The contemporary medical device market is characterized by an increasing number of products on the borderline between medical devices and medicinal products. It is increasingly common to encounter medical devices containing medicinal substances, whose presence significantly affects the process of technical documentation assessment, as well as regulatory and clinical requirements. In light of Regulation (EU) 2017/745 (MDR) and current MDCG guidance, the proper classification and assessment of such devices represent a significant challenge for both manufacturers and notified bodies. The purpose of this article is to discuss the impact of the presence of a medicinal substance on the assessment of medical device documentation, taking into account legal and normative requirements, as well as the case law of the Court of Justice of the European Union (CJEU).
Regulation (EU) 2017/745 (MDR) introduces precise definitions of a medical device and a medicinal substance. According to Art. 2 MDR, a medical device is an instrument, apparatus, appliance, software, implant, reagent, material, or other article intended by the manufacturer to be used for human beings for a specific medical purpose, whose primary intended action is not achieved by pharmacological, immunological, or metabolic means, although it may be assisted by such means.
A medicinal substance, in accordance with the MDR and Directive 2001/83/EC (MPD), is a substance or mixture of substances that may be used in human beings to restore, correct, or modify physiological functions by exerting a pharmacological, immunological, or metabolic action.
A key issue in assessing a product containing a medicinal substance is distinguishing whether the product is a medical device or a medicinal product. The MDR emphasizes that the characteristics of the substance and the primary intended action of the product are of decisive importance. If the effect is achieved through the pharmacological, immunological, or metabolic action of the substance - the product should be qualified as a medicinal product. In the case of mechanical, physical, or chemical action - as a medical device.
Beyond the MDR itself, the legislator points to interpretations of the provisions in guides and manuals:
· MDCG 2022-5 Rev.1 Guidance on borderline between medical devices and medicinal products under Regulation (EU) 2017/745 on medical devices The MDCG 2022-5 guide constitutes a key source of interpretation for borderline products. This document emphasizes that product classification should be based on an analysis of the mechanism of action of individual substances, the intended purpose, and available scientific data, rather than on intentional claims.
· Borderline Manual 2025 - Manual on borderline and classification for medical devices under Regulation (EU) 2017/745 on medical devices and Regulation (EU) 2017/746 on in vitro diagnostic medical devices, Version 4 – September 2025
The latest Borderline Manual (2025) contains practical examples of qualification and classification of products that may be both medical devices and medicinal products. This document highlights the importance of analyzing the composition, mechanism of action, and the manufacturer's declared intended use of the product.
The presence of a medicinal substance in a medical device significantly increases the requirements regarding technical documentation. The manufacturer must demonstrate not only the device's compliance with MDR requirements but also the safety and efficacy of the active substance in the context of the intended use. The documentation should include:
· A detailed description of the medicinal substance, its concentration, and the method of release.
· Data concerning the interactions of the substance with other components of the device.
· Results of biocompatibility and toxicology studies (in accordance with ISO 10993).
· Clinical data confirming the efficacy and safety of the substance in the given application.
According to the MDR, the presence of a medicinal substance in a medical device has a direct impact on its classification, which translates into the scope of required documentation and the rigor of conformity assessment.
The key factors here are:
· Rule 14 (Annex VIII MDR): Concerns medical devices that contain a substance which, if used separately, could be considered a medicinal product and which is liable to act upon the body with an action ancillary to that of the device. These devices are always classified as Class III. This means that any medical device containing such a substance, regardless of its quantity or mode of action (if it is not the primary action of the device), is subject to the most stringent conformity assessment requirements.
· Rule 21 (Annex VIII MDR): Concerns devices that contain substances or mixtures of substances intended to be introduced into the human body via a body orifice or applied to the skin and which are absorbed by or locally dispersed in the human body. These devices are classified as Class IIa, IIb, or III depending on the site and mode of action of the substance:
o Class IIa: substances absorbed by the mucous membranes of the mouth, nose, digestive tract, rectum, or vagina.
o Class IIb: substances absorbed by other mucous membranes or the skin surface.
o Class III: substances intended to be absorbed by the body in order to achieve a systemic effect.
The presence of a medicinal substance that performs an ancillary function relative to the intended action of the device automatically raises the class of the medical device in accordance with Rule 14, which results in the necessity of meeting more rigorous requirements regarding preclinical and clinical studies, as well as post-market surveillance.
However, a medicinal substance used in a device does not always lead to Class III according to Rule 14, because for this rule to apply, the substance must perform an ancillary function to the intended action of the device. As an example (from MDCG 2022-5), one can cite heparin-coated or antibiotic-coated catheters, or bone cements containing antibiotics, where the primary intended action of the device is different from the action of the medicinal substance used, which is only intended to support the action by maintaining an appropriate microbial environment or preventing stent clogging through the formation of clots.
In such situations, the application of Rule 14 is predictable and obviously appropriate; however, the MDR introduces a slightly different term within Rule 14, pointing to substances that could be considered a medicinal product if used separately, which means that the mechanism of action of the substance is based on a pharmacological, immunological, or metabolic mechanism. The aforementioned MDCG also clarifies these definitions, where, for example, pharmacological action is understood as an interaction, typically at a molecular level, between the substance or its metabolites and a constituent of the human body, resulting in the initiation, enhancement, reduction, or blocking of physiological functions or pathological processes. Examples of human body constituents may include, among others, cells and their components (cell membranes, intracellular structures, RNA, DNA, proteins, enzymes), extracellular matrix components, and body fluid components. Interactions are recognized as effects on covalent bonds, electrostatic forces, and van der Waals forces. This clearly indicates that medicinal substances compliant with the MDR will not only be substances registered as medicinal products but also those that base their action on a pharmacological, immunological, or metabolic mechanism. Additionally, the MDCG indicates that the quantity used in the device, the route of administration, or the bioavailability for the body is irrelevant in determining the status of the substance, as is the manufacturer's intent. The guide also reminds us of herbal medicinal products, which are equivalent medicinal products and, when used ancillarily to the device's action, will direct the device to Class III.
However, the use of a medicinal substance does not always lead to classification according to Rule 14; it may point to Rule 21 or qualify the device as a medicinal product.
An example of a substance that could be considered a medicinal product if used separately is, for example, peppermint oil with spasmolytic, antiseptic, analgesic, and cooling effects, where it is registered in medicinal products for such use. In a device, it may be used as a flavor, solely for taste or smell correction, or as a main ingredient.
· If it is used in the device as a flavor, solely for taste or smell correction, such use of a medicinal substance in the device excludes an ancillary action to the intended action of the device and does not meet the definition of Rule 14; however, this does not change the nature of the substance, therefore the manufacturer must demonstrate through strong scientific data that the substance will not act upon the human body, in which case Rule 14 will not apply and another rule should be used, e.g., Rule 21, if it is a device composed of substances.
· If, in turn, the mentioned peppermint oil (or menthol) is used in an aerosol that cools through a physical mechanism (the gas mixture in the aerosol cools) and it has an ancillary action to that effect, then such a device will be classified according to Rule 14 in Class III.
· Conversely, if peppermint oil (or menthol) is intended for medical purposes, such as relieving discomfort and pain in muscles and joints, where the action results from a pharmacological mechanism involving interaction with cold-sensitive receptors in the skin, it will be a medicinal product and will not be subject to MDR classification.
These examples clearly show that the device class will not depend only on the substance used, but also on the type of device, the indications of the device, the purpose of adding the medicinal substance, and its availability to the body. Only after a thorough analysis of scientific evidence can the classification rule and the device class be correctly determined. If a device is classified as Class III under Rule 14, one can point to general documentation requirements:
· Data concerning the absorption and pharmacokinetics of the active substance.
· Assessment of long-term safety of use.
· Results of clinical trials confirming efficacy and safety.
| Documentation Element | Class IIb | Class III |
|---|---|---|
| Device description and intended purpose | Required | Required |
| Risk analysis | Required, in accordance with ISO 14971 | Required, highly detailed, in accordance with ISO 14971 |
| Biocompatibility studies | Required, in accordance with ISO 10993 | Required, full scope of studies, including long-term |
| Clinical data | Possible to rely on literature data | Own clinical trials required, often randomized |
| Preclinical studies | Required, scope depending on risk | Required, full scope, including in vivo and in vitro studies |
| Assessment of the active substance | Required, if present | Highly detailed, including pharmacokinetics, pharmacodynamics, toxicology |
| Consultation procedure (Art. 117 MDR) | Not always required | Required for devices with a medicinal substance (Rule 14) |
| Cooperation with the Notified Body | Required, audit of documentation and process | Required, full assessment of documentation, audit, consultations with the medicines authority |
| PMS/PMCF/PSUR plan | Required, updated every 2 years | Required, updated at least once a year, detailed PSUR reports |
The conformity assessment process also differs depending on the device class and the potential content of a medicinal substance:
· Class IIb:
o Conformity assessment conducted by a Notified Body based on technical documentation, risk analysis, and clinical data (possible to rely on literature and equivalence).
o Quality management system audits and an assessment of the technical documentation are required.
o In the case of devices containing active substances, the scope of the assessment is extended to include an analysis of the safety and efficacy of the substance.
· Class III under Rule 14:
o The highest level of regulatory rigor.
o A full assessment of the technical documentation is required, including own clinical trials and a detailed analysis of the pharmacokinetics and toxicology of the active substance.
o Documentation of the medicinal substance in CTD format or similar is required.
o Mandatory consultation procedure with the competent authority for medicinal products (Art. 117 MDR).
o The Notified Body conducts detailed audits and assesses the plan and results of PMS/PMCF, as well as annual PSUR reports.
o In the event of any doubts regarding the mechanism of action or safety, additional studies and consultations are required.
The Polish Office for Registration of Medicinal Products, Medical Devices and Biocidal Products specifies which documents should be attached to the technical documentation of the device regarding the medicinal substance:
· relevant parts of Module 3.2.S in CTD format,
· if it is a pharmacopoeial substance, also a reference to the relevant section of the European Pharmacopoeia (PhEur) or another,
· relevant parts of Module 2.3 (Quality Overall Summary (QOS)) in CTD format.
The case law of the Court of Justice of the European Union (CJEU) plays a key role in the interpretation of provisions regarding the demarcation between medical devices and medicinal products. The most important judgments that influence the assessment of documentation for devices containing medicinal substances are:
· Judgment of the Court of Justice of the European Union of 3 October 2013 in case C-109/12, which stated that: "A product which, while not identical to another product classified as a medicinal product, nonetheless contains the same ingredient and acts in the same way as it, cannot, in principle, be marketed in one and the same Member State as a medical device within the meaning of Directive 93/42, as amended by Directive 2007/47."
· Judgment of the Court of Justice of the European Union of 13 March 2025 in case C-589/23 Cassella-med and MCM Klosterfrau, which concerns the interpretation of the concept of a "medicinal product by function" and "pharmacological action" in the context of the distinction between a medical device and a medicinal product.
· Judgment of the Court of Justice of the European Union of 13 March 2025 in cases C-495/21 and C-496/21, which concerns the demarcation between medical devices and medicinal products (medicines) in light of European Union law.
The aforementioned judgments also indicate the direction of the interpretation of regulations and have often served as a pretext for addressing topics related to different types of substances in guides or manuals.
The presence of a medicinal substance in a medical device significantly affects the technical documentation assessment process, the scope of required studies, and the device classification in accordance with Regulation (EU) 2017/745 (MDR).
Of key importance here are the MDR classification rules, in particular Rule 14 and Rule 21, as well as determining the scope of the substance used in the device – whether it has an ancillary action, is responsible for the intended action, or constitutes merely a technological background in the form of a flavor, pH regulator, or preservative. Each of these paths leads in different directions and entails the necessity of a different approach to the preparation of technical documentation; therefore, the choice of the path must be supported by strong scientific evidence.
The documentation requirements for Class III devices are significantly more stringent than for Classes IIb and IIa. They include the obligation to conduct own clinical trials, a detailed assessment of the pharmacokinetics and toxicology of the active substance, as well as a mandatory consultation procedure with the competent authority for medicinal products. In the case of Class IIb devices, it is possible in some cases to rely on scientific literature and data regarding equivalent devices; however, the presence of an active substance always requires a detailed analysis of safety and efficacy.
In market practice, products on the borderline between medical devices and medicinal products are increasingly common, which requires manufacturers and notified bodies to adopt an interdisciplinary approach and closely monitor current MDCG guidelines and CJEU case law. The judgments of the Court of Justice of the European Union clearly indicate that the classification of a product is determined by the primary intended action and the mechanism of action of the active substance, and not solely by the manufacturer's intent or the way the product is presented.
The proper assessment of the technical documentation of a medical device containing a medicinal substance requires:
· a detailed analysis of the mechanism of action and the intended purpose of the product,
· full compliance with MDR requirements, ISO standards, and MDCG guides,
· documentation of the safety and efficacy of the active substance.
Tomasz Ogórka, PhD in Medical Sciences, in his article “The Impact of a Medicinal Substance on the Assessment of Medical Device Documentation”, available in our MDR Knowledge Base.
Tomasz is a pharmacist and an expert in medical devices and quality management systems, as well as a Lead Quality Management Systems Auditor and Technical Expert at TÜV NORD Polska.
He combines extensive experience in pharmacy and healthcare with expertise in medical device regulation and certification in accordance with MDR and ISO 13485. He holds a PhD in Medical Sciences in the field of Medical Biology and specializes, among other areas, in devices composed of mixtures of substances and devices incorporating medicinal substances.
His professional background also includes medication management, clinical pharmacy, counselling in onco-haematology therapies, and hospital pharmacy management. This multidisciplinary perspective enables him to combine regulatory requirements with practical knowledge of medicinal products, patient safety, and the effective operation of quality management systems.