Recipient NameJean-Francois Delforge
2 Rue Paul Millert
- Issuing Office:
- Center for Devices and Radiological Health
10903 New Hampshire Avenue
Silver Spring, MD 20993
NOV 10, 2016
VIA UNITED PARCEL SERVICE
Alseal and Alcis Group
2 Rue Paul Millert
Dear Mr. Delforge:
During an inspection of your firm located in 2 Rue Paul Millert, Besancon, France, on June 6, 2016, through June 9, 2016, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures catheter introducers. 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.
We received and reviewed a response from you dated July 7, 2016, and July 27, 2016, concerning our investigator's observations noted on the Form FDA 483 (FDA 483), List of lnspectional Observations, which was issued to your firm.
Your firm 's response dated October 31, 2016, to the Form FDA 483 (FDA 483) was not reviewed; this response will be evaluated along with any other written material provided in response to the violations cited in this Warning Letter. These violations include, but are not limited to, the following:
1. Failure to establish and maintain procedures to ensure that the design requirements relating to a device are appropriate and address the intended use of the device, including the needs of the user and patient, as required by 21 CFR 820.30(c). For example:
a. Your firm's design control procedure "Product Design & Development," PRO CONC-01, and the associated procedure, "Putting devices on the market (CE Marking)," PRO AFR-02, do not include adequate requirements to ensure that the design input requirements are documented, reviewed and approved by designated individuals.
b. The design input specifications for the (b)(4) were not approved until the end of the design project. Your firm does not have records to demonstrate that the design inputs for (b)(4) are approved, including the date and signature of the individuals approving the requirements in the early state of design phase, prior to completing the design project.
We reviewed your firm's response and conclude that it is not adequate. Your firm conducted a gap assessment to ensure that the design control requirements are adequately established. Your firm also revised its design control procedure, PRO CONC-01, to clearly define the design input requirements and trained relevant employees on the revised procedure. However, your firm should also evaluate whether changes to the design control procedure should have been applied to the validation/verification of the design (b)(4) devices.
2. Failure to establish and maintain adequate procedures for verifying the device design to confirm that the design output meets the design input requirements, as required by 21 CFR 820.30(f). For example, the Design History File for the (b)(4) design project does not have records of identification of the design, the methods used, the date of design verification testing, and the individual performing the verification testing, as required by Test Plans (b)(4) and (b)(4).
We reviewed your firm's response and conclude that it is not adequate. Your firm conducted a gap assessment to ensure that the design verification requirements are adequately established. Your firm also implemented a new instruction and templates where it provided instructions for conducing and documenting verification activities. However, your firm should also evaluate whether it should re-verify the design of the (b)(4) devices using the newly established design verification instruction.
3. Failure to establish and maintain procedures for implementing corrective and preventive action (CAPA), as required by 21 CFR 820.100(a). For example:
a. Your firm's CAPA procedure, "Manage Nonconformity (NC), Concession and Corrective Action & Preventive Action (CAPA)," PRO M-04 7, does not include adequate requirements for:
i. Analyzing processes, work operations, concessions, quality audit reports, quality records, service records, complaints, returned product, and other sources of quality data to identify the existing and potential causes of nonconforming product, or other quality problems;
ii. Employing appropriate statistical methodology where necessary to detect recurring quality problems;
iii. Verifying or validating CAPAs to ensure that such actions do not adversely affect the finished devices; and
iv. Disseminating information related to quality problems or nonconforming product to those directly responsible for assuring the quality of such product or the prevention of such problems.
b. Two CAPA files, 16/010 and 15/031, do not have documentation of all activities and their results, including documentation of root cause investigations, as required by your firm's CAPA procedure.
We reviewed your firm's response and conclude that it is not adequate. Your firm conducted a gap assessment to ensure that CAPA regulatory requirements are established. Your firm also revised its CAPA procedures, PRO M-04 and ENR M-22, to include the above procedural requirements, and trained relevant employee on the revised CAPA procedures. However, your firm should also evaluate its previous CAPA files to ensure that the lack of procedural requirements did not result in the release of nonconforming products, and take action to mitigate any adverse health consequences to the user where appropriate.
4. Failure to adequately ensure that when the results of a process cannot be fully verified by subsequent inspection and test, the process shall be validated with a high degree of assurance and approved according to established procedure, as required by 21 CFR 820.75(a). For example:
a. Your firm has not established process validation procedures for any of its processes, including the(b)(4) process.
b. Deficiencies were noted in the operational and process qualification (OQ/PQ) of the (b)(4) devices. For example:
i. Your firm has not conducted testing to determine the (b)(4) for the (b)(4). Only (b)(4) was used to conduct OQ.
ii. Your firm has not conducted PQ and OQ testing under variable condition (e.g. with different operator, day, and production lot) to demonstrate that the (b)(4) can consistently produce device to its predetermined specifications.
We reviewed your firm's response and conclude that it is not adequate. Your firm conducted a gap assessment to address the procedural deficiencies. Your firm additionally implemented a procedure, PRO CONC-03, which describes the process validation requirements and trained relevant employees on the procedure. Your firm also plans to conduct an analysis of devices, including the HQS introducer and XCath, to verify if process validation activities are properly documented. Based on this analysis, your firm will determine which processes would require a re-validation. In addition, the response indicated your firm expects to conduct process validation for the products distributed for the US market. However, your firm should also demonstrate that it conducted an evaluation to determine whether the lack of procedure and process validation could have resulted in the release of nonconforming products in distribution, and take action to mitigate any adverse health consequences to the user where appropriate.
5. Failure to establish and maintain procedures that define the responsibility for review and the authority for the disposition of nonconforming product, as required by 21 CFR 820.90(b)(1). For example:
a. Your firm's nonconforming handling procedure, "Manage Nonconformity (NC), Concession and Corrective Action & Preventive Action (CAPA)," PRO M-04, does not:
i. Set forth the review and disposition process for nonconforming products; and
ii. Ensure that the disposition of nonconforming product is documented, and documentation should include justification for the use of nonconforming product and the signatures of the individuals authorizing the use.
b. Deficiencies are noted in the evaluation and disposition of nonconforming products. For example:
i. Nonconformance (b)(4) was initiated to rework (b)(4) of HQS Introducer from lot 15/3339, which were damaged (b)(4). Your firm does not have evaluation records showing the effects of rework on the devices.
ii. Nonconformance (b)(4) was initiated when it was (b)(4) challenging. Your firm has not assessed the risk associated with this nonconformance; however, recommended to use the device as is.
We reviewed your firm's response and conclude that it is not adequate. Your firm conducted a gap assessment to ensure that the handling of non-conforming product regulatory requirement is adequately established. Your firm also revised its nonconforming product handing. procedure and form to address the above procedural deficiencies, and trained relevant employee on the revised procedure and form. However, your firm should also address how deficiencies noted in several nonconformance records will be addressed. Your firm should also demonstrate that it conducted a review of previous nonconformance records to determine whether the lack of adequate evaluation of disposition of nonconforming products could have resulted in the release of defective products in distribution, and take action to mitigate any adverse health consequences to the user where appropriate.
6. Failure to establish and maintain procedures, where appropriate, for identifying valid statistical techniques required for establishing, controlling, and verifying the acceptability of process capability and product characteristics, as required by 21 CFR 820.250(a). For example, your firm has not established procedures for identifying valid statistical techniques for verifying the acceptability of process capability and product characteristics for the verification testing conducted on the (b)(4) Test Plans (b)(4). The number of test samples identified in the Test Plans is not based on a valid statistical rationale.
We reviewed your firm's response and conclude that it is not adequate. Your firm conducted a gap assessment to ensure that statistical method procedures are established. Your firm also revised its procedure, PRO CONC-04, which defines statistical techniques to justify the sampling plan used when design verification, process validation and incoming inspection are conducted, and trained relevant employee on the revised procedure. However, your firm should also demonstrate that it conducted a review of all processes and test methods to ensure that statistical techniques are applied in accordance with the revised procedure, PRO CONC-04.
7. Failure to maintain a record of investigation, when an investigation is made under 21 CFR 820.198, by the formally designated unit identified in paragraph (a) of 21 CFR 820.198, as required by 21 CFR 820.198(e). For example, the records of complaint investigations do not include the required information. Eleven complaint files (e.g., RC 15/036, 15/046, and RC 15/054 and eight others) associated with either broken HQS catheter introducer sheath, valve leakage, and rupture of XCath do not include the complaint receipt date, the address and phone number of the complainant, the dates of the investigations and any reply to the complainants.
Your firm's response to this observation appears to be adequate.
Our inspection also revealed that your firm's devices 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 803 - Medical Device Reporting. Significant violations include, but are not limited to, the following:
8. Failure to report 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 it markets has malfunctioned and this device or a similar device that your firm 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, your firm became aware of an event, Complaint 15/051, that describes a breakage of an HQS Introducer during surgery, and that the surgeon was not able to locate the missing piece of the device. There was no injury to the patient; however, your firm did not provide any follow-up information regarding attempts to get any additional information regarding the patient. Additionally, your firm initiated correction and removal of the affected lots. However, your firm failed to report the device malfunction that would be likely to cause or contribute to a serious injury as required by 21 CFR 803.50(a)(2).
Your firm's response to this observation appears to be adequate.
Our inspection also revealed that your firm's HQS Introducer 18F-26F devices 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 Devices; Reports of Corrections and Removals. Significant violations include, but are not limited to, the following:
9. Failure to submit a Report of Correction or Removal within 10 working days of initiating such correction or removal, as required by 21 CFR 806.10. For example: your firm stated that it received two complaints related to flaking or breakage of the HOS Introducer sheaths in November 2015 and January 2016. After testing and noting the same failure, your firm determined which lots had been affected and drafted a Field Safety Notice for distribution to all affected countries. Your firm implemented a Field Safety Action for product potentially affected by the device deficiency and all Alseal concerned customers received the notice. However, your firm has not submitted a written report to FDA of the correction and removal.
The adequacy of your firm's responses cannot be determined at this time. Your firm's responses did not address this issue. Your firm should update its procedures to follow the requirements under 21 CFR 806, and the guidance provided by the 21 CFR 7.40, Recall Policy, to ensure that all required information is provided to the FDA. Your firm should also conduct health risk assessment following the definition of risk to health ·under 21 CFR 806.20), to support the reporting decisions for future medical device corrections and removals.
Given the serious nature of the violations of the Act, catheter introducers 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 violations described in this letter. We will notify you regarding the adequacy of your firm's responses 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 #507073 when replying. If you have any questions about the contents of this letter, please contact: Daniel Walter, Branch Chief, Foreign Enforcement Branch at firstname.lastname@example.org (email) or +1-240-402-4020 (telephone).
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 lnspectional 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.
CAPT Sean M. Boyd, MPH, USPHS
Deputy Director for Regulatory Affairs
Office of Compliance
Center for Devices and Radiological Health
Crofton, MD 21114