Inspections, Compliance, Enforcement, and Criminal Investigations
ViroMed Laboratories 3/30/07
Department of Health and Human Services
|Public Health Service |
Food and Drug Administration
Minneapolis District Office
March 30, 2007
RETURN RECEIPT REQUESTED
Refer to MIN 07-16
Robert S. Fogerson
Associate Vice President/General Manager
Laboratory Corporation of America
6101 Blue Circle Drive
Minnetonka, Minnesota 55343
Dear Mr. Fogerson:
The Food and Drug Administration conducted an inspection of Laboratory Corporation of America ViroMed Laboratories located at 6101 Blue Circle Drive, Minnetonka, MN 55343, between October 26, 2006, and January 12, 2007. During the inspection FDA investigators documented serious deviations from the regulations for human cells, tissues, and cellular and tissue-based products (HCT/Ps) set forth in Title 21, Code of Federal Regulations (21 CFR), Part 1271, and issued under the authority of Section 361 of the Public Health Service Act. The observed deviations include the following:
1. Failure to follow the test kit manufacturer's instructions and your written procedures for performing relevant communicable disease testing of donor specimens [21 CFR 1271.80(c) and 21 CFR 1271.47(a)]. Between November 22, 2005, and February 24, 2006, donor specimens from forty-seven (47) living reproductive tissue donors that tested initially reactive by the [redacted] HIV-1/HIV-2 PLUS 0 Enzyme Immunoassay (EIA) were not retested in accordance to the manufacturer's test kit instructions and the firm's standard operating procedure (SOP) 22-SERO-02-0030 rev. D entitled "HIV1/HIV-2 Plus 0 Antibody Detection by Peptide EIA" dated October 1, 2005, which required that original donor specimens that test initially reactive by the [redacted] HIV-1/HIV-2 Plus 0 EIA must be retested in duplicate with the HIV-1 /HIV-2 Plus O ETA to verify the initially reactive result. For example:
a. Forty-four (44) donor specimens that tested initially reactive by the HIV-1/HIV-2 Plus O EIA were not retested in duplicate using the HIV-1/HIV2 Plus 0 EIA. You instead retested the specimens using the [redacted] LAV for HIV-1 EIA and [redacted] HIV-2 EIA. All the donor specimens were negative upon retesting and were incorrectly reported as nonreactive for the antibody to the human immunodeficiency virus types 1 and 2 (anti-HIV-1 and anti-HIV-2);
b. One donor specimen that tested initially reactive by the HIV-1/HIV-2Plus 0 EIA was retested in triplicate using the HIV-1/HIV-2 Plus 0 EIA. The subsequent triplicate testing produced one reactive and two nonreactive test results. With this information, you should have reported the donor specimen as reactive for anti-HIV-1 and anti-HIV-2. You subsequently performed additional testing on the donor specimen using the rLAV for HIV-1 EIA and the HIV-2 EIA, obtaining negative test results for both assays. You incorrectly reported the donor specimen as nonreactive for anti-HIV-1 and anti-HIV-2;
c. One donor specimen that tested initially reactive by the HIV-1/HIV-2Plus 0 EIA was reactive upon retesting in singlet (rather than in duplicate, as provided in the manufacturer's instructions and your procedures) using the HIV-1/HIV-2 Plus 0 EIA. With this information, you should have reported the donor specimen as reactive for anti-HIV-1 and anti-HIV-2. You subsequently performed additional testing on the donor specimen using the rLAV EIA and HIV-2 EIA, obtaining negative test results for both assays. You incorrectly reported the donor specimen as nonreactive for anti-HIV-1 and anti-HIV-2; and
d. One donor specimen that tested initially reactive by the HIV-1/HIV-2Plus 0 EIA was negative upon retesting in singlet using the HIV-1/HIV-2 Plus 0 EIA. The donor specimen was subsequently retested a second time in singlet using the HIV-1/HIV-2 Plus 0 EIA producing a reactive result. You did not perform retesting in duplicate, as provided in the manufacturer's instructions and your procedures. No testing was performed using the rLAV EIA and/or HIV-2 EIA. The donor specimen was incorrectly reported as nonreactive for anti-HIV-1 and HIV-2.
2. Failure to verify corrective actions relating to core CGTP requirements to ensure that such actions are effective and are in compliance with CGTP [21CFR 1271.160(b)(3)]. As part of your corrective actions to address the findings of an investigation into the cause of an increase in reactive HIV test results for living reproductive tissue donors, you implemented significant changes to your procedures for performing the [redacted] HIV-1/HIV-2 Plus 0 EIA. Those new procedures were not consistent with the test kit manufacturer's instructions, and accordingly were not consistent with GTP [21 CFR 1271.80(c)].
The above identified violations are not intended to be an all-inclusive list of deficiencies at your facility. It is your responsibility to ensure that your establishment is in compliance with all applicable requirements of FDA regulations. You are responsible for investigating, determining causes of, and correcting the violations identified by FDA correct these violations. You should take prompt action to without further notice. Failure to do so may result in additional regulatory action. Such action may include, but is not limited to, an order to retain, recall, destroy or cease manufacture of HCT/Ps.
We acknowledge receipt of your response dated March 6, 2007, to the Form FDA-483 issued to you at the conclusion of the most recent inspection of your establishment. We have completed our review of your response and have the following comments:
In your response to observation 1 of the Form FDA-483, you acknowledged that the test kit manufacturer's instructions for the [redacted] HIV-1/HIV-2 PLUS 0 EIA were not followed to completion and stated that "The reason for not completing the testing for the 47 donors cited was the implausibility of the data that was being generated as a result of the testing using the [redacted] HIV-1/HIV-2 PLUS 0 EIA." You stated that you conducted an investigation to determine the potential cause(s) of the problem, and noted that "During the initial investigation of this phenomenon, we were concerned about analyte contamination or cross reactivity in the samples," and "Our findings indicated that handling of specimens prior to their arrival at ViroMed could have potentially caused a cross-contamination event leading to a false positive result." As a result of your investigation, you modified your donor testing procedures, causing them to be inconsistent with the test kit manufacturer's instructions and, therefore, with GTP. You stated in your response that "ViroMed erroneously assumed that since the FDA approved all 3 of these tests for donor testing, the above scenario would not only improve the accuracy of the test results, but also be in regulatory compliance." FDA approved the [redacted] HIV-1/HIV-2 PLUS 0 EIA the [redacted] LAV for HIV-1 EIA, and [redacted] HIV-2 EIA based on the assessment of scientific and clinical information, including labeling, provided in the Biologics License Application (BLA) for the products. As approved tests, these tests must be used in accordance with the test kit manufacturer's instructions. Furthermore, we question your decision for modifying your donor testing procedures without fully addressing or further investigating your theory regarding potential sample contamination. We also believe that your rationale for modifying your donor testing procedures based on the "implausibility of the results obtained with the [redacted] HIV-1/HIV-2 PLUS 0 EIA" is inadequate and unjustified.
Additionally, as part of your corrective action, you stated that "ViroMed understands the regulatory requirements and our SOPs outline the correct processes to follow." However, you do not explain why, if you understood these regulatory requirements, you did not comply with them, and proceeded to improperly alter your procedures.
Lastly, in your response to Observation 3, you stated that "In this situation, the science of the problem had been well investigated and documented but not enough emphasis had been given to justify the decision to depart from the SOPs and manufacturer's instructions." Please note that 21 CFR 1271.47(d) provides for documentation and justification of any departure from your procedures for donor eligibility determination. The regulation does not authorize departures from the requirement to follow manufacturer's test kit instructions, set out in 21 CFR 1271.80(c).
We request that you notify this office in writing, within 15 working days of receipt of this letter, of the specific steps you have taken to correct the noted deviations and to prevent their recurrence. If corrective action cannot be completed within 15 working days, state the reason for the delay and the time within which the corrections will be completed.
Your reply should be sent to Jane Nelson, Compliance Officer, Food and Drug Administration, 212 Third Avenue South, Minneapolis, MN 55401.
W. Charles Becoat