- DRG Instruments GmbH
- Issuing Office:
- Center for Devices and Radiological Health
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10903 New Harrpshire Avenue
Silver Spring, MD 20993
VIA UNITED PARCEL SERVICE
DRG Instruments GmbH
Marburg, 35039 Germany
Dear Mr. Sänger:
During an inspection of your firm located in Marburg, Germany on October 24, 2016, through October 28, 2016, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures 17-alpha-OH Progesterone ELISA, Salivary Cortisol ELISA, Estradiol ELISA, Salivary Testosterone ELISA and Testosterone ELISA. 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 a response from your firmdated January 16, 2017, 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 and maintain process control procedures that describe any process controls necessary to ensure conformance to specifications where deviations from device specifications could occur as a result of the manufacturing process, as required by 21 CFR 820.70(a).
For example, review of Device History Records (DHRs) for microplate (b)(4) of ELISAs indicates that (b)(4) microplates were reworked due to QC test failures by changing (b)(4) of antibodies. However, written procedures for storing antibody vials and preparing antibody solutions for microplate (b)(4) have not been established. The DHRs contain no reference documents (b)(4) antibodies and you were not able to provide any written procedure for preparing antibody solutions for microplate manufacturing to address repeat plate QC test failures. Furthermore, for incoming Estradiol antibody storage, the (b)(4) for Estradiol (b)(4), indicates that the antibody is required to be stored at -20°C temperature condition. You were not able to provide any written procedure for storing (b)(4) antibody vials. You were also not able to provide any information on the number of times a partially (b)(4) antibody vial is (b)(4) for use (b)(4), and indicated that a freeze and thaw study has not been conducted. In addition, you indicated that incoming antibody (liquid) is aliquoted and (b)(4) lot production. Review of the list of the released Estradiol ELISA microplate lots revealed that the antibody in various volumes (b)(4) was used for (b)(4) (e.g., (b)(4)).
We reviewed your firm’s response and conclude that it is not adequate. You provided various attachments and CAPA documents but you did not provide a cover letter or an itemized response to each observation listed in the Form 483; thus, a response to this item could not be clearly identified. For the microplate (b)(4), the document titled “aa-9_1015, Work Instruction - Quality Control inspection of incoming goods Antibodies, Rev. 2” does not appear to contain procedures for preparing antibody (b)(4) manufacturing to address repeat microplate QC test failures. You should provide clear documentation which includes a description and evidence of implementation of the correction and the corrective action for the production and process control deficiency described above. In addition, the response must consider systemic Quality System problems (e.g., other manufacturing processes or products) related to the deficiency and provide a description of how these were identified and addressed.
2. Failure to (i) identify the actions needed to correct and prevent recurrence of nonconforming product and other quality problems; (ii) verify or validate the corrective and preventive action to ensure that such action is effective and does not adversely affect the finished device; (iii) implement and record changes in methods and procedures needed to correct and prevent identified quality problems; and (iv) ensure that information related to quality problems or nonconforming product is disseminated to those directly responsible for assuring the quality of such product or the prevention of such problems, as required by 21 CFR 820.100(a).
For example, CAPA Report No. 2016-16 indicates that the manufacturing errors that led to many low patient results with Estradiol Salivary ELISA, Catalog No. SLV4188, Lot No. 68K056, were caused by a failure to update the manufacturing procedures or standard matrices after a design change of the standard matrixes. Although you identified the cause of the issue within the CAPA report, you did not identify the actions needed to correct the failure of communicating approved manufacturing changes and did not have procedures to verify the effectiveness of such action. You were not able to provide any written procedures to communicate approved manufacturing changes to the manufacturing employees in a timely manner. A documentation change control system has not been established.
We reviewed your firm’s response and conclude that it is not adequate. You provided various attachments and CAPA documents but it did not provide a cover letter or an itemized response to each observation listed in the Form 483; thus, a response to this item could not be clearly identified. Although the document titled “va-422, Control of Documents” appears to specify the situations under which document changes may be initiated; and “aa-6220_EN, Proof of Document Training” states that “the relevant employees will be informed in a 2-week rhythm about new or modified documents”, the above corrective and preventive actions do not contain procedures to verify the effectiveness of the proposed actions, as required by 820.100(a)(4). You should provide clear documentation which includes a description and evidence of implementation of the correction and the corrective action to demonstrate that procedures have been established to ensure the effectiveness of their corrective and preventive actions. In addition, the response must consider systemic Quality System problems (e.g., other CAPAs) in their CAPA sub-system as they related to the deficiency noted above and provide a description of how these were identified and addressed.
3. Failure to establish procedures for identifying training needs and ensure that all personnel are trained to adequately perform their assigned responsibilities, as required by 21 CFR 820.25(b).
For example, there is a lack of employee training records for the up-to-date versions of written procedures (e.g., va-831, Control of Nonconforming Products and Complaints, Rev. 11, dated 9/21/2016).
We reviewed your firm’s response and conclude that it is not adequate. You provided various attachments and CAPA documents but it did not provide a cover letter or an itemized response to each observation listed in the Form 483; thus, a response to this item could not be clearly identified. The document “aa-6220_EN, Proof of Document Training” does not cover training needs beyond new document training. Further, it does not specify procedures to ensure that all personnel are trained adequately to perform their assigned duties. You should provide clear documentation which includes a description and evidence of implementation of the correction and the corrective action for the particular deficiency described above. In addition, the response must consider systemic Quality System problems (e.g., other training) related to the deficiency and provide a description of how these were identified and addressed.
Our inspection also revealed that your firm’s salivary estradiol ELISA device 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 806 – Medical Devices; Reports of Corrections and Removals. Significant violations include, but are not limited to, the following:
Failure to submit a Report of Correction or Removal to remedy a violation of the Act caused by the device which may present a risk to health, as required by 21 CFR 806.10. For example: Complaint No. 2016-41 indicates that Estradiol Salivary ELISA, Catalog No. SLV4188, Lot No. 68K056, had low results with many patients and had no separation between the kit standard 0 and standard 1. On 7/14/16, you notified your headquarters and distributor, DRG International Inc., and requested that DRG International Inc. advise the customers not to use the product lot. Your Product Recall SOP document “aa-8322” titled “Product Recall to FDA” states, “Recalls may be conducted by DRG‐International Inc.'s or DRG Instruments GmbH own initiative, or by FDA.” However, you were not able to provide any information on whether or not DRG International has reported the field correction to FDA.
We reviewed your firm’s response and conclude that it is not adequate. CAPA #20 states that you will “1. Rework documents regarding reporting to FDA (aa-832; aa-8322; aa-8323); 2. Report for complaint No. 2016‐41 -Estradiol Salivary ELISA; [and] 3. Training of the revised documents.” However, you have not reported the correction or removal nor provided evidence of updated documents. You should update your procedures to follow the requirements under 21 CFR Part 806‐Medical Devices; Reports of Corrections and Removals, and the requirements by the 21 CFR Part 7‐Recall Policy, to ensure that all required information is provided. You should also conduct health risk assessments following the definition of risk to health in 21 CFR 806.2(j), to support the reporting decisions for future medical device corrections or removals.
Our inspection also revealed that the Salivary Cortisol ELISA is 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 device is 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 device into commercial distribution, as required by section 510(k) of the Act, 21 U.S.C. § 360(k).
Specifically, your firm failed to submit a premarket notification submission to the Food and Drug Administration for significant changes to your firm’s Salivary Cortisol ELISA that could significantly affect the safety or effectiveness of the device, as required by 21 CFR 807.81(a)(3)(i). Your firm utilized (b)(4). 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.
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.
Given the serious nature of the violations of the Act, Salivary Cortisol ELISA 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,” until these violations are corrected. In order to remove the devices from detention, your firm should provide a written response to this Warning Letter as described below and correct 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.
Also, U.S. federal agencies may be advised of the issuance of Warning Letters about devices so that they may take this information into account when considering the award of contracts. Additionally, premarket approval applications for class III devices to which the Quality System regulation deviations are reasonably related will not be approved until the violations have been corrected.
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 correct 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 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.
Your firm’s response should be sent to: Food and Drug Administration, Center for Devices and Radiological Health, Office of Compliance, Field Inspections Support Branch, White Oak Building 66, Rm 3540, 10903 New Hampshire Ave., Silver Spring, MD 20993.Refer to CMS case #522669 when replying. If you have any questions about the contents of this letter, please contact: Rebecca Keenan at 301-796-6215 or 301-847-8515.
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 the violations, and take prompt actions to correct the violations and bring the products into compliance.
Alberto Gutierrez, Ph.D.
Office of In Vitro Diagnostics and Radiological Health
Center for Devices and Radiological Health