September 1, 2022 | The FDA’s Center for Devices and Radiological Health (CDRH) is seeking to advance innovation in microfluidics-based medical devices with the development of a regulatory science tool for leakage testing, according to Rucha Natu, Ph.D., a mechanical engineer in CDRH’s Office of Science and Engineering Laboratories, speaking at the recent Next Generation Dx Summit in Washington, D.C. A growing number of diagnostic and therapeutic medical devices use microfluidics technology—including about 30% of Emergency Use Authorizations (EUAs), 40% of 510(k) pre-market submissions, and 27% of pre-submissions—and leakage testing has emerged as a nontrivial issue that can contribute to device failure.
Leakage testing is designed to identify cracks and delamination in microfluidic devices, which might be stored, shipped, and used quite differently from conventional electronic devices, Natu says. The targeted products often incorporate microfluidic components, versus being standalone microfluidic devices, she notes, and typically have a card or small chip that is read by an analyzer.
The CDRH controls more than 236,000 regulated devices and deals with more than 25,000 medical device manufacturing firms making everything from thermometers and reagents to devices for managing ADHD, she shares. During the COVID pandemic, it has also issued over 2,000 EUA submissions.
For review purposes, says Natu, devices get sorted into one of three classes: low-risk items such as band aids and tongue depressors with general labeling requirements and some Good Manufacturing Practices; intermediate-risk products such as surgical masks as well as most microfluidic-based devices, which may require clinical data or bench testing; and high-risk devices that include pacemakers and heart valves where clinical trials are necessary.
Standards around medical devices do not always benefit small-time manufacturers, especially in the emerging microfluidics field, Natu says, pointing to the value of the FDA’s Medical Device Development Tools (MDDT) program in helping companies bring their products to market. Regulatory science tools provide a peer-reviewed resource where standards and MDDTs do not yet exist.
In terms of leakage testing, the objective is to develop test methods and protocols for flow testing of microfluidic devices where there are challenges related to bubble formation or channel coagulations, she continues. The steps to developing a regulatory tool include datamining of internal and public databases to learn how many different devices are using microfluidics, stakeholder engagement to identifying gaps, and challenges affecting the entire medical device development lifecycle, and prioritization of which regulatory science tools to pursue over the next two to three years that would address the major challenges.
Standards are needed in the field of microfluidics in areas that include common testing methods, interconnections, and inter-compatibility, modularity and assembly, and flow control, as covered in a perspective published in Lab on a Chip (DOI: 10.1039/D0LC00963F). Notably, microfluidics-based devices have higher sensitivity for pressure compared to macro devices, says Natu.
Datamining of submissions made to the FDA over the last few years indicate that most microfluidic devices, other than infusion pumps, are diagnostic devices, use less than one milliliter of fluid, have an analysis time of one hour or less, and most often use blood, she says. Detection methods are typically one of four types: optical/visual, fluorescence, mechanical, or electrical.
Leakage is one of the more commonly seen issues with microfluidic devices, says Natu. Among the consequences of leakage are analyte loss and the need to redraw sample. It can also affect the decision-making of physicians, create a safety issue due to biocompatibility or leaching behavior in the device, and, in the case of insulin pumps, result in inadequate dosage.
Key considerations for leakage testing, as shared during Natu’s presentation, include the test medium (liquid versus gas, density, viscosity, surface tension), operating conditions (e.g., pressure and temperature, especially if the device will be used at home), duration of use (a device may start leaking once liquid is able to break the surface tension), static versus dynamic, measurement technique (since pressure requires higher sensitivity when measured in a microfluidic device), and pumping mechanics (e.g., peristaltic pumping, centrifugation, capillary flow), sample size selection, and pre-conditioning of the device.
A regulatory science tool for leakage testing could be available as early as 2023. Currently, Natu says, the microfluidics program is working on a journal article reviewing different leakage testing practices used by industry as well as a white paper. Two years of inter-laboratory studies in the U.S. and Europe are expected to be underway between 2023 and 2025 and, if all goes well, a standard will be established shortly thereafter.
The leakage testing tool could be useful across the total product life cycle of microfluidics-based medical devices, she says, starting at the design phase as well as during bench testing, FDA assessment based on review of premarket submissions, and the post-market phase to observe for adverse events.
Industry input is being sought to help prioritize objectives, says Natu. Feedback on the knowledge gaps the agency should be targeting can be submitted via email to OSEL_Microfluidics@fda.hss.gov.