Some of the most innovative products in healthcare do not fit neatly into a single regulatory category. A drug-eluting stent combines a device (the stent) with a pharmaceutical (the drug). An insulin pen combines a device (the injection mechanism) with a biologic (the insulin). A wound dressing with antimicrobial silver combines a device (the dressing) with a substance that has a pharmacological action.

These are combination products — and their regulatory pathway under MDR is one of the most complex areas in medical device regulation.

If your startup is developing a product that incorporates or is used with a medicinal product, a substance derived from human blood or plasma, or tissues or cells of human or animal origin, this post maps the regulatory terrain.

How MDR Defines Combination Products

MDR does not use the term "combination product" as a defined regulatory category (unlike the FDA, which has a formal combination product framework). Instead, MDR addresses devices that incorporate or are integral with substances that, if used separately, would be considered medicinal products.

The key provisions are in MDR Article 1(8) and (9), and in the classification rules of Annex VIII.

Devices Incorporating a Medicinal Substance

MDR Article 1(8) addresses devices that incorporate, as an integral part, a substance which, if used separately, would be considered a medicinal product (as defined in Directive 2001/83/EC) and which is liable to act on the human body with action ancillary to that of the device.

The critical concept is "ancillary." The substance's action must be ancillary (secondary, supporting) to the device's primary action. The device is the primary mode of action; the substance supports the device's function.

Example: A bone cement that incorporates an antibiotic (gentamicin). The primary function is mechanical (bone fixation). The antibiotic action (preventing infection) is ancillary to the device function.

Example: A drug-eluting coronary stent. The primary function is mechanical (keeping the artery open). The drug's action (preventing restenosis) is ancillary.

If the substance's action is the primary mode of action and the device merely delivers it, the product is likely a medicinal product regulated under the pharmaceutical framework (Directive 2001/83/EC or Regulation (EC) No 726/2004), not a medical device under MDR.

Devices Incorporating Substances Derived from Human Blood or Plasma

MDR Article 1(9) addresses devices incorporating substances derived from human blood or human plasma that, if used separately, may be considered medicinal products derived from human blood or human plasma. These are regulated under MDR but with additional requirements involving consultation with relevant medicinal product authorities.

Devices Used with Medicinal Products

Separate from devices that incorporate substances, MDR also covers devices intended to administer a medicinal product. An injection device, an infusion pump, or a drug delivery system is a medical device — the medicinal product it administers is regulated separately. The device needs its own CE marking; the drug needs its own marketing authorization.

Classification Rules for Combination Products

Rule 13: Devices Incorporating a Medicinal Substance

MDR Annex VIII Rule 13 classifies devices incorporating a substance which, if used separately, can be considered a medicinal product, and which acts on the body with action ancillary to that of the device, as Class III.

This is important for startups: incorporating a medicinal substance into your device almost automatically makes it a Class III device, triggering the most rigorous conformity assessment pathway.

Rule 14: Devices Used for Contraception or Prevention of Transmission of Sexually Transmitted Diseases

Devices incorporating substances that are absorbed by the human body for these purposes are also classified under specific rules.

Rule 18: Devices Utilizing Tissues or Cells of Human or Animal Origin

Devices that are manufactured utilizing tissues or cells of human or animal origin, or their derivatives, which are non-viable or rendered non-viable, are classified as Class III (with some exceptions for devices manufactured from rendered non-viable animal tissues or derivatives that only contact intact skin).

The Conformity Assessment for Combination Products

Because combination products are typically Class III, the conformity assessment follows the most rigorous pathway — Annex IX (full QMS assessment + technical documentation assessment per device).

The Consultation Procedure

Here is where combination products get particularly complex. When a device incorporates a medicinal substance, the Notified Body must seek a scientific opinion from a competent authority for medicinal products (or the European Medicines Agency, EMA) on the quality and safety of the substance, including the benefit-risk profile of incorporation of the substance into the device.

This means: 1. You submit your technical documentation to the Notified Body 2. The Notified Body reviews the device aspects 3. The Notified Body sends the medicinal substance aspects to a medicines authority (such as a national competent authority or EMA) for their opinion 4. The medicines authority reviews and provides a scientific opinion 5. The Notified Body considers the opinion in its overall conformity assessment

This consultation adds time — typically 3-6 months, sometimes longer — and requires specific documentation addressing the substance: - Quality of the substance (identity, purity, stability) - Safety of the substance (toxicological data, clinical safety data) - Benefit-risk of incorporating the substance into the device - Interaction between the substance and the device (does the device affect the substance's quality or action? does the substance affect the device's performance?)

For Substances Derived from Human Blood or Plasma

The consultation procedure is similar but involves specific requirements for blood and plasma-derived substances, reflecting the additional safety concerns (viral safety, prion disease risk, etc.).

For Tissues and Cells

Devices incorporating human tissues or cells also require specific consultation and must meet additional requirements related to the sourcing, processing, and safety of biological materials.

Practical Implications for Startups

Expect Class III

If your product incorporates a medicinal substance, plan for Class III classification and everything that entails: - The most extensive technical documentation - The most rigorous Notified Body assessment - Expert panel consultation for Class III implantable devices - Medicines authority consultation for the incorporated substance - The highest clinical evidence bar (likely requiring clinical investigation data) - The longest timeline (24-36+ months) - The highest cost (EUR 600,000 - 1,500,000+)

Build the Substance Dossier Early

The documentation package for the medicinal substance is essentially a mini-pharmaceutical dossier. You need: - Full characterization of the substance - Manufacturing process description for the substance - Quality control specifications - Stability data - Toxicological data - Clinical data supporting safety of the substance at the used dose and route - Interaction studies (substance + device)

If you are using a well-established substance (like gentamicin in bone cement), much of this data may be available from published literature and existing pharmaceutical dossiers. If you are using a novel substance, you may need to generate significant original data.

The Regulatory Timeline Includes Medicines Authority Review

Factor the consultation with the medicines authority into your timeline. This is not under your control or the Notified Body's control — it depends on the authority's workload and review speed.

Engage Pharmaceutical Regulatory Expertise

Medical device regulatory professionals may not have expertise in pharmaceutical quality and safety assessment. For combination products, you may need regulatory expertise from both the device and pharmaceutical domains. Consider engaging a pharmaceutical regulatory consultant alongside your medical device regulatory team.

Tibor's candid assessment: "Combination products are the most complex regulatory territory in MedTech. You are dealing with two regulatory frameworks — medical device regulation and pharmaceutical regulation — simultaneously. The companies that succeed are the ones that respect both domains and build expertise in both. The companies that try to treat the substance component as a footnote to their device dossier run into serious problems during the medicines authority consultation."

The Boundary Decision: Device or Medicinal Product?

The most fundamental regulatory decision for a combination product is: is the primary mode of action the device or the substance?

  • If the device is primary and the substance is ancillary: Regulated under MDR (with consultation)
  • If the substance is primary and the device merely delivers it: Regulated under pharmaceutical legislation (with device aspects potentially assessed under MDR through a different consultation procedure)

This determination can be genuinely difficult. Some products have both significant device action and significant pharmacological action, and reasonable experts may disagree on which is primary.

MDR Article 1(6)(a) addresses this borderline: products that combine a medicinal product and a device, where the principal mode of action is pharmaceutical, are regulated under pharmaceutical legislation but the device component must comply with the relevant GSPRs of MDR.

For startups, the boundary decision has enormous regulatory and business implications: - The regulatory pathway is completely different - The regulatory expertise needed is different - The timeline and cost are different - The commercial model may be different

If you are near the boundary, seek regulatory advice from experts in both domains before committing to a path. In ambiguous cases, consulting the competent authority can provide clarity.

Examples for Clarity

Drug-eluting stent: Device primary (mechanical opening of artery), drug ancillary (preventing restenosis). Regulated under MDR, Class III, medicines authority consultation required.

Prefilled insulin syringe: The syringe is a device (regulated under MDR). The insulin is a medicinal product (regulated under pharmaceutical legislation). These are regulated separately — the syringe gets CE marked, the insulin gets a marketing authorization.

Medicated wound dressing (silver-containing): If the silver's antimicrobial action is ancillary to the device function (wound protection), it is an MDR device with substance incorporation. If the primary purpose is the antimicrobial treatment, it may be a medicinal product.

Gene therapy delivery device: The gene therapy is the primary mode of action (pharmaceutical). The delivery device is ancillary. Regulated under pharmaceutical legislation, with device aspects assessed under MDR.

The Bottom Line

Combination products sit at the intersection of device and pharmaceutical regulation. For startups, this means higher complexity, longer timelines, higher costs, and the need for dual-domain expertise.

The key decisions — is this a device or a pharmaceutical? is the substance ancillary? — must be made early and made correctly. They determine your entire regulatory path.

If your product incorporates a medicinal substance, plan for Class III, plan for the medicines authority consultation, plan for the extended timeline, and build a team (internal or external) that can navigate both the device and pharmaceutical regulatory domains. The intersection of these domains is not a place for guesswork.