When Your Device Contains a Drug: The Ancillary Substance Trap

Written by HATEM RABEH, MD, MSc Ing

Your Clinical Evaluation Expert And Partner

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This happens more often than it should. A device incorporates a substance with pharmacological, immunological, or metabolic action. The manufacturer treats it as a minor feature. The regulatory consequence is severe.

The issue is not whether the substance is present. The issue is how that substance acts and what role it plays in achieving the device’s intended purpose.

MDR Article 1 defines an ancillary medicinal substance as one that supports the device’s action but is not itself the principal mode of action. Annex I Rule 14 triggers a classification jump to Class III when such a substance is present. But the real regulatory work begins when you need to demonstrate that the substance is truly ancillary and justify its clinical benefit-risk profile.

Most deficiencies I see in this area come from three failures. First, manufacturers misunderstand what qualifies as ancillary. Second, they underestimate the additional clinical and regulatory burden. Third, they fail to consult with competent authorities early enough.

What Qualifies as an Ancillary Medicinal Substance

An ancillary medicinal substance has pharmacological, immunological, or metabolic action. It is intended to support the device but not to be the principal mechanism of action.

This is where confusion starts. Many manufacturers see a substance that enhances device performance and assume it is simply part of the device formulation. They do not recognize that if the substance acts through one of these mechanisms, regulatory classification changes.

Consider a bone void filler containing an antibiotic. The filler provides mechanical support. That is the principal action. The antibiotic prevents infection at the site. That is ancillary. The antibiotic does not fill the bone void. But it acts pharmacologically.

Now consider a hydrogel wound dressing with silver ions. The hydrogel maintains a moist environment. The silver provides antimicrobial action. If the antimicrobial effect is part of the intended purpose and relies on the pharmacological properties of silver, you have an ancillary medicinal substance.

The distinction between ancillary and principal is critical. If the substance provides the principal action, the product is a medicinal product, not a medical device. If the substance supports the device action, it is ancillary and the product remains a device but moves to Class III.

The MDR does not provide a detailed list of what counts as ancillary. It provides a functional definition. That means each case requires judgment. That judgment must be documented.

Why This Changes Your Regulatory Strategy

When a device contains an ancillary medicinal substance, several things happen at once.

First, classification jumps to Class III. This means a Notified Body with specific competence must be involved. Not all Notified Bodies are designated for devices with ancillary medicinal substances. You need to confirm your chosen body has the right scope.

Second, the competent authority of an EU Member State must be consulted. This is not optional. The Notified Body must seek a scientific opinion on the quality and safety of the substance and the benefit-risk ratio of incorporating it into the device. This adds time and introduces another layer of scrutiny.

Third, your clinical evaluation must address the substance. You cannot treat it as a passive component. You must demonstrate that its incorporation is justified, that its safety profile is acceptable in the context of the device, and that it contributes to the overall clinical benefit without introducing unacceptable risk.

The clinical data you provide must show that the substance performs as intended when incorporated into the device. If the substance is released over time, you need to demonstrate the release profile, the local concentration, and the tissue exposure. If the substance acts systemically, you need pharmacokinetic data.

This is not theoretical. I have seen manufacturers submit devices with antibiotics and provide only in vitro dissolution data. No tissue concentration studies. No clinical outcome data showing that the local antibiotic level reduces infection without causing local toxicity.

The competent authority rejected the application. The manufacturer had to generate clinical data that should have been planned from the beginning.

The Clinical Evaluation Challenge

The clinical evaluation for a device with an ancillary medicinal substance is more complex than a standard device evaluation.

You need to address two parallel questions. Does the device perform its principal function safely and effectively? Does the ancillary substance add benefit without adding unacceptable risk?

The literature search must cover both. You need device data and data on the substance. If the substance is a well-known drug, you will find literature on its use in other indications. You need to assess whether that data is relevant to your device context.

For example, if your device contains an antibiotic that is commonly used systemically, the safety data from systemic use may not fully apply to local delivery from a device. The local concentration may be much higher. The tissue exposure duration may be different. The patient population may include people who would not receive the systemic drug.

You must explain these differences. You must either provide data from similar local delivery contexts or generate new data.

The SOTA section must reflect the use of the substance in devices. If other manufacturers have similar devices with the same substance, that is relevant comparator data. If your device is the first to use the substance in this way, you need to acknowledge that and explain your rationale for choosing it.

The appraisal must be rigorous. If the available data does not answer all the clinical questions, you must identify the gaps and explain how your clinical investigation will address them. The competent authority expects this level of detail.

When Consultation Happens Too Late

The biggest strategic mistake is treating the competent authority consultation as a formality at the end of the process.

Some manufacturers design the device, generate clinical data, prepare the technical file, and only then discover that the competent authority will ask questions they cannot answer with the data they have.

This is costly. It delays certification. It sometimes requires reformulation or additional studies that could have been planned earlier.

The smart approach is to engage early. Before finalizing the device design, before running the pivotal clinical investigation, consult with the competent authority or seek scientific advice.

Explain what you plan to do. Ask whether the approach is acceptable. Ask what data they will need to see. Ask whether the proposed clinical investigation design will answer their questions.

This is not required by regulation, but it is a practical necessity. The competent authority has seen many similar cases. They know what data gaps cause problems. They can guide you toward a more efficient path.

I worked on a case where a manufacturer used a corticosteroid in a device applied to mucosal tissue. They assumed the systemic safety data for the corticosteroid was sufficient. The competent authority asked for local tissue effect data and absorption data specific to mucosal application.

The manufacturer had not done those studies. They had to conduct them post hoc. This added eighteen months to the timeline.

If they had consulted earlier, they would have included those studies in the original development plan.

What Belongs in the Clinical Evaluation Report

Your CER must include a dedicated section on the ancillary medicinal substance.

Start with a clear description. What is the substance? What is its chemical identity? What is its known pharmacological, immunological, or metabolic action?

Then explain why you chose this substance. What clinical benefit does it provide? Why is it necessary? What would happen if the device did not include it?

Next, address safety. What is known about the substance’s safety profile from other uses? What is the dose delivered by your device? What is the local tissue concentration? What is the systemic exposure?

If systemic exposure is negligible, demonstrate that with data. If systemic exposure is measurable, address whether it is within safe limits.

Then address the clinical benefit. Provide clinical data showing that the substance improves outcomes when incorporated into the device. This may come from your own clinical investigation or from literature on similar devices.

If no such data exists, you need a plan to generate it. That plan must be in place before you submit for certification.

Finally, address the long-term safety. If the device is used chronically or repeatedly, what is the cumulative exposure? Are there risks of sensitization, resistance, or tissue damage over time?

These are the questions the competent authority will ask. Your CER should answer them before they are asked.

The Interface with Pharmaceutical Quality Requirements

Because the ancillary substance is a medicinal substance, pharmaceutical quality requirements apply.

This means you need to demonstrate that the substance meets appropriate quality standards. If it is a pharmacopoeial substance, reference the monograph. If it is not, provide specifications and demonstrate how they are controlled.

You need stability data. The substance must remain stable in the device throughout its shelf life. You need to demonstrate that the substance does not degrade, that it does not interact with other device components, and that it remains effective until the expiry date.

You need to demonstrate sterility or appropriate microbial control if the device is sterile or applied to non-intact skin or mucosa.

These are pharmaceutical manufacturing and quality control issues. They are not typically part of device development. This is why devices with ancillary medicinal substances require a different level of quality system maturity.

Notified Bodies will look for this. If your quality system is built for standard devices and does not address pharmaceutical quality requirements, you will face deficiencies.

What Happens If You Get the Classification Wrong

Some manufacturers try to argue that the substance is not ancillary. They claim it is part of the device material, not a separate active component.

This works only if the substance does not act through pharmacological, immunological, or metabolic mechanisms to achieve the intended purpose.

If the intended purpose includes antimicrobial action, anti-inflammatory action, or any effect that depends on the substance’s biological activity, you cannot avoid classification as ancillary.

If you misclassify, the Notified Body will catch it. If the Notified Body does not catch it, the competent authority will. If the competent authority does not catch it during certification, a market surveillance authority might catch it later.

The consequence is not just a classification correction. It is a stop in certification, a need for additional data, possible withdrawal of certificates already issued, and reputational damage.

The classification must be justified in your technical documentation. That justification must reference MDR Annex VIII and explain your reasoning. If there is any doubt, consult with your Notified Body before finalizing the design.

What This Means for Your Development Timeline

If your device contains an ancillary medicinal substance, plan for a longer timeline.

The competent authority consultation adds months. The need for pharmaceutical quality data adds development time. The need for substance-specific clinical data may require additional studies.

You cannot compress this timeline by submitting incomplete documentation. The Notified Body will not proceed without the competent authority opinion. The competent authority will not issue an opinion without sufficient data.

Build this into your project plan from the start. If you discover the issue late in development, you may face significant delays.

This is not a reason to avoid ancillary medicinal substances. In some cases, they are clinically necessary. But the decision to include one must be made with full awareness of the regulatory path.

Final Consideration

Devices with ancillary medicinal substances sit at the intersection of two regulatory frameworks. They are devices, but they borrow requirements from pharmaceuticals.

This makes them more complex to develop, more complex to evaluate clinically, and more complex to certify.

The key is early recognition. If your device includes a substance with pharmacological, immunological, or metabolic action that supports the intended purpose, treat it as ancillary from day one.

Engage the competent authority early. Plan the clinical data you will need. Build pharmaceutical quality into your development process.

This is not optional. It is the only path to certification.

In the next part of this series, we will look at devices that incorporate tissues or cells of human or animal origin. The regulatory requirements there are equally demanding, and the clinical evaluation challenges are different again.

Peace,
Hatem
Clinical Evaluation Expert for Medical Devices
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