MDCG Guidance documents summary series:
MDCG 2022-5 – Guidance on borderline between medical devices and medicinal products under Regulation (EU) 2017/745 on medical devices
Borderline medical devices and Combination Products
The MDCG 2022-5: “Guidance on borderline between medical devices and medicinal products under Regulation (EU) 2017/745 on medical devices,” replaces the MEDDEV 2.1/3 Rev3 “Borderline products, drug-delivery products and medical devices incorporating, as an integral part, an ancillary medicinal substance or an ancillary human blood derivative” under MDD.
It provides guidance and clarification on the differences between the MDD and MDR, taking into account the relevant definitions and making practical examples, particularly focusing on herbal products, substance-based devices and combinations of medical device and medicinal product.
In the Helsinki Procedure 2021, published in September 2021, the exchange of information between medical device competent authorities on borderline and classification cases is made transparent.
For correctness of the information in this summary is based on the quotes from the MDCG 2022-5.
Borderline medical devices products: medical devices/medicinal products
Section 1 is about general principles and definitions. The general principle that a product is regulated either by the MDR 2017/745 or by the MPD 2001/83/EC, and the determining principle mode of action did not change with MDR 2017/745 in place.
The general principal is based on three concepts:
1. Specific medical purpose’ (referred to in Article 2(1) MDR, first paragraph)
The specific medical purpose is specified by the manufacturer from those listed in the indents of Article 2(1) MDR.
2. Principal intended action’ (referred to in Article 2(1) MDR, second paragraph)
The principal intended action of a medical device is described in manufacturer’s labelling and claims and must be based on state-of-the-art scientific data regarding the principal mode of action, on a case-by-case basis.
3. Principal mode of action’ (referred to in Article 1(6)(b) MDR)
The principal mode of action represents the means by which the product achieves its principal intended action, i.e. pharmacological, immunological, metabolic, physical or other. It is objective and must be based on state-of-the-art scientific data.
Further provided relevant definitions of medical device and medicinal product are:
1.2.1.1 Definition of medical device (Article 2 (1) MDR)
1.2.1.2 Definition of an accessory of a medical device (Article 2 (2) MDR)
1.2.1.3 Definition of medicinal product (Article 1(2) MPD)
1.2.2 Definitions of pharmacological, immunological, metabolic means
“Pharmacological means’ is understood as an interaction typically at a molecular level between a substance or its metabolites and a constituent of the human body which results in initiation, enhancement, reduction or blockade of physiological functions or pathological processes. Examples of constituents of the human body may include, among others: cells and their constituents (cell membranes, intracellular structures, RNA, DNA, proteins, e.g. membrane proteins, enzymes), components of extracellular matrix, components of blood and components of body fluids.
Examples of action via pharmacological means:
- interaction between a ligand (e.g. agonist, antagonist) and a receptor;
- interaction between a substance and membrane lipids;
- interaction between a substance and components of the cytoskeleton.
- ‘Immunological means’ is understood as an action initiated by a substance or its metabolites on the human body and mediated or exerted (i.e. stimulation, modulation, blocking, replacement) by cells or molecules involved in the functioning of the immune system (e.g. lymphocytes, toll-like receptors, complement factors, cytokines, antibodies).
Examples of action via ‘immunological means’:
- modulation of an immune response (e.g. suppressing, blocking, activating, enhancing);
- replacement, reconstitution or introduction of natural or modified immune cells or molecules;
- triggering an immune response against the targeted tissues, cells or antigens by immune- specific recognition;
- targeting action of other linked or coupled substances.
- ‘Metabolic means’ is understood as an action of a substance or its metabolites which involves an alteration, including stopping, starting or changing the rate, extent or nature of a biochemical process, whether physiological or pathological, participating in, and available for, function of the human body.
The term ‘biochemical processes’ is understood as reactions available for the human body including anabolic and catabolic reactions and transport of substances between compartments. An interaction with a known receptor is not a prerequisite for the metabolic means of action.
Examples of action via ‘metabolic means’:
- the movement of water due to active transport of electrolytes mediated by e.g. Na/K ATPase pumps;
- inhibition of endogenous enzymes, including the digestive enzymes;
- altering the electrolyte balance of the serum.”
- Note 1: In the context of these modes of action, a definition of the term ‘substance’ is given in Directive 2001/83/EC
- Note 2: Examples of ‘interactions’ include the following: covalent bonding, H-bonds, electrostatic, and van der Waals forces
1.2.3 Definition of medical diagnosis
- Products used in vivo or ex vivo to distinguish between healthy and pathological tissue meet the definition of “medical diagnosis” and are regulated as Medicinal Products, while products whose purpose is to visualise an area for surgery do not meet the definition and are regulated as devices, a list of products regulated as medical devices is provided.
- Products intended for diagnosis in vitro are in vitro diagnostic medical devices in scope of Regulation (EU) 2017/746.
1.2.4 Determining if a product fulfils the definition of a medical device is shown by a flowchart.
1.2.5 The concepts of “a substance (ref. to MPD Art. 1 (2)) which, if used separately, would/may/can be considered a medicinal product” and “and that has an action ancillary to that of the device” provides further clarification in:
1.2.5.1 The concept of ‘a substance which, if used separately, would/may/can be considered a medicinal product’
1.2.5.2 The concept ‘and that has an action ancillary to that of the device’
1.2.6 lists several examples of Medical Devices, accessories of medical devices, and medicinal products-.
Herbal products
Section 2 provides definitions of an herbal medicinal product and traditional herbal medicinal product; an Herbal medicinal product as per Art. 1 (30), 1 (31), 1 (32) and 16(a) MP, and a traditional herbal medicinal product (Art. 1 (29) and 16(a)1 MPD)
A reference to the EU monographs (established by the EMA Committee on Herbal Medicinal Products – HMPC) is made. When a substance included in these monographs complies with the monograph regarding its composition or preparation, dosage and indication, it is a good indicator that the substance in question falls into the definition of herbal medicinal product.
Examples of herbal medicinal products are listed.
Substance-based medical devices
A substance-based medical device is a medical device which:
- is composed of substances that are permitted in a medical device, and
- does not achieve its principal intended action by pharmacological, metabolic or immunological means.
When it comes to substances, attention should be paid that Art. 1(6) MDR lists substances that are not permitted in medical devices. This guidance gives some examples out of this list:
- viable biological material or viable organisms, including living micro-organisms, bacteria, fungi or viruses;
- viable animal tissues or cells or their derivatives;
- viable human tissues and cells or their derivatives.
Besides the general principles for substance based medical devices, the guidance provides further clarification and examples for:
2. Medical devices consisting of a substance or mixture of substances used in vitro in direct contact with human cells, tissues, organs, or human embryos before their implantation or administration, and
3. Medical devices composed of substances or of combinations of substances that are intended to be introduced into the human body or applied to the skin
Medical device and medicinal product combinations
For medical devices which are intended for use with a medicinal product in a different configuration than a combination product, as per MDR regulatory scenarios in Art. 1(8) and Art 1(9), a helpful flow chart is provided.
The driving factor here is what is meant by “integral”:
- “integral part – Article 1(8) 1st paragraph, referring to devices incorporating a substance which, if used separately, would be considered a medicinal product.
- integral product – Article 1(8) 2nd paragraph, referring to devices incorporating a substance which, if used separately, would be considered a medicinal product.
- single integral product – Article 1(9) – 2nd paragraph, referring to devices intended to administer a medicinal product”
MDCG provides helpful clarification and a range of examples for:
4.2 Medical device and medicinal product integral combinations regulated as medicinal products
4.3 Medical device for administration of medicinal products
4.4 Medical devices incorporating, as an integral part, an ancillary medicinal product
Key take aways for classification:
“Annex IX, 4.1 Rule 13 ‘All devices incorporating, as an integral part, a substance which, if used separately, can be considered to be a medicinal product, as defined in Article 1 of Directive 2001/83/EC, and which is liable to act on the human body with action ancillary to that of the devices, are in Class III.’
Annex VIII, Rule 14 makes use of the same concept ‘Rule 14: All devices incorporating, as an integral part, a substance which, if used separately, can be considered to be a medicinal product, […], and that has an action ancillary to that of the devices, are classified as class III.’ [emphasis added]
Furthermore, Annex IX section 5.2(a), also applicable for Annex X section 6, requires that ‘Where a device incorporates, as an integral part, a substance which, if used separately, may be considered to be a medicinal product […] and that has an action ancillary to that of the device, the quality, safety and usefulness of the substance shall be verified by analogy with the methods specified in Annex I to Directive 2001/83/EC.’.
Under the MDR Annex VIII there are two classification rules applying specifically to substance-based devices that take into account the relevant risks, these are rule 3 and 21. Not all substance-based devices fall under these two rules and in that case they would be classified under the general rules.
- Medical device consisting of a substance or mixture of substances used in vitro in direct contact with human cells, tissues, organs, or human embryos before their implantation or administration (classified by Rule 3, Annex VIII MDR)
- Medical device composed of substances or of combinations of substances that are intended to be introduced into the human body via a body orifice or applied to the skin and that are absorbed by or locally dispersed in the human body (classified by Rule 21, annex VIII MDR)
III. Other substance-based devices (no specific rule for these devices)
All other rules and requirements should also be considered. For examples, where a substance-based device incorporates a substance, which, if used separately, would be considered a medicinal product and where the action of the medicinal product is ancillary to that of the device, a consultation with a competent authority or EMA is necessary according to section 5.2 of Annex IX, MDR.”
The Helsinki Procedure 2021: Exchange of information between medical device competent authorities on borderline and classification cases
The Helsinki Procedure for borderline and classification under MDR & IVDR describes the consultation process for borderline devices when requests for decision on borderline or classification issues are received by the CA. “The system was revised following the entry into application of the Regulation (EU) 2017/745 on medical devices (MDR) and Regulation (EU) 2017/746 on in vitro diagnostic medical devices (IVDR) by the Borderline & Classification Working Group (BCWG)1 of the Medical Devices Coordination Group (MDCG) in 2021”
This document provides several flow-charts for visualization of the processes until publication in the Manual on Borderline and Classification, and written explanation for the different flows, which are:
Flow A. Majority view exists following initial CA consultation
Flow B. No majority view exists following initial CA consultation
Flow C. Favourable majority vote achieved
Flow D. No favourable majority vote achieved
Flow E. Preliminary agreement reached in the CA discussion
Flow F. No preliminary agreement reached in the CA discussion
The cooperation with other MDCG Working Groups is also described and an overview of the timelines would be of a total length of procedure is 5 months, 2 weeks until finalization and publication. The Manual is updated every three months.
Other helpful Guidance
- MDCG 2021-24 Guidance on classification of medical devices
- Exchange of information between medical device competent authorities on borderline and classification cases Helsinki Procedure 2021
- MANUAL ON BORDERLINE AND CLASSIFICATION IN THE COMMUNITY REGULATORY FRAMEWORK FOR MEDICAL DEVICES, Version 1.22 (05-2019)
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