Rontis Hellas S.A.

During an inspection of your firm located in Larissa, Thessaloniki, 415 00 Greece on July 22, 2024 through July 25, 2024, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures Cronus HP PTA OTW Balloon Catheter. 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 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 Irene Tsaliki, QA Manager & RA Coordinator dated August 2, 2024, September 10, 2024, and September 30, 2024 concerning our investigator’s observations noted on the Form FDA 483 (FDA 483), List of Inspectional Observations, which was issued to your firm. We address this response below, in relation to each of the noted violations.

1. A process where results cannot be fully verified by subsequent inspection and test, the process has not been validated with a high degree of assurance and approved according to established procedures as required by 21 CFR 820.75(a).

For example, in regard to sterilization validation conducted to meet ISO 11135-1:2007, Validation Infrastructure Utilities Ethylene Oxide (EtO) Sterilization Process, Protocol, Validation Code C1/2013, 10/1/2013, Validation Infrastructure Utilities EtO Sterilization Process Annual Qualification of EtO Sterilization Process Protocol, C1/2013-R/2023, 15/3/2023, Validation of Infrastructure Utilities Annual Qualification of EtO Sterilization Process Report, and EtO Sterilization Report on 14/3/2013:

a. The 2013 validation was performed on (b)(4) without EtO gas. b. The 2023 validation was performed with (b)(4) without EtO gas. c. The 2013 report of CC BE Iliac Stent sterilized with EtO on 14/3/2013 with (b)(4) noted a deviation yet a discussion and evaluation of the impact of the deviation and a justification for the use of the CC BE iliac stent for supporting the sterilization validation for the Cronus HP PTA Balloon Catheter was not provided. d. All of the above identified reports do not provide a justification for the product selected as required by ISO 11135-1:2007 and the more recent ISO 11135:2014, which is the current version of the FDA recognized standard. Further, the validation was not completed with EtO gas or with full sterilization cycles. Your 510(k)s (K151141 and K190037) and validation reports state that “the validation study has been performed in full compliance with the relevant validation protocol and in conformity with ISO 11135-1:2007”. However, Per ISO 11135:2007 and the more recent ISO 11135:2014, Section 9.4.3.2, the process performance qualification (PPQ) shall confirm the process such that gaseous EtO has been admitted to the sterilizer chamber, and the pressure rise and quantity of EtO used or the concentration of EtO in the sterilizer chamber have been established. Additionally, per ISO 11135-1:2007 and ISO 11135:2014, temperature and humidity in the chamber should be measured during the PPQ, as it is possible that temperature and humidity readings may be impacted by the presence and absence of EtO gas. Lastly, ISO 11135:2014 states, “Demonstration of the ability to maintain process parameters within defined limits during the proposed full cycle is necessary.” e. The product adoption of the Cronus HP PTA catheter into the existing EtO sterilization cycle was not documented in the 2023 revalidation report. If the product has not been adopted into the completed 2023 revalidation studies per AAMI TIR28:2016, “Product adoption and process equivalence for ethylene oxide sterilization”, then it is unclear if the completed adoption in 2023 demonstrates that the Cronus HP PTA catheter is adequately sterilized.

The adequacy of your responses dated August 2, 2024, September 10, 2024, and September 30, 2024 cannot be determined at this time as the establishment and completion of the process performance qualification validation report has not been completed. Please perform all corrective actions and provide the associated documentation including, but not limited to, full test reports of a full sterilization cycle with EtO gas.

Our inspection also revealed that your firm’s Cronus HP PTA OTW Balloon Catheter 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 803 - Medical Device Reporting. Significant violations include, but are not limited to, the following:

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 document titled “RC_SOP-10-003: Medical Device Reporting”, Edition 7, dated 3/7/2023 as its written MDR procedure. However, this procedure does not meet the requirements of 12 CFR 803.17. For example:

1. 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). a. The procedure omits definitions of the terms ‘become aware’, ‘caused or contributed’, ‘malfunction’, and ‘serious injury’, from 21 CFR Part 803.3. The exclusion of the definitions for these term from the procedure 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). b. 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.

2. 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 making determinations in a timely manner.

3. 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, your procedure does not include: a. Instructions for how to obtain and complete the FDA 3500A form. b. The circumstances under which your firm must submit supplemental or follow-up report and the requirements for such reports. c. 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 21 CFR 803.12(a); and d. 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.

4. The procedure does not describe how your firm will address documentation and recordkeeping requirements, as required by 21 CFR 803.17(b), including 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).

We reviewed your firm’s responses dated August 2, 2024, September 10, 202, and September 30, 2024, and conclude that they are not adequate. In your September 30, 2024 response, you provided the revised procedure “RC_SOP-10-003: Medical Device Reporting”, Edition No. 8, dated 30/09/2024. Your revised procedure continues to not meet the requirements of 21 CFR 803.17. For example:

1. The revision 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, a. The procedure omits definitions of the terms ‘caused or contributed’ and ‘malfunction’ from 21 CFR Part 803.3. The exclusion of the definitions for these term from the procedure 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). b. The term ‘serious injury’ is incorrectly referred to as ‘serious adverse event’, which might not allow your firm to correctly identify complaints as reportable events. c. The revision, 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. For example, terms including but not necessarily limited to, ‘serious incident’ and ‘serious adverse event’, which are intended for OUS vigilance reporting, are included in the procedure within the context of the US MDR reporting requirements.

2. The revision 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, your procedure does not include: a. Instructions for how to obtain and complete the FDA 3500A form. b. 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 21 CFR 803.12(a). c. 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.

Additionally, the FDA verified that, as of October 17, 2024, your firm still does not have an active ESG production account for the electronic submission of MDR reports. Information about the ESG and creating an account can be found at: How to Enroll in eMDR Program | FDA (https://www.fda.gov/medical-devices/emdr-electronic-medical-device-reporting/how-enrollemdr-program).

Please note that your firm’s response dated October 15, 2024 to the Form FDA 483 (FDA 483) was not reviewed because it was received too late in the review cycle after issuance of the FDA 483. Therefore, the October 15, 2024 response will be evaluated along with any other written material provided in response to the violations cited in this Warning Letter.

Other federal agencies may take your compliance with the FD&C Act and its implementation 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.

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, including 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 action (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. Please provide a translation of documentation not in English to facilitate our review. We will notify you regarding the adequacy of your firm’s response(s) and the need to re-inspect your firm’s facility to verify that the appropriate corrections and/or corrective actions have been made. 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 via email to CDRHWarningLetterResponses@fda.hhs.gov or by mail to Food and Drug Administration, Center for Devices and Radiological Health, Office of Regulatory Programs, Division of Regulatory Programs 2, FDA Regulatory Inspections and Audits Team, White Oak Building 66, 10903 New Hampshire Ave., Silver Spring, MD 20993. Refer to CMS case #695160 when replying. If you have any questions about the contents of this letter, please contact: Ariel Ash-Shakoor at ariel.ash-shakoor@fda.hhs.gov or 240-402-4912.

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.