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Dialysis giant Fresenius is at odds with the FDA following a protracted effort to address concerns about its hemodialysis machines.

In a posted in December, the FDA listed violations related to Fresenius Medical Care's slow response to finding potentially harmful chemicals in the silicone tubing of the machines.

"You did not take a corrective and preventative action until almost 2 years after you learned of a potential issue impacting your Hemodialysis Machines that contain peroxide crosslinked silicone tubing," the letter stated.

The company also "failed to adequately investigate the potential health impact of PCB [polychlorinated biphenyl] related compounds leaching from the components," and "failed to document your first awareness of PCB related compounds finding in peroxide crosslinked silicone," according to the letter.

FDA says Fresenius first learned of the potential problem with its silicone tubing in December 2020, but it wasn't until November 2022 that Fresenius took a corrective action, and an official recall wasn't posted to FDA's website until almost a year after that, in October 2023.

In the interim, FDA in March 2023 that the problems could impact other dialysis machines. It said it didn't have any definitive information on the risks at that time, but was working with device makers to collect data.

FDA told MedPage Today it couldn't comment on active investigations.

FDA's first action came in May 2022, when it sent a letter to that various 2008-series hemodialysis machines from Fresenius could expose their patients to non-dioxin-like polychlorinated biphenyl acids (NDL-PCBAs) and NDL polychlorinated biphenyls (NDL-PCBs). These substances were coming from the silicone tubing used in the hydraulics and dialysate lines of the machine, the contents of which eventually enter a patient's blood. No adverse events had been reported at the time.

Around that same time, Fresenius posted a "field notification" . By then, according to the FDA's most recent warning letter, the company had known about the problem for a year and half -- since December 2020.

The company, through testing to satisfy the most current International Organization for Standardization (ISO) standards, wrote that it had "discovered that non-dioxin-like polychlorinated biphenyl acids ["NDL-PCBAs"] may leach from silicone tubing manufactured with a peroxide-based catalyst."

According to the company, however, unused 2008-series machines posed the biggest risk. Toxicologists determined that there were "no detectable levels of the NDL-PCBAs" in dialysate specimens from machines that had been in use more than 30 days, meaning that "the burden of subject PCBAs in the dialysate resulting from exposure to the tubing will be highest at the tubing's first exposure and will decrease rapidly."

The chemicals, Fresenius concluded, "do not pose an immediate risk to patients' health when balanced against the need of the substantial chronic hemodialysis patient population for frequent and continuing treatment."

Nevertheless, Fresenius said it would be taking "precautionary measures" including replacing peroxide catalyst silicone tubing with platinum catalyst tubing. It recommended switching out Fresenius machines that had been in use for less than a month. The company would also conduct further testing and develop a protocol for additional "pre-use rinsing" of new machines and replacement parts.

In October 2022, the FDA "cleared" the updated platinum catalyst silicone tubing for use, based on a report that neither chemical was detected in the modified tubing.

Platinum curing of silicone, as opposed to peroxide curing, is a newer, more expensive process, according to a handful of companies that make such products. The key advantage of platinum curing, according to post: "there are no by-products which can leach from the final polymer."

PCBs, part of a group known as "forever chemicals" bioaccumulate, and are persistent in the environment. According , PCBs are "probable" or "reasonably anticipated to be" carcinogens. Indeed, in recent guidance, the agency recommended blood testing for per- and polyfluoroalkyl substances (PFAS), another class of persistent chemicals with harmful health effects.

Less is known about NDL-PCBs than DL-PCBs, though the EU places limits on NDL-PCB content . According to the EU's , NDL-PCBs "have a different mechanism of toxicity but can also cause adverse effects on health."

In the field notice, Fresenius stated, "There is evidence in medical literature from which to conclude that DL-PCB compounds in general may be toxic in some settings, but evidence in humans is lacking for the NDL-PCBs."

The next came in March 2023, announcing that the agency had become "aware of other hemodialysis and peritoneal dialysis systems that have parts made of chlorinated peroxide cured silicone."

However, the agency said at the time that it didn't know "whether there is any risk of exposure to NDL PCBAs or NDL PCBs."

"The FDA is working with these manufacturers to further collect and evaluate data to determine the risk of exposure to NDL PCBAs and NDL PCBs on patients and develop strategies to address the issue, if needed," the letter stated.

Baxter, another leading company in kidney care, did not respond to requests for comment on such correspondence with the FDA. The agency declined to comment to MedPage Today on "possible or ongoing investigations."

In October 2023 -- nearly 3 years after Fresenius was alerted to the issue -- FDA posted a notice of a , its most serious type of recall, for 2008 series Fresenius dialysis machines. It noted that the recall "is a correction, not a product removal."

The FDA's states that only 207 devices were affected -- ostensibly, those that have been in use for less than 36 days, or 486 total hours.

"The use of affected machines may cause serious adverse health consequences months to years after exposure, including endocrine dysfunction, liver issues, neurobehavioral changes, skin problems [acne, rashes], and male infertility," the notice stated, adding that there were no reports of death.

The notice also mentions that Fresenius had sent an "Urgent Medical Device Correction letter" to affected customers a month prior, in September 2023.

It also mentions that machines purchased from Fresenius after October 2022 are unaffected, as those devices were made using the platinum cured silicone tubing.

In the midst of the tubing issue, three lots of single-use syringes for the same 2008 dialysis machine models, "due to blood or heparin leaking back or from the syringe," according to the FDA's recall notice, with "an unknown black material inside the syringe."

FDA's warning letter soon followed in December, citing issues found during an inspection that took place over the summer of 2023. In addition to the problems with the 2-year delay in a corrective action and failing to adequately investigate the potential health impacts of PCB leaching, the letter noted that Fresenius started using the platinum cured silicon tubing in its new machines without a formal notice to the FDA.

In an emailed statement, Fresenius wrote in part that it "did not find any reports of known health risks or impact of PCBAs in medical literature. ... The Warning Letter issued by the FDA expresses that the Agency is seeking additional information to assess the adequacy of Fresenius Medical Care's responses and the associated [corrective action plans]."

"Fresenius Medical Care takes very seriously the concerns identified by the FDA, and management is fully committed to addressing the Agency's observations," the statement read. "The company is working diligently to fully address the points noted in this Warning Letter and will continue to provide full information to the FDA to demonstrate regulatory compliance and our commitment to quality."

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