WARNING LETTER

DRG Instruments GmbH MARCS-CMS 700918 — March 31, 2025

Delivery Method:: VIA Electronic Mail
Product:: Medical Devices

Recipient:: Recipient Name

Jörg Schlöβer; Recipient Title

Managing Director; DRG Instruments GmbH; Frauenbergstr. 18
Marburg
35039 Hassia
Germany; (b)(6)@drg-diagnostics.de

Issuing Office:: Center for Devices and Radiological Health; United States

WARNING LETTER

March 31, 2025

Dear Mr. Schlöβer:

During an inspection of your firm located in Marburg, Germany on November 4 through 7, 2024, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures in vitro diagnostic devices including the Salivary Cortisol ELISA (REF No. SLV-2930), the Salivary Testosterone ELISA, and the Salivary Cortisol ELISA RUO (REF No. SLV-2930R). 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.

Unapproved Device Violations

FDA has reviewed evidence collected during the inspection and your firm’s website and determined that the Salivary Cortisol ELISA (REF No. SLV-2930) and Salivary Cortisol ELISA RUO (REF No. SLV-2930R) 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 (IDE) under section 520(g) of the Act, 21 U.S.C. § 360j(g). The Salivary Cortisol ELISA and Salivary Cortisol ELISA RUO 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 these devices into commercial distribution, with major changes or modifications to the intended use, without submitting a new premarket notification to FDA as required by section 510(k) of the Act, 21 U.S.C. § 360(k).

Salivary Cortisol ELISA

You currently have clearance dated December 7, 2005, for a version of the Salivary Cortisol ELISA which was cleared under K051733 as a class II device under 21 CFR 862.1205 with the following indications:

“An enzyme immunoassay for the quantitative in vitro diagnostic measurement of active free cortisol (hydrocortisone and hydroxycorticosterone) in saliva. Measurements of cortisol are used in the diagnosis and treatment of disorders of the adrenal gland.”

However, as discussed in FDA’s Warning Letter dated September 19, 2017 issued to your firm, your firm has failed to submit a premarket notification submission to the Food and Drug Administration for significant changes that could significantly affect the safety or effectiveness of the device, as required by 21 CFR 807.81(a)(3)(i). As discussed in the 2017 Warning Letter, a new 510(k) is needed due to the use of a new monoclonal (mouse) antibody for the Salivary Cortisol ELISA. In addition, a new 510(k) is needed because of the change to the assay measuring range. As described in the FDA’s Decision Summary, the device that was reviewed and cleared by FDA under K051733 included 8 wells coated with rabbit anti-cortisol antiserum and had an assay measuring range of 0.537 - 80 ng/mL. However, the package insert of the IVD-labeled Salivary Cortisol ELISA obtained during the 2024 inspection is described as containing microtiter wells that are coated with a monoclonal (mouse) antibody and the assay measuring range is described as 0.09 – 30 ng/mL. The modified measuring range is narrower than the clinically relevant range. This change raises concerns that some patient samples with salivary cortisol higher than 30 ng/mL may yield inaccurate results using the new assay which could place patients with normal cortisol levels at increased risk of misdiagnosis (e.g. elevated cortisol may be an indicator of Cushing Syndrome) or could lead to missed diagnosis of Cushing Syndrome if results are erroneously low. Such changes could significantly impact the safety and effectiveness of the device because such devices are often used in people with cortisol levels greater than 30 ng/mL. Your firm was notified in the 2017 Warning Letter that the Salivary Cortisol ELISA devices manufactured by your firm are subject to refusal of admission under section 801(a) of the Act, 21 U.S.C. § 381(a), in that they appear to be adulterated and that, as a result, FDA was taking steps to refuse entry of these devices into the United States, known as “detention without physical examination,” until these violations were corrected. To date, your firm has not received 510(k) clearance for your Salivary Cortisol ELISA devices that incorporate this significant change.

Salivary Cortisol ELISA RUO

The inspection revealed that your firm also markets and distributes the Salivary Cortisol ELISA RUO. Based on labeling collected during FDA’s inspection, the Salivary Cortisol ELISA RUO, like the Salivary Cortisol ELISA for in vitro diagnostic use, is designed to include monoclonal mouse antibodies and has an assay measuring range of 0.09 - 30 ng/mL. Specifically, your firm's website www.drg-international.com describes the Salivary Cortisol ELISA RUO as “an enzyme immunoassay for the quantitative in vitro diagnostic measurement of active free cortisol (hydrocortisone and hydroxycorticosterone) in saliva.”

Based on evidence obtained during the inspection and a review of your firm’s website, the Salivary Cortisol ELISA RUO appears intended for clinical diagnostic use instead of for research use only. Such evidence includes:

Your firm’s website includes product descriptions, images, and statements that suggest the Salivary Cortisol ELISA RUO device is intended for clinical diagnostic use. [https://store.drg-international.com/pc_product_detail.asp?key=2EAFBB068F3341EF8772F433DA7255B4]. For example:
o A statement on your firm’s product page for the Salivary Cortisol ELISA RUO says that the “intensity of colour developed is inversely proportional to the concentration of cortisol in the patient sample.”
Labeling collected during the inspection which your firm distributes with the Salivary Cortisol ELISA RUO device includes information that appears to conflict with RUO and suggests the device is actually intended for clinical diagnostic use despite the RUO labeling. For example:
o The instructions for use that your firm distributes with the Salivary Cortisol ELISA RUO contains a specimen collection and preparation section that describes how samples should be collected from individuals (e.g. “Eating, drinking, chewing gums or brushing teeth should be avoided for 30 minutes before sampling.”) and gives directions on how saliva samples should be collected and over what time period to collect samples from individuals. The instructions for use also contain a Quality Control section which notes that “[a] statistically significant number of controls should be assayed to establish mean values and acceptable ranges to assure proper performance” and that users should ensure that assay results fit the established range of control materials or else be considered invalid. This type of language is typically included for IVDs that are intended for clinical diagnostic use, as this type of information is consistent with the prospective testing of patients and is not the type of information that is necessary for an assay in the laboratory research phase of development.
A review of the customer records collected during the 2024 inspection shows that your firm sold and shipped Salivary Cortisol ELISA RUO to multiple companies in the business of performing clinical analysis. There is no indication that these companies also conduct research.
Your firm’s website (last accessed March 11, 2025) https://drg-international.com/salivary-elisa-kits/ describes the Salivary Cortisol ELISA RUO, along with other Salivary ELISA Kits, as having clear advantages, including:
o “Simple, painless collection”
o “Simple and patient-friendly measurement of hormone profiles”
o “Can be performed also by patients”
o “Easy sampling in babies and kids”
o “Provides accurate, low level detection”
o Clinical applications such as:
 “Diagnosis of systemic/local conditions”
 Obstetrics & Gynecology”
 “Drug Monitoring”
Your firm’s website also provides a comparison of the Salivary Cortisol ELISA RUO to a reference test and states it provides “Industry Leading Accuracy with Kit Components Calibrated to Mass Spectrometry,” which implies that the Salivary Cortisol ELISA RUO is intended for clinical diagnostic use and not for research use only.

In addition, during the inspection, your firm provided to the FDA investigator copies of certification letters from certain customers of the Salivary Cortisol ELISA RUO as evidence that these customers were aware that they were only supposed to use these products for research purposes. However, your firm admitted no such certification letter was received from one customer. A review of these customers’ websites strongly suggests that these customers are engaged in clinical diagnostic testing. As such, your statements that Salivary Cortisol ELISA RUO is intended for research use only are inconsistent with the evidence obtained during the inspection and the statements on your firm’s website, and FDA has determined that your Salivary Cortisol ELISA RUO is intended for clinical diagnostic use.

Your Salivary Cortisol ELISA RUO appears to be intended for the quantitative in vitro diagnostic measurement of active free cortisol (hydrocortisone and hydroxycorticosterone) in saliva. You were required to submit to FDA a 510(k) for this device, because either it is a new device (21 CFR 807.81(a)(1)) or, if your Salivary Cortisol ELISA RUO represents a change or modification from the device cleared in K051733, it has been significantly changed or modified in design, components, method of manufacture, or intended use (21 CFR 807.81(a)(3)). 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.

Separately, we also note that your firm’s website includes a tab called “FDA Cleared Tests” (https://drg-international.com/) and lists several devices for which there is no record of a 510(k) clearance held by your firm. For example, a Thyroid Stimulating Hormone (TSH) assay for in vitro diagnostic use is included on your firm’s website. However, a review of our records indicates that DRG Instruments does not have a 510(k) for a TSH assay. FDA requests that you review those devices listed under the “FDA Cleared Tests” tab on your website and either provide FDA with evidence that those devices are legally marketed or take corrective actions to address any additional uncleared devices marketed on your website.

Further, during our review of your firm’s website (https://drg-international.com/hybrid-xl/) we also noted that your firm states that DRG Hybrid XL is “Now FDA Approved” but also separately indicates that the DRG Hybrid XL is “FDA exempt for Class I.” We request that you clarify this statement on your website because indicating that a class I 510(k) exempt product has been reviewed and approved by FDA could be misleading. We request that your firm address these two additional issues in your response to this Warning Letter.

Quality System Regulation (QSR) Violations

This inspection also revealed that the devices manufactured in your facility 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 Ina Hairston, U.S. Agent, DRG Instruments GmbH and Head of Regulatory Affairs, DRG International, Inc. dated November 26, 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. These violations include, but are not limited to, the following:

1. Failure to adequately establish and maintain procedures for implementing corrective and preventive action, as required by 21 CFR 820.100(a). For example, CAPA No. 2024-14 was initiated July 1, 2024 due to a customer complaint of the low-level quality control for their Salivary Testosterone ELISA being invalid. However, your firm did not adequately investigate the cause of the nonconformity. Your firm confirmed the complaint by testing the remaining kits in inventory from two lots and found 21.3% (17 out of 80 bottles) of the low controls were out-of-specification (OOS). Your firm determined that the cause was due to the operator not washing the filling tube, nor discarding the first ten bottles, after switching from a higher to lower concentration of bulk solution, which were typical but not defined in the manufacturing procedure. Your firm's corrective action was to revise procedure aa-9131 to define a rinsing step and to require discarding of the first 20 bottles. However, the determined root cause of incomplete rinsing instructions does not demonstrate how such a lack of written procedures would reasonably be expected to result in 21.3% of retained low controls being OOS. Further, during the inspection, Mr. Polleichtner, Head of Quality Management & Regulatory Affairs, indicated that there may be additional causes for the nonconformity and that your firm did not confirm that the operator failed to perform the rinse and discard step.

The adequacy of the response dated November 26, 2024 cannot be determined at this time. Your firm has opened CAPA# 2024-22 and planned the following actions:

update of root cause analysis for CAPA 2024-14 by December 20, 2024;
review of all open CAPAs and all CAPAs which actions are completed, but the effectiveness check is still pending regarding comprehensive root cause analysis by January 31, 2025; and
update CAPAs identified to have inadequate root cause analysis to update the process of determining the root cause and affirm the root cause by February 28, 2025.

Your firm should provide an update on the above actions, including evidence of implementation. Copies of revised procedures and evidence of training on new or revised procedures should also be provided. Additionally, your firm should provide a summary of the results of their retrospective review.

2. Failure to adequately maintain records of complaint investigations that include required information, according to 21 CFR 820.198(e). For example, records of complaint investigations do not include required information, including any unique device identifier (UDI) or universal product code (UPC). Your firm's complaint records consistently did not include adequate contact information for the complainant, to include telephone number and address, and consistently did not include the Unique Device Identifier (UDI) code for the device which was the subject of the complaint. Specifically, complaint records for Complaint Nos. 47 and 49 do not list the complainant’s telephone number, complainant’s address, or the UDI code for the device.

The adequacy of your firm's response dated November 26, 2024 cannot be determined at this time. Your firm has opened CAPA# 2024-24 and planned the following actions:

add UDI and contact information to all open complaint files by December 15, 2024;
review of the complaint handling process and form regarding conformity with applicable regulations (EN ISO 13485, 21 CFR, IVDR) by December 15, 2024;
file a change request based on finding(s) of complaint review process. At minimum, the requirement to provide the UDI/UPC and complete customer contact information with every complaint is required by December 15, 2024;
inform and provide immediate information to the complaint-handling personnel emphasizing the importance of recording complete information;
review of Medical Device Single Audit Program (MDSAP) guidance documents, as these outline US-specific requirements, and are based on EN ISO 13485 by December 31, 2024;
request implementation of gaps identified to the MDSAP guidance if applicable by January 10, 2025; and
train revised documentation as required by January 31, 2025.

Medical Device Reporting (MDR) Violations

Our inspection also revealed that you have failed to develop, maintain, and implement written Medical Device Reporting (MDR) procedures, as required by 21 CFR 803.17. For example: during the inspection, your firm identified the document titled “Reporting to Regulatory Authorities (and recall), Document aa-8.2.3.1, Revision 1, undated,” as its written MDR procedure. After reviewing the procedure, the following deficiencies were noted:

There is no evidence that the procedure has been implemented. For example, there is no effective date for your firm’s MDR procedure.
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:
o The definition of the term “Reportable Event” in section 5 of your firm’s procedure only focuses on whether the device at issue would be likely to cause or contribute to a death or serious injury if the malfunction were to recur and does not include a consideration of whether a similar device marketed by your firm would be likely to cause or contribute to a death or serious injury if the malfunction were to recur, as required in 21 CFR 803.3(o)(2)(ii).
o 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.
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 following are not addressed:
o Instructions for how to obtain and complete the FDA 3500A form.
o The circumstances under which your firm must submit an initial 30 days, supplemental or follow-up, 5-day report and the requirements for such reports.
o How your firm will submit all information reasonably known to it for each event. Specifically, which sections of 3500A will need to be completed to include all the information found in your firm’s possession and any information that becomes available as a result of a reasonable follow-up within your firm.
The procedure does not describe how your firm will address documentation and record-keeping requirements, as required by 21 CFR 803.17(b), including:
o Information that was evaluated to determine if an event was reportable.
o 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.
o Systems that ensure access to information that facilitate timely follow-up and inspection by FDA.

Your firm’s procedure includes references to annual certifications. We note that annual certifications are no longer required, and we recommend that all references to an Annual Certification be removed from your firm’s MDR procedure. See 65 Fed. Reg. 4112 (Jan. 26, 2000). Furthermore, the procedure includes references to submit paper MDR reports. Please note, paper reports are generally no longer accepted from manufacturers and importers. See 21 CFR 803.11(a). The manufacturer is generally required to electronically submit MDRs following its established electronic submission process. 21 CFR 803.11(a).

The adequacy of your firm’s response dated November 26, 2024, cannot be determined at this time. The response notes that your firm plans to update its MDR procedure to include a reportability determination process, add evaluation recording process, and conduct staff training. However, your firm did not provide documentation or evidence demonstrating the implementation of these corrective actions, as they are still ongoing.

We note that a device is deemed to be misbranded under section 502(t)(2) of the Act, 21 U.S.C. § 352(t)(2), if there was a failure or refusal to furnish any material or information required by or under section 519 of the Act, 21 U.S.C. § 360i, which includes adverse event reports required under 21 CFR Part 803, respecting the device.

Given the serious nature of the violations of the Act, the Salivary Cortisol ELISA and the Salivary Cortisol ELISA RUO devices manufactured by your firm are subject to refusal of admission under section 801(a) of the Act, 21 U.S.C. § 381(a), in that they appear to be adulterated. As a result, FDA is taking steps to refuse entry of these devices into the United States, known as "Detention Without Physical Examination of Devices without Approved PMA's or IDE's and Other Devices Not Substantially Equivalent or Without a 510(k)," until these violations are addressed. To remove the devices from detention, your firm should provide a written response to this Warning Letter as described below and address the violation(s) described in this letter. 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.

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.

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 actions (which should 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. 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 by email to CDRHWarningLetterResponses@fda.hhs.gov. Refer to CMS case 700918 when replying. If you have any questions about the contents of this letter, please contact: Kimberly Mapp at Kimberly.mapp@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 or associated with your firm’s devices. 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/

Courtney H. Lias, Ph.D.
Director
OHT7: Office of In Vitro Diagnostic Devices
Office of Product Evaluation and Quality
Center for Devices and Radiological Health

CC:
Ina Hairston
U.S. Agent, DRG Instruments GmbH and
Head of Regulatory Affairs, DRG International, Inc.
(b)(4)@drg-international.com

Mr. Simon W. Huang, Chief Executive Officer
BioCheck, Inc.
(b)(4), (b)(6)@biocheckinc.com

Mr. Stephen A. Baliani, Comptroller
DRG International, Inc.
(b)(4), (b)(6)@drg-international.com