Combination products, which integrate pharmaceutical and medical device components, are an innovative and expanding sector in medical solutions. This article, based on insights from expert Richard Young, covers the unique regulatory challenges faced by manufacturers and developers working with these products, especially in Europe and the US. This guide will explore crucial elements of combination products, classification complexities, regulatory pathways, and practical considerations for professionals.

What Are Combination Products?

Combination products are medical solutions that include both medical devices and pharmaceutical elements. For example, a drug-eluting stent—used to support coronary arteries—is a combination product where a stent acts as the device, and an embedded drug provides therapeutic benefits. The blending of device and drug requires a dual approach to meet safety and performance standards across both domains.

Regulatory Pathways and Classification

The classification and regulation of combination products hinge on the primary mode of action. This determines whether a combination product will be regulated as a medical device or a pharmaceutical. Understanding the primary function of each component is essential, as it dictates the regulatory pathway and ultimately affects product design, testing, and approval requirements.

1. Primary Mode of Action: The primary function of a combination product indicates the main regulatory framework. For instance:
   • A drug-eluting stent has a mechanical action and is classified as a medical device.
   • A prefilled syringe (e.g., for vaccine delivery) is mainly pharmaceutical, with the device (syringe) acting as a secondary component.
2. Borderline Devices: Some products blur the lines between device and pharmaceutical, leading to regulatory ambiguity. For example, antibiotic bandages could be considered a medical device (providing a barrier) or a drug delivery system. In such cases, consultation with notified bodies in Europe or the Office of Combination Products in the US is advised.
3. Class III Classification in Europe: Most combination products with a medical device component are classified as Class III in Europe, indicating high-risk status. This classification requires stringent design, testing, and documentation to meet regulatory standards.

Understanding Regulatory Requirements: EU and US Differences

European Union (EU)

In the EU, Medical Devices Regulation (MDR) guides the regulatory framework for combination products. The MDR requires:

• Annex 1 Compliance: Combination products must comply with the General Safety and Performance Requirements outlined in Annex 1, covering state-of-the-art standards for biocompatibility, sterilisation, and other safety measures.
• Documentation and Submission: Even when classified as pharmaceuticals, combination products must still demonstrate compliance with device standards in their documentation. This involves rigorous testing for interactions between the device and drug elements, focusing on factors like drug delivery rates and contamination risk.

United States (US)

The US FDA follows a different approach through its Office of Combination Products. Here’s how the process compares:

• Office of Combination Products: Unlike Europe, the US centralises combination product regulation under one office, simplifying classification and approval processes.
• Advisory Role: This office offers guidance on the classification and regulatory approach, using the primary mode of action as a flexible guideline, rather than a rigid classification determinant. This approach provides developers with a streamlined regulatory pathway.

Challenges and Considerations in Combination Product Development

Creating combination products involves navigating additional layers of complexity beyond traditional device or pharmaceutical development. Key challenges include:

1. Product Design and Documentation: Manufacturers must consider interactions between the device and drug, such as compatibility, drug delivery mechanics, and contamination potential. Detailed documentation is required to illustrate compliance with both device and drug regulations, which can be cumbersome for developers new to either field.
2. Enhanced Communication with Notified Bodies: Engaging early and frequently with notified bodies is crucial, especially when classifying complex or borderline products. Notified bodies provide essential guidance on classification and ensure regulatory alignment before product submission.
3. Borderline Product Resolution: In cases where classification is unclear, developers should consult resources like the Borderline Manual from the Medical Device Coordination Group in Europe or directly consult the Office of Combination Products in the US.
4. Multi-disciplinary Expertise: Collaboration between device and pharmaceutical experts is critical to comprehensively address the regulatory requirements for combination products. This ensures all facets of product design, testing, and compliance are properly managed.

Practical Guidance for Manufacturers and Developers

Richard Young’s expertise offers valuable insights into the practical steps manufacturers should take to streamline development and regulatory approval:

• Identify the Primary Mode of Action Early: Clarifying the primary function of the product helps define its classification and regulatory pathway.
• Utilise External Expertise: Working with experienced consultants or attending dedicated training courses can provide developers with a comprehensive understanding of both device and pharmaceutical perspectives.
• Develop a Robust Documentation Process: Detailed and well-organised documentation is critical for regulatory approval. It should include state-of-the-art compliance, safety testing, and risk management documentation.
• Engage with Regulatory Authorities: Establishing communication early with notified bodies or the Office of Combination Products can clarify regulatory expectations and avoid costly rework or misclassification issues.

Insights from Educo Life Sciences: Training for Combination Product Developers

Educo Life Sciences offers a comprehensive training programme led by experts like Richard Young, which addresses the specific challenges of combination product development. This course provides developers and manufacturers with essential knowledge on:

• Regulatory Requirements: Understanding MDR and FDA expectations for combination products.
• Documentation Practices: Building documentation that meets both device and pharmaceutical standards, with real-world examples and case studies.
• Cross-disciplinary Collaboration: Insight into integrating pharmaceutical and device development practices, ensuring a seamless product journey from design to market.

Participants in Educo’s training have the unique opportunity to engage with experts across both medical device and pharmaceutical sectors, fostering an in-depth understanding of the regulations, classification, and practical considerations specific to combination products.

Conclusion

Combination products represent a rapidly growing area in medical solutions, driven by innovations in drug delivery and integrated therapeutic devices. However, navigating the regulatory landscape is complex and requires a deep understanding of both device and pharmaceutical standards. By focusing on the primary mode of action, engaging with regulatory bodies, and maintaining robust documentation practices, developers can confidently approach combination product development and bring innovative products to market successfully. Educo Life Sciences’ training offers a valuable resource for those aiming to build this expertise, helping professionals tackle these challenges with informed guidance and practical tools.

Watch the interview below:

Written by Educo Life Sciences Expert, Richard Young

Richard Young has over 25 years of experience in the medical device and IVD industry with products such as class 3 implants to electromedical infusion systems. Richard has extensive experience in regulatory affairs, GMP (quality), GLP (laboratory testing) and clinical affairs. Richard has held various positions within the industry such as QA/RA Manager and Director, Quality Assurance and Regulatory Compliance at various companies including Biomet, Plasma Surgical and Zimmer Limited.

This article was written from the video interview above and materials from the course, Regulatory Affairs for Combination Products