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WARNING LETTER
CMS# 671249

January 4, 2024

Dear Mr. Antonelli:

During an inspection of your firm, Fresenius Kabi USA, LLC, located at 50 High Street, Suite 50, North Andover, MA 01845-2620 on August 15, 2023, through September 7, 2023, an investigator from the United States Food and Drug Administration (FDA) determined that your firm is a specification developer and manufacturer of the Ivenix Infusion System which includes the Ivenix Infusion Pump, Infusion Safety Management Software, and Intravascular Administration Set. 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 these 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.

We received responses from Benjamin Powers, Vice President, Research and Development, and Rebecca McCandless, Senior Director, Quality, dated September 28, 2023, October 27, 2023, November 28, 2023, and December 28, 2023, concerning our investigator’s observations noted on the Form FDA 483 (FDA 483), List of Inspectional Observations, that was issued to your firm. We address this response below, in relation to each of the noted violations. These violations include, but are not limited to, the following:

1. Failure to establish procedures for implementing corrective and preventive action, as required by 21 CFR § 820.100(a). Specifically, your CORRECTIVE AND PREVENTIVE PROCEDURE, Doc.ID: 410-0013-01, Revisions 12, 13, and 14, are inadequate in that:

a. Health risk assessments, health hazard evaluations, and root cause analyses investigations are routinely not completed within the required ten-day timeframe, per your CORRECTIVE AND PREVENTIVE PROCEDURE, Doc.ID: 410-0013-01. Specifically,

i. CAPA-00041 was initiated on July 20, 2022, to address (b)(4) and (b)(4) on the Ivenix Large Volume Infusion Pump, and the Health Risk Assessment/Health Hazard Evaluation has been in draft form since January 3, 2023, and was still open during the current FDA inspection.

ii. CAPA-00047 was initiated on March 22, 2023, after becoming aware that your contract manufacturer continued to use the previous revision of the (b)(4) component, and the Health Risk Assessment/Health Hazard Evaluation has been in draft form since July 10, 2023, and was still open during the current FDA inspection.

b. Your ROOT CAUSE ANALYSIS, 420-0001-01, Revision 2.0 Work Instruction has not been adequately implemented, and the root cause analysis investigation conducted as part of CAPA-00040 is inadequate. CAPA-00040 was initiated on May 13, 2022, after becoming aware of a software bug, indicates that your out-of-business firmware vendor had previously conducted a software code review, but no further documentation of such review is available, and no further root cause investigation is documented. Additionally, the quality issue related to CAPA-00040, resulted in the Class I recall RES 90845, initiated on September 8, 2022.

c. The verification of effectiveness of CAPA-00044, which was initiated on January 13, 2023 to address fluid ingress into the Ivenix Large Volume Infusion Pump, is inadequate in that the required validation was not conducted. Specifically, a leak test, as required by the verification and effectiveness plan and the verification protocol was not followed as both the assembler and inspector did not use magnification to conduct the visual inspection. Finally, CAPA-00044 resulted in the Class I recall RES 91783, initiated on March 10, 2023, and is still on-going.

The adequacy of your firm’s responses cannot be determined at this time. Your responses document that you have implemented corrections to the specific instances detailed above. Your responses also indicate that you plan to implement additional corrective actions by updating related written procedures and work instructions, as well as implementing training. Alternatively, the adequacy of your responses cannot be determined at this time, as there is no available evidence to document that your planned corrective actions will prevent recurrence of these violations.

2. Failure to establish and maintain procedures to control the design of the device in order to ensure that specified design requirements are met, as required by 21 CFR § 820.30(a). Specifically, the ECO-00089 Impact Assessment and FAI-3552, do not document that your firm evaluated the apparent risk of the continued use of the Rev B (b)(4) or evaluated to ensure that specified design requirements could continue to be met, as required per the CHANGE ORDER PROCESSING, Doc.ID: 410-0011-01, Rev: 17 and CHANGE CONTROL, Doc.ID: 410-0011-01, Rev: 13 procedures. Additionally, your firm has no supporting evidence to demonstrate verification of the remaining inventory quantities of the Rev B (b)(4), nor does your firm have documentation to demonstrate how long the Rev B component continued to be used by your supplier/vendor after the implementation of ECO-00089.

We have reviewed your responses and determined they are inadequate. Your responses document that FAI-3552 has been updated to include a justification for the continued use of the Rev B (b)(4) component and that your firm planned to update the CHANGE ORDER PROCESSING, Doc.ID: 410-0011-01 on/around November 15, 2023. Additionally, your responses do not indicate that you performed a retrospective review of design changes to determine if you adequately documented the (b)(4) justification for other changes that have been made. Therefore, your responses are inadequate, as there is no available evidence to document that your planned corrective actions will prevent recurrence of these violations.

3. Failure to establish procedures for validating the device design and failure to include software validation and risk analysis, where appropriate, as required by 21 CFR § 820.30(g). Specifically, your risk analysis is inadequate in that it was not updated as required per Risk Management Procedure, 410-0009-01, Revision: 17.

The Ivenix Large Volume Pump’s Software Failure Analysis, 550-0015-04, Rev 2.0, did not include the hazard of extended start-up time to achieve the stated flow rate accuracy of +/-5%, nor was it revised to include this hazard after becoming aware of a product defect that allowed the device to exhibit this issue when infusing fluids at a rate of >50 ml/hr. and <200 ml/hr., as documented and identified in CAPA-00038 and FAI-4446. CAPA-00038 was initiated on April 1, 2022, due to startup time failures in high flow of the Ivenix Large Volume Infusion Pumps. Furthermore, this quality issue resulted in the issuance of a customer notification on April 22, 2022, and ultimately the Class II recall RES 92973.

We have reviewed your responses and determined they are inadequate. Your responses document that your risk analysis has been updated and that your firm planned to update the related risk analysis procedures and provide training to affected personnel on/around (b)(4). Your responses are inadequate because they do not indicate that you plan to perform a retrospective review of CAPAs to ensure your risk analysis has been adequately updated, and there is no available evidence to document that your planned corrective actions will prevent recurrence of these violations.

4. Failure to establish procedures for the identification, documentation, validation, or where appropriate verification, review, and approval of design changes before their implementation, as required by 21 CFR § 820.30(i). Specifically, the design change documented in FAI-3552, which was meant to address an issue found in reliability testing of the Ivenix Large Volume Infusion Pumps, was not verified or validated as required by the verification requirements outlined in FAI-3552, or as required by your PROBLEM RESOLUTION PROCESS, 410-0053-01, Rev: 02 procedure.

The adequacy of your firm’s responses cannot be determined at this time. Your responses indicate that you planned to update your Change Order Processing and Defect Resolution procedures, on/around (b)(4), and (b)(4), respectively. Alternatively, the adequacy of your responses cannot be determined at this time, as there is no available evidence to document that your planned corrective actions will prevent recurrence of these violations.

Our inspection also revealed that your firm’s Ivenix Infusion System is 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 803 - Medical Device Reporting. Significant violations include, but are not limited to, the following:

1. Failure to report to us the information required by § 803.52 in accordance with the requirements of § 803.12(a), no later than 30 calendar days after the day that you receive or otherwise become aware of information, from any source, that reasonably suggests that a device that you market has malfunctioned and this device or a similar device that you market would be likely to cause or contribute to a death or serious injury, if the malfunction were to recur, as required by 21 CFR § 803.50(a)(2).

For example, the information included for Complaints CMT-00401, CMT-00429, CMT-00460, CMT-00477, CMT-00487, CMT-00493, CMT-00494, CMT-00511, CMT-00512, CMT-00519, and CMT-00535 reasonably suggests that your firm’s Ivenix Infusion System malfunctioned (i.e. loss of electrical function) while in use. Although your firm submitted the corresponding MDRs (MDR# 3014732157-2023-00107, 3014732157-2023-001078, 3014732157-2023-001079, 3014732157-2023-00110, 3014732157-2023-00111, 3014732157-2023-00112, 3014732157-2023-00113, 3014732157-2023-00114, 3014732157-2023-00115, 3014732157-2023-00116, 3014732157-2023-00080) for each of these reportable events, the MDRs were not received by FDA within the required 30 calendar day timeframe.

The adequacy of your firm’s responses cannot be determined at this time. Your responses indicate that your firm conducted a retrospective review of complaints associated with all the malfunctions identified during the inspection and has submitted the newly identified MDRs. Furthermore, your firm committed to rectifying regulatory gaps in your complaint investigation process and are in the process of conducting a retrospective review of all complaints received since March 1, 2022, in alignment with the revised process. However, your responses do not include documentation of the completion of these corrective actions as they are currently ongoing.

2. Failure to adequately develop, maintain, and implement written MDR procedures as required by 21 CFR § 803.17. For example, during the inspection, your firm presented the following documents:

• “Reporting of Medical Device Events”, Global-SOP-VI-000003141, Version 4.0, dated 31-Oct-2022
• “Product Complaint Management”, Doc. ID: 410-0022-01, Rev. 11, undated
• “Complaint management – Propel DB Work Instruction”, Doc. ID: 420-0023-01, Rev. 08, undated

Upon a collective review of these documents as your firm’s MDR procedure, the following deficiencies were noted:

a. The procedure does not establish internal systems that provide for timely and effective identification, communication, and evaluation of events that may be subject to MDR requirements, as required by 21 CFR § 803.17(a)(1). For example:
    i. There are no definitions of what your firm will consider to be a reportable event under 21 CFR § Part 803. The exclusion of definitions from 21 CFR § 803.3 for the terms “become aware”, “caused or contributed”, “malfunction”, “MDR reportable event”, and “serious injury”, and the definition for the term “reasonably suggests”, found in 21 CFR § 803.20(c)(1) may lead your firm to make an incorrect reportability decision when evaluating a complaint that may meet the criteria for reporting under 21 CFR § 803.50(a).
    ii. The procedure, as written, combines language from the requirements of other regulatory or competent authorities with the requirements in 21 CFR § 803 in a manner that will result in incomplete, inadequate, or even non-reporting of adverse events that meet the reportability requirements under 21 CFR § 803.

b. The procedure does not establish internal systems that provide for a standardized
review process to determine when an event meets the criteria for reporting under this part, as required by 21 CFR § 803.17(a)(2). For example, although the procedure includes instructions for how your firm will evaluate information about an event to make a reportability decision, it fails to include instructions for

c. The procedure does not establish internal systems that provide for timely transmission of complete medical device reports, as required by 21 CFR § 803.17(a)(3). Specifically, the procedure does not include:
    i. Instructions for how to obtain and complete the FDA 3500A form.
    ii. The circumstance under which your firm must submit initial 30 days, supplement, or follow-up, 5-day reports and the requirements for such reports.
    iii. A process for submitting initial and supplement or follow-up reports to FDA in an electronic format that FDA can process, review and archive in accordance with 21CFR 803.12(a).
    iv. How your firm will ensure that all information reasonably known to you is submitted for each event. Specifically, which sections of the Form 3500A will need to be completed to include all information found in your firm’s possession and any information that becomes available as a result of a reasonable follow-up within your firm.

d. The procedure does not describe how your firm will address documentation and recordkeeping requirements, as required by 21 CFR § 803.17(b), including:
    i. Information that was evaluated to determine if an event was reportable.
    ii. Documentation of the deliberations and decision-making processes used to determine if a device-related death, serious injury, or malfunction was or was not reportable, as required under 21 CFR § 803.18(b)(1)(i).

Additionally, it is important to note that your procedure acknowledged that your firm's Quality Assurance operations, situated at your sister facility in Lake Zurich, Illinois, was designated to make the reportability determination and submit the MDRs. However, your firm has ultimate responsibility for ensuring that MDR reportable events for devices it markets are submitted within the required regulatory timeframe.

Your firm’s responses do not adequately address the procedural deficiencies as they were not included in the FDA Form 483.

Our inspection also revealed that your firm’s Ivenix Infusion System which includes the Ivenix Infusion Pump, Infusion Safety Management Software, and Intravascular Administration Set devices, 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:

Failure to submit a correction or removal initiated to reduce a risk to health posed by the device and required to be reported to the FDA by 21 CFR § 806.10(a), was not reported in writing within 10-working days of initiating such correction or removal, as required by 21 CFR § 806.10(b).

Specifically, your firm issued a customer notification letter on April 22, 2022, and implemented a related field correction and software update by July 26, 2022, as documented by FAI-4446, FAI-4237, and CAPA-00038. Alternatively, your firm did not submit the required written report of this correction and removal to the FDA until August 23, 2023, approximately sixteen months after the customer notification letter was issued and approximately thirteen months after implementing the field correction and software update. FDA classified this correction and removal, RES 92973, as a Class II recall on September 25, 2023.

We reviewed your firm’s responses and concluded that they are not adequate. Your responses confirm that your firm submitted a written report documenting RES 92973 on August 23, 2023, and a termination request on October 25, 2023. Although, your responses do not address the correction and removal reporting well beyond the required ten-day timeframe, per 21 CFR § 806.10(b).

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 FD&C 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 FD&C 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 # 671249 when replying. If you have any questions about the contents of this letter, please contact Katelyn Staub-Zamperini, Compliance Officer, at 412-644-3394 ext. 20 or katelyn.staub-zamperini@fda.hhs.gov.

We are also proposing a virtual Regulatory Meeting on Friday, January 19, 2024, at 2:00 PM EST to discuss our concerns. At this meeting, you should be prepared to discuss the status of your proposed corrections. Please confirm this scheduled meeting with Ms. Staub-Zamperini at the above contact information.

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.

Sincerely yours,
/S/

Joseph Matrisciano, Jr.
Program Division Director
Office of Medical Device and Radiological Health
Division 1/East

/S/

Kellie B. Kelm, Ph.D.
Acting Director
OHT3: Office of GastroRenal, ObGyn, General
Hospital and Urology Devices
Office of Product Evaluation and Quality
Center for Devices and Radiological Health

cc:

Benjamin Powers, Vice President,
Research and Development,
Fresenius Kabi USA, LLC,
50 High Street, Suite 50,
North Andover, MA 01845