--- title: How to Apply MDR Classification Rule 13: Devices Incorporating a Medicinal Substance description: MDR Annex VIII Rule 13 covers devices that incorporate a medicinal substance. Here is how to apply it and the combination-product boundary. authors: Tibor Zechmeister, Felix Lenhard category: Device Classification & Conformity primary_keyword: MDR Rule 13 medicinal substance canonical_url: https://zechmeister-solutions.com/en/blog/mdr-rule-13-devices-incorporating-medicinal-substance source: zechmeister-solutions.com license: All rights reserved. Content may be cited with attribution and a link to the canonical URL. --- # How to Apply MDR Classification Rule 13: Devices Incorporating a Medicinal Substance *By Tibor Zechmeister (EU MDR Expert, Notified Body Lead Auditor) and Felix Lenhard.* > **Rule 13 of Annex VIII to Regulation (EU) 2017/745 classifies all devices incorporating, as an integral part, a substance which, if used separately, can be considered to be a medicinal product, and whose action is ancillary to that of the device, as Class III. Rule 13 sits tight against the combination-product boundary in Article 1(8) and Article 1(9) of the MDR. When the medicinal action is principal rather than ancillary, the product is regulated as a medicinal product under Directive 2001/83/EC, not as a device under the MDR. Drug-eluting stents, antibiotic bone cement, heparin-coated catheters with ancillary anticoagulant action, and drug-coated balloons are the canonical Rule 13 devices. Classification is governed by Article 51 of the MDR, interpreted in MDCG 2021-24 (October 2021).** **By Tibor Zechmeister and Felix Lenhard. Last updated 10 April 2026.** --- ## TL;DR - MDR Rule 13 classifies all devices that incorporate a medicinal substance with ancillary action as Class III. The class is fixed — there is no IIa or IIb option inside Rule 13. - The "ancillary" test is the entire game. If the medicinal action is principal, the product is a medicinal product under Directive 2001/83/EC, and the MDR does not govern the marketing authorisation at all. - Rule 13 sits tight against Article 1(8) and Article 1(9), which define the combination-product boundary between devices and medicinal products. Get the boundary wrong and you build the wrong technical file for the wrong regulator. - Typical Rule 13 devices include drug-eluting stents, antibiotic bone cement, heparin-coated central lines with ancillary anticoagulant action, drug-coated balloons, and hormone-releasing intrauterine systems (where the device action is principal). - A Rule 13 classification triggers a consultation with a medicinal product competent authority or the EMA on the quality, safety, and usefulness of the medicinal substance. Plan for this early — it is not a rubber stamp. --- ## Why Rule 13 matters the moment a medicinal substance touches your device A startup that coats a catheter with heparin, impregnates a bone cement with gentamicin, embeds an antibiotic in a mesh, loads a stent with paclitaxel, or combines a biomaterial scaffold with a growth factor is in Rule 13 territory from the first line of the intended purpose. The only question is whether the medicinal substance is ancillary or principal — and that one answer decides whether the product is a device at Class III under the MDR or a medicinal product outside the MDR entirely. Founders underestimate how often the ancillary/principal judgment is made wrong. A team building a drug-coated balloon "for restenosis prevention" often drafts the intended purpose as if the drug does the work, then tries to classify the whole thing as a device. A team building an antibiotic-loaded bone void filler often assumes Class IIb because bone cement is IIb — forgetting that the antibiotic pushes the whole product to Class III under Rule 13. Rule 13 rewards the startups that name the substance, characterise its action honestly, walk the Article 1(8)–(9) boundary in writing, and accept the Class III conformity assessment workload when the substance stays ancillary. This post is the walkthrough. ## What Rule 13 actually says Rule 13 of Annex VIII, Section 4 (Chapter IV — Special rules) of Regulation (EU) 2017/745 reads, in substance: > 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 device, are classified as Class III. (Regulation (EU) 2017/745, Annex VIII, Rule 13.) Three elements have to be true together for Rule 13 to apply. First, there has to be a substance that, if used separately, would qualify as a medicinal product under Directive 2001/83/EC. That is a low bar — any pharmacologically, immunologically, or metabolically acting substance that meets the Directive 2001/83/EC definition counts, whether or not it currently holds a marketing authorisation in that form. Second, the substance has to be incorporated as an integral part of the device. A drug in a separate vial used alongside the device does not trigger Rule 13. A drug bonded into, coated onto, impregnated into, or loaded within the device does. Third, the action of the substance has to be ancillary to the action of the device. If all three are true, the device is Class III. There is no lower class available inside Rule 13. The only way out of Class III under this rule is to demonstrate that Rule 13 does not apply at all — usually because the substance is not a medicinal product in the Directive 2001/83/EC sense, or because the substance is not incorporated as an integral part, or because the action of the substance is principal rather than ancillary (in which case the product leaves the MDR and enters the medicinal product regime). Article 51 of the MDR is the framework article that makes Annex VIII binding, and MDCG 2021-24 (October 2021) is the authoritative interpretation guide for classification, including Rule 13 and its boundary with the medicinal product regime. ## What counts as incorporating a medicinal substance The word "incorporating" is doing real work in Rule 13. The substance has to be an integral part of the finished device as placed on the market. This usually means one of the following configurations: **Coating.** The substance is bonded to a surface of the device during manufacture. Drug-eluting stents, drug-coated balloons, and heparin-coated vascular catheters are coating cases. The patient never sees the substance as a separate entity — it is already on the device when the device leaves the factory. **Impregnation.** The substance is absorbed into a matrix during manufacture — into a polymer, a collagen sponge, a bone cement, a textile mesh, or a ceramic. Antibiotic bone cements and antibiotic-impregnated meshes are the classic impregnation cases. **Loading into a reservoir.** The substance sits inside a compartment of the device and is released over time through diffusion, erosion, or active mechanism. Drug-releasing implants and some long-term intrauterine systems use this pattern. **Chemical binding.** The substance is covalently bound to the device material. This is common with enzyme-inhibiting coatings and with some advanced biomaterial surface treatments. Configurations that are **not** "incorporation" for Rule 13 purposes include: a drug supplied in a separate primary container alongside the device (that is a co-packaged combination, not an integral combination), a drug drawn into the device at the point of use (that is typically a Rule 12 administration scenario, not Rule 13), and a drug administered before or after device use (no combination at all). The test is whether the substance is present in the device at the moment the device is placed on the market and whether it is physically integral to the device. If yes, Rule 13 is in play and the next question is the ancillary/principal one. ## The Class III trigger — why Rule 13 has no lower class Rule 13 produces Class III and only Class III. There is no duration escalation, no body-site escalation, no mode-of-application escalation. The logic is straightforward: any device that carries a medicinal substance intended to contribute to the clinical outcome is a device where the patient is exposed to drug-like effects on top of device-like effects. The combined risk profile is treated as high enough to warrant the full Class III conformity assessment in every case. The Class III consequences are real: - **Conformity assessment route.** Class III devices go through the most demanding route under Article 52, typically Annex IX (QMS and technical documentation assessment) combined with the Annex IX Section 5.1 requirements for Class III devices, or Annex X plus Annex XI depending on the product type. - **Clinical investigation expectation.** Article 61 sets a strong default expectation of pre-market clinical investigations for implantable and Class III devices, with the exemption pathway in Article 61(4)–(6) available only in specific cases. - **Medicinal substance consultation.** The Notified Body must seek a scientific opinion from a competent authority designated by a Member State under Directive 2001/83/EC or from the European Medicines Agency (EMA) on the quality and safety of the ancillary medicinal substance, including the clinical benefit/risk profile of its incorporation into the device. This is not a formality. It adds months to the conformity assessment timeline and often triggers additional questions on the substance dossier. - **Post-market surveillance depth.** PMS for Class III devices is at the highest depth, with PSUR obligations under Article 86 at least annually. A founder who runs the Rule 13 analysis and finds the substance is ancillary has to plan the project around a Class III timeline, a Class III budget, and a medicinal substance consultation with a competent authority or the EMA. There is no shortcut inside the rule. ## The combination-product boundary — Rule 13 vs. medicinal products regulation The boundary between Rule 13 and the medicinal product regime lives in Article 1(8) and Article 1(9) of the MDR. It is the single most consequential boundary in this rule, and the one most frequently misread. Article 1(8) addresses the case where a device incorporates a medicinal substance whose action is **ancillary** to that of the device. In that case, the product is a device, regulated under the MDR, classified under Rule 13 as Class III, and the medicinal substance is assessed as part of the device conformity assessment via the consultation with a competent authority or the EMA. Article 1(9) addresses the case where a device and a medicinal product form a single integral product, intended exclusively for use in the given combination and not reusable, and where the action of the **medicinal product is principal**. In that case, the product as a whole is regulated as a medicinal product under Directive 2001/83/EC or Regulation (EC) No 726/2004. The device part still has to meet the relevant general safety and performance requirements set out in Annex I of the MDR, but the marketing authorisation is a medicinal product authorisation, not a CE certificate, and Rule 13 does not apply because the MDR classification rules do not apply at all. The boundary question is: what does the clinical outcome primarily depend on? If the clinical outcome primarily depends on the mechanical, physical, structural, or energy-based action of the device, and the medicinal substance only supports that (for example, by preventing thrombus formation on a surface so the device can function), the substance is ancillary and the product is a device. If the clinical outcome primarily depends on the pharmacological, immunological, or metabolic action of the substance, and the device part is essentially a delivery mechanism, the substance is principal and the product is a medicinal product. A drug-eluting stent is a device: the stent provides mechanical scaffolding to keep the vessel open (principal action), and the drug prevents neointimal hyperplasia on the stent surface (ancillary action). A pre-filled syringe containing a biologic is a medicinal product: the syringe delivers the drug, but the clinical effect comes entirely from the drug. A hormone-releasing intrauterine system is typically a device because the contraceptive effect depends primarily on the IUS as a physical device, with the hormone supporting that effect locally — though in some configurations regulators have taken different views, and this is exactly the kind of case where the boundary has to be walked carefully with Article 1(8)–(9) in hand. Walk this boundary in writing before committing to Rule 13. A founder who skips it and builds a Class III device file for a product that is actually a medicinal product has wasted quarters of work and has to restart with a completely different regulator. ## Common Rule 13 misclassifications **Classifying the base device and ignoring the substance.** A bone cement is Class IIb under Rule 8. A bone cement with an incorporated antibiotic is Class III under Rule 13. The substance changes the class — the base device class does not carry over. **Assuming the substance must hold a marketing authorisation to trigger Rule 13.** Rule 13 is triggered by a substance that, if used separately, would be a medicinal product in the Directive 2001/83/EC sense. No existing authorisation is required for the trigger to apply. **Treating "ancillary" as a small quantity.** The ancillary/principal test is about the contribution to the clinical outcome, not about the amount of substance present. A small quantity can still be principal if the clinical effect depends on it, and a large quantity can still be ancillary if the device action is what produces the outcome. **Skipping the Article 1(8)–(9) boundary walk.** Founders sometimes jump straight to Rule 13 without first confirming the product belongs in the MDR regime at all. If the action is principal, Rule 13 is not the answer — the medicinal product regime is. **Forgetting the medicinal substance consultation.** A Class III device under Rule 13 requires a Notified Body consultation with a competent authority or the EMA on the ancillary medicinal substance. Projects that do not plan for this consultation lose months at the end of the conformity assessment. **Using a co-packaged drug/device kit to claim Rule 13 applies.** Rule 13 requires incorporation as an integral part. A kit containing a device and a drug in separate containers is not a Rule 13 product — it is a co-packaged combination handled under different rules and possibly under different regulators. ## The Subtract to Ship angle on Rule 13 The [Subtract to Ship framework for MDR compliance](/blog/subtract-to-ship-framework-mdr) treats classification as the second of four passes. Inside a Rule 13 analysis, the subtraction move is not "find a lower class" — the rule has no lower class. The subtraction move is upstream, in the Purpose Pass: do you actually need the medicinal substance in the product, or can the intended clinical outcome be achieved with a pure device? We have seen startups add a drug coating because the scientific literature shows an incremental benefit, then discover the Rule 13 pathway doubles the timeline and the budget, and the incremental benefit does not justify the delta. In some cases the right subtract-to-ship move is to remove the substance from the v1 product, certify the pure device first, and study the drug-combined version as a second-generation product with the runway that the v1 revenue produces. In other cases the substance is load-bearing for the clinical claim and removing it would destroy the product. Then Subtract to Ship means accepting Class III, planning the medicinal substance consultation early, and subtracting every activity that belongs to a higher regulatory bar than Class III under Rule 13 actually requires — not every consultant's Class III default matches the real Rule 13 workload. Subtract to Ship never means hiding from Class III when the substance is ancillary. The rule is binding. The discipline is to make the ancillary/principal decision deliberately, document it, and then do the Class III work that the rule requires — nothing more, nothing less. ## Reality Check — Have you applied Rule 13 correctly? 1. Can you name the exact substance incorporated in your device, and can you state whether it would qualify as a medicinal product under Directive 2001/83/EC if used separately? 2. Is the substance physically integral to the device at the moment of placing on the market, or is it supplied separately and combined at the point of use? 3. Have you written a paragraph characterising the action of the substance as ancillary or principal, with reference to the clinical outcome the device is intended to achieve? 4. Have you walked the boundary in Article 1(8) and Article 1(9) in writing, and concluded that the product belongs in the device regime rather than the medicinal product regime? 5. Have you accepted the Class III conformity assessment workload, including the Notified Body consultation with a competent authority or the EMA on the ancillary substance? 6. Have you planned the medicinal substance consultation into your timeline, or is it a surprise waiting at the end of the project? 7. Have you checked whether any other rule also applies to the device, so you are not missing a parallel classification consequence? ## Frequently Asked Questions **What is MDR Rule 13 and which devices does it cover?** MDR Rule 13, in Annex VIII of Regulation (EU) 2017/745, classifies all devices that incorporate a medicinal substance with ancillary action as Class III. It covers drug-eluting stents, antibiotic bone cement, heparin-coated catheters where the anticoagulant action is ancillary, drug-coated balloons, and similar combination configurations. The rule is fixed at Class III with no lower option available inside the rule itself. **What does "ancillary" mean in Rule 13?** "Ancillary" means the action of the medicinal substance supports the action of the device rather than producing the clinical outcome on its own. The clinical outcome has to depend primarily on the device action — mechanical, physical, structural, or energy-based — with the substance supporting that action. If the clinical outcome depends primarily on the pharmacological, immunological, or metabolic action of the substance, the action is principal and the product is regulated as a medicinal product under Directive 2001/83/EC, not as a device. **Is a drug-eluting stent regulated under Rule 13?** Yes. A drug-eluting stent is a device where the stent provides the principal action (keeping the vessel mechanically open) and the drug provides an ancillary action (reducing restenosis by inhibiting neointimal hyperplasia on the stent surface). Rule 13 applies and the device is Class III. The conformity assessment includes a consultation between the Notified Body and a competent authority or the EMA on the ancillary medicinal substance. **How does Rule 13 differ from Rule 12?** Rule 12 covers active devices that administer or remove substances to or from the body — the substance moves through the device but is not physically integral to it. Rule 13 covers devices that incorporate the medicinal substance as an integral part of the device as placed on the market. An infusion pump filled with a drug at the hospital is Rule 12. A stent with a drug coating applied during manufacture is Rule 13. **Does Rule 13 apply if the drug is not yet approved as a medicinal product?** Yes. Rule 13 is triggered by a substance that, if used separately, would qualify as a medicinal product in the sense of Directive 2001/83/EC. An existing marketing authorisation is not required for the trigger to apply. The question is the nature of the substance, not its regulatory status. **What is the medicinal substance consultation in a Rule 13 conformity assessment?** When a Class III device falls under Rule 13, the Notified Body is required to seek a scientific opinion from a competent authority designated by a Member State under Directive 2001/83/EC, or from the European Medicines Agency, on the quality and safety of the incorporated medicinal substance, including its clinical benefit/risk profile within the device. The opinion is a substantive regulatory step that typically adds several months to the conformity assessment timeline. **What happens if the medicinal action turns out to be principal rather than ancillary?** The product leaves the MDR regime entirely. It is regulated as a medicinal product under Directive 2001/83/EC or, for centrally authorised products, Regulation (EC) No 726/2004. The device part still has to meet the relevant general safety and performance requirements in Annex I of the MDR, but the marketing authorisation is a medicinal product authorisation rather than a CE certificate. This is the Article 1(9) scenario and it is a completely different regulatory pathway. ## Related reading - [The Subtract to Ship Framework for MDR Compliance](/blog/subtract-to-ship-framework-mdr) — the methodology that treats classification as the second of four passes. - [MDR Annex VIII Classification Rules: The Complete Guide for Startups](/blog/mdr-annex-viii-classification-rules-complete-guide) — the rule-by-rule walk across all twenty-two classification rules. - [MDR Device Classification Explained](/blog/mdr-device-classification-explained) — the pillar post on how classification works across all four classes. - [MDR Classification Rule 12: Active Devices That Administer Medicinal Products](/blog/mdr-rule-12-active-devices-medicinal-products) — the sibling rule for active administration and removal devices. - [MDR Classification Rule 14: Devices Incorporating Non-Viable Tissues or Cells](/blog/mdr-rule-14-devices-incorporating-non-viable-tissues) — the adjacent special rule for human or animal tissue-derived components. - [MDR Article 51 and the Classification Framework](/blog/mdr-article-51-classification-framework) — the framework article that makes Annex VIII binding. - [Intended Purpose Under MDR Article 2(12)](/blog/intended-purpose-mdr-article-2-12) — the definition layer that drives every Rule 13 boundary decision. ## Sources 1. Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical devices, Article 1(8) (devices incorporating an ancillary medicinal substance), Article 1(9) (single integral product where the medicinal action is principal), Article 2(12) (intended purpose), Article 51 (classification), and Annex VIII Rule 13 (devices incorporating, as an integral part, a substance which if used separately would be a medicinal product and whose action is ancillary to that of the device). Official Journal L 117, 5.5.2017. 2. MDCG 2021-24 — Guidance on classification of medical devices, October 2021 (Medical Device Coordination Group). 3. Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use, as amended — the definitional anchor for "medicinal product" used by Rule 13. --- *This post is part of the Device Classification & Conformity Assessment series in the Subtract to Ship: MDR blog. Authored by Felix Lenhard and Tibor Zechmeister. The Rule 13 walkthrough above is the orientation layer — the classification of a specific combination device must always be made against the full text of Annex VIII Rule 13 and Article 1(8)–(9), cross-checked with MDCG 2021-24, and documented with a specific characterisation of the medicinal substance, its mode of action, and its ancillary or principal status. When a combination product sits close to the Article 1(9) boundary, a classification working session with a sparring partner who has walked this boundary across fifty-plus certifications is usually the fastest path to a defensible answer.* --- *This post is part of the [Device Classification & Conformity](https://zechmeister-solutions.com/en/blog/category/classification) cluster in the [Subtract to Ship: MDR Blog](https://zechmeister-solutions.com/en/blog). For EU MDR certification consulting, see [zechmeister-solutions.com](https://zechmeister-solutions.com).*