5 Fatal Pitfalls in Drug-Device Submissions (And How to Avoid Them)

The clock-stop notification lands in her inbox at 9:47 AM.
Three months into what was supposed to be a straightforward MAA.

What the regulation doesn't tell you:
A single phrase buried in page 47 of their Notified Body opinion—"partial compliance with relevant GSPRs"—triggered everything.

That phrase—just two words—triggered a chain reaction.
Now her team faces months of rework, a new NB opinion, and a launch delay that will cost millions.

She's not alone.
Across the EU, drug-device combination submissions fail for the same handful of preventable reasons.
Here's how to avoid walking into these known traps.

The Five Fatal Mistakes in DDC Submissions

After analysing the EMA's Q&A on MDR/IVDR Implementation and the Draft Guideline on Quality Requirements for Drug-Device Combinations, a clear pattern emerges. Teams aren't failing because they don't understand the regulations—they're failing because the regulations contain hidden tripwires that only become visible after you've stepped on them.

Let's examine each pitfall in detail—and more importantly, how to prevent it.

Pitfall 1: Getting PMOA Wrong

Why this matters: Incorrect Principal Mode of Action determination doesn't just delay your submission—it puts you on an entirely wrong regulatory pathway.

The PMOA determination is the first critical decision point. Get it wrong, and you'll apply inappropriate regulatory requirements for months before discovering the error.

According to EMA guidance (Q1.1-1.3), the qualification and classification of borderline products are determined by National Competent Authorities for medicinal products and/or medical devices. Manufacturers are advised to consult these authorities—but this advisory language often gets treated as optional when it should be treated as essential.

For deeper guidance on PMOA determination, see our comprehensive guide on Principal Mode of Action Assessment.

Pitfall 2: Integral vs Non-Integral Confusion

Why this matters: The integral vs non-integral distinction determines whether you follow the medicinal product framework or the medical device framework—and they are fundamentally different pathways.

The MDR defines integral drug-device combinations (iDDCs) under Articles 1(8) and 1(9). Understanding which article applies to your product is crucial:

Conversely, if a device incorporates a medicinal substance where the action is ancillary to the device, the product is regulated as a medical device—requiring a scientific opinion on the quality and safety of the ancillary substance from an NCA or EMA.

For the complete framework on DDC classification, see our guide on Drug-Device Combinations under EU MDR.

Pitfall 3: The Partial Compliance Trap

Why this matters: This is the single biggest killer of DDC submissions. A Notified Body opinion concluding on partial GSPR compliance triggers automatic rejection.

The EMA's Q&A document (Q2.4, Rev. May 2025) states this explicitly and unambiguously:

Read that again: cannot be accepted. Not "may require additional justification." Not "will be evaluated on a case-by-case basis." It cannot be accepted.

The reason is structural. CHMP and NCAs simply don't have the authority to assess GSPR compliance themselves. That's the Notified Body's role. If the NBOp says "partial compliance," the evaluation cannot proceed—it will result in an evaluation issue requiring an updated opinion confirming full compliance.

This connects directly to the Article 117 Consultation Procedure—where partial compliance statements are equally fatal.

Pitfall 4: Missing Documentation at Submission

Why this matters: Missing documents at initial MAA submission cause clock stops—extending your timeline by weeks or months for something entirely preventable.

EMA guidance (Q2.3, Rev. May 2024) is clear on this point. EMA and NCAs strongly recommend submitting the Declaration of Conformity, EU Certificate, or Notified Body Opinion at the time of initial MAA submission.

The word "strongly recommend" is regulatory speak for "you really should do this or you'll regret it." Missing documents don't cause rejection—but they cause clock stops. And clock stops mean delays.

Pitfall 5: Scope Mismatch and Lifecycle Gaps

Why this matters: Your NBOp scope must precisely match the device's intended purpose for that specific MAA. Any mismatch = evaluation issue.

According to EMA guidance (Q2.1-2.2), the Notified Body must be designated for the device type in question, and the scope of their opinion must correspond exactly to the intended purpose stated in the MAA.

This sounds obvious—but in practice, scope creep happens. The device evolves during development. The intended use expands. Marketing requests new indications. And suddenly your NBOp covers a narrower scope than your MAA claims.

Post-Authorisation Lifecycle Management

The pitfalls don't end at authorisation. EMA guidance (Q4.1-4.2) is clear: for Notified Body opinions issued without a contractual arrangement between the NB and MAH to cover device changes, the MAH is responsible for determining when a new or updated NB opinion is needed.

Changes to the device—or its intended use—require the MAH to assess whether they impact GSPR compliance. If they do, an updated NBOp is required. Failure to manage this creates post-market compliance risk.

The Pre-Submission Verification Checklist

If you can verify these items before submission, you eliminate the majority of clock-stop triggers:

This checklist emerged from mapping every pitfall back to a specific pre-submission checkpoint. If you can catch these issues before submission, you eliminate the clock stops entirely.