For three decades, the ISO 10993 international standard series has provided the overarching guidance on evaluating medical devices for biocompatibility. The new international standard, ISO 18562, addresses gaps. Here’s what you need to know.
Matthew Jorgensen, Erin Bakes and Robert Mueller, Nelson Laboratories
(Image courtesy of Nelson Labs)
Here’s an example of a gap in ISO 10993: When a gas is the carrier in an externally communicating device, the risk profile is different than if the carrier were a liquid, and liquids are the suggested matrices of ISO 10993. Consider a device with brass connectors. If tested by methods suggested by ISO 10993, the connector will be extracted in minimal essential media (MEM) fluid for a cytotoxicity test, and will certainly fail because MEM fluid will oxidize enough copper and zinc to be cytotoxic. The failed cytoxocity of a brass connector in a gas path is not meaningful, however, because air cannot dissolve metals to carry them to the patient.
The new international standard, ISO 18562, addresses gaps such as these by recommending alternative test methods to evaluate the risks mentioned within the broader context of ISO 10993.
Endpoints recommended by ISO 10993
Consider, for example, an oxygen concentrator, which enriches the oxygen concentration in air through the use of a synthetic zeolite material. The device’s materials have permanent, external communicating exposure to the patient (though none of the materials physically contact patient tissue). The following endpoints must be addressed, according to ISO 10993-1:
- Cytotoxicity;
- Sensitization;
- Irritation;
- Acute systemic toxicity;
- Material-mediated pyrogenicity;
- Subacute toxicity;
- Genotoxicity;
- Implantation;
- Chronic toxicity;
- Carcinogenicity.
Addressing the endpoints recommended by ISO 10993 for devices like an oxygen concentrator is challenging using traditional methods. For example, how does one implant a complex machine into an animal? The relevance of toxic effects from a direct cell or liquid extraction of an oxygen concentrator is questionable when the toxic materials may not be transferred via a gas pathway. In an oxygen concentrator, zeolite is in the gas path and has a violent exothermic reaction with aqueous solutions. It is not surprising that this would kill cells, and at the same time, it is equally not surprising that this test would be irrelevant.
ISO 18562 addresses the incompatibility between the methods of ISO 10993 and the goal of proving patient safety using a risk-based approach. The only way dry gas devices can communicate risk to the user is through the gas itself; therefore, analytical testing should focus on the gas with the aim of providing data of sufficient quality for toxicological risk assessment. Dry gas is expected to be capable of carrying volatile organic compounds (VOCs), particulates, and in special cases, inorganic gases. All of the toxicological risks related to these classes of devices are expected to be addressable by understanding VOCs, particulates, and (if applicable) inorganic gases.
Testing worst-case conditions for VOCs and particulates
Worst-case for VOCs must be viewed within the context of the laws of diffusion. The total amount of volatiles released by device materials is independent of the gas flow rate, being solely determined by the diffusion of the volatile through the device material. The rate of diffusion depends on the intrinsic properties of the material, the volatile compound and the temperature. Therefore, the worst-case temperature is the highest clinically relevant operating temperature for the device. The worst-case flow rate is the lowest that is clinically relevant, as this will result in the highest concentration of VOCs per volume of gas passed on to the patient.
To understand worst-case conditions for particulates, consider their source. The primary source of particulate matter in gas-path devices is residual dust from the manufacturing and packaging processes. This particulate material is expected to blow out of the device during the first few seconds of operation. The friction of moving parts also generates residual dust.
A toxicologist using worst-case clinical conditions should measure and assess the biological risk of VOCs and particulates released by a device per ISO 18562. For VOCs measured in a dry gas path, these conditions are the maximum operating temperature with minimum relevant flow rate. For particulates, it is maximum flow rate to blow out residual dust.
ISO 18562 offers a common-sense, risk-based approach to medical devices with external communicating gas path contact to patient tissue. To conduct a robust study, use sampling parameters that capture all possible clinical conditions in which the device could be used. Selecting a relevant high temperature and a low flow rate for VOCs and a high flow rate for particulates will help accomplish that goal.
Matthew Jorgensen is a chemistry and materials scientist. Erin Bakes is an associate extractables & leachables specialist. Robert Mueller is a chemistry project coordinator. They serve on the technical consulting team at Nelson Laboratories.
The opinions expressed in this blog post are the author’s only and do not necessarily reflect those of Medical Design and Outsourcing or its employees.
