Fresenius Medical Care AG & Co. KGaA

December 4, 2023 Dear Ms. Giza:

The United States Food and Drug Administration (FDA) conducted an inspection of your firm’s medical device operations, Fresenius Medical Care Holdings, Inc. (Fresenius), d.b.a. Fresenius Care North America, located at 920 Winter Street, Building 920, Waltham, MA 02451-1521, from June 26, 2023, through August 2, 2023. During the inspection, FDA investigators determined that your firm is a medical device specification developer responsible for complaint handling, recall management, and quality system oversite of your North American manufacturing of dialysis systems and accessories, such as the 2008 Series Hemodialysis Machine. Under section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. § 321(h), these products are devices because they are intended for use in the diagnosis of disease or other conditions or in the cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body.

This inspection revealed that the above devices are adulterated within the meaning of section 501(h) of the Act, 21 U.S.C. § 351(h), in that the methods used in, or the facilities or controls used for, their manufacture, packing, storage, or installation are not in conformity with the current good manufacturing practice requirements of the Quality System regulation found at Title 21, Code of Federal Regulations (CFR), Part 820, and Title 21 CFR Part 806, Medical Devices, Reports of Corrections and Removals.

We received your responses dated August 24, 2023, and September 22, 2023, from Kathleen Storro, Vice President, Quality Management System, North America, which responded to the Form FDA 483, List of Inspectional Observations issued to your firm on August 2, 2023. We address your responses below.

Violations include, but are not limited to, the following:

1. Failure to establish and maintain procedures for implementing corrective and preventive actions, as required by 820.100(a). Specifically, your Corrective Action and Preventive Action, Procedure No. S100016-03, Rev E. Dated January 30, 2023, is inadequate in that:

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. You were notified on December 3, 2020, of PCB emissions that were detected from the peroxide crosslinked silicone tubing component, and you did not open CAPA 1100660 until June 15, 2022. The devices were not recalled until November 25, 2022.

You failed to adequately investigate the potential health impact of PCB related compounds leaching from the components of your 2008 K, 2008 K2 and 2008 T Hemodialysis Machines that use peroxide crosslinked silicone tubing. The risk calculation you performed to determine the risk level of PCB related compounds leaching was inadequate to determine the overall risk of the device. You did not include the minimum body weight of 20 kg, as listed in the instructions for use (IFU) when calculating the Health Hazard Assessment (HHA-FA-2022-19-W) for the 2008 series of Hemodialysis Machines with peroxide crosslinked silicone tubing.

You failed to verify the corrective actions were effective for CAPA 932073, as required by your CAPA procedure. CAPA 932073 resulted in a recall of the 2008T and 2008T Bluestar Hemodialysis Machine with CDX-Indicated for acute and chronic dialysis therapy due the false alarm "Remove USB 2 Device" (RES 91154).

We reviewed your firm’s responses and have concluded that the adequacy of your response cannot be determined at this time because you have not completed your proposed corrective and preventive actions. Please provide an update on the status of your corrective actions.

2. Failure to document all activities and their results required under this section (Corrective and preventive action) as required by 21 CFR 820.100(b). Specifically:

CAPA 1100660 dated June 15, 2022, opened for the PCB related compounds issue failed to adequately document all the activities you performed after you became aware of PCB related compounds finding. The CAPA states that there are no actions required however you had action plans for PCB related compounds which you implemented via design change, product hold and a rework which were covered by NCs 1145819 and 1150080 and Quality Event 1057552. Your CAPA also failed to document your first awareness of PCB related compounds finding in peroxide crosslinked silicone which you received from your supplier. As well as corrections to distributed devices, which you initiated on November 25, 2022, to update/correct the silicone tubing.

We reviewed your firm’s responses and have concluded that the adequacy of your response cannot be determined at this time because you have not completed your proposed corrective and preventive actions. Please provide an update on the status of your corrective actions.

3. Failure to establish and maintain procedures for validating the device design, as required by 21 CFR 820.30(g). Specifically, Design Validation Procedure, S100021-13, was not followed when conducting retrospective design validation of your 2008T, 2008 K and 2008 K2 Hemodialysis Machines to determine if the devices can be used safely and effectively by the intended users. (b)(4) rounds of real-world studies were conducted to detect PCB related compounds, and if detected, determine which day of use the PCBs were detected. For example:

Failure to establish the protocols for the (b)(4) rounds of studies and for round (b)(4) failed to adequately establish the protocol.

The test method was not specific regarding background blank dialysate usage to repeating the test.

The round (b)(4) study, initial results found PCB related compounds present after 60 days of usage; however, the device was later identified as never have been used.

Samples were collected for (b)(4) for the study; however, the protocol identifies samples were to be collected for (b)(4) only. You failed to update the protocol when they made changes.

Failure to approve the protocol before performing the formal validation.

We reviewed your firm’s responses and have concluded that the adequacy of your response cannot be determined at this time because you have not completed your proposed corrective and preventive actions. Please provide an update on the status of your corrective actions.

Exposure to PCBs can have long-term health consequences linked to hepatic effects (including serum hepatic enzyme elevation), dermal changes (acne, rashes), certain cancer (e.g., liver, gallbladder, biliary tract, gastrointestinal tract, brain, malignant melanoma, non-Hodgkin’s lymphoma), neurodevelopmental and behavioral toxicity via lactational exposure, endocrine dysfunction (thyroid), neurobehavioral alterations, immune system alterations, anemia, and male reproductive effects. Additionally, patients with end stage renal disease on dialysis are vulnerable and adverse events may get magnified or present differently in this population due to their altered physiology.

Our inspection also revealed that your firm’s hemodialysis machines are misbranded under section 502(t)(2) of the Act, 21 U.S.C. § 352(t)(2), in that your firm failed or refused to furnish material or information respecting the device that is required by or under section 519 of the Act, 21 U.S.C. § 360i, and 21 CFR Part 806 – Medical Devices; Reports of Corrections and Removals. Significant violations include, but are not limited to, the following:

4. A correction or removal, conducted to reduce a risk to health posed by a device, was not reported in writing to FDA within 10-working days of initiating such correction or removal, as required by 21 CFR 806.10(b). Specifically, to reduce a risk to health posed by the device, you initiated a field action starting on November 25, 2022, for your 2008 Hemodialysis Machines by going to customers’ sites to change the silicone tubing associated with PCBA related compounds leaching. As of the time of the recent inspection, you have updated (b)(4) Hemodialysis Machines with a new silicone tubing “platinum cross linked silicon” without a formal notice to FDA. You field corrected the devices after FDA published a safety communication on potential risk of exposure to toxic compounds when using certain hemodialysis machines manufactured by Fresenius Medical Care.

Our office confirms receipt of your letter, dated September 6, 2023, Report of Corrections and Removal (RES 92788). We reviewed your firm’s responses and have concluded that the adequacy of your response cannot be determined at this time. Your responses state that CAPA 1472083 has been opened and root cause investigation, appropriate process improvements to S100036-01, Coordinating Field Corrections, Removals, or Recalls, will be implemented, as necessary. Please provide an update on the status of this CAPA.

Your firm should take prompt action to address any violations identified in this letter. Failure to adequately address this matter may result in regulatory action being initiated by the FDA without further notice. These actions include, but are not limited to, seizure, injunction, and civil money penalties.

Other federal agencies may take your compliance with the Act and its implementing regulations into account when considering the award of federal contracts. Additionally, should FDA determine that you have Quality System regulation violations that are reasonably related to premarket approval applications for Class III devices, such devices will not be approved until the violations have been addressed. Should FDA determine that your devices or facilities do not meet the requirements of the Act, requests for Certificates to Foreign Governments (CFG) may not be granted.

Please notify this office in writing within fifteen business days from the date you receive this letter of the specific steps your firm has taken to address the noted violations, as well as an explanation of how your firm plans to prevent these violations, or similar violations, from occurring again. Include documentation of the corrections and/or corrective actions (which must address systemic problems) that your firm has taken. If your firm’s planned corrections and/or corrective actions will occur over time, please include a timetable for implementation of those activities. If corrections and/or corrective actions cannot be completed within fifteen business days, state the reason for the delay and the time within which these activities will be completed.

Your firm’s response should be comprehensive and address any violations included in this Warning Letter. If you believe that your products are not in violation of the Act, include your reasoning and any supporting information for our consideration as part of your response.

Your firm’s response should be sent to: Gina Brackett, Director of Compliance Branch, at oradevices1firmresponse@fda.hhs.gov. Refer to CMS # 666791 when replying. If you have any questions about the contents of this letter, please contact Compliance Officer, Richard Cherry at 215-717-3075 or at richard.cherry@fda.hhs.gov.

Finally, you should know that this letter is not intended to be an all-inclusive list of the violations at your firm’s facility. It is your firm’s responsibility to ensure compliance with applicable laws and regulations administered by FDA. The specific violations noted in this letter and in the Inspectional Observations, FDA 483, issued at the close of the inspection may be symptomatic of serious problems in your firm’s manufacturing and quality management systems. Your firm should investigate and determine the causes of any violations and take prompt actions to address any violations and bring the products into compliance.