Is This Combination an MDR Device or a Medicinal Product?

Mark This Product Under Article 1(8) or 1(9), Not Under Article 117

When developing a healthcare product that integrates both physical hardware and a pharmacological constituent, regulatory affairs teams face a critical initial decision under the European Union regulatory framework: is this product governed by Regulation (EU) 2017/745 on medical devices (MDR), or is it governed by medicinal product legislation under Directive 2001/83/EC or Regulation (EC) No 726/2004? Answering it correctly decides whether this product is still CE-marked under the MDR, including the Rule 14 class III medicines consultation when that row applies, or is authorised as a medicinal product, with Annex I GSPRs still applying to the device part.

A frequent and costly error across combination-product development programs is treating European combination products as a uniform regulatory category or jumping prematurely into an Article 117 notified-body-opinion dossier. For the overview, see Combination Products (Drug-Device): Complete FDA & EU MDR Regulatory Guide (2026). Unlike the United States Food and Drug Administration (FDA) framework under 21 CFR Part 3—which establishes a unified combination product rubric and assigns jurisdiction based on primary mode of action—the European Union provides no standalone combination product regulation. Instead, European law separates combination healthcare products into four distinct statutory scenarios anchored strictly within MDR Article 1(8) and Article 1(9).

To establish the correct regulatory classification, manufacturers must evaluate their product against two sequential structural questions:

1. Physical Integration Test: Does the device incorporate a substance as an integral part when placed on the market or put into service (Article 1(8)), or is the device intended to administer a medicinal product (Article 1(9))?

2. Therapeutic Action and Integration Rule: If incorporated, is the substance's therapeutic action ancillary to the device (Article 1(8) first subparagraph, MDR Class III Rule 14), or principal (Article 1(8) second subparagraph, medicinal product)? If intended for administration, is the device placed on the market separately (Article 1(9) first subparagraph, MDR device), or does it form a single integral, non-reusable product intended exclusively for that specific combination (Article 1(9) second subparagraph, medicinal product)?

The matrix below delineates these four canonical regulatory scenarios, establishing their legal bases, governing frameworks, conformity assessment pathways, and statutory review clocks.

Is a Substance Incorporated, or Is This an Administration Device?

The foundational threshold test in European combination regulation distinguishes between incorporation as an integral part under Article 1(8) and a device intended for administration of a medicinal product under Article 1(9). Regulatory teams must analyze this distinction at the exact point of placing the product on the market or putting it into service.

The Substance Qualification Test

Both Article 1(8) and Article 1(9) rely on the foundational definition of a medicinal product established in point 2 of Article 1 of Directive 2001/83/EC:

• Presentation criterion: Any substance or combination of substances presented as having properties for treating or preventing disease in human beings.

• Function criterion: Any substance or combination of substances which may be used in or administered to human beings either with a view to restoring, correcting, or modifying physiological functions by exerting a pharmacological, immunological, or metabolic action, or to making a medical diagnosis.

In addition, Article 1(8) explicitly incorporates point 10 of Article 1 of Directive 2001/83/EC, which covers medicinal products derived from human blood or human plasma—specifically industrially prepared blood constituents such as human albumin, coagulation factors, and immunoglobulins. If the constituent does not satisfy either point 2 or point 10, Article 1(8) does not apply.

Demarcating Incorporation from Administration

Under Article 1(8), the substance must be incorporated into the device as an integral component before commercial release. The Medical Device Coordination Group guidance MDCG 2022-5 Rev. 1 (Guidance on borderline between medical devices and medicinal products under Regulation (EU) 2017/745, endorsed in October 2024) establishes that an integral product exists if and only if the device and the substance form a single entity when placed on the market or put into service. If the combination takes place only at the time of clinical administration (such as bedside drug loading, compounding, or reconstituting a lyophilized drug with diluent), the product is not an integral device.

Conversely, Article 1(9) governs devices intended to administer a medicinal product. Administering means physically introducing, metering, guiding, or delivering an external drug into the human body. Common administration devices include syringes, needles, infusion sets, drug delivery pumps, nebulisers, and metered-dose inhalers.

If Incorporated, Is the Medicinal Action Ancillary or Principal?

Once incorporation as an integral part is established under Article 1(8), the regulatory classification pivots entirely on whether the therapeutic action of the incorporated substance is ancillary or principal relative to the mechanical or physical performance of the device.

Ancillary Action: Article 1(8) First Subparagraph

The action of an incorporated substance is ancillary when it supports, enhances, or facilitates the primary intended clinical purpose of the medical device, without that pharmacological, immunological, or metabolic action being the principal means by which the medical effect is achieved. The medical device must achieve its principal intended action by physical, mechanical, optical, or structural means.

MDCG 2022-5 Rev. 1 lists illustrative examples of devices incorporating an ancillary medicinal substance. The lists are not a census of identity packets:

• Drug-Eluting Stents (DES): The metallic scaffold physically maintains luminal patency of the coronary or peripheral artery (principal mechanical action). The antiproliferative substance (such as sirolimus or paclitaxel) acts ancillarily to inhibit vascular smooth muscle cell proliferation and prevent in-stent restenosis.

• Catheters with Antimicrobial or Antithrombotic Coatings: The catheter provides vascular access, fluid infusion, or blood drainage (principal physical action). The coated heparin or antimicrobial agent exerts an ancillary effect to prevent catheter-related thrombosis or biofilm colonisation.

• Antibiotic-Loaded Bone Cements: The polymethylmethacrylate (PMMA) matrix provides structural, mechanical fixation for joint prostheses (principal action). The incorporated gentamicin or tobramycin provides ancillary local antimicrobial prophylaxis.

• Dermal Fillers Containing Local Anaesthetics: Cross-linked hyaluronic acid gel physically restores tissue volume or corrects contour defects (principal physical action). The incorporated lidocaine provides ancillary local analgesia during injection.

• Wound Dressings Impregnated with Antimicrobial Agents: The dressing absorbs exudate and provides a physical barrier over the wound bed. The silver or chlorhexidine prevents local microbial contamination as an ancillary action.

Whenever the incorporated substance's action is determined to be ancillary, Article 1(8) first subparagraph dictates that the device shall be assessed and authorised in accordance with the MDR. This triggers classification under EU MDR Classification Rules (Annex VIII): Complete Guide to All 22 Rules with 2026 Updates as a Class III device.

Principal Action: Article 1(8) Second Subparagraph

If the action of the incorporated substance is principal rather than ancillary, the entire integral product falls under the second subparagraph of Article 1(8) and is governed by Directive 2001/83/EC or Regulation (EC) No 726/2004 as a medicinal product.

In such cases, the product requires a full Marketing Authorisation Application (MAA). However, the MDR does not step aside entirely: Article 1(8) second subparagraph specifies that the relevant General Safety and Performance Requirements (GSPRs) set out in EU MDR GSPR Annex I: General Safety and Performance Requirements Guide apply as far as the safety and performance of the device part are concerned.

A classic example identified in the EMA implementation guidance is an ingestible sensor incorporated into a pharmaceutical tablet. The primary intended effect is the pharmacological or metabolic treatment provided by the active pharmaceutical ingredient. The embedded micro-sensor records ingestion timing and transmits telemetry. Because the primary therapeutic purpose is pharmaceutical, the combination is evaluated under medicinal product law, with MDR Annex I GSPRs applied to verify the physical integrity, biocompatibility, and electrical safety of the sensor.

If This Is Still a Rule 14 Device, Consultation Is the Next File, Not a CE Shortcut

Once an integral combination is classified as an Article 1(8) first subparagraph device, it enters the highest regulatory scrutiny tier in the medical device system. Under MDR Annex VIII Rule 14, all devices incorporating as an integral part a substance which, if used separately, can be considered a medicinal product with ancillary action, are classified as Class III. There are no lower-risk classifications under Rule 14.

The Article 52(9) and Annex IX Section 5.2 Consultation Procedure

Conformity assessment cannot proceed solely within the notified body. MDR Article 52(9) mandates that the notified body must satisfy the statutory consultation procedure defined in Annex IX Section 5.2 (or Annex X Section 6 for type-examination):

1. Usefulness Verification: Before seeking the opinion, the notified body must have verified the usefulness of the substance as part of the device, taking account of the intended purpose of the device. The manufacturer supplies the usefulness data used for that verification.

2. Authority Selection: The notified body seeks a scientific opinion from one of the competent authorities designated under Directive 2001/83/EC or from EMA. Annex IX Section 5.2 requires the EMA opinion where the device incorporates a human blood or plasma derivative or a substance which, if used separately, may be considered a medicinal product falling exclusively within the scope of the Annex to Regulation (EC) No 726/2004.

3. The 210-Day Statutory Review Clock: The consulted medicines authority takes into account the manufacturing process and the notified body's usefulness data, and evaluates the quality and safety of the substance including the benefit or risk of incorporating it into the device. It shall provide its opinion within 210 days of receipt of all the necessary documentation.

4. The Binding Negative Opinion Bar: Under Annex IX Section 5.2, the notified body shall not deliver the EU technical documentation assessment certificate if the scientific opinion is unfavourable. While termed an 'opinion', an adverse finding from the medicines authority legally bars the notified body from issuing CE certification.

5. Lifecycle Changes (60-Day Clock): Where the ancillary substance incorporated in the device is modified, in particular related to its manufacturing process, the notified body consults the medicines authority again. That authority has 60 days to issue a supplemental opinion. The notified body cannot issue a certificate supplement if this opinion is unfavourable.

Technical File Requirements: GSPR 12.1 and Annex II Section 6.2(a)

To support the Annex IX Section 5.2 consultation, the manufacturer's technical documentation must align with Annex I GSPR 12.1, which mandates that the quality, safety, and usefulness of the incorporated substance be verified by analogy with the methods specified in Annex I to Directive 2001/83/EC.

Furthermore, under Annex II Section 6.2(a), the documentation shall identify the source of the 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. Those are the statutory file contents of identity after the Rule 14 row is marked. Typical consultation files often also include source-file cross-references, matrix stability, and release data; those extras are file practice, not additional Article 1(8) identity tests.

If This Is an Administration Device, Are All Three Single-Integral Conditions True?

When a device is intended to administer a medicinal product under Article 1(9), manufacturers must determine whether the device remains regulated under the MDR or shifts entirely into the medicinal product framework. This demarcation hinges upon three strictly cumulative conditions laid down in Article 1(9) second subparagraph.

The Three Cumulative Placing-on-the-Market Conditions

Under Article 1(9) second subparagraph, an administration device is governed by Directive 2001/83/EC or Regulation (EC) No 726/2004 if and only if all three of the following conditions are simultaneously met when the product is placed on the market:

1. Single Integral Product: The administration device and the medicinal product form a single unified product when placed on the market. The drug constituent is pre-loaded, pre-filled, or mechanically integrated into the device during manufacturing.

2. Exclusive Combination Use: The single integral product is intended exclusively for use in the given combination. The device constituent cannot be utilized with alternate drug formulations or independent medicinal products.

3. Non-Reusable Architecture: The product is not reusable. Once the pre-filled medicinal dose is discharged, the product cannot be re-loaded, refilled, re-sterilised, or used for another administration cycle.

The matrix below illustrates how common drug delivery platforms map across these three cumulative criteria.

For comprehensive analysis of autoinjector and prefilled delivery device design controls, review our technical guide on Pre-Filled Syringes and Auto-Injectors: Combination Product Regulatory Strategy.

If the Product Is Already a Medicinal Product, Article 117 Is Later Dossier Evidence

When a healthcare product satisfies the criteria for either Article 1(8) second subparagraph (integral product with principal medicinal action) or Article 1(9) second subparagraph (single integral, non-reusable administration product), the entire product is placed on the market as a medicinal product. At this juncture—and only at this juncture—MDR Article 117 enters the regulatory pathway.

The Statutory Mechanism of Article 117

MDR Article 117 amends Annex I to Directive 2001/83/EC by replacing point 12 of Section 3.2. Under this revised statutory requirement, the Marketing Authorisation Application (MAA) dossier submitted to the medicines authority must include evidence verifying that the device constituent conforms to the relevant General Safety and Performance Requirements (GSPRs) of MDR Annex I.

Article 117 then chooses among available device-part GSPR evidence. It does not reopen identity:

1. Tier 1: Pre-Existing CE Marking: Where available, the marketing-authorisation dossier includes the results of the assessment of conformity of the device part with the relevant Annex I GSPRs, contained in the manufacturer's EU declaration of conformity or the relevant certificate issued by a notified body allowing the manufacturer to affix a CE marking.

2. Tier 2: Notified Body Opinion (NBOp): If those results are not in the dossier and, if the device were used separately, notified-body involvement would be required, the authority shall require an opinion on the conformity of the device part with the relevant GSPRs from a notified body designated for that type of device.

3. Tier 3: Manufacturer GSPR Declaration: EMA's implementation Q&A adds that, when a declaration of conformity is not available for class I devices excluding sterile (Is) and measuring (Im) devices, a marketing-authorisation holder's statement of compliance with the relevant Annex I GSPRs can be acceptable. That statement is later dossier evidence on an already second-subparagraph product. It is not a Rule 14 consultation and does not CE-mark the device part for separate sale.

EMA Quality Documentation Guideline (EMA/CHMP/QWP/BWP/259165/2019)

In effect since 1 January 2022, the EMA Guideline on quality documentation for medicinal products when used with a medical device (EMA/CHMP/QWP/BWP/259165/2019) is Module 3 documentation after the product is already on a second-subparagraph medicinal-product path. It uses 'integral' for those two second subparagraphs. It is not this identity worksheet, and it is not permission to skip the three cumulative Article 1(9) second-subparagraph conditions. A notified-body GSPR opinion, where required under Article 117, does not CE-mark the device part for separate sale.

Labeled Boundaries: Article 1(10), Rule 21, UDI, US PMOA, and the 2025 Proposal

To maintain regulatory compliance, manufacturers must recognize five specific adjacent regulatory regimes and prevent them from distorting the Article 1(8) and Article 1(9) classification process.

Detailed Boundary Distinctions

• Article 1(10) Human Tissue Derivative Boundary: Devices incorporating non-viable tissues or cells of human origin or their derivatives (such as human demineralized bone matrix) are governed by MDR Article 1(10) and Article 52(10). They must satisfy Directive 2004/23/EC donation, procurement, and testing standards, and their consultation follows Annex IX Section 5.3 with human-tissues competent authorities, not Annex IX Section 5.2.

• Annex VIII Rule 21 Substance-Based Devices Boundary: Rule 21 governs devices composed of substances introduced via body orifices or applied to the skin that are absorbed or locally dispersed (such as oral antacid suspensions, saline nasal sprays, or simethicone drops). In Rule 21 products, the substance itself constitutes the device mechanism. For systemically absorbed Rule 21 devices, Annex IX Section 5.4 requires a medicines consultation with a 150-day statutory clock, distinctly separate from the 210-day Rule 14 clock.

• MDCG 2019-2 UDI Marking Boundary: Under MDCG 2019-2, UDI assignment and EUDAMED registration apply to the device constituent only if the finished product is assessed and authorised under the MDR (Article 1(8) first subparagraph and Article 1(9) first subparagraph). If the product is governed as a medicinal product under a second subparagraph, UDI obligations do not apply to the device part. For distributor and EUDAMED duties, see our guide on MDCG 2026-5 UDI Assignment: Manufacturer vs Distributor Decision Tree.

• US 21 CFR Part 3 Primary Mode of Action Boundary: In the United States, 21 CFR 3.2(m) assigns lead center jurisdiction (CDER, CBER, or CDRH) based on the single primary mode of action (PMOA). A product designated as a drug-led combination in the US does not automatically become a medicinal product in the EU. For example, a drug-eluting stent is a CDRH-led device combination in the US and an MDR Class III device under Rule 14 in Europe.

• COM(2025) 1023 Legislative Reform Status: On 16 December 2025, the European Commission published COM(2025) 1023 final, a proposal to amend the MDR and IVDR to simplify and reduce burden. It is a proposal. It is not in force and does not rewrite Article 1(8), Article 1(9), or Annex IX Section 5.2 identity.

Fictional Identity Packet: Mark the Four Rows

To synthesize this regulatory methodology, the diagram below maps the complete decision logic from physical product presentation through final statutory routing.

flowchart TD
    Start["Product Integrating Device & Substance"] --> Q1{"Incorporated as Integral Part at Placing on Market (Art. 1(8))\nor Intended for Drug Administration (Art. 1(9))?"}

    Q1 -- "Incorporated as Integral Part" --> Q2{"Is the substance action Ancillary\nor Principal to device?"}
    Q1 -- "Intended to Administer Medicine" --> Q3{"Are ALL 3 Conditions Met at Placing on Market?\n1. Single integral unit\n2. Exclusive combination\n3. Non-reusable"}

    Q2 -- "Ancillary Action" --> R1["Scenario 1: MDR Article 1(8) 1st Subparagraph\n• Governed by MDR as Medical Device\n• Annex VIII Rule 14 (Class III)\n• Annex IX Sec 5.2 Medicines Consultation (210 Days)\n• GSPR 12.1 & Annex II 6.2(a) Dossier\n• Binding Negative Opinion Bar"]
    Q2 -- "Principal Action" --> R2["Scenario 2: MDR Article 1(8) 2nd Subparagraph\n• Governed by Directive 2001/83/EC / Reg 726/2004\n• Marketing Authorisation Application (MAA)\n• MDR Annex I GSPRs apply to device part\n• Article 117 Dossier Evidence Required\n• Not a Rule 14 Device"]

    Q3 -- "No (Any Condition Fails)" --> R3["Scenario 3: MDR Article 1(9) 1st Subparagraph\n• Governed by MDR as Medical Device\n• Reusable Injectors, Pumps, Co-packaged Empty Syringes\n• Medicinal Product Governed Separately\n• Standard MDR Conformity Clocks"]
    Q3 -- "Yes (All 3 Cumulative)" --> R4["Scenario 4: MDR Article 1(9) 2nd Subparagraph\n• Governed by Directive 2001/83/EC / Reg 726/2004\n• Prefilled Syringes, Single-Use Autoinjectors\n• Marketing Authorisation Application (MAA)\n• MDR Annex I GSPRs apply to device part\n• Article 117 Dossier Evidence Required"]

Fictional Specimen Review: Heparin-Coated Femoral Cannula (Model HC-CAN-500-FICTITIOUS)

Below is a fully articulated, labeled fictional identity packet demonstrating how a manufacturer documents this four-scenario evaluation for an intravascular access device.

Summary of Manufacturer Implementation Priorities

When navigating combination product development under European law, regulatory leaders should enforce four cardinal operating rules across cross-functional engineering, clinical, and regulatory teams:

• 1. Never confuse incorporation with administration: Co-packaging an empty delivery device with a vial does not create an Article 1(8) integral combination. Reusable administration devices stay under MDR Article 1(9) first subparagraph.

• 2. Respect the Rule 14 consultation timeline: If your product falls under Article 1(8) first subparagraph, the consulted authority shall provide its Annex IX Section 5.2 opinion within 210 days of receipt of all the necessary documentation. The notified body shall not deliver the certificate if that opinion is unfavourable.

• 3. Reserve Article 117 for medicinal product pathways: Do not request a Notified Body Opinion for a Rule 14 device or a separately placed administration device. Article 117 applies exclusively to products governed as medicinal products under the second subparagraphs.

• 4. Exclude unenacted reforms and foreign frameworks: Base current technical documentation on authentic MDR text, endorsed MDCG guidance, and EMA procedural instructions. Legislative proposals such as COM(2025) 1023 and US FDA PMOA designations must not dictate your European conformity assessment filings.

Related reading, not this identity

This worksheet marks one product under Article 1(8) or 1(9). It does not recast the published combination encyclopedia, product-class strategy pages, Annex VIII encyclopedia, notified-body process, Article 22 packs, US Pre-RFD, 21 CFR Part 4 or 4.4 streamlining, UDI assignment, or yesterday's 807.81 change identity.

• Combination Products (Drug-Device): Complete FDA & EU MDR Regulatory Guide (2026)

• Pre-Filled Syringes and Auto-Injectors: Combination Product Regulatory Strategy

• GLP-1 Drug Delivery Devices: Combination Product Pathways 2026

• Connected Autoinjectors and Smart Pens: Drug Delivery Pathways in 2026

• EU MDR Classification Rules (Annex VIII): Complete Guide to All 22 Rules with 2026 Updates

• EU MDR Notified Bodies and Conformity Assessment Guide

• EU MDR GSPR Annex I: General Safety and Performance Requirements Guide

• EU MDR Article 22: Systems and Procedure Packs — Producer Obligations Guide

• How to Get FDA to Tell You Which Center Will Regulate Your Product: The Pre-RFD Playbook

• Which Combination-Product 4.4 Path Still Applies After QMSR?

• 21 CFR Part 4: Combination Product cGMP Quality Systems for Drug-Device Manufacturers

• MDCG 2026-5 UDI Assignment: Manufacturer vs Distributor Decision Tree

• MDCG 2026 Updates: Classification, EMDN Codes, and Borderline Guidance

• Borderline Product Classification Across FDA, EU MDR, ANVISA, and COFEPRIS

• FDA 2026 Container Closure Draft: Device-Constituent CCS, 510(k), & October Clock

• Does This Change Need a New 510(k), or Does a PCCP Cover It?