Rule 21 of Annex VIII MDR is a newly introduced rule, deemed necessary as under MDD, the rules applied to invasive devices did not sufficiently take into account the level of invasiveness and potential toxicity of certain devices which are introduced into the human body. Rule 21 takes into account the place where the device performs its action in or on the human body, where it is introduced or applied, and whether a systemic absorption of the substances of which the device is composed, or of the products of metabolism in the human body of those substances occurs. Additionally, there was divergence in opinion on the regulatory classification of some ingested products across the EU Member States with the same product being a medicinal product in some EU Countries and accepted as a medical device in others.
Rule 21 applies to substance-based devices that are absorbed or locally dispersed and in general these types of devices are widely available as self-care products, often with limited medical supervision. The rule has four indents describing the risk categorisation for different device types. It is important to note that these substance-based devices may also include a constituent that has a pharmacological, immunological, or metabolic action that is ancillary to that of the device. In this case Rule 14 may be applicable or the product may be regulated as a medicinal product rather than a medical device, depending on the principal mechanism of action.
Examples of these are given in MDCG 2021-24 (1). It is noted in this guidance that there is no example in the first indent. Indeed, no devices of this type have been seen at BSI and as far as we are aware anywhere. Only devices from the first indent require a scientific opinion from one of the competent authorities designated by the Member States in accordance with Directive 2001/83/EC (Annex IX 5.4(b)); however, as no such devices have been identified this process has not been initiated. To fit under the first indent a device would need to be systemically absorbed and then have a physical (non-pharmacological, immunological or metabolic) action to perform its intended use.
One of the most commonly points of misinterpretation with respect to Rule 21 relates to the term local dispersion, an aspect that is usually ignored, with manufacturers only justifying the non-applicability of Rule 21 based only on the lack of systemic absorption of the device. MDCG 2021-24 provides definitions of the relevant terms from Rule 21 with Local dispersion defined as “The condition by which substances remain in a specific site without being distributed into the body via the blood and/or lymphatic system.” Therefore, topical substance-based devices are covered under Rule 21, note: topical ultrasound gels are excluded from Rule 21, due to their complete removal following use and application as a conductive gel for ultrasound waves (1).
Additional requirements as a result of Rule 21 includes a review of the quality and safety of devices in respect of the requirements not covered by this Regulation, in accordance with the relevant requirements laid down in Annex I to Directive 2001/83/EC for the evaluation of absorption, distribution, metabolism, excretion (ADME), local tolerance, toxicity, interaction with other devices, medicinal products or other substances and potential for adverse reactions (MDR Annex IX 5.4 a). For substance-based devices where it can be shown there is no absorption, the ADME portion is typically covered under the biological safety review of the MDR and ISO 10993-1 as is tolerance and toxicity. Commonly used constituents of substance-based devices are also well characterized and often also used in either medicinal or cosmetic products as excipients, so the use of literature to support their safe use and ADME characteristics is a widely accepted approach.
The potential for interactions with concomitantly used medical devices, medicinal products or other substances are expected to be covered in the risk assessment but in accordance with GSPR 12.2, additional scrutiny on these aspects is required to be assessed for these devices.
There are also additional labelling requirements for these devices as detailed in GSPR 23.2(r) and GSPR 23.4(t), with a requirement to include qualitative and quantitative details of the device composition. This requirement is commonly misinterpreted with Manufacturers reticent to divulge their proprietary formulation information; however, while qualitative information is required for the device the quantitative information is limited to the main constituent or constituents responsible for achieving the principal intended action.
References
- MDCG 2021-24 Guidance on classification of medical devices. [Online] October 2021.
Previous Articles:
- An overview of the impact of the MDR (EU) 2017/745 for Combination Products and Substance based Devices. A Notified Body experience
- Integral Drug-Device Combinations (IDDCs) and MDR Article 117
- Device-Drug Combinations and MDR Rule 14
