with the supporting bibliography, is not sufficient to cover the endpoints indicated by the standard, a suitable testing plan is proposed within the BEP.
The production of a scientifically robust BEP requires a multidisciplinary team with cross-cutting skills and qualifications, including both regulatory and toxicological expertise.
The Biological Evaluation Report
Once the tests are carried out, the next step is drafting the Biological Evaluation Report (BER). The BER integrates the considerations from the plan (BEP) and records the conclusions on the device’s biocompatibility based on the test results. To conduct a proper risk assessment of a device, a step-wise approach must be followed, starting with categorization—that is, studying the nature and duration of the device’s contact with the user’s body. Next, chemical-physical characterization, appropriate literature analysis, and possible testing are carried out.
The biological risk assessment process does not end with the development of the BEP and BER but continues throughout the entire life cycle of the device via post-market surveillance activities. The risk assessment must, in fact, be updated based on new information that becomes available through post-marketing monitoring, the medical device’s performance, and its clinical safety.
In this case, as with other aspects of technical documentation (e.g., clinical evaluation, risk analysis, etc.), there is concrete evidence of the importance that real-world use data of a medical device has in ensuring that the market is supplied with safe and effective products.
The technical documentation of a medical device, in order to comply with current regulations, is a complex and diverse set of data that brings together experts from different fields (toxicologists, analytical chemists, regulatory professionals, etc.). For these reasons, it is necessary to maintain transparent and open communication among all parties involved. Understanding and implementing new procedures will be essential to performing increasingly high-level toxicological and biological risk assessments in order to meet the regulatory requirements for medical devices.
