How to Document Biological Safety for Combination Products (Device + Drug)

Combination products, which incorporate both medical devices and pharmaceutical components, present unique regulatory challenges, particularly in biocompatibility and biological safety documentation. Manufacturers must ensure that both device and drug components meet strict safety requirements, aligning with both medical device and pharmaceutical regulatory frameworks.

1. Understanding the Regulatory Landscape

Combination products fall under both:

• Medical Device Regulations (e.g., MDR in Europe, FDA in the U.S.), which emphasize physical, mechanical, and material safety of the device component.

• Pharmaceutical Guidelines (e.g., ICH, EMA, FDA drug requirements), which focus on pharmacokinetics, drug stability, and toxicology assessments.

Regulatory classification depends on the primary mode of action (PMOA), determining whether the product is reviewed primarily as a medical device or a pharmaceutical. If the device provides the main therapeutic effect, medical device regulations take precedence. If the drug component is primary, pharmaceutical guidelines dominate.

2. Key Aspects of Biological Safety Documentation
3. Material Biocompatibility

• Conduct ISO 10993-1 risk-based evaluation, identifying all potential biological risks associated with device materials.

• Perform detailed chemical characterization and extractables & leachables (E&L) studies, focusing on potential toxicological interactions between device materials and drug components.

• Assess long-term effects, considering whether prolonged exposure alters the safety profile of either component.

1. Drug-Device Interaction Analysis

• Evaluate whether drug formulation components impact device biocompatibility, such as solvents altering material properties or causing degradation.

• Consider potential device-related leachables affecting drug stability, ensuring no chemical interactions compromise efficacy or safety.

• Demonstrate compatibility with container closure systems, as these can also contribute to extractable risks.

1. Stability and Shelf-Life Testing

• Ensure that biocompatibility remains stable throughout the intended shelf life.

• Conduct accelerated and real-time stability studies to assess degradation products and potential toxicity risks.

• Include environmental stress testing (e.g., temperature, humidity) if the combination product has unique storage conditions.

1. Risk Assessment and Justification

• Develop a comprehensive Biological Evaluation Plan (BEP) integrating both device and pharmaceutical testing strategies.

• Justify test exemptions based on historical safety data and prior approvals.

• Align risk assessments with both device (ISO 10993-1) and pharmaceutical (ICH M7, Q3D) frameworks to address regulatory expectations.

3. Best Practices for a Compliant Submission

• Engage with Regulatory Authorities Early: Pre-submission meetings help clarify expectations for combination product testing.

• Prepare an Integrated Biological Safety Report: A single, structured document combining device and drug safety data streamlines review.

• Work with an Experienced Testing Laboratory: Ensure all biocompatibility and toxicology assessments align with the latest standards.

Final Thoughts

By collaborating with a specialized biocompatibility testing lab like EBI, manufacturers can confidently prepare regulatory submissions that meet all compliance requirements efficiently. If you need guidance, EBI offers expert support in biocompatibility evaluations, regulatory strategies, and risk assessments.

About the Author: Prof. Łukasz Szymański

Prof. Łukasz Szymański is an expert in medical device biocompatibility testing, serving as the Chief Scientific Officer (CSO) of the ISO 17025-accredited and GLP-certified European Biomedical Institute (EBI) and North American Biomedical Institute (NABI). As a dedicated researcher and a key contributor to advancing safety standards in the biomedical field, Prof. Szymański plays an integral role in shaping scientific innovations and regulatory compliance within the industry.