In the medical device industry, ensuring safety and compliance with regulatory standards is paramount. Chemical characterisation and biocompatibility testing are essential steps in this process, guided by frameworks such as ISO 10993. These evaluations help manufacturers understand the materials in their devices and assess potential health risks to patients.

This article explores the nuances of chemical characterisation, including the role of extractables and leachables studies, how they can complement or replace biocompatibility tests, and the importance of selecting the right laboratory for testing.

Is an Extractables and Leachables Study Necessary?

Regulatory Framework: ISO 10993-1

The ISO 10993 series sets the international standards for evaluating the biocompatibility of medical devices. Part 1 of this series requires complete chemical characterisation of a device. In theory, this can be achieved through paper-based calculations, assuming the worst-case scenario of all potential leachables being released. However, this theoretical approach is often impractical for several reasons.

Practical Challenges with Paper-Based Characterisation

1. Incomplete Knowledge of Materials
   Manufacturers often lack detailed information about all materials, additives, and processing aids involved in the production of their devices. This issue is compounded by the complexity of supply chains, where suppliers and subcontractors may use substances not fully disclosed to the manufacturer.
2. Regulatory Trends
   Due to these uncertainties, regulatory bodies increasingly demand extractables and leachables studies to fill gaps in knowledge. These studies provide empirical data that theoretical models cannot replicate, ensuring a more robust assessment of chemical risks.

The Industry Norm

While extractables and leachables studies are not strictly required under ISO 10993, they have become the de facto standard for compliance. Conducting these studies is a proactive approach to meet the expectations of notified bodies and competent authorities, reducing the risk of delays in regulatory approval.

Can Extractables and Leachables Studies Replace Biocompatibility Testing?

Addressing Systemic Toxicity

Extractables and leachables studies are particularly valuable for evaluating systemic toxicity endpoints. The data generated can inform toxicological risk assessments, which may eliminate the need for certain biological tests. Systemic toxicity endpoints that can often be addressed include:

• Subacute toxicity: Effects from short-term exposure.
• Subchronic and chronic toxicity: Impact of medium to long-term exposure.
• Reproductive toxicity: Effects on fertility or embryonic development.

Limitations for Local Effects

However, these studies have limitations. They are less effective in addressing endpoints that involve localised biological responses. Examples include:

• Irritation: Assessing whether a device causes inflammation when in contact with tissues.
• Sensitisation: Evaluating the potential for allergic reactions.
• Cytotoxicity: Determining whether a device is toxic to cells.

Regulators typically require supplementary biological testing to address these endpoints. For most devices, a combination of extractables and leachables data and targeted biocompatibility tests is necessary to satisfy regulatory requirements.

Testing Representative Samples

Importance of Testing the Final Device

The ideal scenario for chemical characterisation is testing the finalised medical device. This ensures the sample reflects the product as it will be used by patients, including all manufacturing steps, sterilisation, and packaging processes. Testing the final device provides the most accurate representation of potential risks.

Testing During Product Development

In practice, manufacturers often conduct chemical characterisation early in product development, before the final device is ready. When testing non-finalised samples, it is critical to justify any differences between the test sample and the finished product. Key considerations include:

• Material Composition: Are the materials and additives in the sample identical to those in the final device?
• Manufacturing Variations: Have all manufacturing steps, such as sterilisation, been applied to the test sample?

Lifecycle Considerations

Increasingly, regulators require manufacturers to demonstrate that chemical characterisation data remains valid throughout the device’s lifecycle. This involves answering questions such as:

• Does the chemical composition of the device change over time?
• Are the results still accurate at the end of the device’s shelf life?

Including lifecycle-based evaluations in testing protocols is crucial for regulatory approval.

How to Choose the Right Laboratory

Criteria for Laboratory Selection

Choosing the right testing laboratory can significantly impact the accuracy and reliability of chemical characterisation data. Here are key factors to consider:

1. GLP Compliance
   Ensure the laboratory complies with Good Laboratory Practice (GLP) standards. GLP compliance indicates that the lab follows rigorous protocols for data quality and reliability.
2. Experience with Medical Devices
   Not all analytical laboratories have expertise in testing medical devices. Medical device testing requires specialised knowledge, particularly in interpreting data in the context of biocompatibility and regulatory standards.
3. Spectral Libraries
   Comprehensive and high-quality spectral libraries are essential for identifying unknown compounds during chemical characterisation. Laboratories with limited or outdated libraries may struggle to provide accurate results.

Leveraging Industry Insights

Industry recommendations and consultations can be valuable in identifying reputable labs. Professionals or consultants with experience in medical device testing can provide insights into which laboratories consistently deliver high-quality work. Avoid relying solely on a laboratory’s claims about its capabilities.

The Role of Chemical Characterisation in Biocompatibility

Chemical characterisation is more than a regulatory requirement; it is a foundational element of medical device safety. Understanding the chemical profile of a device helps manufacturers identify potential risks and address them proactively. Key benefits include:

• Risk Mitigation: Identifying harmful substances early reduces the likelihood of adverse patient reactions.
• Regulatory Compliance: Meeting or exceeding regulatory expectations streamlines the approval process.
• Product Innovation: Comprehensive chemical characterisation supports the development of safer, more innovative devices.

Conclusion

Chemical characterisation and biocompatibility testing are essential components of medical device development. While extractables and leachables studies provide critical insights, they are not a complete substitute for biological testing. Manufacturers must adopt a balanced approach, combining chemical data with targeted biocompatibility tests to ensure safety and compliance.

The process is further complicated by the need to test representative samples and consider lifecycle stability. Selecting the right laboratory is equally critical, as it ensures the reliability of data and the success of regulatory submissions.

By understanding these complexities and adhering to best practices, professionals in the medical device industry can navigate regulatory requirements effectively, bringing safe and innovative products to market with confidence.

Watch the interview below:

Written by Educo Life Sciences Expert, Phil Clay

Philip Clay is Director and principal toxicologist with Chorley Consulting. He is a registered toxicologist and specialises in product safety assessment with over 30 years’ experience. He has published and presented widely in his expert field of genetic toxicology and in the wider area of safety assessment. Phillip has recently joined the BSI Ch/194 Committee to provide UK input to ISO/Tc 194 and CEN/TC 206 for standards relating to biological evaluation of medical devices.

This article was written using the video interview which you can watch above.