Future Diagnostics Solutions B.V.

During an inspection of your firm located in Gelderland, Netherlands on January 16 through 19, 2023, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures STAT-IntraOperative-Intact PTH (Parathyroid Hormone) Immunoassay Kits (STAT-IO-I-PTH). 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. These violations include, but are not limited to, the following:

1. Failure to verify or validate corrective and preventive actions (CAPA) to ensure that such actions are effective and do not adversely affect the finished device, as required by 21 CFR 820.100(a)(4).

For example, CAPAs 2021-4, 2021-13, and 2021-16 were initiated to address production non-conformities associated with the STAT-IntraOperative-Intact-PTH Immunoassay Kit. Each report indicates that corrective actions were found to be effective, implemented, and the CAPAs were closed. During the inspection, the investigator requested to review the firm’s documentation of the verification or validation of the corrective action to ensure the action is effective and does not adversely affect the finished device. However, the firm’s Operations Manager, Mr. Jochem van Woezik, stated there was no objective evidence available for review.

2. Failure to adequately establish and maintain procedures to control product that does not conform to specified requirements, including, the identification, documentation, evaluation, segregation, and disposition of nonconforming product, and to ensure that the evaluation includes a determination of the need for an investigation, as required by 21 CFR 820.90(a).

For example, the relative humidity for (b)(4), the (b)(4) compartment, used to (b)(4) and are used during the (b)(4), was found to be out of specification when re for calibration. Specifically, the calibration report documented that the following relative humidity readings were out of range:

The relative humidity reading was measured at (b)(4)% (outside the stated tolerance of (b)(4)%RV)

The relative humidity reading was measured at (b)(4)% (outside the stated tolerance of (b)(4)%RV)

The relative humidity reading was measured at (b)(4)% (outside the stated tolerance of (b)(4)%RV).

During the inspection, the investigator determined that a non-conformance report was not initiated. Your operation Manager, Mr. van Woezik, confirmed that the evaluation of the nonconformance was not documented.

3. Failure to establish and maintain procedures for identifying valid statistical techniques and to ensure that sampling plans are adequate for their intended use, as required by 21 CFR 820.250.

For example, for recall Z-1016-2023, your firm documented the investigation in Investigation report NCP2022-14, dated 29 November 2022. The report documents, among other things, experiments to investigate the problems with the seals and accusphere integrity. (b)(4) RTU plates out of (b)(4) plates from lot M78493 were tested. During the inspection, the investigator asked about your firm’s justification for selecting (b)(4) plates. Your Head of Research & Science, Dr. Lindhout, stated there is no statistical basis for selecting a sample size of five plates. In addition, your firm’s Operations Manager, Mr. van Woezik, stated that your firm does not have procedures pertaining to statistical techniques.

4. Failure to adequately establish procedures for quality audits and conduct such audits to ensure that the quality system is in compliance with the established quality system requirements and to determine the effectiveness of the quality system, as required by 21 CFR 820.22.

For example, your firm's procedure, SOP-048, Internal Audit, version 30, effective 10 Nov 2022 states, "The audit frequency will be such that at least once a year a total facility audit will be performed." Previous versions, version 29, effective 4 Jul 2022 and version 28, effective 24 Jun 2020 include the same requirement. A list of audit topics for 2020, 2021, and 2022 was reviewed but it did not include Management responsibility, Design controls, or Corrective and Preventive Actions subsystems. Additionally, your Operations Manager, Mr. van Woezik, stated that your firm has never conducted internal audits of these subsystems.

Our inspection also revealed that your firm’s STAT-IntraOperative-Intact-PTH (STAT-IO-IPTH) Immunoassay kits 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 adequately develop, maintain, and implement written Medical Device Reporting (MDR) procedures as required by 21 CFR 803.17(a). For example, during the inspection, your firm identified the document titled “SOP Medical Device Reporting,” SOP-087, Rev. 14, dated 11/7/2022, as its 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. The procedure omits definitions of the terms “become aware” and “caused or contributed” from 21 CFR Part 803.3, and the definition of the term “reasonably suggest” found in 803.20(c)(1). The exclusion of the definitions for these terms 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). 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 nonreporting 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:

i. There are no instructions for conducting an investigation of each MDR reportable event and evaluating the cause of the event. ii. 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.

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. 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).

2. Failure to submit a report to FDA no later than 30 calendar days after the day that your firm received or otherwise became 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).

For example, the information included for Complaints NCP 2022-14 and NCP 2020-29 reasonably suggests that your firm’s STAT-IntraOperative-Intact-PTH (STAT-IO-I-PTH) Immunoassay Kit malfunctioned (i.e., defective component resulting in high coefficients of variation) while in use. Although the information from the complaints state that there was no indication of patient impact, your firm should evaluate each malfunction for reportability. Your firm-initiated recall Z-1016-2023 for a malfunction that results in high coefficients of variation. Per the Preamble, in the Medical Devices; Medical User Facility and Manufacturer Reporting, Certification and Registration; Final Rule, 60 Fed. Reg. 63585 (December 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. There is no information included for the complaints that indicates that the high coefficients of variation were not the result of the referenced component failure and whether it would not be likely to cause or contribute to a death or serious injury if it were to recur. Your firm became aware of one event described in NCP 2022-14, from (b)(4) hospital (Texas) on 11/17/2022, two from (b)(4) Hospital (Pennsylvania) on 11/21/2022, and two more events from Hospital (b)(4) (Spain) on 12/1/2022. Additionally, your firm became aware of one event from (b)(4) hospital (Arizona) identified in NCP 2020-29 on 11/10/2020. However, your firm failed to submit an MDR for each of the six referenced events within the required 30-calendar day timeframe at the conclusion of the inspection.

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 Refer to CMS case #653493 when replying. If you have any questions about the contents of this letter, please contact: Helen Yousefi at helen.yousefi@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.