Frontida BioPharm, Inc. receives a significant warning letter for cross contamination (08/15/16) during an audit that extended from June 15 through July 17, 2015. The FDA deemed the drug products adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the FD&C Act), 21 U.S.C. 351(a)(2)(B).
The FDA investigators observed specific violations including, but not limited to, the following.
- Your firm failed to establish an adequate quality control unit with the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging material, labeling, and drug products; and the authority to review production records to assure that no errors have occurred or, if errors have occurred, assure that they have been fully investigated. (21 CFR 211.22(a))
Significant findings indicate that your quality unit is not fully exercising its authority and responsibilities. We detail three examples (my highlights) below. Your firm must provide the quality unit with the appropriate authority and sufficient resources to carry out its responsibilities and consistently ensure drug quality.
Release of potentially contaminated product
Your quality unit knowingly released 27 lots of various strengths of clonidine HCl tablets on or about March 5, 2015, despite evidence that active pharmaceutical ingredient (API) used in their manufacture (lot (b)(4)) was potentially contaminated. Your supplier recalled this lot of API based on (b)(4) inspectional findings that indicated inadequate controls to prevent cross contamination of the API. Your firm was notified of this recall as early as July 16, 2014.
Based on your supplier’s recall notice, your firm initially placed 27 lots of clonidine HCl tablets on hold starting on July 16, 2014. You then hired a contract testing laboratory to analyze retain samples of the clonidine API lot for cross contamination. However, your contract laboratory provided documentation that its test method was not validated to detect low levels of cross contamination, and explicitly stated that the test results “may not be used for batch release.” Despite this, your firm released the 27 lots of clonidine HCl in March 2015 without testing your finished products using a method that was both validated and sufficiently sensitive to detect cross contamination. On July 9, 2015, during our inspection, your firm recalled all 27 lots.
In your response you committed to engaging a third party to assess your supplier program to determine when you should take additional steps to assess your API supplier.
Frontida and its predecessors violated several significant GMP areas to include data integrity, validation of the API lot, and testing of the finished products to assess their meeting of the specifications. Only when the FDA was present (June 15 to July 17, 2015), did the firm decide to recall all 27 lots that were manufactured from the contaminated API lot.
Inadequate investigation of stability failure
You did not adequately investigate the stability failure of lot (b)(4) of felodipine 2.5-mg tablets for an unknown impurity. The product specification for unknown impurities is (b)(4) percent, but your three-month stability test result for this lot was (b)(4) percent impurities. You opened an investigation into the stability failure on February 12, 2015. Your own records indicate that as of April 29, 2015, you were aware that benzophenone had leached into the tablets from the ink and varnish on the primary container label, but you did not recall this lot until July 16, 2015, during the FDA inspection.
In your response, you committed to developing a method to quantify benzophenone in your products as well as a method to screen labels prior to use.
Awaiting the FDA arrival to recall a product known to have failed stability does not provide assurance that a firm has the integrity to be in compliance with GMPs. Also, it does not allow the customers to have any confidence in the products they may purchase when they discover that the FDA has become the Company’s Quality Control Unit.
Discrepancies in CGMP-related records
Your quality unit failed to ensure that CGMP-related records are accurate, contain appropriate documentation, and are consistent with your standard operating procedures (SOP). We found multiple discrepancies in quality unit-approved records, such as:
investigation reports containing data and documentation from unrelated investigations,
records signed with only a first name, records missing dates, illegible entries in
logbooks and laboratory notebooks
During the inspection, you attributed some of the documentation discrepancies to your practice of cutting and pasting between different investigation reports. You also committed to correcting other deficiencies.
Again, as in the previous Citation, the FDA became the Quality Control Unit for this Company. While many of us have observed the practice of “cutting and pasting between different investigation reports”, it remains totally unacceptable to perform this task in such a sloppy fashion. GMP records are supposed to reflect accuracy, contain appropriate documentation and are consistent with standard operating procedures.
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