Apotex Research Private Limited (ARPL), part of the generics company, Apotex Inc., has received a Warning Letter from the US Food and Drug Administration (FDA) based on the agency’s inspection of the company’s manufacturing facility in Bangalore, India. The inspection, which was held June 23, 2014 through July 1, 2014, cited violations of current good manufacturing practice (cGMP) regulations for finished pharmaceuticals. The agency reviewed the firm’s response dated July 22, 2014 and acknowledged additional correspondence dated August 11, 2014, August 29, 2014, September 30, 2014, October 31, 2014, December 5, 2014, and January 9, 2015.

In issuing the Warning Letter, the agency said that ARPL failed to investigate out-of-specifications (OOS) results, failed to contemporaneously document failures and report failures, and selected only passing results without the oversight of a quality unit. Among the issues noted were that the firm failed to ensure that laboratory records included complete data derived from all tests necessary to assure compliance with established specifications and standards. The FDA said that its inspection of the facility documented multiple incidents of performing “trial” testing of samples, whereby the firm disregarded test results and reported only those results from additional tests. The agency also said that 2,803 of 44,643 injection results were not processed or reported in the official data folder for dissolution analysis via high-performance liquid chromatography. The agency also said that the firm failed to exercise appropriate controls over computer or related systems to assure that only authorized personnel instituted changes in master production and control records or other records.

“In correspondence with the Agency, you indicate that no malicious data integrity patterns and practices were found,” said the FDA in its report. “Also, you state that no intentional activity to disguise, misrepresent, or replace failing data with passing data was identified and no evidence of file deletion or manipulation was found. Your response and comments focus primarily on the issue of intent, and do not adequately address the seriousness of the cGMP violations found during the inspection. In addition, FDA's inspection did not include observations related to deletion of specific files, intentionally or otherwise. Rather, FDA's concern pertains to the practice of disregarding failing results, conducting trial injections, and retesting products without any investigation. We are also concerned that you do not have documentation to support your decision to retest samples of lots that had initially failed to meet specifications, and you allowed manufacturing activities to occur without the oversight of your quality unit.”

The FDA is requesting that the company provide a comprehensive evaluation and risk assessment, including a detailed description of all computerized systems in the facility used for testing drugs. The agency is also requesting specific information about all retests during these time frames, where an initial OOS or out-of-trend result was disregarded without an investigation and the date on which the firm became aware such information had been disregarded. In addition, for each batch, the agency is asking that the firm provide the number of injections performed and chromatograms reviewed, and of those, the number that were used to generate a reported result as well as an updated assessment on the possible effects of the firm's practices on the quality, safety, and efficacy of the drugs that it manufactures or plan to manufacture, including drugs covered by approved or pending applications.

The agency also said the firm failed to establish and follow appropriate written procedures, designed to prevent objectionable microorganisms in drug products not required to be sterile. The agency also said that the firm failed to follow written procedures applicable to the quality control unit and that the quality control unit failed to review and approve all drug product production and control records to determine compliance with all established, approved written procedures before a batch is released or distributed.

The FDA said that Apotex was notified of the agency’s concerns with the practice of “trial” injections during the FDA's January 2014 inspection at its Apotex Pharmachem India Pvt. Ltd. in Bangalore, India, but that the agency’s findings during this inspection suggest that corrective actions were not implemented globally.

Source: FDA