The article outlines the basics of chemical analysis in the context of biocompatibility of medical devices.
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The Food and Drug Administration (FDA or the Agency), the US regulating authority in the sphere of healthcare products, has published a draft guidance document dedicated to chemical analysis for biocompatibility assessment of medical devices. Once finalized, the guidance will provide an overview of the applicable regulatory requirements, as well as additional clarifications and recommendations to be taken into consideration by medical device manufacturers and other parties involved in order to ensure compliance.
At the same time, provisions of the guidance are non-binding in their legal nature, nor are they intended to introduce new rules or impose new obligations. Moreover, the authority explicitly states that an alternative approach could be applied, provided such an approach is in line with the underlying legislation and has been agreed with the authority in advance.
Introduction
The FDA has developed this draft guidance to outline recommended approaches for chemical analysis during the biocompatibility assessment of medical devices. This document offers a standardized approach aimed at improving the consistency and reliability of chemical analyses in premarket submissions.
While manufacturers may adopt alternative strategies for chemical characterization, the guidance is based on the FDA’s extensive experience in evaluating such studies. Thus, the main focus is on improving the process, yet manufacturers have the flexibility to design assessments that suit their devices’ specific characteristics and intended uses.
According to the document, chemical characterization is considered a pivotal method in assessing the overall biocompatibility of medical devices, as outlined in this guidance. Although the guidance provides a standardized approach, the FDA allows for different methods as long as they satisfy the requirements laid out by applicable statutes and regulations.
In addition to this, for the current edition of FDA-recognized consensus standards mentioned in the document, stakeholders can refer to the FDA’s database of consensus standards.
Regulatory Background
As per the FDA guidance, biocompatibility assessment is done through a risk management process. The FDA recognizes International Standard ISO 10993-1, which addresses the biological evaluation of medical devices.
Biocompatibility risks are identified through a risk assessment process and mitigated via relevant data such as published literature, animal studies, or biocompatibility testing. Chemical characterization, as described in ISO 10993-18, plays a significant role in characterizing chemicals that may be released from a medical device into the body.
This helps to mitigate certain risks associated with biocompatibility evaluation. In some cases, chemical characterization can serve as an alternative to biological testing when used in conjunction with toxicological risk assessment (TRA).
This is supported by another standard, ISO 10993-17, which outlines the toxicological risk assessment of medical device constituents. Furthermore, chemical characterization can be particularly helpful in establishing chemical equivalency during the evaluation of changes in materials or manufacturing processes of a device.
The use of chemical characterization can expedite the biocompatibility evaluation by addressing multiple endpoints at once and minimizing the need for animal testing. ISO 10993-18 details several chemical characterization approaches, including information gathering, compositional analysis, and extractable studies.
Among these, extractable studies are most frequently used, focusing on identifying and quantifying substances that are released from medical devices under laboratory conditions. Chemical analysis of device extracts is a crucial aspect of this process.
It involves identifying and semi-quantifying chemical constituents extracted from a device, especially when the full chemical composition is unknown. Both non-targeted and targeted analyses can be used depending on the specific constituents expected to be present in the device.
However, there is no standardized methodology for conducting extractable studies and chemical analyses. This variability in approach has often resulted in inconsistent and unreliable data.
Therefore, the FDA has provided detailed recommendations in this draft guidance to enhance the consistency of these studies and align them with relevant standards like ISO 10993-18.
Scope
This draft guidance offers recommendations for collecting and reporting chemical characterization data.
This data can be used to support several activities, including:
- Non-Targeted and Targeted Analysis for Biocompatibility Evaluation: The guidance suggests methods for screening non-specified extractables (non-targeted analysis) or testing specified extractable (targeted analysis) for evaluating biocompatibility endpoints such as acute, subacute, subchronic, and chronic systemic toxicity, genotoxicity, carcinogenicity, and reproductive or developmental toxicity. These studies should be used in conjunction with toxicological risk assessments (TRA).
- Chemical Equivalency Comparisons: Chemical characterization can be employed to compare a new device with a previously biocompatible device. This comparison can serve as part of a biological equivalency evaluation to confirm that the new device shares chemical similarities with the biocompatible device, which could reduce the need for further biocompatibility testing.
The methods suggested in this draft guidance are meant to be widely applicable across various medical devices. However, there may be exceptions for certain device categories, such as ophthalmic or respiratory devices, where different methodologies may be necessary due to specific materials or established testing approaches.
For instance, devices like contact lenses, dental materials, or gas pathway devices may require adherence to specific consensus standards (e.g., ISO 11979-5, ISO 18562-3).
Device-Specific Considerations
The authority further acknowledges that some medical devices require additional considerations during studies due to their unique characteristics. These include devices that are absorbable, degradable, or those that contain animal tissues.
Combination products, as well as devices that change their physical state during use (e.g., expand or absorb), also pose unique challenges in chemical characterization. While this list is not exhaustive, it highlights the complexity of chemical analysis for certain medical devices.
For these complex cases, manufacturers may need to adapt the recommendations to fit their specific devices. It is recommended that manufacturers consult with the FDA before initiating studies in these cases.
The Q-submission process can be particularly useful for obtaining FDA feedback on study designs. In some cases, a supplemental study that simulates clinical use of the device may be justified.
Simulated-use or leachables studies, which fall outside the scope of this draft guidance, can help refine the exposure estimate and lead to more accurate toxicological risk assessments. As with other complex cases, manufacturers are encouraged to discuss the planned approach with the FDA beforehand.
The Q-submission process can be used to obtain further guidance from the FDA on such study designs.
Conclusion
In summary, this draft guidance provides a framework for improving the consistency and reliability of chemical analysis in the biocompatibility assessment of medical devices. At the same time, manufacturers are given the flexibility to tailor their chemical characterization approaches to suit the specific characteristics of their medical devices. The authority also encourages the parties involved to reach out for additional consultations in case of any concerns arising.
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