Combination products pose regulatory difficulties as the requirements of medical devices must merge with pharmaceuticals and biotech. As biotech and advanced therapeutics grows, so too does the need for specialised device delivery systems resulting in an increase in combination products. Similarly, device companies are increasingly adding medicinal substances to improve products.

Educo delivers the course “Regulatory Affairs for Combination Products (Drug/Device and Device/Drug)” which includes a free-to-attend module 1 training session. Over the years, attendees of the free session have raised insightful questions that led to detailed discussions. Below, we compile key questions and responses to provide clarity on crucial aspects of combination products such device development, regulatory approval routes and product specific issues.

You can register for the free training session here.

To learn more about the full course, click here. 

General Regulatory Framework for Combination Products

Q: Is there something similar to scientific advice from notified bodies that applicants can consult for development advice?

A: No, notified bodies do not provide scientific advice, as they view it as consultancy, which they are prohibited from offering. Typically, companies must develop their regulatory strategy based on published standards and guidelines and then present their plan to the notified body for assessment.

Q: How can we determine the responsibility of each party involved in the development of a combination product, such as a pen injector?

A: The development strategy should outline each phase, from concept to design verification and validation. It’s important to integrate drug and device development early and to clearly define interactions between teams to ensure compliance with both pharmaceutical and medical device regulations.

Q: Would an IVD instrument, such as a digital pathology slide scanner, be considered a combination product when paired with reagents?

A: Generally, no. If the scanner is used to examine patient-derived samples, it would likely be classified as an in vitro diagnostic (IVD) under the Medical Devices Regulation (MDR). However, if the scanner and reagents are intended to function together as part of a treatment pathway, additional regulatory considerations may apply.

Q: Can a pharmaceutical not already registered be clinically tested simultaneously with a medical device?

A: Yes, provided regulatory authorities approve the study. The need for simultaneous testing depends on whether the device is integral to the pharmaceutical’s function, such as an inhaler for an asthma medication.

Q: Once a combination product is approved, can the different components be sold separately?

A: If the individual components of the combination product are to be sold separately, they must have the appropriate regulatory approvals in place. For example, syringes and needles are often separately approved as medical devices and then assembled into kits. If they are integral to the combination product, selling them separately could require additional regulatory considerations.

Human Factors and Device Considerations

Q: If developing a biosimilar approved via the centralised procedure, how do we waive human factors and PK bridging studies for a prefilled pen?

A: Human factors engineering should be incorporated into the design process rather than treated as a standalone study. Consult the EMA regarding waivers, but notified bodies may still expect evidence of usability.

Q: What are the key considerations for human factors studies in combination products?

A: Human factors should be integrated early in development. Both formative and summative studies should be conducted to ensure usability and patient safety. Human factors testing should address device handling, training materials, and user instructions.

Q: Does an oral solution with a graduated syringe qualify as a combination product?

A: Yes, if the syringe is intended for dosing accuracy, it is regulated as part of the combination product.

Q: What are the tolerance limits for medical devices within combination products?

A: Tolerance limits depend on the required accuracy for drug delivery. For example, dose accuracy requirements for pharmaceuticals influence the selection of medical devices with appropriate tolerances. The tolerance should be designed to ensure patient safety and consistency in treatment delivery.

Regulatory Approvals and Compliance Strategies

Q: What are the implications of MDR extensions to 2027-2028 for Article 117 compliance?

A: The MDR extension applies primarily to legacy products, but combination products still require notified body opinions under Article 117. Companies should verify their specific regulatory pathway and compliance timelines.

Q: Would an MRP submission for a generic combination product be considered a legacy product?

A: It depends on whether the reference product is classified as a legacy product. If the reference medicinal product remains under older regulations, a new combination product may still need to meet MDR requirements.

Q: Will regulations beyond the US and EU be discussed in the course, such as Japan, China, and Canada?

A: The course focuses primarily on the EU and US, but Japan is briefly covered. China’s regulatory landscape is complex and evolving, and discussions on other regions are limited.

Product-Specific Regulatory Challenges

Q: Does a drug-device combination nasal spray need a notified body opinion (NBO) if it is transient use and the device is Class I?

A: Yes, even a Class I device requires a preliminary notified body opinion if it is part of a combination product.

Q: Are alcohol swabs now regulated as cosmetics under MDR, making them harder to source with CE marking?

A: There has been regulatory reclassification of certain alcohol swabs. It is best to confirm with a regulatory expert to determine whether CE marking applies.

Q: What are the expectations of FDA and EMA for drug-device compatibility studies?

A: The FDA has specific requirements for compatibility studies, particularly for prefilled syringes and inhalers. Module 3 of the CTD should include data demonstrating compatibility, stability, and performance.

Q: What is the regulatory strategy for design studies for drug-device compatibility?

A: The FDA and EMA require specific studies to ensure compatibility between drug and device components. This includes interaction studies, stability tests, and performance evaluations, particularly for prefilled syringes and combination products.

Conclusion

This Q&A compilation provides insights into the complexities of regulatory affairs for combination products, highlighting key considerations for compliance, usability, and global submissions. Understanding these regulatory expectations is crucial for successfully bringing combination products to market while maintaining compliance with evolving guidelines.

For further insights and training, consider attending the full Educo Life Sciences course on Regulatory Affairs for Combination Products.

Answers from our Educo Life Sciences Experts, Andrew Willis and Richard Young

Andrew Willis is a regulatory and development consultant with 35 years of experience. His management roles have seen him act as global Vice President of Regulatory Affairs and Medical Affairs, creating business and marketing strategies for complex pharmaceutical development projects. Andrew has gained therapeutic experience in areas covering CNS, oncology, urology and pain management.

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.