Combination products such as auto-injectors, inhalers, and pre-filled syringes present a usability challenge that neither the medicinal product world nor the device world fully owns. EN 62366-1:2015+A1:2020 handles the device side. The medicinal product is governed under its own legal framework. Between them sits the user, who performs a single sequence of steps that crosses both domains. The use specification must model the entire sequence. MDR Annex I §12.1 and, depending on the integration, Annex VIII Rule 14 or Article 1(8) and 1(9) determine how the device is regulated, and EMA coordination may be required when the medicinal product is in scope of centralised authorisation.

By Tibor Zechmeister and Felix Lenhard.

TL;DR

  • MDR Article 1(8) and Article 1(9) set the legal boundary between device legislation and medicinal product legislation for combination products.
  • MDR Annex VIII Rule 14 classifies devices that incorporate, as an integral part, a substance which, if used separately, would be considered a medicinal product, and whose action is ancillary to that of the device.
  • MDR Annex I §12.1 covers devices incorporating a medicinal substance, setting safety and performance expectations for the combined article.
  • EN 62366-1:2015+A1:2020 applies to the device side regardless of how the combination is regulated. The usability engineering file must model the full use sequence the user performs, not only the device-side steps.
  • For single-integral products regulated as medicinal products, the notified body issues an opinion on the device part under Article 117 amendments to the medicinal product legislation. Consultation with the competent authority or EMA follows procedures outside MDR itself.
  • Summative evaluation must use the real drug product or an equivalent placebo that replicates the relevant human factors. A dry run with an empty device is not a summative evaluation.

Why this matters

Tibor has reviewed a use specification for an auto-injector that stopped at "press the device firmly against the thigh and hold for ten seconds". The actual user sequence started several steps earlier. The user had to retrieve the device from refrigerated storage, allow it to reach room temperature, check the label, check the expiry, inspect the drug through the viewing window, remove the cap, and only then reach the press-and-hold step. Each earlier step carried its own use error potential. An audit finding was unavoidable.

Felix has watched startups pick the wrong anchor. A team building a novel inhaler assumed the medicinal product colleagues would own usability because the active substance drove the therapy. The medicinal product side assumed the device side would own it because the user interaction was mechanical. Nobody owned it. When summative evaluation was finally scheduled, the use specification had no agreed owner and no agreed scope.

Combination products live in a seam. The seam has legal consequences under MDR Article 1(8) and Article 1(9). It has classification consequences under Annex VIII Rule 14. It has safety consequences under Annex I §12.1. And it has usability consequences that neither side can delegate because the user does not know where the device ends and the drug begins.

What MDR actually says

Article 1(8) covers the situation where a device is intended to administer a medicinal product. The device part is regulated under MDR. The medicinal product part is regulated under Directive 2001/83/EC or Regulation (EC) 726/2004, depending on the authorisation route.

Article 1(9) covers devices that incorporate, as an integral part, a medicinal substance, and where the device and the substance form a single integral product intended exclusively for use in the given combination and not reusable. Such products are regulated under the medicinal product legislation, with a notified body opinion on the device part.

Annex VIII Rule 14 classifies devices that incorporate, 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, as Class III. Rule 14 is where drug-eluting stents, antibiotic-coated catheters, and similar devices are classified.

Annex I GSPR §12.1 applies to devices incorporating a medicinal substance. It requires that the quality, safety, and usefulness of the substance are verified by analogy with methods specified in the medicinal product legislation. The notified body must seek a scientific opinion from a national competent authority or, where applicable, the European Medicines Agency.

Annex I GSPR §5 and §22, covered in the earlier posts on usability, still apply. They are the foundation on which EN 62366-1:2015+A1:2020 builds the usability engineering process for the device.

The standard itself, EN 62366-1:2015+A1:2020, is agnostic to the regulatory framework the product sits under. Its process applies to the device part of any combination. What the standard demands is a use specification that covers the entire interaction the user actually performs. Clause 5.1 is clear: the use specification includes the intended medical indication, patient populations, intended users, conditions of use, and principles of operation. For a combination product, the conditions of use include handling the drug.

A worked example

A startup is developing a pre-filled auto-injector delivering a biologic for a chronic autoimmune condition. The device is new. The drug is partnered from a pharmaceutical company with an existing marketing authorisation. The combination, drug plus auto-injector, is intended for home self-administration by adult patients after clinician prescription.

The first legal question is the regulatory path. Under MDR Article 1(9), if the device and drug form a single integral product intended exclusively for use in this combination, the combined product is regulated as a medicinal product under Directive 2001/83/EC or Regulation (EC) 726/2004. The notified body issues an opinion on the device part. Under MDR Article 1(8), if the device is intended to administer a medicinal product but is not a single integral product, the device is regulated under MDR and the drug under the medicinal product legislation separately.

The worked example assumes a single integral product regulated as a medicinal product, with a notified body opinion on the device part. The usability obligations on the device part are unchanged.

The use specification, clause 5.1 of EN 62366-1:2015+A1:2020, models the full user sequence:

  1. Remove the device from refrigerated storage.
  2. Allow it to reach room temperature for a defined period.
  3. Check the label, batch, and expiry.
  4. Inspect the drug through the viewing window for particulates and discolouration.
  5. Select the injection site per the IFU guidance.
  6. Clean the injection site.
  7. Remove the cap.
  8. Place the device against the skin.
  9. Activate the injection.
  10. Hold for the prescribed dwell time.
  11. Remove and inspect the device to confirm completion.
  12. Dispose of the used device safely.

Each step is a task. Each task has potential use errors. Steps 1 to 4 involve the drug. Steps 5 to 12 involve the device. The user does not experience a boundary. Neither can the usability file.

The user interface specification lists every element that supports the sequence. Device markings, cap design, viewing window, activation button, audible confirmation, visual confirmation, IFU, quick-reference card, and the pharmacy label affixed by the dispensing pharmacist. All of it is part of the user interface under EN 62366-1.

Known use problems analysis draws on published post-market data for auto-injectors in the same therapeutic area, vigilance data from the medicinal product partner, and existing literature on biologic self-administration errors.

Hazard-related use scenarios include: injecting a drug that has not reached room temperature, injecting into an inappropriate site, releasing the device before dwell time ends, reusing a device, and mixing up a legacy device from a previous batch.

Summative evaluation is conducted with representative adult patients matching the intended indication. The devices used in the evaluation contain either the real drug or a placebo equivalent that replicates the relevant sensory cues. An empty plastic shell does not meet this requirement because temperature, weight, resistance, and audible feedback may differ and use error rates will not be representative.

The notified body opinion on the device part, required under the medicinal product legislation when the combination is a single integral product, will include the usability engineering file as evidence. The medicinal product dossier will cross-reference it.

For the coordination with the European Medicines Agency, procedures for centralised authorisation of the medicinal product run under the medicinal product legislation, not MDR. The device-side evidence, including the usability file, flows to EMA through the medicinal product applicant. The notified body issues its opinion on the device part according to the procedures established for such opinions. The exact procedural details for centralised authorisations involving an integral device part are managed jointly by EMA and the notified body and evolve with guidance documents.

The Subtract to Ship playbook

Step 1. Settle the regulatory framing first. Is this Article 1(8), Article 1(9), or Annex VIII Rule 14? The answer determines who issues the authorisation, who issues the notified body opinion, and how the dossiers cross-reference each other. Do not start the usability file until this is agreed with regulatory counsel.

Step 2. Make one owner for the combined use specification. The drug side and the device side each have their own workflows. The use specification must not. Nominate one owner, usually on the device-side regulatory team, who draws both sides into one document.

Step 3. Model the full sequence. Storage, preparation, inspection, administration, disposal. No step is out of scope because "the drug side owns it". Under EN 62366-1:2015+A1:2020 the device manufacturer is responsible for the use error outcomes that touch the device part, and the user does not compartmentalise.

Step 4. Use real or equivalent placebo in summative. The sensory cues of weight, temperature, activation force, and audible signals must match. Clause 5.9 of EN 62366-1 requires summative evaluation under realistic conditions.

Step 5. Keep risk management linked to both dossiers. The risk file under EN ISO 14971:2019+A11:2021 logs hazards that arise from the drug side, the device side, and the interaction. The same file feeds both the notified body opinion and the medicinal product dossier.

Step 6. Plan the notified body opinion on the device part early. For Article 1(9) single integral products, this opinion is a critical deliverable. Book the notified body slot when the device design is stable enough to support a meaningful review, not at the last moment.

Step 7. Align with the medicinal product partner on vigilance and PMS. Post-market data from self-administration errors will flow to both sides. Agree how it is shared and who updates which file.

Step 8. Do not underestimate the IFU. In a combination product the IFU is often the primary control for correct preparation and administration. It must be translated, tested, and treated as part of the user interface under EN 62366-1.

Reality Check

  1. Do you know whether your combination product is regulated under MDR Article 1(8), Article 1(9), or classified under Annex VIII Rule 14, and is that decision documented?
  2. Does your use specification model the entire user sequence, from storage to disposal, or does it start at device activation?
  3. Who owns the use specification when the drug side and device side are separate organisations?
  4. Is the usability engineering file consistent with the risk management file on the drug-related use errors, or do the two diverge?
  5. Is summative evaluation planned with real drug or a sensory-equivalent placebo?
  6. Has the notified body slot for the opinion on the device part been booked, and is the device design stable enough to support the review?
  7. Does the IFU cover preparation steps as carefully as administration steps, and has it been translated into every target-language market?
  8. Is the post-market surveillance plan aligned with the medicinal product partner's pharmacovigilance workflow?

Frequently Asked Questions

Is the auto-injector regulated as a device or as a medicinal product? It depends. Under MDR Article 1(9), a single integral combination intended exclusively for use in that combination and not reusable is regulated as a medicinal product, with a notified body opinion on the device part. Under Article 1(8), a device intended to administer a medicinal product that is not a single integral combination is regulated under MDR, with the drug under medicinal product legislation. Confirm with regulatory counsel before starting the file.

Does EN 62366-1 apply if our product is regulated under medicinal product legislation? Yes. The notified body opinion on the device part of a single integral combination evaluates the device against device requirements, including usability. EN 62366-1:2015+A1:2020 is the reference process. The medicinal product regulatory path does not exempt the device part from usability engineering.

What about drug-eluting stents or antibiotic-coated catheters? Those fall under MDR Annex VIII Rule 14 as devices incorporating, as an integral part, a substance which if used separately would be a medicinal product, and whose action is ancillary. They are classified as Class III devices under MDR. MDR Annex I §12.1 requires the notified body to consult a competent authority or EMA on the quality and safety of the ancillary medicinal substance. Usability engineering for the device still follows EN 62366-1.

Can we run summative evaluation with an empty device? No. Clause 5.9 of EN 62366-1 requires realistic conditions. Weight, activation feel, audible and visual cues, and temperature affect user behaviour. An empty shell is a training aid, not a summative test article.

How does EMA fit in? For centralised medicinal product authorisations, EMA coordinates the authorisation procedure. The device part opinion is issued by the notified body according to procedures that link the notified body opinion to the medicinal product dossier. The exact procedural details evolve with joint EMA and notified body guidance.

Who owns pharmacovigilance for use errors? Use errors that affect dosing or drug administration feed both device vigilance under MDR Articles 87 to 92 and pharmacovigilance under the medicinal product legislation. Agree the flow with the medicinal product partner in writing, document it in the PMS plan, and make sure both files are updated when a signal is detected.

Sources

  1. Regulation (EU) 2017/745 on medical devices. Article 1(8), Article 1(9), Annex I §12.1, Annex VIII Rule 14.
  2. EN 62366-1:2015+A1:2020, Medical devices – Application of usability engineering to medical devices.
  3. EN ISO 14971:2019+A11:2021, Medical devices – Application of risk management to medical devices.
  4. EN ISO 13485:2016+A11:2021, Medical devices – Quality management systems, clause 7.3.
  5. Directive 2001/83/EC on the Community code relating to medicinal products for human use. Regulation (EC) No 726/2004 on centralised authorisation procedures.