Combination products consist of the combination of a medical device and a medicinal product. Since both medical device and medicinal product law could be applicable here, there are some special features that must be taken into account for products of this type.
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EU law does not officially include the term “combination product”. It is outlined in several regulations, but never expressly used.Regulation EG 1394/2007 (medicinal products for novel therapies), for example, defines the term “combined advanced therapy medicinal product” as an
advanced therapy medicinal product that incorporates, as an integral part of the product, one or more medical devices.[…].
The MDR and Directive 2001/83/EC for medicinal products do not use the term “combination product” or a similar term. The MDR does, however, set out specifications for products that are a combination of a medicinal product or active substance and a medical device.
Article 1(8) and (9) of the MDR sets out rules for when manufacturers either need to use the MDR or Directive 2001/83/EC for medicinal products.
(8) Any device which, when placed on the market or put into service, incorporates, as an integral part, a substance which, if used separately, would be considered to be a medicinal product as defined in point 2 of Article 1 of Directive 2001/83/EC, including a medicinal product derived from human blood or human plasma as defined in point 10 of Article 1 of that Directive, and that has an action ancillary to that of the device, shall be assessed and authorised in accordance with this Regulation.
However, if the action of that substance is principal and not ancillary to that of the device, the integral product shall be governed by Directive 2001/83/EC or Regulation (EC) No 726/2004 of the European Parliament and of the Council, as applicable. In that case, the relevant general safety and performance requirements set out in Annex I to this Regulation shall apply as far as the safety and performance of the device part are concerned.
Art. 1 para. 8 MDR
(9) Any device which is intended to administer a medicinal product as defined in point 2 of Article 1 of Directive 2001/83/EC shall be governed by this Regulation, without prejudice to the provisions of that Directive and of Regulation (EC) No 726/2004 with regard to the medicinal product.
However, if the device intended to administer a medicinal product and the medicinal product are placed on the market in such a way that they form a single integral product which is intended exclusively for use in the given combination and which is not reusable, that single integral product shall be governed by Directive 2001/83/EC or Regulation (EC) No 726/2004, as applicable. In that case, the relevant general safety and performance requirements set out in Annex I to this Regulation shall apply as far as the safety and performance of the device part of the single integral product are concerned.
Art. 1 para. 9 MDR
This enables us to conclude that the MDR is aware of the principle of “combination products”, even though it does not define them. The MDR regulations also mean that either the MDR or Directive 2001/83/EC is primarily applicable for medicinal products in the case of these products, but not both at the same time.
There is no specific regulation, directive or law for combined products consisting of a medicinal product or active substance and a medical device. However, the rules mentioned allow us to derive the following definition of combination products:
A product is considered to be a combination product if a combination of a medicinal product or active substance and a medical device combine to form a single product
In contrast to the EU, the term Combination Product does officially exist in the US (21 CFR 3.2(e)). This term describes products that meet one of the following conditions:
Combination of medicinal products and medical devices and/or a biological product
Examples of FDA conditions (allocated to the conditions):
Accordingly, combination products in the sense of the FDA are
combinations of medical devices and medicinal products that are either physically combined, co-packaged, or cross-labeled.
It is clear that the FDA understands the term “combination products” much more deeply than the MDR. Of all of the variants of “combination products”, only one overlaps with the MDR’s understanding of combination products, namely variant one, “manufactured as a unit (physically chemically, or otherwise)”.
The term “combination” needs to be understood in the sense of “integrated”, “belonging to”, or “inseparable”. Combination products (medicinal product-device units) are therefore not:
Products that are only intended to release medicinal product (substances) and have not been tailored to a specific medicinal product are handled as medical devices (see MDR Article 1(9)1)). Examples of products of this type are syringe pumps for general purposes.
In the EU (unlike in the US), systems and procedure packs are not considered to be combination products. There are special rules for systems and procedure packs in Article 22 MDR.
“Procedure pack” ‘procedure pack’ means a combination of products packaged together and placed on the market with the purpose of being used for a specific medical purpose;
Source: Article 2 (10) MDR
“System” means a combination of products, either packaged together or not, which are intended to be inter-connected or combined to achieve a specific medical purpose;
Source: Article 2 (11) MDR
If systems or procedure packs of this type contain medicinal products, the provisions in Article 22 MDR (“systems and procedure packs”) apply to this aggregated entity.
If systems and procedure packs are co-packaged or cross-labeled with medicinal products, the FDA considers them to be combination products.
You can find out more about systems and procedure packs in our article on the topic.
Either Directive 2001/83/EC for medicinal products and Regulation 726/2004 or the MDR for medical devices applies. They are therefore either primarily treated as medicinal products or primarily as medical devices, but not as both at the same time.
Depending on the field of law that is primarily relevant, manufacturers also need to check the combination product broadly as a medicinal product or broadly as a medical device.
This has an effect, for example, on:
Combination products must already meet the requirements from Annex I for both fields of law.
In the MDR this is the underlying safety and performance requirements while in Directive 2001/83/EC it is analytical, pharmacological and clinical standards and protocols in respect of the testing of medicinal products.
The rules of Art. 1 (8) and (9) MDR concerning the field of law that is primarily relevant:
The main ingredient is the ingredient which achieves the intended use, indication or effect.
The component is integral if both components are firmly and inseparably connected with each other. Furthermore, it is required that the combination serves a specific purpose.
Combined products must always meet the requirements from the respective Annex I of both regulations.
In the MDR, these are the essential safety and performance requirements; in Directive 2001/83/EC, these are analytical, toxicological, pharmacological, and medical or clinical requirements and evidence of testing of medicinal products.
Variants Art. 1(8) MDR
Medical device, if:
Medicinal product if:
Variant Art. 1(9) MDR
Medical device if:
Medicinal product, if:
There are situations in which both definitions, medicinal product and medical device, apply.
Example: The primary effect of a plaster wetted with antiseptic can be claimed by the manufacturer as:
In domestic use the physical protection is the main feature while the antiseptic effect is more important in clinical use due to the higher germ load. The plaster is authorized for both areas.
In cases where there is doubt, the directive for medicinal products applies (see Article 2(2) 2001/83/EC and Medicinal Products Act Section 2(2) No. 7).
If primarily the medical device regulation is applicable, the notified body must involve the competent authority of a member state or the EMA and obtain a scientific opinion.
Section 5.2 of Annex IX of the MDR states that in the case of a medical device containing a medicinal product as defined in Art. 1 No. 2 of Directive 2001/83/EC for medicinal products, the notified body must consult the competent authority for medicinal products. Without their positive vote, the combination product will not receive a certificate of conformity.
This is a deviation from the MDD/AIMDD. The MDR explicitly states that the notified body may not issue a certificate if the opinion of the medicinal products authority is negative (Annex IX 5.2 (e) and (f)).
The same applies in reverse for combination products authorized according to medicinal product law. A notified body is involved here (Article 117 MDR).
Article 117 MDR regulates the procedure for how the notified body is included in the case of combination products that are primarily medicinal products.
The rules for Companion Diagnostics (Cdx) are similar. There is more about this in our article on the topic.
The combination of medical device and medicinal product results in new hazards in terms of interoperability and compatibility that are also addressed in Annex I of the MDR. Other requirements apply with regard to these hazards.
The manufacturer must demonstrate that they meet paragraph 12 of Annex I, Article II MDR.
Annex I paragraph 12.2 MDR:
Devices that are composed of substances or of combinations of substances that are intended to be introduced into the human body, and that are absorbed by or locally dispersed in the human body shall comply, where applicable and in a manner limited to the aspects not covered by this Regulation, with the relevant requirements laid down in Annex I to Directive 2001/83/EC for the evaluation of absorption, distribution, metabolism, excretion, local tolerance, toxicity, interaction with other devices, medicinal products or other substances and potential for adverse reactions, as required by the applicable conformity assessment procedure under this Regulation.
The impact assessment also applies to certain manufacturing technologies, such as sterilization (Annex I paragraph 11.4); the manufacturer should evaluate whether the technology/method used has any effect on the safety and performance of the medical device part. In addition to this, the authority responsible for evaluating the approval dossier (EMA) and/or (NCAs) focuses on the evaluation of medicinal product part.
Annex II paragraph 6.2 a) MDR states:
Where a device incorporates, as an integral part, a substance which, if used separately, may be considered to be a medicinal product within the meaning of point 2 of Article 1 of Directive 2001/83/EC, including a medicinal product derived from human blood or human plasma, as referred to in the first subparagraph of Article 1(8), a statement indicating this fact. In this case, the documentation shall identify the source of that substance and contain the data of the tests conducted to assess its safety, quality and usefulness, taking account of the intended purpose of the device.
Information must therefore be provided on the medical device on:
For individual product classes, the FDA has published special guidance documents on human factors engineering.
The conformity assessment procedure and the approval (as described in medicinal product law) are initially based on whether the product needs to be qualified as a medicinal product or a medical device.
If the MDR primarily applies, the combination products come under risk class III according to Rule 14.
7.1. Rule 14
All devices incorporating, as an integral part, a substance which, if used separately, can be considered to be a medicinal product, as defined in point 2 of Article 1 of Directive 2001/83/EC, including a medicinal product derived from human blood or human plasma, as defined in point 10 of Article 1 of that Directive, and that has an action ancillary to that of the devices, are classified as class III.
High requirements are placed on class III products according to the MDR. This means a high cost
Manufacturers should be strategic in order to get a combination product through the conformity assessment procedure or the approval procedure as well as possible. They may choose, for example, the following strategies:
The purpose of the product is to measure an enzyme level via the skin. The sensor consists of the sensor head (1) with a measuring chamber and a measuring cell (2) with a mixture of substances that generates the measuring signal in the exchange with tissue fluid. The measuring signal is calculated into a measurement value and shown on the display (3).
Combined product parts
The mixture of substances 92) is used to make a medical diagnosis and must be qualified as a medicinal product according to the definition in Article 1(1)(b) 2001/83/EC.
The sensor head (2) and the display (3) are a device/apparatus for the purpose of diagnosing and monitoring a disease and are therefore the medical device.
The medicinal product is an integral part of the medical device and the whole product is therefore an integrated product (combination product).
The main effect is the calculation of the enzyme level using the measuring signal generated by the mixture of substances.
The change in pressure as a result of the measured value is enhanced by the mixture of substances, making the measurement more precise and more stable
The MDR is authoritative, as the main effect is in the medical device.
The requirements of Annex I of 2001/83/EC continue to apply on the basis of Annex I paragraph 12.2.
Class III due to Rule 14
Notified body (class III authorization) for the medical device
The product is used to provide treatment of a disease with medication. The medication is pre-dosed by manufacturer A and delivered in ampoules (1). The medication is administered using the smart applicator (2), which controls and fully releases the medication and sends the data on the procedure to a mobile app (3). The mobile app (3) records the time series that a doctor can evaluate remotely via the cloud (4). The manufacturer of the smart applicator and the software products is manufacturer B. Manufacturer B packages parts (2) and (1) together. The user can buy additional ampoules (1) in a pharmacy.
Combined product parts
The ampoule (1) containing the medication is the medicinal product. The ampoule is the primary packaging.
The smart applicator (2) is the medical device (not an accessory as accessories are bound to medical devices and not to medicinal products)
Ampoule (1) is not an integral, permanently installed part of the smart applicator (2), so there is no combination in the sense of the article.
Article 1(9) MDR
The smart applicator (2) is intended to release the medication and is therefore subject to the MDR
Manufacturer A: Ampoule containing medicinal product according to 2001/83/EC
Manufacturer B: Components 2, 3, 4 according to the MDR (see Article 1(9))
Manufacturer B must issue a declaration of conformity according to Article 22 for the unit packaged together. The product parts must both be labeled for joint use.
The smart applicator (2) and the software (3, 4) can be classified separately
Manufacturer A: with EMA/NCA for the ampoule with medicinal product
Manufacturer B: with the notified body for the medical device
The term “combination product” means those medical devices that contain a medicinal product as an integral part. Under EU law, these devices must be regarded either primarily as medical devices or primarily as medicinal products. The rules are derived from Art. 1 (8) and (9) MDR.
For combined medicinal products of this type, the MDR integrates its Annex I requirements directly into the Directive for medicinal products by means of Article 117. This change has an impact on manufacturers of combined medicinal products of this type, as a declaration of conformity or EU certificate or opinion from a notified body of the medical device is also needed for the submission.
If the medical device part is affected by a higher classification as a result of the shift to the MDR (the involvement of a notified body becomes necessary), medicinal product manufacturers must request the corresponding certification from the manufacturer of the medical device before the end of the transition periods for class I products.
Additional requirements in terms of interaction as set out in Annex I of the MDR apply for manufacturers of combined products for which the MDR is authoritative due to the main effect. The requirements laid down in Annex I to Directive 2001/83/EC also apply to medicinal product components. These products are classified in class III in and of themselves. A scientific opinion from the competent authority (EMA) and/or NCAs may be necessary to estimate the risks of the combination.
Manufacturers that package medicinal products and medical devices together or separately that are intended to be used together must meet the requirements of the MDR together with Article 22 of the MDR.
If you have questions about combination products or need help with the conformity assessment process, please contact the experts at Johner Institute.
We want to thank TÜV SÜD for important input to this article.