- Qiagen Sciences LLC
- Issuing Office:
- Baltimore District Office
| || |
Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
| ||Baltimore District Office|
6000 Metro Drive, Suite 101
Baltimore, MD 21215
Telephone: (410) 779-5455
FAX: (410) 779-5707
May 16, 2016
Mr. Peer Schatz, CEO
Qiagen Strasse 1
40724 Hilden, Germany
Dear Mr. Schatz:
During an inspection of your firm located in Germantown, Maryland between January 19,2016 and February 5, 2016, 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. § 32l(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.
We received responses from your firm dated February 26, 2016 and April 8, 2016 concerning our investigators observations noted on the Form FDA 483 (FDA 483), List of lnspectional Observations, issued to your firm on February 5, 2016. We address these responses below, in relation to each of the noted violations. These violations include, but are not limited to, the following:
Quality System Violations
This inspection revealed that the QuantiFERON®-TB Gold (QFT®) test device is 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.
1. Procedures for corrective and preventive actions (CAPA) were not adequately established to ensure that CAPAs are effective, as required by 21 CFR 820.100(a) Several CAPAs were ineffective due to inadequate corrective actions and/or verifications. For example,
i. Multiple CAPAs had been open due to repeated complaints for high false positive rates. As a result, the endotoxin specifications for the TB and Nil bloodcollection tubes (b)(4) in April 2013. This corrective action was not effective because the contract manufacturer could not meet the new specification and there were no endotoxin spiking studies to determine what amount of endotoxin contamination of the Nil tube could cause a false negative result. Furthermore since the endotoxin specification change was implemented, the TB Antigen and Nil tubes were manufactured without process validation and released.
ii. CAPA 2014-14 was opened due to endotoxin contamination being found in two lots of Nil blood collection tubes, which could lead to potentially false negative results. This CAPA was not effective as portions from both lots were released despite multiple failures being obtained during lot release testing.
We have reviewed your firm's responses and concluded that they are not adequate. Your firm's responses noted that a study will be conducted to appropriately establish an endotoxin specification and conduct additional validation based on the results of your assessments. Additionally, your firm committed to discontinuing partial lot releases. However, we should note that the validation documents included in your response do not directly address endotoxin levels and do not provide evidence that your current process has been appropriately validated.
2. Requirements that must be met by suppliers and contractors were not adequately established, as required by 21 CFR 820.50(a). Specifically, your contract manufacturer did not have process validation for the following destructive final release tests for the QuantiFERON blood collection tubes:
Furthermore, the documented quality requirements that must be met by your contract manufacturer of QuantiFERON blood collection tubes do not include endotoxin.
We have reviewed your firm's responses and concluded that they are not adequate. Your firm's responses note that you have begun a collaborative evaluation of the tube manufacturing process with your contract manufacturer that will include process validation studies. However, your responses do not address any updated quality requirement(s) with your contract manufacturer to assure that appropriate endotoxin levels can be met. In your response to this letter, include an updated agreement with your contract manufacturer that includes endotoxin levels.
3. Procedures for design change were not adequately established, as required by 21 CFR 820.30(i). Specifically, design changes were not opened for changes in design outputs for the TB Antigen and Nil blood collection tubes.
The design output for endotoxin contamination of the QuantiFERON TB Antigen and Nil blood collection tubes was changed (b)(4), but a design change was not opened for either one and the specification change was not verified adequately. In addition, the design verification performed for the determination of the endotoxin contamination that can cause false positives in the TB Antigen tube lacked a verification protocol with predefined acceptance criteria. Finally, there was no verification performed for the Nil blood tube.
We have reviewed your firm's responses and they may be adequate. A follow-up inspection will be needed to verify that your procedure for design and development (GLO-SOP-32-01-001) is being appropriately followed.
4. Procedures for design output were not adequately established, as required by 21 CFR 820.30(d). Specifically, design outputs for the mitogen, Nil, and TB Antigen blood collection test tubes did not have all their design outputs adequately established. For example,
i. A design output for the acceptable amount of endotoxin contamination in the Nil blood collection tube potentially causing a false negative was not defined or verified.
ii. A design output for (b)(4) was not defined for the mitogen test tube.
iii. Design outputs for the physical/functional aspects (b)(4) were not defined for these tubes.
iv. A design output for the amount of (b)(4) was not defined for the tubes.
v. Tube composition values for (b)(4) were not documented on the design output document.
We have reviewed your firm's responses and they may be adequate. A follow-up inspection will be needed to verify that the traceability matrix (DHF-QFT-3G-TRM-001) described in your responses has been established appropriately.
5. Complaints involving the possible failure of a device to meet any of its specifications were not evaluated and investigated where necessary, as required by 21 CFR 820.198(c). Specifically, complaints for high positivity or discrepant results were not adequately evaluated and investigated where necessary. Approximately (b)(4) complaints were received in 2014 and 2015 for the QuantiFERON-TB Gold blood collection tubes. Tube lot information was obtained for only 12 of these complaints and only two of these complaints had retains tested for (b)(4).
We have reviewed your firm's responses and concluded that they are not adequate. Your firm's responses note that an investigation will be initiated when an adverse trend is identified. However, your procedure for handling and investigating complaints (GLO-SOP-47-01-001, Rev. 007) that was included in your February 2016 response does not define what an adverse trend would be. In your response to this letter, include an updated complaint procedure that includes this information. Additionally, for any referenced complaints you did not mention if there were retain samples available for test or if you were able to get return samples from customers. In your response to this letter, include results from any testing that may have been conducted on retain or return samples.
6. Sampling plans are not written and based on valid statistical rationale, as required by 21 CFR 820.250(b). Specifically, the following process validations did not have sampling plans based on valid statistical rationale:
i. Validation of Mitogen Tube Potency Test was performed using (b)(4) for each run. Mitogen blood collection tube production lots are typically between (b)(4) tubes.
ii. Validation of QuantiFERON-TB Gold Antigen Tube Reproducibility tested (b)(4) of the TB antigen blood collection tubes. The (b)(4) was performed on (b)(4). The (b)(4) was performed using (b)(4) tests tubes run for each subject. Typical blood collection lots are between (b)(4).
We have reviewed your firm's responses and they may be adequate. A follow-up inspection will be needed to verify that the revised sampling plans described in your responses have been established appropriately.
Medical Device Reporting Violations
Our inspection also revealed that the QuantiFERON-TB® Gold Test 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 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:
7. 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 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).
Based on the evidence provided for review, the information in Complaint #'s (b)(4); and in Compliant Cases (b)(4) describe events in which your firm's device malfunctioned. The malfunctions referenced in the complaints are associated with a Japanese recall, and with recalls# Z-0888-2013 and Z-0889-2013. A malfunction MDR should have been submitted for the referenced events within a 30 calendar day timeframe.
We reviewed your firm's response dated February 26, 2016, and conclude that it is adequate. (b)(4) were received by FDA on February 2, 2016. (b)(4) was received by FDA on February 3, 2016. Your firm revised its procedure, GLOSOP-4 7-01-002, "Removals and Corrections" to include an instruction to review any complaints that are associated with a recall to determine MDR reportability. Additionally, personnel at the Germa10town location responsible for implementing recalls were trained on the new procedure.
8. 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 "Medical Device Reporting," NA-SOP-47-010, Revision 9, effective date, September 9, 2015, the following issues were noted:
a. NA-SOP-47-010 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. The definition of the term "caused or contributed" is not consistent with the definition of the term in 21 CFR 803.3 and will not allow your firm to correctly identify complaints as reportable events.
b. NA-SOP-47-010 does not establish internal systems that provide for timely transmission of complete medical device reports. Specifically, the following are not addressed:
i. The circumstances under which your firm must submit supplemental or follow-up reports, and the requirements for such reports.
ii. How your firm will submit all information reasonably known to it for each event. Specifically, which sections of the 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.
Your firm's procedure includes references to baseline reports. 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 Notice 53686, dated September 17, 2008).
Corrections and Removal Violations
Our inspection also revealed that your firm's QuantiFERON-TB Gold (QFT) test device 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 respecting the device that is required under section 519 of the Act, 21 U.S.C. § 360(i), 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 written report to FDA of a correction or removal of a device initiated to reduce a risk to health posed by the device, or to remedy a violation of the Act caused by the device, which may present a risk to health, as required by 21 CFR 806.10. For example:
a. In 2013, after complaints of a higher than normal positivity rate, your firm conducted a product recall of TB antigen tubes, lot A1210004, Nil Tubes, lot number Al210008, and mitogen tubes, lot number Al210006, in Japan. Your firm documented that elevated TB values are known to be caused by the presence of endotoxin in tubes. The endotoxin levels ranged from (b)(4), some of which exceeded the manufacturer's specification. Your firm did not submit a Report of Correction or Removal to FDA.
b. In 2014, after complaints for (b)(4) of TB3G ELISA lot 059452521 were returned from Japan. Your firm attributed the issue to (b)(4). The devices were reworked, and then distributed in the US. Your firm did not submit a Report of Correction or Removal to FDA.
We reviewed both of your firm's responses, and conclude that they are not adequate. Your firm should be aware that all products manufactured in the U.S. are subject to 21 CFR 806. As of April 13, 2016, there is no record of Qiagen submitting a Report of Correction or Removal to FDA for these two medical device removals.
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.
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.
Your firm's response should be sent to:
U.S. Food and Drug Administration
Baltimore District Office
6000 Metro Drive, Suite 101
Baltimore, Maryland 21215
Refer to CMS case# 490174 when replying. If you have any questions about the contents of this letter, please contact: Ernest Bizjak at (301)796-4081.
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.
Baltimore District Office
Mr. Douglas J. Liu,
Senior VP Global Operations
19300 Germantown Road
Germantown, MD 20874