In an ever-evolving world of pharmaceutical and medical technology innovation, the combination products are changing the way in which patients are being treated. From prefilled syringes, nasal sprays, inhalers, ophthalmic, MDI/DPI, pen injectors, auto injectors to drug-eluting stents, these combination products offer potential life-saving therapies — but they also carry with them unique regulatory hurdles.
European combination product regulations can be complex and baffling for manufacturers that are confronted with the melding of pharmaceutical and medical device directives. Even industry veterans can trip up if they fail to nail important compliance details.
In this blog, we’ll cover the top 6 most widespread pitfalls in guidance for combination products, as a result of which you’re laying an egg – including how your company can successfully steer clear of them and ensure compliance and jolt approvals for long-term market success.
European regulations for combination products
Before diving into the trap it is important to understand what combination products are and how they are regulated.
Combination products are products which combine a drug, device and, sometimes a biological component in one product or system. Examples include:
- Drug-coated catheters
- Pre-filled injection pens
- Implantable drug delivery systems
Identification of the primary mode of action (PMOA), which in turn derives into primary and secondary mode of action (PMOA and SMoA) is a key step as required under the European Union Medical Device Regulation (EU MDR 2017/745) and Medicinal Products Directive (2001/83/EC). This would determine the product’s main regulation either as a medical device or as a medicinal product.
If the device is what drives the intended purpose, it will fall under EU MDR; if the pharmaceutical drug product dominates, it falls under EMA. (European Medicines Agency)
This dual-lane classification can be confusing — and one of the most dangerous compliance traps.
Top Downfalls in Combination Product Compliance
So then, at a very high level, how do combination product manufacturers get it wrong in Europe?
1. Misclassification of the Product
The biggest error in compliance is a mistake in determining the predominant mode of action.
An unclear or poorly defined PMOA can result in companies to select the wrong regulatory pathway, causing delays, rejections or expensive design changes.
How to avoid it:
- Performing an early scientific examination on PMOA.
- Refer to both EU MDR guidelines and EMA definitions.
- Consult your Regulatory Advisor or a Notified Body prior to submission.
2. Insufficient risk management and lack of clinical trial
Risk management for combination products should be based on total product risk including drug and device risks. A lot of this stuff doesn’t get pulled together, so you wind up with a very fragmentary risk analysis.
How to avoid it:
- Develop one, integrated risk management plan consistent with ISO 14971 principles.
- Combine both pharmacovigilance and devices vigilance systems.
- Carry out clinical assessment and performance assessments according to MDR Annex XIV.
3. Lack of Documentation and Preparation of Technical File
Poor quality documentation is another common reason for regulatory delays. COMBINATION PRODUCTS Some combination products require two sets of documentation — one for the device and one for the medicinal component.
How to avoid it:
- Maintain the current technical file with consistent labelling, usage and safety guidelines.
- Please add the quality and manufacturing evidence for these two parts.
Pro Tip: Gap analysis can show what documents are lacking before submitting the regulatory dossier.
4. Overlooking Cross-Functional Communication
The job of the RA team is not the only one with responsibility for regulatory compliance of combination products. It creates a need for cross-functional activities between R&D, quality and manufacturing organizations.
How to avoid it:
- Establish a compliance cross discipline team early in product development.
- Keep the doors open for regulatory, clinical and technical convergence.
- Leverage document control solutions for versioning and consolidated review.
5. Ignoring Post-Market Surveillance Obligations
After the combination product is cleared, it must be continually tracked — but many firms do not have robust post-market surveillance systems.
How to avoid it:
- Develop a comprehensive PMS ref: Endorsed for Issue 1 November RefType) plan and include pharmacovigilance reporting.
- Take a continuous look at product performance and safety trends.
- Keep the PSUR up-to-date as per EU MDR.
6. Disregarding Evolving EU Regulatory Environment
EU regulations are dynamic. Manufacturers who rely on outdated directives risk non-compliance or suspension of market access.
How to avoid it:
- Keep abreast of EU MDR guidance documents and EMA notices.
- Engage in discussions / attend workshops with Notified Bodies.
- Work with regulatory consultants that have experience with combination product submissions.
Best Practice and Tips for Seamless Compliance
Avoiding these potholes demands an active, formalized compliance plan. Below are a few best practices to follow for success:
- Conduct a Pre-regulatory Assessment: Determine classification and submission path prior to development of product.
- Documentation Integration: Harmonization of device and pharmaceutical documentation into a common technical file.
- Consult a Notified Body early in the process: Particularly for marginal products where classification is not clear.
- Train: Train internal groups on MDR and medicinal product needs.
- Collaborate With The Experts: Regulatory consultants such as 3iconcept medical solutions can handle the plethora of requirements with world class technical accuracy.
Why Expert Guidance Matters
To be in compliance with combination product regulations, you need a strong intermediary knowledge of drugs and devices regulation. Just one trip-up — in classification, documentation or testing — can derail your timeline for launch by months.
For these manufacturers the following benefits can be attained by using experienced consultants who understand EU MDR, as well as EMA guidance and ISO quality standards:
- Accelerate regulatory approval
- Minimize audit risks
- Build sustainable compliance systems
Conclusion: Get Regulated and Give a Margin of Confidence 3iconcept Medical Solutions
Navigating Combination Product Regulations in Europe Shouldn’t Be Difficult… and It Isn’t! By identifying and addressing common pitfalls—such as misclassification and post market evaluation—you can remain in compliance, ensure patient safety, and even keep up with the competition.
3iconcept Medical Device Solutions is where specialists support medical device and drug manufacturers to seamlessly comply with regulations. From EU MDR classification, to documentation, gap analysis and technical support we offer full-cycle guidance tailored for drug–device combination products.
Contact 3iconcept Medical Device Solutions today to ensure your combination product fulfills all regulatory needs – and does it right the first time.