- Delivery Method:
- VIA UNITED PARCEL SERVICE
Ms. Else Beth Trautner
- Euro Diagnostica AB
P.O. Box 50117
202 11 Malmo, Skane
- Issuing Office:
- Center for Devices and Radiological Health
10903 New Hampshire Avenue
Silver Spring, MD 20993
SEPT 20, 2017
VIA UNITED PARCEL SERVICE
Ms. Else Beth Trautner
Chief Executive Officer
Euro Diagnostica AB
Lundavagen 151, P.O. Box 50117
Malmo, Skane, SE-202 11 Sweden
Dear Ms. Trautner:
During an inspection of your firm located in Malmo, Skane, Sweden on 01/16/2017 through 01/19/2017 an investigatorfrom the United States Food and Drug Administration (FDA) determined that your firm manufactures multiple class II in vitro diagnostic (IVD) devices, including the Euro-Diagnostica CCPoint. 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 Elsa Beth Trautner, Chief Executive Officer, dated 02/07/2017 concerning our investigator’s observations noted on the Form FDA 483 (FDA 483), List of Inspectional Observations, which was issued to your firm as well as an additional response from Hanne Harbo Hanson, Quality Assurance Director dated 03/31/2017. We also received further responses dated 06/20/2017 and 08/31/2017 which will be evaluated along with any other written material provided in response to the violations cited in this Warning Letter. We address the 02/07/2017 and 03/31/2017 responses in relation to each of the below noted violations.
These violations include, but are not limited to, the following:
1. Failure to establish and maintain procedures for receiving, reviewing, and evaluating complaints by a formally designated unit as required by 21 CFR 820.198(a). Specifically, your firm's procedures with document number M-01-0001-10 and titled “COMPLAINT HANDLING” “Valid from” 05/20/2016 (and previous revisions reviewed) were not adequately established to ensure complaints are handled in a timely manner and that all complaints are adequately evaluated for Medical Device Reportability as is required under 21 CFR 820.198(a).
Additionally, during review of a sampling of 10 complaints, it was noted that when investigations are conducted not all of the required data elements including the dates and results of the investigations and any reply to the complainants are recorded in the files as is required under 21 CFR 820.198(a).
We reviewed your firm’s responses to the FDA 483 and conclude that they are not adequate. Your firm provided a corrective preventive action (CAPA) plan, CAPA 2017-03, which describes the complaint; describes the investigation into the complaint; and describes the corrective or preventative action to address the complaint. Also, included in CAPA 2017-03 your firm has provided minutes from a meeting to discuss FDA audit observations.
Your firm’s responses are not adequate because your firm has not provided evidence that procedures have been established to address complaints in a timely manner and to ensure complaints are adequately evaluated for Medical Device Reportability (see 21 CFR 820.198(a)). Evidence that procedures to address complaints in a timely manner are in place and approved by management are necessary to ensure that concerns about product safety, which ultimately impacts patient safety, are quickly addressed. Additionally, procedures that outline the required documentation of results from investigation or replies to complainants are imperative to ensure that complaints were thoroughly addressed and accepted by both the complainants and your firm. Therefore, your firm should provide an approved and updated Complaint Handling procedures form that clearly outlines the procedures to thoroughly address complaints in a timely manner.
2. Failure to document all corrective and preventive action activities and their results, as required by 21 CFR 820.100(b). Specifically, all activities with results were not documented in CAPA 2015-12 including the correspondence with the supplier investigating the batch of slides under investigation.
We reviewed your firm’s responses to the FDA 483 and conclude that they are not adequate. In your response to the FDA 483, your firm provided a corrective preventive action (CAPA) plan, attachment 2017-02, which outlines your firm’s plan to address and implement corrective actions for Observation 6. Also, your firm provided updated instructions and procedures, document number “A-01-0057-09E,” to be used internally for addressing future CAPAs, “CAPA 2017-02 Attachment 7.” Further, your firm has provided an internal form titled “CORRECTIVE AND PREVENTIVE ACTIONS”, document number “A-22-0094-04E”, for recording CAPAs.
Your firm’s responses are not adequate because your firm has not provided evidence that it has formally documented and recorded activities associated with CAPA 2015-12 as is required under 21 CFR 820.100(b). Also, your firm has not provided evidence that a retrospective review has been performed to determine if past activities associated with the aforementioned CAPA were adequately documented. Adequate documentation of activities to address a CAPA is necessary to demonstrate that your firm has thoroughly investigated the issues that initiated the CAPA and found solution to resolve the CAPA. You should provide evidence that your firm has formally documented these activities which includes consideration of a systemic corrective and retrospective review of documentation in your CAPA system.
3. Failure to establish and maintain procedures to ensure that formal documented reviews of the design results are planned and conducted at appropriate stages of the device’s design development, as required under 21 CFR 820.30(e). Specifically, your firm's document titled “Design Control Instructions”, document number “U-01-0011- 00” (and other revisions reviewed) were not adequately established to ensure that all design review meeting minutes were included in the Design History File (DHF) for “(b)(4)” for CCPoint. Nor were the procedures established to ensure the individual without responsibility for the design stage under review were present.
We reviewed your firm’s responses to the FDA 483 and conclude that they are not adequate. Your firm has provided an internal CAPA report, “CAPA 2017-06 1 (2)”, which outlines your firm’s plan to address FDA-483bservation 4. Included in this CAPA is a copy of your firm’s existing document titled “DESIGN CONTROL INSTRUCTIONS”, document number “U-01-0011-00”, which outlines your firm’s procedures for reviewing design controls. Your firm provided meeting minutes, dated 09/21/07, from a meeting that was conducted to discuss quality control and design review issues for your firm’s CCPoint product. Your firm included a risk management report, A-22-0134-06, dated 09/14/2015 that includes a post-market surveillance report, which includes tables for products sold, the number of CCPoint products sold, and the number of complaints for CCPoint. The post-market report does not identify additional risk that need to be controlled. Your firm has included training materials for design controls from 2013. Additionally, your firm provided updated design control instructions, document number “U-01-0011-10”, and a design review form that includes a signing box for an independent reviewer. Further, your firm has provided an outline of training topics and a training log with participant names and signatures for design control training performed by your firm.
Your responses are not adequate because your firm has not provided sufficient documentation of the design review meeting minutes in the DHF for “(b)(4)” for CCPoint. Also, your firm has not identified the independent reviewer involved in the various design stages for the CCPoint product. Also, no evidence was provided to demonstrate that systemic corrective action has been conducted to determine if design reviews for your firm’s other devices have included an independent reviewer. Additionally, your firm has not identified the independent reviewer involved in the various design stages for the CCPoint product. Proper documentation of the design review meeting minutes are necessary to ensure that design changes and updates are properly controlled, involve all responsible stakeholders, and to ensure that complete records are available to reference in case there are issues with the design changes in the future. Additionally, an individual without responsibility for the project is required to ensure the proper procedures and policies are followed to ensure product safety and protect the health of users of the device. Therefore, your firm should provide the formal meeting minutes from design change meetings held and identify the individual without responsibility involved in the design changes for “(b)(4)” for CCPoint. Further, your firm should also perform a systemic corrective action to ensure that design changes for your firm’s other products are properly documented and determine if an individual without responsibility was involved in design change meetings and decisions.
4. Failure to establish and maintain procedures for verifying the device design; to confirm that the design output meets the design input requirements; and to document in the DHF the results of the design verification, including identification of the design, method(s), the date, and the individual(s) performing the verification, as required under 21 CFR 820.30(f). Specifically, your firm's document “Design Control Instructions”, document number “U-01-0011- 00” (and other revisions reviewed) were not adequately established to ensure that all design verification results are included in the DHF including identification of the design, methods, the date, the results of the testing and the individual conducting the test for “(b)(4)” for CCPoint. No test results for the correlation testing between CCPoint and an existing (b)(4) were available in the DHF.
We reviewed your firm’s responses to the FDA 483 and conclude that they are not adequate. Your firm provided document number “A-22-094-03,”“CAPA nummer: 2017-07”, which identifies the gaps in your firm’s design control instructions and outlines your firm’s plan to address the observation. “CAPA nummer: 2017-07” also includes your firm’s design control instructions, a test verification report template, and a design input/design output/design verification worksheet.
Your firm’s responses are not adequate because your firm does not provide test results for correlation testing between CCPoint and the existing (b)(4). Additionally, your firm does not provide updated Document Control instructions, approved by management or another responsible individual(s), that clearly states that all design verification information and results (i.e., identification of the design, methods, the date, the results of the testing) are included in the DHF. Records of design verification results are required to ensure that your firm confirmed that design changes did not significantly change the analytical performance (i.e., precision, limit of detection, linearity, interference, etc.). Therefore, your firm should provide the DHF that demonstrates that your firm performed correlation testing and confirmed the results. Additionally, your firm should provide evidence that a systemic corrective action has been carried to ensure that correlation testing was performed and confirmed by responsible individuals for your firm’s other products in which design changes were made.
5. Failure to establish procedures for quality audits and conduct such audits to assure 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, quality audits were not performed at defined intervals to determine whether the quality system activities and results comply with quality system procedures. Specifically, your firm's document for Internal Audits, document number “A-01-0059-14” valid from 09/30/2016 (and previous revisions reviewed) define the frequency of audits in Appendix 1 which requires the ISO 13485 and FDA 21 CFR Parts 801, 803, 806 and 820 regulations which must be audited each year. However, it was noted that eight (8) of the sixteen (16) areas to be audited were not audited within the one year time-frame as per procedure. For example, the audit of nonconforming product handling was not audited for 18 months between 03/12/2015 to 09/30/2016.
We reviewed your firm’s responses to the FDA 483 and conclude that they are not adequate. Your firm provided the document with “CAPA nummer: 2017-08”, document number “A-22-0094-03”, which identifies the root cause for the lapse in the frequency of performing audits and documentation of audits. The CAPA also outlines your firm’s plans for corrective action. Also, “CAPA nummer: 2017-08” contains an updated protocol for performing audits, document number “A-01-0059-15.” Additionally, your firm has provided the document titled “CAPA2017-08 Completed”, dated 02/21/2017, that includes a list of participants for a training session relevant to the EIR observation.
Your firm’s responses are not adequate because your firm has not provided documentation of an audit of your firm’s quality systems. Documentation of audits is important to ensure that a firm’s quality systems are up to date and adequate to maintain product performance, quality, and safety. Therefore, you should provide documentation of an audit of your firm’s quality systems and associated regulations.
Our inspection also revealed that the Antibodies, Anti-Cyclic Citrullinated Peptide (CCP) 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 regarding 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 deviations include, but are not limited to:
Failure to adequately develop, maintain and implement written MDR procedures, as required by 21 CFR 803.17.
For example: After reviewing your firm’s MDR procedures titled “MEDICAL DEVICE REPORTING FOR THE US MARKET,” “Document no.: A-01-0169-01,” “Valid from 5/31/2016,” the following issues were noted:
1. A-01-0169-01 does not establish internal systems that provide for timely and effective identification, communication, and evaluation of events that may be subject to MDR requirements. For example:
a. The procedure omits the definition of the terms “become aware” and “caused or contributed” from 21 CFR Part 803.3 and the definition for the term “reasonably suggests” found in 803.20(c)(1). The exclusion of the definition 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).
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. A-01-0169-01 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. For example:
a. There are no instructions for conducting a complete investigation of each event and evaluating the cause of the event.
b. There are no instructions for how your firm will evaluate information about an event to make MDR reportability determinations in a timely manner.
3. A-01-0169-01 does not establish internal systems that provide for timely transmission of complete medical device reports. Specifically, the following is not adequately addressed:
a. The circumstances under which your firm must submit initial 30 days, supplemental or follow-up, and 5 day reports and the requirements for such reports.
b. The procedure does not include a reference for the submission of MDR reportable events using the mandatory reporting Form FDA 3500A or electronic equivalent.
d. How your firm will submit all information reasonably known to it for each event. Specifically, which sections of the Form FDA 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.
The adequacy of the firm’s responses dated February 7, 2017, February 28, 2017, and March 31, 2017, for Observation 1 cannot be determined at this time. Your firm included a corrective action plan listing an approved date of completion to revise your MDR procedure, to address those items listed in the Observation. Your firm included an action completion date of “2017-10-31” with each response. This documentation has not yet been received for review.
Your firm’s procedure includes reference to baseline reports (FDA 3417). Baseline reports are no longer required and we recommend that all references to a Baseline Report be removed from your firm’s MDR procedure (see 73 Federal Register 53686, dated September 17, 2008).
Additionally your firm’s procedure (Section 4.4 Information) includes reference to an “MDR Telephone Number for General Assistance: (301) 796-6670 for use to make arrangements to fax Medical Device Reports to FDA and to obtain assistance in filling out report forms as well as to receive 5-day reports of events requiring remedial action” and “5-Day Phone / Fax Report.” FDA’s MDR Reportability General Inquiry Line: (301) 796-6670, can be used for assistance with general reportability guidance; however, it is not for use in assisting with preparing and sending facsimiles/copies in accordance with FDA requirements. We recommend that your firm remove all references to the general assistance telephone number from your firm’s MDR procedure in connection with making arrangements to fax MDR reports to FDA. Defer to the process for submitting MDRs electronically as provided in the instructions above.
Our inspection also revealed that your firm’s FANA 200 Test Kits 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 806 – Medical Device; Reports of Corrections and Removals. Significant violations include, but are not limited to, the following:
Failure to submit any report required within 10-working days of initiating such correction or removal, as required by 21 CFR Part 806.10. Specifically, no justification was documented for not reporting the correction action to FDA involving increased false positive test results related to Product Code FANA200 Test Kits for Lot SS2009.
Your firm received customer complaints, numbers C2426 on July 13, 2015, and C-2445 on September 2, 2015, relating to an increased ratio of positive results. Your firm conducted an investigation. Your firm, on September 21, 2015, made the decision to not conduct a recall despite your standard operating procedures (SOP) and the confirmation that the higher incidence of false positive results was confirmed. According to your firm’s Quality Review Board (QRB), your firm decided that it should inform affected customers as a matter of customer relations. In the letter sent to customers, your firm offered the replacement of kits. However, the QRB also determined that there is no patient risk involved for these batches and a recall of affected batches was not required. Your firm did not report these actions to FDA.
We reviewed your firm’s responses to the FDA 483 and conclude that these are not adequate. Your firm acknowledged and agreed with the observation. Your firm provided the document with “CAPA nummer: 2017-05” which outlines your firm’s action plan to address Observation 3. However, the action plan does not include reporting the correction and removal actions. Your firm also indicated that the recall procedures will be updated to reflect reporting requirements. However, your firm did not provide evidence.
In addition, we recommend that your firm update the procedures to follow the requirements under 21 CFR Part 806 - Medical Devices; Reports of Corrections and Removals, and the guidance provided by the 21 CFR Part 7 - Recall Policy, to ensure that all required information is provided. CDRH recommends that your firm refer to CDRH recall classifications to evaluate future corrections and removals, thereby maintaining consistency in your Health Hazard Evaluations and compliance with reporting requirements. We further recommend that your firm conduct health risk assessments following the definition of risk to health in 21 CFR 806.2(k), to support reporting decisions for future medical device corrections or removals.
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 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.
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 # 524316 when replying.If you have any questions about the contents of this letter, please contact: Nisar Pampori at 301-796-6144or email Nisar.Pampori@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 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
Ms. Rene Van De Zande
Emergo Group, Inc.
816 Congress Avenue, Suite 1400
Austin, TX 78701