Public Health Service
Food and Drug Administration
December 18, 2015
WARNING LETTER
Mr. Paul R. Hays, President and CEO
Virbac Corporation, North America
3200 Meacham Blvd.
Ft. Worth, Texas 76137-4611
Dear Mr. Hays:
We acknowledge that you initially responded to the FDA 483 in January 8, 2015 and described numerous corrective actions. However, we remain concerned about quality practices and quality culture at your facility. We note that many of the observations from your previous inspection are repeat observations from several prior inspections after which you also asserted corrective actions would be implemented.
Significant deviations from the cGMP regulations observed during the inspection at your firm include, but are not limited to, the following:
1.Your firm failed to establish and adequately staff a quality control unit capable of meeting the responsibilities outlined in 21 CFR 211.22. This is a repeat observation from your 2007, 2008, and 2010 FDA inspections. In addition, your firm failed to have written procedures covering significant responsibilities of the Quality Unit, as required by 211.22(d).
As discussed further throughout this letter, examples of the failure of your firm’s Quality Unit include, but are not limited to:
a.Your Quality Unit failed to prevent the release of animal drug products that fail to meet specifications.
b.Your Quality Unit failed to conduct investigations and resolve all discrepancies/failures/deviations, and complaints.
c.Your Quality Unit failed to extend investigations of failures to other products or processes which may also be affected.
d.Your Quality Unit failed to use a change control process to update equipment, processes or written procedures, work instructions, and forms.
e.Your Quality Unit failed to ensure changes made to an approved application were submitted to the appropriate regulatory agency.
While we acknowledge the steps your firm has taken recently, it appears that your firm has historically lacked quality practices and a quality culture, which has resulted in numerous repeat violations.
2.Your firm failed to reject drug products failing to meet specifications
We observed that when you obtained out-of-specification (OOS) results, in some instances you re-tested multiple times without scientific rationale for doing so until passing results were obtained, and then reported either the average of the OOS results and the re-test results, or just the re-test results. We also observed instances in which you re-sampled in order to achieve passing results.
Your firm’s response states you have revised your “Out-of-Specification Results” SOP to ensure that all OOS results are properly recorded, reported, and investigated. This SOP revision states that if the OOS investigation determines the OOS result is valid, then the OOS result is reported. However, the two previous versions of this SOP also required the OOS result to be reported if the OOS investigation found the OOS result to be valid; yet your practice was to re-test. Your firm’s practices even included that if the re-test results were still OOS, then the employee would re-sample in order to attain passing results. In addition to revising your SOP, you should take steps to ensure that your employees follow it.
3.Your firm failed to establish control procedures which validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product.
4.Your firm failed to establish and follow written procedures for the storage of drugs products under appropriate conditions of temperature and humidity so that their identity, strength, and purity are not affected, as required by 211.142(b). This is a repeat observation from 2007 and 2008 FDA inspections.
In your May 28, 2015 response, you indicated you implemented SOP “Warehouse Area Temperature Monitoring” and performed a winter performance qualification (March 2015) for your receiving warehouse, but your temperature mapping had failures. Your conclusion was that your qualification protocol for the Virbac Receiving Warehouse temperature profile met cGMP and Virbac requirements for resourced material, component, and drug storage, and therefore is acceptable for continued use. You indicated that an assessment of the areas that did not meet the temperature requirements and all storage areas in relation to temperature-sensitive materials and products will be performed; relocation of any materials and products will be determined and performed; and an evaluation will also be made to determine what changes or improvements to air circulation and heating or cooling can be made to improve those areas that do not meet proper storage temperature requirements. While we acknowledge these planned corrective actions, your performance qualification failed to meet your acceptance criteria, and your qualification should be performed again.
5.Your firm failed to thoroughly investigate any unexplained discrepancy and the failure of a batch or any of its components to meet any of its specifications whether or not the batch has already been distributed. This is a repeat observation from your 2013 FDA inspection.
Additionally, your responses state that your firm has revised the “Out-of-Specification Results” SOP to ensure that all OOS results are properly recorded, reported, and investigated. However, based on your past history, your firm’s problems may not only be rooted in deficiencies in a given SOP, but instead in a lack of quality practices. While we acknowledge that you have attempted to evaluate and closeout overdue investigations since your last FDA inspection, we note that you had an OOS procedure prior to the inspection, yet you still reported approximately 2000 overdue investigations of test results. In addition to revising your SOP, it is necessary to establish quality oversight and provide adequate training of your employees.
6.Your firm failed to extend investigations of an unexplained discrepancy and failure of a batch or any of its components to meet any of its specifications to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy.
7. Your firm failed to establish and follow written procedures describing the handling of all written and oral complaints regarding a drug product, including provisions for review by the quality control unit of any complaint involving the possible failure of a drug product to meet any of its specifications and, for such products, a determination as to the need for an investigation in accordance with 211.192, as required by 21 CFR 211.198(a).
Specifically, your “Product Complaints” SOP in effect prior to the most recent inspection (SOP 0300-004 effective May 29, 2012) stated: “Oral and written complaints on finished products are directed to Quality Assurance by Contract Costumers via Virbac Ft. Worth Veterinary Technical Support Services.” However from January 2014 through November 2014, your Pharmacovigilance Department received approximately 1900 complaints regarding approved products. Only approximately 21 of those complaints were forwarded to Quality Assurance. Out of those approximately 21 complaints received by Quality Assurance, only approximately 8 were investigated. Of the approximately 30 death complaints our investigators reviewed, your Pharmacovigilance Department failed to forward approximately 28 of them to the Quality Assurance for their review and investigation.
The issues and violations noted above are not intended to be an all-inclusive list of violations that exist with respect to the manufacture of veterinary drugs at your facility. You are responsible for investigating and for preventing recurrence of these, or other violations, to ensure that you comply with all requirements of the federal law and FDA regulations.
(Edited for length)
Sincerely,
/S/
Cheryl A. Bigham
District Director
Kansas City District