The world of Medical Devices (DM) is in great ferment. The chemical-physical characterization of DMs is an increasingly important topic that involves the regulatory fields. The reflections on the theme are particularly relevant also in light of the new version of ISO 10993-1 published recently. With Chiara Picotti, Senior Consultant and Eurofins Medical Device Testing Italy team leader, PharmaWorldMagazine analyses the latest news, trying to understand what changes for the manufacturers.

What is required by the regulatory framework of reference regarding the chemical-physical characterization of DMs?

CP: The new Regulation for DM n. 2017/745 mentions the chemical-physical characterization in different sections. This must be taken into account in the design and manufacture of DMs to ensure that the device meets the general safety and efficacy requirements; it is also referred to as part of the technical documentation that the manufacturer is required to elaborate and provide evidence of the verification and validation of the product.

From a regulatory point of view the new version of the ISO 10993-1 published recently places a particular focus on the chemical-physical characterization of the devices. Although even in the previous version the characterization of materials was already considered a crucial and initial step of biological evaluation, many manufacturers relied directly on the table of Annex A of ISO 10993-1 in which the chemical-physical characterization was not explicitly indicated among the endpoints to be evaluated.

The new ISO 10993-1 version gives more emphasis to the chemical characterization that is now considered a prerequisite for biological risk assessment and must precede the evaluation or testing of any biological effect such as systemic toxicity, genotoxicity, etc.

The chemical-physical characterization is an indispensable prerequisite (ISO 10993 latest version). What will therefore change for manufacturers compared to the past?

CP: The fundamental objective of the insertion of the chemical characterization as a prerequisite to the biological evaluation of the device is to increase the level of knowledge of the materials or ingredients that make up the device, the manufacturing process, sterilization and other post-manufacturing processes such as packaging. According to the new ISO 10993-1 the characterization should evaluate at least the so-called “constituents” of the device and possible residues of the production process as additives and agents to identify the potential unintentional release of substances. In addition, it also indicates that some physical information may be required associated with implantable devices or devices in contact with blood. All this with the final aim of having a greater control of these aspects by the manufacturer.

Furthermore, the results of the chemical characterization must be evaluated in order to identify the correct approach to biocompatibility tests, including those in vivo. In this way the manufacturer is called upon to make a careful selection of the biocompatibility tests to be carried out, rather than resorting to the complete battery of tests.

Will the new ISO requirements lead to a reduction of in vivo studies?

CP: Certainly yes. The chemical characterization not only allows to obtain more information on the device and the residues of the production process, but also allows to evaluate some biological effects such as subacute, subchronic, chronic systemic toxicity, genotoxicity and carcinogenesis going therefore to reduce the need to perform tests in vivo.

In order to cover these biological effects, the chemical characterization must be structured in such a way as to allow identification of the extractable or releasable profile of the device; in addition, the data obtained must be analyzed from a toxicological point of view to evaluate the potential patient exposure scenario.

With regard to local effects, it has been recognized that these may not be adequately covered by chemical characterization.

However, there is fervent international activity focused on validating alternative in vitro methods to evaluate biocompatibility. Recently a very important milestone has been reached in this field: an in vitro skin irritation test has been validated on DM extracts. Soon the regulatory framework will be updated with the publication of ISO 10993-23 which will describe a method for assessing skin irritation without the need for in vivo studies.

Can the demands of the new ISO lead to an advantage in economic and temporal terms for the manufacturer?

Even in this case the answer is yes. As indicated before, characterizing the device from a chemical-physical point of view and toxicologically analyzing the obtained data, it is possible to omit tests such as subacute, subchronic, chronic, systemic toxicity and carcinogenesis, notoriously long and expensive tests. The physical-chemical characterization therefore represents an opportunity for the manufacturer to reduce the times and costs associated with the pre-clinical evaluation of the device that must be registered and placed on the market. It can also be used to manage the changes to be made to the DM already on the market. Analyzing the “old” device and the “new” from a chemical-physical point of view and comparing the results obtained, we can verify if the identified differences are toxicologically relevant or not. In this way, it is possible to extend the biocompatibility evaluations carried out on the “old” device to the new one, avoiding to perform new tests.

How should the physical and chemical characterization required be carried out in practice?

CP: The new ISO 10993-1 indicates that the chemical characterization should be performed according to the indications of ISO 10993-18, standard currently under revision and for which an updated version will be available in the coming years.

However, ISO 10993-18 will not include the test protocols to follow: the world of medical devices is so varied and diversified that it is not possible to identify test procedures suitable for evaluating all types of devices from a physical-chemical point of view.

In general, there are two main categories of tests: direct characterization of materials and evaluation of substances that can potentially be released from the device. The first group evaluates the intrinsic chemical properties of the materials while the second identifies the release through tests called “Extractable and Leachable” which is then evaluated in terms of toxicological risk.

The new ISO 10993-18 will provide indications on how it is possible to characterize the device going to evaluate, for example, its configuration, identifying and analyzing the composition of the starting materials and the release of the device to verify the presence of substances potentially introduced into the device due to of the production process.

Which tools are available to device manufacturers to help them identify an appropriate test strategy?

Both ISO 10993-1 and ISO 10993-18 (which will be published in the near future) provide indications to understand how to approach chemical characterization.

In particular, ISO 10993-18 will include flowcharts that will be very useful for identifying the prerequisites of some steps and the subsequent phases that follow. However, as explained above, it will not give indications on which protocols to follow and under what circumstances. It is therefore essential to involve the manufacturer who, on the basis of the information already available and the nature of his device, is called upon to identify the most appropriate strategy for the chemical-physical characterization.

When specific tests are necessary and not necessary and what determines their choice?

CP: As indicated by ISO 10993-1, the extension of the chemical-physical characterization must reflect the nature and duration of contact with the patient and take into account the physical state of the device (eg cream, gel, liquid), the level of knowledge of the formulation of materials and existing data of clinical and non-clinical safety.

As a first step it is therefore necessary to collect all the information already available on the device. If the combination of all materials, chemicals and processes have a consolidated safety history for the same intended use and physical properties have not been modified, it is possible to conclude, after rationalization, that no further chemical characterization of the device. If “Gap” are identified, by evaluating the type of interaction between the device and the body, the most appropriate test approach is identified to collect the missing data. In some cases, screening tests may be sufficient while in others, methods aimed at quantifying the presence of some compounds must be used. The choice of the approach depends on what is being researched and what needs to be evaluated.

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