WARNING LETTER

Greiner Bio-One North America, Inc. MARCS-CMS 606266 — April 16, 2020

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

Recipient:: Recipient Name

Arnaldo C. Marchionne; Recipient Title

Chairman of the Management Board; Greiner Bio-One North America, Inc.; 4238 Capital Drive
Monroe, NC 28110
United States; a.c.marchionne@gbo.com

Issuing Office:: Division of Medical Device and Radiological Health Operations Central; United States

WARNING LETTER
CMS # 606266

April 16, 2020

Dear Mr. Marchionne:

The United States Food and Drug Administration (FDA) conducted an inspection of your firm’s medical device operations at Greiner Bio-One North America, Inc., located at 4238 Capital Drive, Monroe, North Carolina, from December 9 – 13, 2019. During the inspection, FDA investigators determined that your firm is a manufacture of Vacuette brand blood collection tubes. 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.

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 responses on January 7, 2020 and March 13, 2020 from Manfred Abel, Quality and Regulatory Affairs and Roland Keller, EVP of Operations, concerning our investigators observations noted on the Form FDA 483, List of Inspectional Observations (FDA 483) that was issued on December 13, 2019. We address the responses 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 the identification, documentation, validation or where appropriate verification, review, and approval of design changes before their implementation, as required by 21 CFR 820.30(i). Specifically, you failed to complete validation testing prior to release of change CC17-2000-087 for the qualification of a new supplier for (b)(4) used in manufacturing your Vacuette brand product line. Documentation revealed your design requirement draw volume testing was not completed before the change was approved for manufacturing and that testing would be continued post-change. The incomplete testing did not adequately evaluate the potential of this change to affect the performance (safety) of the device prior to approval of the new (b)(4) supplier.

Your responses indicate you have opened CAPA C19-2000-028 to address this observation. You indicate you found no significant difference between the proposed material and a reference produced under the same conditions and acknowledge that testing should have been finished before releasing the material. You indicate you have identified a root cause and have initiated action items including a check for finished Change Plan and a retrospective check on all major changes since 2016. The adequacy of your response cannot be determined at this time. Your corrections are in progress, an assessment of your Corrective and Preventive Action (CAPA) along with an evaluation of the implementation of your corrective actions, and the effectiveness of the corrections you have taken will be reviewed during the next inspection.

2. Failure to adequately establish procedures for receiving, reviewing, and evaluating complaints by a formally designated unit as per 21 CFR 820.198(a). Specifically, your Technical Services Department is responsible for entering complaints into your complaint system. Review of the Technical Services e-mail log for the month of June 2019 noted four (4) reports of device failures that were not entered into your complaint system:

A. on June 19, 2019 noting:
i. Caps popping off tubes
ii. Slow fill rate on blue top citrate tubes
B. on June 3, 2019 noting tubes cracking and leaking during pneumatic tube system
C. on June 17, 2019 noting Vacuette EDTA lot number B19033GS expiration date 7/12/20 yield inaccurate hemoglobin levels.
D. on June 14, 2019 noting Greiner Bio-One needles:
i. cap falling off
ii. difficulty putting safety on the butterfly

Your responses indicate you have opened CAPA C19-2100-011 to address this observation. You indicate you have identified a root cause and have initiated action items including revise SOPs and perform retrospective review of Technical Service emails. The adequacy of your response cannot be determined at this time. Your corrections are in progress, an assessment of your Corrective and Preventive Action (CAPA) along with an evaluation of the implementation of your corrective actions, and the effectiveness of the corrections you have taken will be reviewed during the next inspection.

3. Failure to adequately validate with a high degree of assurance, a process whose results cannot be fully verified by subsequent inspection and test, as required by 21 CFR 820.75(a). Specifically, you use molding machines for the manufacture of your Vacuette blood collection tubes.

A. Review of your Performance Qualification Report for Molding Machine IMM08 with (b)(4), dated March 11, 2019 noted the following:
i. The press sensors (b)(4) were not calibrated prior to executing the performance qualification. The IM 08 sensors have not been calibrated since the unit was initially placed in service prior to 2009 and were overdue for calibration per your Injection Molding Machine Calibration Schedule.
ii. The performance qualification was for a single lot and did not demonstrate the process was repeatable.
iii. There was no justification for the rationale of using a single dimension (inner diameter) for the qualification rather than including other tube dimensions such as length, outer diameter, etc., as called out in the shop drawing.

B. On December 9, 2019 FDA Investigators observed (b)(4) being recycled on Molding Machine IM 04. Your Management indicated (b)(4) during the manufacture of Vacuette components. You have no documentation of validation for (b)(4) in the manufacture of your Vacuette medical components.

Your responses indicate you have opened CAPA C20-2100-001 to address this observation. You indicate you have identified a root cause and have initiated action items including updating and establishing procedures and you will assess and review production equipment to incorporate into the local calibration process. You indicate you will establish critical dimensions for injection molding finished part components and finished devices and you will perform a gap assessment of existing validation documents to determine compliance. The adequacy of your response cannot be determined at this time. Your corrections are in progress, an assessment of your Corrective and Preventive Action (CAPA) along with an evaluation of the implementation of your corrective actions, and the effectiveness of the corrections you have taken will be reviewed during the next inspection.

4. Failure to establish and maintain procedures for implementing corrective and preventive actions with documentation of activities and results as required by 21 CFR 820.100. Specifically,

A. CAPA C17-2100-025 was issued on August 28, 2017 to address validation records for manufacturing processes and software validation that do not include required data to meet established requirements. The validation records lack calibration reports, a record of the personnel that performed the individual task, the date, and an adequate description of the manufacturing process that would be supported by the validation activities. The CAPA was closed as effective on June 27, 2018; however, the corrective action identified in the CAPA, to create a detailed SOP that defines requirements and explains how to do site validations, was not taken.
B. CAPA C19-2100-008 dated November 22, 2019 was initiated in response to your Vacuette product recall of November 26, 2019 for tubes damaged by (b)(4) causing no or low vacuum in Vacuette tubes. On December 6, 2019 you verbally initiated a corrective procedure to the Vacuette production line maintenance activities. The corrective procedure was not documented and was initiated without receiving management approved.

Your responses indicate you have opened CAPA C19-2100-010 to address this observation. You indicate you have identified a root cause and have initiated action items. The adequacy of your response cannot be determined at this time. Your corrections are in progress, an assessment of your Corrective and Preventive Action (CAPA) along with an evaluation of the implementation of your corrective actions, and the effectiveness of the corrections you have taken will be reviewed during the next inspection.

5. Failure to adequately establish procedures for finished device acceptance, as required by 21 CFR 820.80(d). Specifically, your management indicated the final release of Vacuette medical devices include a Draw Volume Test (U TP 10.01.02-120 Rev 02) that conforms to standard ISO 6710. Investigators observed differences in the application of the protocol in the laboratory and the ISO 6710 standard:

A. ISO standard 6710 tares the test container (tube) prior to filling. You only tare 1 container (tube) from 8 to 20 nozzle samples in the test sample set.
B. ISO Standard 6710 indicates the test shall be carried out in ambient conditions of 101kPA and 20°C and make corrections if other conditions are used. Your blood draw test procedure and data sheets do not require or consider recording ambient temperature and pressure and do not provide method or procedure for making corrections should ambient conditions be other than ISO Standard 6710 conditions.

Your responses indicate you have opened CAPA C19-2100-014 to address this observation. You indicate you have identified a root cause and have initiated action items including revising the draw volume testing procedure for clarification between the ISO 6710 draw volume test, and the functional test and establish a procedure for final acceptance of the Vacuette tube products. The adequacy of your response cannot be determined at this time. Your corrections are in progress, an assessment of your Corrective and Preventive Action (CAPA) along with an evaluation of the implementation of your corrective actions, and the effectiveness of the corrections you have taken will be reviewed during the next inspection.

6. Failure to establish and maintain schedules for the adjustment, cleaning and other maintenance of equipment to ensure that manufacturing specifications are met, as required by 21 CFR 820.70(g)(1). Specifically, your “Annex-Injection Molding Machine Calibration Schedule-IMP, U AN SOP 09.04.03-23 Rev. 00” documents the calibration status of (b)(4) injection molding machines; (b)(4) of which were due or overdue for calibration.

Your responses indicate you have opened CAPA C19-2100-002 to address this observation. You indicate you have identified a root cause and have initiated action items. Your response indicates you have completed calibration of your molding machines and are working on establishing calibration and maintenance plans with an automatic alert function and will review plans for Injection Molding Preanalytics and will update as needed. Your corrections are in progress, an assessment of your Corrective and Preventive Action (CAPA) along with an evaluation of the implementation of your corrective actions, and the effectiveness of the corrections you have taken will be reviewed during the next inspection.

7. Failure to clearly define the extent of control to be exercised over the product, services and consultants as required by 21 CFR 820.50(a)(2). Specifically, the quality agreement between Greiner Bio-One North America, Inc., and (b)(4) does not define the type or extent of controls to be exercised by Greiner Bio-One International GmbH; for example, the responsibility for design validation was not included in the existing Quality Assurance Agreement.

Your responses indicate you have opened CAPA C19-2100-009 to address this observation. You indicate the Quality Agreement from 2019 between Greiner Bio-One North America and (b)(4) is not set up in this detail. (b)(4) is currently the design center and specification developer for Preanalytics medical products that is supported by Quality Management Instructions and procedures which regulated the responsibilities and exchange of information, (b)(4). For this Observation you have identified a root cause and have initiated action items to include performing a gap analysis of quality agreements, and that further actions will be defined based on the results of the GAP analysis. The adequacy of your response cannot be determined at this time. Your corrections are in progress, an assessment of your Corrective and Preventive Action (CAPA) along with an evaluation of the implementation of your corrective actions, and the effectiveness of the corrections you have taken will be reviewed during the next inspection.

8. Failure to ensure sampling plans are based on a valid statistical rationale as required by 21 CFR 820.250(b). Specifically, documentation could not be provided for:

A. the rationale used to determine your production and validation sampling plans such as “Vacuette Blood Collection Tubes: Common Tests and Sampling Intervals, U TP 10.01.02-100 Rev. 18, Valid from September 05, 2019”;
B. not using the first analysis of a verified test but require additional testing to verify the first test results; and,
C. not reporting the failure of the first test as a nonconformance, for example, procedure 5.2 states if a value is out of production limits two more measurements must be accomplished with new tubes, if either one of the second two tested is also out of production limits then the production must be stopped. Procedure requires a verification of the first test. There is no procedure to investigate the cause of a first analysis which identified a nonconformance and was not used. The procedure requires two out of three tests to identify a production failure.

Your responses indicate you have opened CAPA C19-2100-029 to address this observation. You indicate you have identified a root cause and have initiated action items. You will revise sampling plans according to the results of your gap analysis. Your corrections are in progress, an assessment of your Corrective and Preventive Action (CAPA) along with an evaluation of the implementation of your corrective actions, and the effectiveness of the corrections you have taken will be reviewed during the next inspection.

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:

1. Failure to submit a report to the FDA 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, the information included for Complaint 17-74 indicate that your firm’s Vacuette Quickshield Complete Plus venipuncture device malfunctioned (e.g. needle disconnection from the holder hub) while in use. Per the 1995 Preamble, a malfunction is reportable if the manufacturer takes, or would be required to take, an action under section 518 or 519(g) of the FD&C as a result of the malfunction of the device or other similar devices. (Refer to 1995 Federal Register Volume 60, Number 237, Page 63585. Please note that the preamble reference is section 519(f), but the appropriate designation for the section is now section 519(g) due to amendments to the FD&C Act). FDA determined that your firm’s field action Z-0179-2012, conducted for its similar device met the criteria under the 1995 Preamble. There is no information included for the complaint that justifies that the malfunction would not be likely to cause or contribute to a death or serious injury if it were to recur. Your firm became aware of the event on May 15, 2017 but didn’t submit an MDR for the referenced event.

Your firm submitted two responses to this charge that we reviewed: a response regarding the MDR decision process was submitted on January 7, 2020 and a response regarding Complaints 19-72-VAC USA, 19-64, CO19-2100-010 and 17-74 was submitted March 13, 2020.

The adequacy of your firm’s response dated January 7, 2020 cannot be determined at this time. In the response, your firm state it planned to complete a retrospective review and improve its MDR decision process. However, your firm did not provide documentation or evidence of implementation of its corrective actions, including the retrospective review of all adverse events in accordance with its revised MDR process.

Your firm’s response dated March 13, 2020 is not adequate. We acknowledge that your response referenced the guidance titled “Needlesticks -Medical Device Reporting Guidance for User Facilities, manufacturers, and Importers”, issued on 11/12/2002, to support that Complaints 19-72-VAC USA, 19-64, CO19-2100-010 don’t represent a reportable malfunction. However, your response did not address Complaint 17-74 and the associated reportability deficiency noted above.

Your firm should take prompt action to correct the violations addressed in this letter. Failure to promptly correct these violations may result in regulatory action being initiated by the FDA without further notice. These actions include, but are not limited to, seizure, injunction, and civil money penalties. Also, 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, 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 corrected. Also, should FDA determine that your devices do not meet the requirements of the Act, requests for Certificates to Foreign Governments (CFG) may not be granted. If you believe that your products are not in violation of the Act, please respond to FDA with your reasoning and any supporting information for our consideration.

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, as well as 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. Your firm’s response should be comprehensive and address all violations included in this Warning Letter.

If you have questions regarding any issues in this letter, please contact Compliance Officer, Demetria Lueneburg at 615-758-7210 or at Demetria.Lueneburg@fda.hhs.gov. Please send your reply electronically to Melissa Michurski, Director of Compliance Branch, at ORADevices2FirmResponse@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.

Sincerely,
/S/
Blake Bevill, M.S.
Program Division Director
Office of Medical Device and Radiological Health
Division 2 Central