The safety of a medical device is of utmost concern and importance at all times during its development, manufacturing, regulatory submission and use. One critical step in establishing the safety of a device is to evaluate how the device interacts with the body. This is better known as the device biocompatibility. Evaluation of biocompatibility can be a complex topic involving many considerations, starting from the materials of construction through device design, processing, sterilization and intended use. The evaluation can be at the material level and the device level.

At the material level, USP Class VI is a group of tests developed to evaluate materials intended for use in medical applications. These rigorous tests evaluate materials and their extractable substances for the potential to cause toxicity and irritation. The process provides basic assurances that the materials are not inherently toxic when used in medical applications. The tests include three in vivo biological reactivity evaluations, generally performed on mice or rabbits to mimic use in humans.

ISO 10993 is a standard that covers evaluation of medical devices that come into direct or indirect contact with the human body for biocompatibility using a risk-based approach. The biological evaluation of the devices (and their materials of construction) based on the overall device risk depends on a large number of considerations, which are explored in part 1 of ISO 10993 (ISO 10993-1) and in the FDA’s recently finalized updated guidance document on this standard.

Device makers’ materials suppliers may be helpful in conducting the evaluations at both the material and device levels.

A risk-based approach

ISO 10993 guidance emphasizes using a risk-based approach. What exactly is a “risk-based approach?”

ISO 14971 defines the term “risk” as “the combination of the probability of occurrence of harm and the severity of that harm.” The standard defines harm primarily as physical injuries and damage to health, but it also includes harm to goods and to the environment.

The risk-based approach adds the harm resulting from regulatory non-compliance and bureaucracy. It is about weighing the likelihood and the consequence of the identified risks and adapting the expenditure of resources accordingly. [Source]

As stated in ISO 10993-1 (page 9), “[T]he biological evaluation of a medical device (or a material component of such) should be conducted within the framework of a risk management process. Such a process should generally begin with assessment of the device, including the material components, the manufacturing processes, the clinical use of the device including the intended anatomical location, and the frequency and duration of exposure. Considering this information, the potential risks from a biocompatibility perspective should be identified. Once the risks have been identified, the [OEM] should assess what information is already available regarding those risks and identify the knowledge gaps that remain. Considering the potential biological impact, a plan should be developed to address the knowledge gaps either by biocompatibility testing or other evaluations that appropriately address the risks.”

The new, risk-based guidance moves away from a check-the-box approach to biocompatibility testing. One of the FDA’s goals is to reduce unnecessary testing, particularly animal testing, by giving preference to chemical constituent testing and in vitro models where these methods yield equally relevant information.

As intended by the FDA, more OEMs seem to be adopting chemical characterization assessments as part of their biocompatibility evaluation process. If an OEM has a good, comprehensive chemical and physical characterization of a material, it may not be necessary to conduct testing for all or a portion of the biocompatibility endpoints suggested by the FDA.

Chemical assessments

Because an understanding of all the chemicals that could contact a patient during the use of a device is critical to the evaluation of biocompatibility, a chemical assessment of the device and its materials of construction may be informative. This assessment may be needed not only during initial development of the device, but also upon any changes, such as manufacturing process or material supply changes. An OEM’s material supplier can support the OEM’s chemical assessment in two ways:

by providing information on chemical composition
by providing guidance to ensure materials are converted with minimal chance for degradation or creation of unintended byproducts during the OEM’s processing and sterilization cycles

For example, some thermoplastics contain chemical building blocks that are susceptible to degradation under extreme environmental conditions. The high heat, temperature, and pressure of an autoclave can degrade some thermoplastics and create potential for harmful byproducts. So, even though the material coming from the supplier passes all the biocompatibility testing, the sterilization process should be carefully considered to prevent creation of additional risk.

Some of the information that could be helpful to an OEM’s chemical assessment may be proprietary to the material supplier. The OEM can provide it to the FDA by reference to the material supplier’s device master file (MAF). The FDA does not mandate any specific content for a device MAF. However, Attachment B of the guidance document lists information that should be included in an MAF to support a biocompatibility evaluation.

Lubrizol supports all of its medical grade thermoplastic polymers (TPUs) with MAFs. We also provide customers with biocompatibility test results for many of our materials in their processed form. OEMs can use this information as a starting point for device risk assessment, as each medical device manufacturing and sterilization process is different. We also frequently consult with OEMs and their toxicology partners on component and device level chemical analysis, especially related to potential extractable/leachable components.

Application-specific considerations

As part of the risk-based evaluation of devices intended for long-term function in the body, OEMs may include consideration of the biostability of the device and its constituent materials. Biostability considers the impact of the body on the device. It often includes consideration of the body’s attempt to encapsulate the device or degrade the device as a result of the foreign body response. (Of course, some devices are intentionally designed to be degradable.) Because the biostability can influence the way a device interacts with the body or can change the device’s biological risk assessment, it may need to be considered in the context of the risk-based approach to biocompatibility testing.

Surface chemistry is important to the biological performance of an implantable device. When in place in the biological environment, biomedical implants are prone to surface biofouling. Proteins, cells, and other substances in biological fluids may adhere to many biomaterials’ surfaces, changing the original characteristics in a way that impacts the performance of the device. For example, it may be important to prevent protein and cell adhesion to the surface of a vascular catheter in order to prevent blood-clotting and other undesirable clinical conditions.

Because Lubrizol understands nuances of biostability/biocompatibility needs in the vascular catheter space, we are well positioned to develop innovative chemistry to address surface biofouling.

Conclusion

Understanding the material, process, clinical use, patient exposure, and design interactions within the risk-based framework is essential for biocompatibility evaluation of devices. Your material suppliers may be helpful in several aspects of the biocompatibility assessment process.

For questions, contact our team of materials experts. For more information on navigating the regulatory process for medical devices incorporating medical-grade polymers, download our eBook.

More than Materials: A Risk-Based Framework for Biocompatibility Assessment