Understanding the New FDA Draft Guidance on Medical Device Chemical Characterization

The US FDA draft guidance entitled “Chemical Analysis for Biocompatibility Assessment of Medical Devices” (released on September 19, 2024) provides a comprehensive framework for chemical characterization in medical devices. This guidance aligns with ISO 10993 Part 18 and focuses on extraction, chemical analysis, and reporting requirements. The aim is to enhance the consistency and reliability of analytical chemistry studies, which are crucial for ensuring the safety and effectiveness of medical devices.

Key areas covered in this guidance include:

• The critical role of thorough information gathering before testing.
• Detailed recommendations on extraction procedures tailored to device types.
• Emphasis on NVR analysis as part of assessing prolonged use devices.
• Comprehensive approaches to chemical analysis using multiple detection methods.
• Clear definitions regarding standards and calibration practices.
• Principles guiding accurate chemical identification processes.

The Importance of Information Gathering

Before embarking on chemical characterization, thorough information gathering is essential. This step lays the groundwork for understanding potential extractables and helps align study design with protocol development. Key aspects to consider include:

Materials of Construction: Understanding the components used in device manufacturing is critical. This includes not only the primary materials but also any manufacturing aids or changes that may affect chemical equivalency.

Device Configuration: The configuration of a device, including its components and how they interact during use, must be clearly understood.

Exposure Parameters: Information about the number of devices used per procedure, duration of contact, and sterilization methods is vital for accurate testing.

The device selected for testing should be a whole or subdivided with justification, finished product that represents the worst-case exposure scenario. This ensures that the testing reflects real-world conditions as closely as possible.

Extraction Procedures: Guidelines and Best Practices

The draft guidance emphasizes the importance of proper extraction procedures. These procedures are designed to obtain worst-case estimates of amounts of analytes. while ensuring that the extraction process does not compromise the integrity of the device.

Extraction Conditions

For limited-duration devices, extraction conditions should be exaggerated to reflect worst-case clinical scenarios. In contrast, prolonged and long-term devices require exhaustive extraction methods. The guidance recommends using a combination of polar and non-polar solvents for limited and prolonged devices, while long-term devices may require polar, semi-polar, and non-polar solvents.

The FDA suggests conducting extractions in sealed containers with minimal dead space to maintain temperature control and facilitate continuous mechanical agitation. Neat alcohol mixtures are preferred for extractions; however, if unsuitable, alcohol-water mixtures can be justified with appropriate rationale.

Solvent Compatibility

Conducting solvent compatibility studies is crucial to determine how different solvents interact with the device materials. It is recommended to evaluate at least three solvents of the same polarity to identify which one causes the least swelling or degradation of the device. Documenting these interactions through photographic evidence enhances understanding and transparency.

Non-Volatile Residue (NVR) Analysis

NVR analysis plays a significant role in assessing prolonged or long-term devices. This analysis should be performed gravimetrically to determine exhaustivity endpoints separately for each solvent used in extraction. The FDA recommends conducting these analyses in triplicate to ensure reliability and consistency across results.

To achieve accurate measurements of NVR, it is essential that the balance capability falls within a range of 10 to 100 micrograms. The initial extraction cycle should yield measurable results that demonstrate less than 10% NVR at the end cycle for exhaustivity.

Chemical Analysis: Techniques and Standards

The guidance outlines various aspects of chemical analysis, emphasizing sample processing and method verification. Sample processing steps such as solvent evaporation and solvent exchanges, need to be qualified. The recovery rates are recommended to be within 80% to 120%.  If recovery rates are lower, recommendations for additional justification steps are provided that include analyzing the non-concentrated and concentrated extraction for solvent evaporation.  Multiple solvent exchanges and/or adjustments in pH levels may be necessary for solvent exchange justification.

Detection Methods

A comprehensive detection strategy is vital for identifying analyte signals accurately. The FDA recommends employing a multi-detector approach that may include ultraviolet detection or charged aerosol detection (CAD) alongside mass spectrometry (MS). This multi-faceted approach ensures that both low and high molecular weight compounds are detected effectively.

For non-volatile substances, electrospray ionization (ESI) should be utilized as the primary analysis method in both positive and negative modes. The mass accuracy requirements are stringent—less than 10 parts per million (ppm) for parent ions and less than 20 ppm for product ions—ensuring high-quality data collection.

Standards for Reference Materials

The draft guidance specifies three types of standards: authentic reference standards, internal reference standards, and surrogate reference standards. Authentic reference standards consist of high-purity substances with known molecular structures used for analytical purposes. Internal reference standards serve as controls within sample matrices to gauge response accuracy during analysis. Surrogate reference standards help demonstrate that non-targeted methods can identify a wide range of analytes across various concentrations.

Calibration Curves

Calibration curves should consist of at least five points to ensure accuracy across a range of concentrations. These curves must bracket the analytical evaluation threshold (AET) while ensuring that methods do not underestimate extractable values.

Chemical Identification Principles

While brief in scope, the section on chemical identification highlights essential principles for accurately identifying compounds within samples. It emphasizes that identification should adequately quantify compounds above AET using targeted analysis approaches when necessary.

The results must provide structural elucidation based on knowledge of materials used in construction and manufacturing processes. When multiple candidate identifications arise from analysis, all possibilities must be reported to ensure comprehensive understanding.

Conclusion

The FDA’s draft guidance on chemical characterization represents a significant step forward in enhancing analytical practices within the medical device industry. By establishing clear protocols for extraction procedures, chemical analysis techniques, and data reporting requirements, this guidance aims to improve safety assessments for medical devices.