Terragene S.A.

CMS #: 667432

November 1, 2023 Dear Mr. Esteban Lombardia:

During an inspection of your firm located in Alvear, Santa Fe, Argentina on June 06, 2023 through June 09, 2023, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures and distributes Biological and Chemical Sterilization Process Indicator Systems under its own brand, and through distributors under private label manufacturers. 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 dated June 30, 2023, 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. These violations include, but are not limited to, the following:

1. Failure to establish adequate procedures for receiving, reviewing, and evaluating complaints by a formally designated unit (21 CFR 820.198(a)(b)).

Specifically, your firm’s complaint handling procedure, (b)(4), does not describe complaint handling requirements that ensure your firm receives, reviews, and evaluates all complaints in a uniform and timely manner. Specifically, though your procedure identifies the timeline for closing out complaints once correspondence with complainants has been established, it fails to specify a definitive timeline to evaluate the complaint and reach out to the complainant. Additionally, the procedure does not describe the process for determining whether an investigation is necessary, and whether the complaint represents an event that is required to be reported to the FDA under 21 CFR Part 803 – Medical Device Reporting (MDR).

Your firm received 96 U.S. market complaints from June 21, 2021 to June 09, 2023 for which your firm was not able to provide documentation to demonstrate how the complaints were reviewed or evaluated to determine whether an investigation is necessary or whether the complaint represents an event that is required to be reported to FDA under 21 CFR Part 803 – Medical Device Reporting.

We reviewed your firm’s responses dated June 30, 2023, and September 13, 2023, and concluded that the adequacy of your response cannot be determined. In your response, you stated that your firm is developing a new “Complaint Handling SOP,” training your personnel to the SOP, and conducting a retrospective analysis of the complaints that have been filed with your company to adjudicate the underlying issues stated in the complaints. Your response estimated a timeframe of September through November 2023 to resolve the above FDA observation. Your September 13, 2023, response only contained “certificates of attendance” for a training that some of your employees took regarding the Quality System Regulation and ISO 13485. However, you did not include documentation or evidence to support the planned corrective actions. You have not provided the new “Complaint Handling SOP” to address the concerns noted by the agency. Additionally, you did not provide the retrospective review analysis as noted on your response.

Our inspection also revealed that your firm’s 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:

2. Failure to develop, maintain, and implement written MDR procedures, as required by 21 CFR 803.17.

Specifically, your firm has not developed, maintained, and implemented Medical Device Reporting (MDR) procedure(s) that address the requirements of 21 CFR Part 803 - Medical Device Reporting.

We reviewed your firm’s responses dated June 30, 2023, and September 13, 2023, and conclude that they are not adequate. Your firm committed to develop and implement MDR reporting procedures and processes; however, your firm did not provide a draft procedure for FDA to assess its adequacy. Additionally, you did not indicate whether you plan to perform a retrospective review of events and, when applicable, report events that were not previously reported to the agency; you also did not provide a timeframe of when you plan to complete these actions.

3. Our inspection also revealed that the Integron IT26-C (own brand), (b)(4) (private label brand), and (b)(4) (private label brand) devices are adulterated under section 501(f)(1)(B) of the Act, 21 U.S.C. § 351(f)(1)(B), because your firm does not have an approved application for premarket approval (PMA) in effect pursuant to section 515(a) of the Act, 21 U.S.C. § 360e(a), or an approved application for an investigational device exemption under section 520(g) of the Act, 21 U.S.C. § 360j(g). The devices are also misbranded under section 502(o) the Act, 21 U.S.C. § 352(o), because your firm did not notify the agency of its intent to introduce the devices into commercial distribution, as required by section 510(k) of the Act, 21 U.S.C. § 360(k). For a device requiring premarket approval, the notification required by section 510(k) is deemed satisfied when a PMA is pending before the agency. 21 CFR 807.81(b). The kind of information that your firm needs to submit in order to obtain approval or clearance for the device is described on the Internet at http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/default.htm. The FDA will evaluate the information that your firm submits and decide whether the product may be legally marketed.

Specifically, your firm obtained 510(k) clearance for the Terragene Integron IT26-C via premarket notification K191021. This device was cleared for traditional steam sterilization cycles such as:

Gravity Displacement: 121° C for 30 minutes, 132° C for 15 minutes, 132° C for 25 minutes, 135° C for 10 minutes;

Dynamic Air Removal (Vacuum Assist): 132° C for 4 minutes, 135° C for 3 minutes; and

Vaporized Hydrogen Peroxide (STERRAD, V-ProMax and Sterizone VP4 cycles) and Ethylene Oxide sterilization cycles.

However, the instructions for use (IFU) for your firm’s own brand and private label brand devices listed above also describe the process and acceptance criteria for “extended cycles.” The IFU(s) also include a diagram showing pass/fail results and describe how to interpret the chemical indicator (CI) post-sterilization. This diagram shows in the noted table what the CI should look like after a passed or failed cycle when using the cycle specifications that were previously cleared under K191021; however, the table also includes a column for “extended cycles,” which describes the use of extended cycles and the interpretation of extended cycle results. Your device was not cleared for extended cycle use. The extended cycle description in the labeling falls outside of the parameters in the cleared IFU as it suggests that the end user can extend the cycle on their own and follow the “accept/reject” diagram to interpret the results. The distribution of these devices for an extended cycle use without authorization results in improper use of the device which could result in improperly sterilized devices leading to patient infections and serious health risks.

CIs are cleared with specific validated cycle parameters that should be clearly specified in the labeling. The addition of “extended cycle” sterilization cycles in the labeling represents a significant change or modification in the intended use of the device; therefore, a new 510(k) is required.

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 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 #: 667432 when replying. If you have any questions about the contents of this letter, please contact: Chris Dugard, Asst. Director, at Ph: 240-402-6031 or at Christopher.dugard@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.