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WARNING LETTER
CMS# 669904

January 19, 2024

Dear Mr. Johnson:

During an inspection of your firm located at 2320 NW 66th Court, Gainesville, Florida on 9/18/2023 through 9/26/2023, an investigator from the United States Food and Drug Administration (FDA) determined that your firm is a manufacturer of Equinoxe aTSA and Equinoxe rTSA devices and other orthopedic implants and accessories. 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 a response from you, Darin B. Johnson, President and CEO on October 13, 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 adequately establish procedures for corrective and preventive actions, as required under 21 CFR 820.100(a). Specifically,

A. Your firm’s CAPA procedures, “Corrective and Preventive Actions”, Document # 701-103-137, and “Quality Data Analysis Review (QDAR)”, Document # 701-103-161 do not adequately describe a standardized process for the analysis of quality data to identify, correct and prevent the recurrence of nonconforming product and other quality problems. For example, trending per QDAR procedure requires “that an overview and discussion (b)(4) complaint failure modes by device type will be reviewed for complaints (b)(4)” to determine the significance of the trend and if actions need to be taken. The lack of additional instructions on the trending of complaint failure modes like those “as reported”, “as analyzed”, primary failure mode and secondary failure mode as well as clinical outcome/findings may fail to identify trends. For instance, the investigator noted that complaints reviewed during the inspection identified inconsistent failure mode coding:

i. CASE-2023-00009390: The as reported failure mode selected was “Pain”, but the reported issue also indicated “Right shoulder shows glenoid wear, will need a revision.” Surgery confirmed “Excessive wear of implant components” and “right shoulder shows glenoid wear”. Failure mode for “Prosthetic Wear” is not selected for trending purposes.
ii. CASE-2023-00009729: Failure code selected was “Osteolysis”, but it was also reported there was “…damage to the polyethylene insert with both delamination of the polyethylene as well as fracture of the polyethylene. There was marked lysis secondary to this. A grossly loose femoral component was debonded”. Failure modes for “Fracture”, “Prosthesis Wear”, and “Loosening” are not selected for trending purposes.

Your firm’s analysis of quality data such as complaint failure modes for orthopedic devices and accessories are used to identify existing and potential causes of nonconforming product as well as to determine if actions should be taken to correct and prevent their recurrence.

B. Your firm has not identified actions needed to correct polyethylene shoulder implants packaged in vacuum bags that did not meet material specifications or oxygen transmission rate requirements. When calculating health risk of polyethylene shoulder implants impacted by nonconforming packaging to determine if a correction and removal was needed, your firm did not evaluate all applicable complaint data and failure codes in your Health Hazard Evaluation analysis. Metrics specified in your SOP Quality Data Analysis Review (QDAR), 701-103-16 were not adequately performed to analyze complaints that describe an adverse event that are more severe than what is expected for the device. For example, Health Hazard Evaluation, document # HHE2021-08-06-02 for the evaluation of risk of the polyethylene shoulder implants in nonconforming packaging indicates complaint data from January 2008 through July 2021 was reviewed and analyzed for “polyethylene wear”, “osteolysis”, “poly component fracture” and “disassociation”. However, your data only included those for “polyethylene wear” with Medical Device Reports citing 11 total complaints found.

Your firm performed additional assessment covering other failure codes in Technical Memo #TM-2021-1128 Equinoxe Poly Analysis Polyethylene Failure modes with the Equinoxe aTSA & rTSA Shoulder Arthroplasty System, Revision C. However, the raw data to support the following assessment could not be provided for review, “Only 1 of the 8,580 patients in this Aibinder et al. [10] had any adverse event specifically caused by polyethylene wear revision (captured in “other”, rTSA column in Table 3 from Aibinder et al. [10]).”

The adequacy of your firm’s response dated October 13, 2023, cannot be determined at this time. The response notes that your firm has undertaken systemic corrective actions to address the issue of complaint coding, quality data analysis. These actions encompass conducting a retrospective review of complaints, revising the procedures, and offering training to staff members. Additionally, an assessment of CAPA2023-042 will be carried out to address coding of historical complaints and to decide if further remediation actions are necessary. However, the response does not furnish specific information regarding the results or outcomes of these corrective actions as they are still ongoing.

2. Failure to establish and maintain design validation procedures to ensure proper risk analysis is completed, as required by 21 CFR 820.30(g). Specifically, your firm’s procedure “Health Hazard Evaluation”, Document # 701-105-546, has not been adequately implemented to evaluate health risk(s). Your firm’s procedure describes requirements for calculating health risk and conducting an analysis of complaint data. The determination of criteria for the complaint search and analysis does not ensure that all applicable or potential failure mode codes are selected. For example, as part of the health hazard evaluation (HHE) for the risk of the polyethylene shoulder implants packaged in bags that do not meet the material specification requirement or oxygen transmission rate requirements, the complaint search criteria for complaints from 2008 through July 2021 included “Polyethylene wear” and “osteolysis”. This yielded a population of 11 complaints (5 for aTSA and 6 for rTSA). However, additional failure modes or complaint text that would be indicative of polyethene wear were not included in the scope or criteria of the analysis for complaints from 2008 through July 2021. For example, Risk Assessment and Controls Report, Exactech Equinox aTSA System Implants, RACR-00098, Revision E identifies the following additional harms for poly device unable to withstand specified shelf-life due to degraded device implanted as noted on Risk ID 4.13, 4.14, 4.16, 4.17:

• Instability
• Subluxation of Joint
• Loss of Range of Motion
• Subsidence
• Migration
• Pain
• Total Joint Dislocation

In addition, the data used in HHE to demonstrate that shelf life and oxidation played no role in these polyethylene wear complaints was limited to 11 complaints/MDRs (5 for aTSA and 6 for rTSA) for the Engineering Evaluation of Reported Complaints with Shelf Life Calculation. The complaint search criteria used in your HHE do not encompass failure modes identified in your Risk Assessment and Controls Report that would be conservatively included and analyzed in your firm’s HHE risk assessment.

The adequacy of your firm’s response dated October 13, 2023, cannot be determined at this time. The response notes that your firm has undertaken systemic corrective actions to address the issue with risk analysis procedures. These actions encompass conducting the retrospective review of all HHEs resulting in a Risk Level (b)(4) (Conditional) since the release of this process in May of 2020, revising risk analysis procedures, and offering training to staff members. Additionally, an assessment of CAPA2023-043 will be carried out to decide if further remediation actions are necessary. However, the response does not furnish specific information regarding the results or outcomes of these corrective actions as they are still ongoing.

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

3. Failure to adequately develop, maintain, and implement written MDR procedures as required by 21 CFR 803.17. For example, during the inspection, your firm identified the document titled “Adverse Event Reporting to Regulatory Authorities”, SOP# 701-103-102, Revision W, dated 2/8/2023 as its written MDR procedure. After reviewing the 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 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 Part 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 Part 803.
  iii. The procedure does not include instructions for how your firm will evaluate information about an event to make MDR reportability determinations in a timely manner.

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, there are no instructions for conducting an investigation of each MDR reportable event and evaluating the cause of the event.

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. 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 record-keeping requirements, as required by 21 CFR 803.17(b), including:
  i. Documentation of adverse event related information maintained as MDR event files.
  ii. Information that was evaluated to determine if an event was reportable.
  iii. 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).

The adequacy of your firm’s response dated October 13, 2023, cannot be determined at this time. The response notes that your firm plans to revise its MDR procedure to address issues related to late reporting and provide clarity to the MDR reporting process. However, the response does not contain documentation supporting this update, as the revision is scheduled for completion by December 31, 2023.

4. Failure to submit a report to FDA no later than 30 calendar days after the day that your firm receives or otherwise become aware of information, from any source, that reasonably suggests that a device that your firm markets has malfunctioned and this device or a similar device that it markets 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).

The information included in Complaint CASE-2022-00006275-1 reasonably suggests that your firm’s GXL liner, a component of orthopedic hip implants, exhibited accelerated wear due to the use of non-conforming packaging, resulting in the need for revision surgery. The same malfunction is also subject to the recall Z-1734-2022 for the same device. Per the Preamble, in the Medical Devices; Medical User Facility and Manufacturer Reporting, Certification and Registration; Final Rule, 60 Fed. Reg. 63585 (Dec. 11, 1995), Comment 12, a malfunction is reportable if the manufacturer takes or would be required to take an action under sections 518 or 519(g) of the act as a result of the malfunction of the device or other similar devices. We consider a malfunction of such devices likely to cause or contribute to a death or serious injury if it were to recur. There is no information included for the complaint that rules out that the referenced device malfunction would not be likely to cause or contribute to a death or serious injury if it were to recur. Your firm became aware of the event on September 1, 2022. However, the corresponding MDR 1038671-2023-00008 was received by the FDA on January 4, 2023, which is beyond the required 30 calendar day timeframe.

The adequacy of your firm’s response dated October 13, 2023, cannot be determined at this time. The response notes that your firm has undertaken systemic corrective actions to address the issue of late reporting. These actions encompass conducting the retrospective review, revising the reporting process, and offering training to staff members. Additionally, an assessment of CAPA2023-041 will be carried out to decide if further remediation actions are necessary. However, the response does not furnish specific information regarding the results or outcomes of these corrective actions as they are still ongoing.

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: Melissa I. Michurski, Director of Compliance Branch, at oradevices2firmresponse@fda.hhs.gov. Refer to CMS # 669904 when replying. If you have any questions about the contents of this letter, please contact: Rafael Padilla, Compliance Officer at 312-596-4212 or Rafael.padilla@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.

Sincerely yours,
/S/

CAPT Raquel Peat
Office Director
OHT 6: Office of Orthopedic Devices
Office of Product Evaluation and Quality
Center for Devices and Radiological Health

/S/

Blake Bevill
Program Division Director
Office of Medial Device and Radiological Health Operations (OMDRHO)
Division 2 Central