VIA UNITED PARCEL SERVICE
Ms. Anja Wiersma
Ede, Netherlands 6716 BS
During an inspection of your firm located in Ede, Netherlands on May 19, 2014 through May 22, 2014, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures multiple Class II (Point of Care) Hematocrit Controls and Reference Materials. 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 you dated June 12, 2014 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 procedures for validating the device design, as required by 21 CFR 820.30(g).
For example, design validation activities did not ensure that the Eurotrol Hematocrit (Hct) Control, epoc® Hematocrit Verification Fluids, and the Eurotrol HemoTrol quality control conform to defined user needs and intended uses. Specifically:
1. The stability study related to the stability claim (b)(4) Eurotrol Hematocrit (Hct) Control and epoc® Hematocrit Verification Fluids unopened ampules was approved in spite of the sample failures observed during the stability study and the related “open” nonconforming report due to the failures. Your firm’s stability study protocol did not indicate to retest samples and accept the retest result. The 510(K) clearance was for a 12 month storage and shelf life and the current Instructions for Use claims unopened storage shelf life of 13 months.
2. The stability study related to the stability claim (b)(4) for the HemoTrol were not adequately documented. The test report reviewed by the investigator indicate that the stability study was performed using the (b)(4) was indicated in the “Method” section of the report. Documentation of a stability study to demonstrate (b)(4) stability for the Eurotrol HemoTrol was not completed by your firm as required.
We reviewed your firm’s response and conclude that it is not adequate. Your firm did not provide evidence that it implemented a correction related to the outlined deficiencies of the stability studies for the Eurotrol Hematocrit Control, Epoc Hematocrit Verification Fluids and Eurotrol HemoTrol found under this observation to include conducting the stability studies as required for the Eurotrol Hematocrit (Hct) Control, epoc® Hematocrit Verification Fluids unopened ampules, and the Eurotrol HemoTrol. In addition, your firm did not provide evidence that it conducted a retrospective review of design validation activities to ensure that these activities were performed and documented as required
2. Failure to adequately ensure that when the results of a process cannot be fully verified by subsequent inspection and test, that the process shall be validated with a high degree of assurance and approved according to established procedures, as required by 21 CFR 820.75(a). For example:
1. Your firm failed to validate the cleaning process used to clean product contact surfaces and equipment such (b)(4).
2. Your firm failed to revalidate its (b)(4) or document a related justification for the decision to not revalidate the (b)(4) when the following (b)(4) were purchased after validation of the original (b)(4). Your firm was unable to provide documented justification that (b)(4) compatible and similar.
We reviewed your firm’s response and conclude that it is not adequate. Your firm did not provide evidence of when the (b)(4) would be revalidated based on the revised procedure-PR003K. In addition, your firm did not provide evidence that employees were trained on the revised procedure. Finally, your firm did not provide evidence that a retrospective review of all processes requiring validation was completed to ensure that these processes were validated as required.
3. Failure to establish and maintain procedures to control product that does not conform to specified requirements, as required by 21 CFR 820.90(a).
For example, your firm failed to initiate a nonconforming report (NCR) and to discard nonconforming product as required by the “Complaint, Nonconformities and Improvement procedure, PRO04C-R07 and “Quarantine products” procedure, (b)(4) respectively.
1. A NCR ticket was not initiated to address the non-conforming (b)(4) Eurotrol Hct Control and epoc® Hematocrit Verification Fluids, Lot# 190-2B249. The wrong raw material was used in this lot and the lot was discarded. The disposal of the lot was not documented on Form (b)(4) as required by your firm’s procedure, (b)(4). Your firm stated that the disposal was not documented.
2. A NCR ticket investigating the cause of lot 190-4-350 for Eurotrol Hct Control and epoc® Hematocrit Verification Fluids made with the incorrect amount (b)(4) was not created and issued before a PCC ticket or product change was performed. According to your firm’s procedure, Creating and Managing NCRs in (b)(4), a NCR ticket entry should be created whenever there is a deviation that leads to nonconforming products and/or process. Your firm stated an NCR was not created prior to initiating a PCC ticket.
We reviewed your firm’s response and conclude that it is not adequate. Your firm did not provide completed NCRs showing evidence of the corrections of the deficiencies of the identified nonconformities. Also, your firm did not present a plan or provide documentation of a comprehensive retrospective review of nonconforming product to ensure all nonconforming reports were initiated as required and that the nonconforming product was quarantined and discarded as required.
4. Failure to establish and maintain procedures for receiving, reviewing and evaluating complaints by formally designated units as required by 21 CFR 820.198(a).
For example: Your firm failed to include the requirements to ensure that all complaints were processed in a timely manner. Your firm stated that all complaints, nonconformities and improvements including CAP are handling according to the Complaints, Nonconformities and Improvement procedure-PRO04C-R07. Your firm’s procedure PRO04C-R07 did not include information regarding the timely handling of complaints by a formally designated unit including oral complaints upon receipt by customers.
We reviewed your firm’s response and conclude that it is not adequate. Your firm did not indicate when it would make the revisions to the procedure and did not provide evidence that it trained appropriate staff on the revised complaint handling procedure. In addition, your firm did not provide evidence that it conducted a retrospective review of all procedures to ensure they were handled in a timely manner as required by the revised procedure. Finally, your firm did not provide evidence that it considered a systemic corrective action to include a retrospective review of other procedures for handling complaints to ensure that these procedures meet regulatory requirements.
5. Failure to establish and maintain procedures to control all documents that are required by this part (21 CFR 820), as required by 21 CFR 820.40.
For example: Your firm failed to update the Complaint, Nonconformities and Improvement Procedure, PRO04C-R07, after it discontinued the use of "(b)(4)" and "(b)(4)" databases used in documentation and handling of tickets for complaints of nonconformities . "(b)(4)" and "(b)(4)" databases were replaced with the "(b)(4)" in December, 2013 according to Mr. Maarten L Arends, the firm’s QA Manager. Your firm’s procedure - Complaint, Nonconformities and Improvement Procedure, PRO04C-R07, did not reflect the replacement of the new database system, (b)(4) that provides communication and full audit trail of all product change controls (PCC), non- conformity reports (NCR), CAPA, and complaints.
We reviewed your firm’s response and conclude that it is not adequate. Your firm should reference the (b)(4)-Creating and Managing NCRs (b)(4), in the document PRO04C-R07. Also your firm did not provide evidence that it conducted a retrospective review of all procedures to ensure that any changes made were reflected in the procedure as well as any changes regarding the update of the (b)(4) were reflected according to RRO04C-R07, PR004E-R03 and (b)(4). In addition, your firm did not provide evidence that it implemented corrective action to ensure oversight of procedure changes would not recur.
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 2622, 10903 New Hampshire Ave., Silver Spring, MD 20993. Refer to CMS case #433999 when replying. If you have any questions about the contents of this letter, please contact: Joshua Levin at (301) 796-6695.
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.
Office of In Vitro Diagnostics and
Center for Devices and