GAITHERSBURG, Md. -- An FDA advisory panel recommended the agency critically evaluate sterility assurance levels for medical products in its efforts to reduce ethylene oxide (EtO) emissions.
The common sterilant is used to disinfect medical devices, everything from wound dressings to endoscopes to surgical kits, but is also a known carcinogen. In February, a commercial sterilization facility in Illinois was ordered to close under a state order related to emissions of the gas. In response, the FDA issued a warning that such closures could lead to a shortage of medical devices. In March, another sterilization facility, this time in Michigan, announced it would close by the end of the year.
More than 50% of all sterilization in the U.S. uses EtO.
As for switching to alternative methods for device sterilization? Such a move would require significant amounts of time and investment, as well as validation of each product with a new method, experts said at the FDA's General Hospital and Personal Use Devices Panel of the Medical Devices Advisory Committee.
"In almost every case the device is dictating the sterilization method," said panelist Stephen Li, PhD, who heads a consulting firm in Palm Harbor, Florida.
The panel met on Wednesday and Thursday with aimed at reducing emissions from EtO during device sterilization "without compromising assurance of sterility or effective processing of medical devices," and to determine whether alternative sterilization methods might be considered as a replacement for EtO.
Scope of the Problem
During public testimony, Chaun Powell, of the healthcare consultancy Premier, said excess capacity of EtO sterilization across the U.S. is "nearly exhausted."
Yet in surveying 600 suppliers, his group found that just 3% of respondents believed there was a "legitimate risk of product disruption."
Following the Illinois and Michigan sterilization plants closures, the country's current excess capacity is about 520 million, Powell explained. The average facility sterilizes roughly 200 million units per year. He noted, as an example, that the combined volume of and is 550 million units -- both of these facilities are at risk of closure.
"Simple math shows that if we close those two plants we exceed the current capacity across the entire U.S. by 30 million units," he said. "Two facilities of average size, you name them, that's all the capacity we have today."
To prevent or at least address this looming potential crisis, Powell urged the FDA to create greater "upstream visibility" for stakeholders, in order to reduce any potential disruptions to the supply of medical devices and products or prevent them entirely. FDA should also seek to extend the authority it already has to deal with drug shortages to include device shortages as well.
Asked whether the dire predictions cast by Powell were accurate, Suzanne Schwartz, MD, MBA, of the FDA's Center for Devices & Radiological Health (CDRH), said the numbers were "consistent" with the FDA's own research and analysis.
"If even one additional facility shut down, we will start to see spot shortages. There's no question about that," Schwartz told reporters. "In terms of a more catastrophic national impact, with two facilities shut down, it's almost a certainty."
The Environmental Protection Agency (EPA) also now has its sights on cutting EtO emissions after a new assessment showed the carcinogen to be 50 times more potent than was previously known. In August 2018, the EPA identified 20 areas in the country where EtO is the main contributor to potential cancer risk.
On Thursday, the EPA by 93% for industrial users of the chemical. Medical device sterilizers are considered commercial users and fall outside of this proposal, but plans were announced to review emissions standards for commercial sterilization operations as well.
Advice to the FDA
Asked what the agency can do to help minimize the impact of closures on healthcare delivery organizations, one panelist suggested framing the question in two time frames.
Any immediate action would fall not to the FDA, but to the HHS Secretary, said Robert Burr, MD, MSc, an endocrinologist whose expertise includes occupational and environmental medicine.
"The Secretary could declare a public health emergency and in doing that simply override the state and override the EPA and get their missing plants back online," he said.
Burr said the technology around abatement (reducing pollutants) is "extraordinarily good" and he sees no reason why with investments in abatement technology, sites would not be able to reach the proper emission standards relatively quickly and "reassure people in the neighborhood that things are okay."
Schwartz agreed with the idea of separating the solutions into long- and short-term strategies. The FDA recently issued two innovation challenges for stakeholders -- one focused on such as identifying new sterilization methods, and the other on more (i.e., cutting EtO emissions). Submissions from stakeholders are currently under review by the agency.
However, she noted that any abatement or structural changes to a facility would be subject to the EPA's authority and not the FDA's.
David Krause, PhD, deputy office director for CDRH, noted that current standards for EtO sterilization are validated at about 10-6 -- meaning that the possibility that a single spore remains nonsterile is one in a million -- and asked whether 10-3 might suffice for some products.
Panelist Gary Socola, CEO of HIGHPOWER Validation Testing & Lab Services in Rochester, New York, suggested that the 10-6 validation makes sense for reusable devices, but not for single-use items -- which were the focus of the discussion.
Industry representative Carol Pekar, MBA, a consultant in Massachusetts, suggested that the FDA put out guidance or a communication explaining that these lower validation levels are acceptable. She also suggested the agency issue sample validation protocols and that review could be accelerated for any related 510(k) applications.
Going a step further, Ashley Faulx, MD, a gastroenterologist at Case Western Reserve University in Cleveland, pointed out that many products are sterile without cause.
"We use sterile water in the colon. That makes no sense," she said.
Michael Saubolle, PhD, of the University of Arizona College of Medicine Phoenix, pointed out that while the idea conceptually makes sense, it would be a non-starter for immuno-compromised patients.
Panel chair Frank Lewis, Jr., MD, seemed confident that allowing new methods of validating EtO sterilization and potentially reducing the amount of sterilant would not impact patient safety or the efficacy of the products.
But he said increasing the patient risk profile for some devices, such as endovascular devices, would not be acceptable.
"What we heard [from industry] was that the level can be reduced and still maintain the same assurance of sterility because the actual sterility that they achieved was several orders of magnitude greater than 10-6," said Lewis.
"Are the standards higher than they need to be?" he said. "The answer to that has already been stated -- 'yes.'"
Alternatives to EtO
Over 2 days, the panel heard presentations from experts in sterilization with hydrogen peroxide, nitrogen dioxide, chlorine dioxide, peracetic acid, gamma rays, x-ray, e-beam, and moist and dry heat.
Lewis concluded that while there were many ideas suggested as a path forward, none could be completed in "the short run."
Most of the gas sterilization methods cannot be used with cardboard or cellulose materials, and many of the beam technologies and other processes like gamma rays could not be used for certain plastics without fear of damaging the device.
In addition, these products would need to be re-validated before any switch was made. For Class III devices, FDA reviews sterilization validation as part of its manufacturing controls to assure the products' safety and effectiveness.
But the panelists agreed with the idea of pursuing alternative sterilization methods for "niche categories," and one even suggested the FDA consider a new innovation challenge to determine which broad categories of devices could be sterilized by which methods.
Jason Dominitz, MD, a gastroenterologist for the Veterans Health Administration in Seattle, suggested that the FDA do whatever is in its purview to fast-track additional sterilization approvals, so that capacity for switching exists.
While experts testified that currently only 2% of medical devices have recorded another means of sterilization besides EtO, the possibility exists that some device makers could use other methods and have not, Schwartz told 鶹ý.
Defining the FDA's Role
Asked by reporters, between sessions, whether the FDA would consider asking Department of Health and Human Services (HHS) Secretary Alex Azar to declare a public emergency and force facilities back into production, Schwartz intimated that such a step was premature.
"When we're dealing with a national crisis that's certainly a lever," she said, noting that it had been used for Ebola and other types of "infectious disease events."
But a decision regarding such an "aggressive measure" would require more discussion with HHS and the Assistant Secretary of Preparedness Response to determine its appropriateness.
Regarding the FDA's own authorities, Schwartz told 鶹ý that the agency has proposed legislation around device shortages similar to those by the Center for Drug Evaluation and Research for its drug shortage program.
In a situation like the current one with the EtO sterilization facility closures or in the case of a natural disaster or all-hazards event, CDRH can only request this kind of information, but companies have no regulatory or legal requirement to comply, she said.
The proposed request for additional authorities, which was published in the , is intended to ensure the agency has "timely and accurate" information related to "likely or confirmed national shortages of essential devices."
The request, if made law, would give the FDA the authority to "require firms to notify FDA of an anticipated significant interruption in the supply of an essential device; require all manufacturers of devices determined to be essential to periodically provide FDA with information about the manufacturing capacity of the essential device(s) they manufacture; and authorize the temporary importation of devices whose risks presented when patients and healthcare providers lack access to critically important medical devices outweigh compliance with U.S. regulatory standards."
The FDA is currently working on the statutory language and will be seeking out sponsors for the bill.