FDA’s Latest Guidance On Chemical Analysis: What Medical Device Manufacturers Need To Know

Introduction

In September 2024, the U.S. Food and Drug Administration (FDA) issued the draft guidance titled "Chemical Analysis for Biocompatibility Assessment of Medical Devices Draft Guidance for Industry." This document provides recommendations on analytical chemistry testing to evaluate the biocompatibility of medical devices and their components. The guidance aims to enhance consistency in chemical characterization studies and facilitate regulatory review during medical device submissions.

This blog explores key highlights from the draft guidance, its implications for medical device manufacturers, and best practices for compliance.

Understanding Chemical Characterization

Chemical characterization of medical device materials involves identifying chemical substances that may be released into the body and assessing their potential risks. It plays a crucial role in biocompatibility evaluation and, in some cases, can replace biological testing when followed by a Toxicological Risk Assessment (TRA) as per ISO 10993-17.

Chemical characterization studies are particularly useful for:

• Supporting chemical equivalence assessments after material or manufacturing changes.
• Comparing devices with similar materials where biocompatibility has already been established.
• Identifying and quantifying extractable and leachable (E&L) substances that may pose a health risk.

Key Highlights of the FDA’s Draft Guidance

1. Scope and Applicability

The guidance applies to:

• Medical devices with direct or indirect patient contact (e.g., implants, catheters, infusion sets, wound dressings).
• Combination products containing device components with potential chemical leaching concerns.
• Devices made with new materials or manufacturing processes where extractables and leachable need evaluation.

2. Recommended Study Approach

The FDA emphasizes the importance of gathering preliminary information on:

• Device materials and manufacturing processes, including base polymers, plasticizers, stabilizers, surfactants, and colour additives.
• The presence of cohorts of concern compounds that require dedicated investigation methods.
• The device’s intended use to determine clinically relevant worst-case exposure scenarios.

The document recommends:

• Non-targeted screening analysis for general extractables identification.
• Targeted analysis for specific compounds exceeding analytical threshold values, such as suspected genotoxic or mutagenic substances.
• Following best practices from sources like the Product Quality Research Institute (PQRI) and United States Pharmacopeia (USP).

3. Testing Recommendations

The FDA outlines specific Extractables & Leachable (E&L) testing methodologies, including:

• Selection of Extraction Conditions:
  • Use of worst-case scenario extraction conditions aligned with ISO 10993-18.
• Analytical Techniques:
  • Gas Chromatography-Mass Spectrometry (GC-MS) and Liquid Chromatography-Mass Spectrometry (LC-MS) for organic compounds.
  • Inductively Coupled Plasma-Mass Spectrometry (ICP-MS) for elemental analysis.
  • Headspace GC-MS for volatile organic compounds.
• Sample Preparation:
  • Individual extractions for each device material to determine the origin of extractables.
  • Special attention to particulates observed during extraction.

4. Toxicological Risk Assessment (TRA)

Once extractables and leachable are identified, a Toxicological Risk Assessment (TRA) is required. The FDA recommends:

• Comparing exposure levels with established safety limits such as Permitted Daily Exposure (PDE) and Threshold of Toxicological Concern (TTC).
• Using in silico toxicology tools for unknown compounds.
• Incorporating compound-specific toxicity data where available.

5. Risk-Based Approach

The FDA emphasizes a risk-based approach, where:

• The level of testing should be proportional to the risk posed by the device.
• Non-contact devices may require minimal or no chemical characterization.
• High-risk devices (e.g., long-term implants) require comprehensive chemical and toxicological evaluations.

6. Extraction Conditions and Solvents

The draft guidance aligns with ISO 10993-18 for extraction conditions and solvents. Deviations from recommended conditions must be justified. The FDA also considers material variability, requiring the extraction and analysis of three material batches to ensure worst-case toxicological evaluation.

7. Use of Alternative Approaches

While the FDA outlines recommended methods, manufacturers may use alternative approaches if scientifically justified, such as:

• Validated in silico modelling to support risk assessments.
• Historical data on similar materials to justify reduced testing.

Implications for Medical Device Manufacturers

1. Enhanced Regulatory Scrutiny

The guidance suggests that FDA reviewers will expect more comprehensive chemical characterization data in premarket submissions such as 510(k), PMA, and De Novo applications. Manufacturers should align testing strategies accordingly.

2. Increased Testing Requirements

Manufacturers may need to invest in:

• Advanced analytical testing capabilities.
• Collaborations with third-party laboratories specializing in extractables and leachable testing.
• Compliance with ISO 10993-18 and other global standards.

3. Greater Emphasis on Toxicological Risk Assessment

Toxicological expertise will be critical for interpreting chemical analysis data. Manufacturers should:

• Work with certified toxicologists to assess risks associated with detected chemicals.
• Justify acceptable exposure levels based on established safety thresholds.

4. Impact on Material Selection and Supply Chain

Stricter chemical evaluation requirements may necessitate:

• Reassessment of material choices for medical devices.
• Engagement with material suppliers to obtain detailed composition data.
• Reduction of unknown chemical constituents in device formulations.

Best Practices for Compliance

• Early Integration of Chemical Characterization – Implement chemical analysis during R&D to avoid costly redesigns.
• Adopt Standardized Testing Protocols – Align with ISO 10993-18 for global regulatory acceptance.
• Maintain Comprehensive Documentation – Prepare detailed reports and justifications for regulatory submissions.
• Engage with Experts – Collaborate with toxicologists and regulatory consultants to ensure compliance.
• Monitor Regulatory Updates – Stay informed on FDA guidance revisions and industry feedback.

Conclusion

The FDA's draft guidance sets clear expectations for chemical characterization in medical device submissions, emphasizing a more structured and scientific approach to evaluating material safety. Adhering to these recommendations will not only streamline regulatory approvals but also ensure a higher level of patient safety.

Manufacturers should proactively incorporate these best practices into their development and compliance strategies to stay ahead of evolving regulatory expectations.

For expert support in FDA compliance, chemical characterization, or toxicological risk assessments, contact Maven’s regulatory team today.