Regulatory Overview of Leachables and Extractables in Flexible Medical Devices

Many factors affect the safety, suitability, and efficacy of the various medical devices used every day in the healthcare setting. Flexible medical devices are utilized both internally and externally. From tubes and drains, to bandages and tapes, they all must pass rigid testing standards that ensure patient safety.

In addition to the necessity of biocompatibility (harmlessness to body tissue), all medical devices must meet stringent requirements pertaining to extractables and leachables as indicated by the Food and Drug Administration (FDA). All test laboratories must refer to the final guidance document published by the FDA on June 16, 2016: Use of International Standards ISO 10993-1, "Biological evaluation of medical devices, Part 1: Evaluation and testing within a risk management process." 

Recorded during a live webinar on July 21, 2016, Irene Aihie of CDRH's Office of Communication and Education, stated, "The final guidance allows manufacturers to use the ISO 10993-1 standard when assessing the potential biological response of the medical devices and materials that come into direct or indirect contact with the human body."

What are Extractables and Leachables? 

Extractables are soluble substances removed from material when treated with solvent. Leachables are chemicals removed from the medical device by the action of water or other liquids related to the use of the device. Both can be composed of organic or inorganic substances. Sources typically include:

• lubricants
• additives
• accelerators
• monomers and high molecular weight oligomers from incomplete polymerization
• degradation products from temperature, absorption, oxidation, hydrolysis, corrosion or dissolution
• residual solvents
• the process itself - like mold release agents and anti-static and anti-stick agents

General Biocompatibility Testing Considerations

After the FDA published the initial draft of the guidance document in April 2013, they received over 700 comments from 36 groups and individuals. Specifically, 11 device companies, seven trade associations, four drug companies, three biocompatibility test labs, two standards development organizations, two consulting groups, and one academic institution.

Since many comments requested more emphasis on risk management for biocompatibility evaluations, this was added to the guidance published in June 2016: 

"The Agency makes a clearance or approval decision for a medical device as it is supplied in its final finished form. The Agency does not clear or approve individual materials that are used in the fabrication of medical devices. Therefore, the risk assessment should evaluate not only the materials used in the device, but also the processing of the materials, the manufacturing methods (including the sterilization process), and any residuals from manufacturing aids used during the process."

Other considerations: the proposed clinical use of the device, including anatomical location, duration of exposure, and intended use population. 

Test-Specific Considerations

The FDA recommends testing the following issues because they are often areas where deficiencies are frequently identified in premarket submissions:

• Cytotoxicity
• Sensitization
• Hemocompatibility
• Pyrogenicity
• Implantation
• Genotoxicity
• Carcinogenicity
• Reproductive and Developmental Toxicity
• Degradation Assessments

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Flexible Medical Device Composition

Medical devices are often made of polymers such as plastics or elastomers (rubber). The main benefits of these materials being flexibility, durability, and lighter weight than metal or glass. Also, additives are sometimes incorporated into polymers. They are used to create transparency, add color, or to give the material a desired physical property. 

The trade-off is that when any substance or chemical is added to enhance these flexible products, their use and application can potentially cause complications due to degradation over time. For this reason, stabilizers are sometimes incorporated. With each additional chemical, the result is a product that is more prone to leaching of chemicals, with possible exposure to the patient.

The solution is responsible and accurate testing of all components used in flexible medical devices to assure minimal risk and maximum safety and efficacy. Pace Analytical suggests, "When selecting the appropriate tests for biological evaluation of a medical device, one must consider the chemical characteristics of device materials and the nature, degree, frequency, and duration of its exposure to the body."

Conclusion

In today's rapidly improving and expanding medical device market, maintaining strict adherence to the established standards for extractables and leachables is imperative. This will lead the industry forward, with patient safety driving success.