Inspections, Compliance, Enforcement, and Criminal Investigations

Cellestis Inc 8/26/15

  

Department of Health and Human Services logoDepartment of Health and Human Services

Public Health Service
Food and Drug Administration
  Los Angeles District
19701 Fairchild
Irvine, California 92612-2506
Telephone (949) 608-2900
Fax (949) 608-4415

 

VIA UNITED PARCEL SERVICE
SIGNATURE REQUIRED                                                                                                       
 
                                                                                                                                                  
August 26, 2015                                                                                                                
                                                                            WL # 33-15
 
Douglas Liu
Sr. V.P. of Global Operations
Qiagen Inc.
19300 Germantown Road
Germantown, Maryland 20874
                                                                                                                       
Dear Mr. Liu:
 
During an inspection of Cellestis, Inc., located in Santa Clarita, California, conducted from March 17 through March 25, 2015, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures the QuantiFERON®-TB Gold (QFT®) test device. Under section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. § 321(h), this product is a device because it is 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 your 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 Mr. Mark Boyle, Vice President, Program Management MDx/TB and Transplant for Cellestis, dated April 14, 2015, to the observations noted on Form FDA-483, List of Inspectional Observations, which was issued to your firm on March 25, 2015. We address these responses below, in relation to each of the noted violations. These violations include, but are not limited to, the following:
 
1)    Failure to establish procedures for receiving, reviewing, and evaluating complaints by a formally designated unit, as required by 21 CFR 820.198(a). 
 
For example, your firm reported six Medical Device Reports to the Agency on April 8, 2015 that referenced deficiencies of the QuantiFERON®-TB Gold (QFT®) test device in meeting effectiveness and performance specifications. Your firm did not process these device deficiencies according to the requirements set forth under 21 CFR 820.198. These Medical Device Reports were referenced as: 3003964343-2013-0001, 3003964343-2013-0002, 3003964343-2013-0003, 3003964343-2013-0004, 3003964343-2013-0005 and 3003964343-2013-0006. We have reviewed Cellestis’ response, and find it inadequate. The response states the firm will be revising the quality agreement between Qiagen and Cellestis, that they are in the process of modifying their procedures, and they will perform training to these new procedures. We cannot verify these activities have occurred. Additionally, the response referenced that the firm will log in the subject events as complaints; however we cannot verify this has been done, nor can we evaluate how these events were processed. Additionally, we cannot verify if all complaints or device failures have been reviewed for appropriate MDR decisions.
 
Our inspection also revealed that the QuantiFERON®-TB Gold (QFT®) test 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 regarding the devices 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:
 
2)    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 procedure titled “Advisory Notices,” SOP 033, Rev. 15, dated March 1, 2013, the following issues were noted:
 
            a)    SOP 33 Rev. 15 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:
                       
i)    There are no definitions of what your firm will consider to be a reportable event under 21 CFR Part 803. The exclusion of definitions from 21 CFR 803.3 for the terms “become aware,” “caused or contributed,” “malfunction,” “MDR reportable event,” and “serious injury,” and the definition for the term “reasonably suggests,” found in 803.20(c)(1) may lead your firm to make an incorrect reportability decision when evaluating a complaint that may meet the criteria for reporting under 21CFR 803.50(a).
 
ii)    Appendix 1, “Advisory Notice Decision Tree”, does not reference a process for identifying and evaluating events occurring outside the United States (U.S.) as potentially reportable to FDA. If an event occurs in a foreign country, it may be reportable under the MDR regulation if the event involves a device that is the same or similar to a device that has been cleared or approved for marketing in the U.S. By not considering events that occur outside of the U.S., potentially reportable MDRs may not be identified and evaluated for MDRdecision making and submission to FDA as required by 21 CFR 803.50 and 21 CFR 803.53.
 
b)    SOP 33, Rev.15 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:
 
i)   There are no instructions for conducting a complete investigation of each event and evaluating the cause of the event.
 
c)    SOP 33, Rev. 15 does not describe how your firm will address documentation and record-keeping requirements, including:
 
i)    Documentation of adverse event related information maintained as MDR event files.
 
ii)    Information that was evaluated to determine if an event was reportable.
 
iii)    Documentation of the deliberations and decision-making processes used to determine if a device-related death, serious injury, or malfunction was or was not reportable.
 
iv)    Systems that ensure access to information that facilitates timely follow-up and inspection by FDA.
 
We reviewed your firm’s response dated April 14, 2015, and conclude that it is not adequate. Your firm submitted a revised Section 6.1 titled “FDA (Medical Device Reporting)” of the document SOP 033 “Advisory Notices,” Ed 14. Based on the submitted information, the issues noted above under 1(a)(i), and 1(c)(i-iv) are still noted.
 
3)    Failure to report to 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 your firm markets has malfunctioned and this device or a similar device that it 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: MDR 3003964343-2013-00002 references an event where your firm’s device, which is the subject of recall numbers Z-0888-2013 and Z-0889-2013, malfunctioned. Your firm became aware of the event on March 4, 2013. The FDA received the referenced MDR on April 9, 2013, which is beyond the 30 calendar day timeframe.
 
We reviewed your firm’s response dated April 14, 2015, and conclude that it appears to be adequate. An MDR (3003964343-2013-00002) for the referenced event was received by FDA. In addition, your firm is revising its MDR procedure.
 
4)    Failure to include information in your reports, if known or reasonably known to you, as described in 21 CFR 803.50(b). Specifically, to include in Block G4 of the FDA Form 3500A, the “Date Received by Manufacturer,” as required by 21 CFR 803.52(e)(4).
 
For example: Your firm submitted MDR 3003964343-2013-00002 for the event described in item 2 above. However, your firm did not identify in Block G4 of the FDA Form 3500A, the “Date Received by Manufacturer.” Your firm became aware of the event on March 4, 2013.
 
We reviewed your firm’s response dated April 14, 2015, and conclude that it is not adequate. Your firm should submit a supplemental report for MDR 3003964343-2013-00002, which includes the information in Block G4 of the 3500A form that was not completed at the time the initial MDR was submitted
 
The eMDR Final Rule requiring manufacturers and importers to submit electronic Medical Device Reports (eMDRs) to FDA was published on February 13, 2014. The requirements of this final rule will take effect on August 14, 2015. If your firm is not currently submitting reports electronically, we encourage you to visit the following web link for additional information about the electronic reporting requirements: http://www.fda.gov/ForIndustry/FDAeSubmitter/ucm107903.htm
 
If your firm wishes to discuss MDR reportability criteria or to schedule further communications, it may contact the Reportability Review Team by email at ReportabilityReviewTeam@fda.hhs.gov
 
Our inspection further revealed your firm’s QuantiFERON®-TB Gold (QFT®) test devices are misbranded under Section 502(t)(2) of the Act [21 USC 352(t)(2)], as your firm failed or refused to furnish material or information regarding the device, as required by Section 519 of the Act [21 USC 360(i)], and 21 CFR 806 – Medical Devices; Reports of Corrections and Removals. Significant violations include, but are not limited to, the following:
 
5)    Failure to keep a record of a correction or removal not required to be reported as required by 21 CFR 806.20. 
 
For example, between September 2012 and June 2013, the (b)(4) used in the (b)(4) tube formulation (positive control) of the QuantiFERON®-TB Gold (QFT®) test device, was a lower concentration than the (b)(4) used in previously distributed (b)(4)  tubes, which caused the user to experience higher than expected rates of (b)(4)  indeterminate results. On 9/23/2013, your firm notified users of the QFT tests that lots of (b)(4) tubes made in 2013 using a new lot of (b)(4) may have given elevated indeterminate results. The firm replaced 207,775 (b)(4) tubes that were distributed to users that reported higher than expected rates of (b)(4) indeterminate results from (b)(4).
 
Your firm’s action has been reviewed and determined by FDA to meet the requirement of a Class III recall, which falls below the threshold for a 21 CFR 806 report, as specified in 21 CF 806.2(j)(2). Therefore, your firm’s actions should have been documented and a justification kept for not reporting, as required by 21 CFR 806.10(b).
 
Your firm’s response to the FDA 483, dated 14 April 2015, does not appear to be adequate. In your firm’s response, it stated “CAPA 2013-11 will be amended to compile associated corrective action activities and records as well as document the rationale for not withdrawing product. Expected Completion: 15 May 2015.” However, your firm does not provide a justification for not reporting the corrections or removal, as required by 21 CFR 806.20.
 
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, premarket approval applications for Class III devices to which the Quality System regulation violations are reasonably related will not be approved until the violations have been corrected. Requests for Certificates to Foreign Governments will not be granted until the violations related to the subject devices 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, 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 (including any systemic corrective actions) 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. Include special identifier FEI: 3003964343 on all correspondence.
 
Your response should be sent to:
 
CAPT Daniel Cline
Acting Director, Compliance Branch
Food and Drug Administration
19701 Fairchild
Irvine, CA   92612-2506
 
If you have any questions about the content of this letter please contact: Dr. William Vitale, Compliance Officer at 949-608-2919.
 
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/
Alonza E. Cruse, Director
Los Angeles District
                                                                                                       
 
Cc: 
 
Mr. Mark Boyle
Vice President, Program Management MDx/TB
Cellestis, LLC
28358 Constellation Re., Suite 698
Santa Clarita, CA 91355-5044
          
David M. Mazzera, Ph.D.
Chief, Food and Drug Branch
California Department of Public Health
Food and Drug Branch
1500 Capitol Avenue, MS-7602
Sacramento, CA   95899-7413

Page Last Updated: 09/03/2015
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