The US Food and Drug Administration (FDA) has just released its long-awaited Warning Letter to Sun Pharmaceuticals following a 483 and import alert announced earlier this year. And as the letter indicates, conditions at the company's Gujarat, India facility are consistent with an ongoing trend of data integrity problems across the Indian pharmaceutical sector.
As Regulatory Focus has previously explained, FDA has been in the midst of a crackdown against deficient manufacturing practices in India, where inspectors have discovered glaring problems and even outright fraud.
Since 2013, FDA has issued at least 10 Warning Letters to Indian companies alleging improper data controls.
For the full list of Indian companies subject to an FDA Warning Letter regarding data integrity issues, please see our data integrity tracking page here.
FDA has also sent several Form 483s, the precursor to most Warning Letters, to Indian companies such as one to Ranbaxy in January 2014.
The letters stick out because unlike manufacturing deficiencies, data integrity issues strike at the very core of good regulation. If FDA is unable to rely upon the data it is given, how can it ensure that drugs are safe, effective or manufactured to appropriate quality standards?
As most of these Indian manufacturers are now finding out, FDA isn't keen on trusting companies if it can't verify regulatory compliance. Most, if not all, of the above referenced companies are now subject to FDA import alerts that prohibit the import into the US of products manufactured at the facilities until FDA determines that changes have brought the facilities into compliance.
FDA: Data Integrity Problems at Sun Pharma
Now FDA has called out Sun Pharmaceuticals for similar problems in a Warning Letter released on 20 May 2014.
The company—which recently bought Ranbaxy, another Indian pharmaceutical manufacturer plagued by longstanding quality problems—was accused of having extensive issues at its Gujarat, India manufacturing facility.
FDA's November 2013 inspection of the facility found workers in the plant were conducting "trial" sample analyses of drug samples—a practice sometimes used to record results "off-book," allowing a sample to be tested and re-tested until it is able to meet specifications, at which time it is tested "officially."
FDA said its inspectors had determined that in at least one case, it had proof that an employee had "deleted" raw data files from a "trial" test, and that there was systemic evidence that the tracking numbers for all trial tests were linked to the numbers for official tests.
As FDA recounted to Sun Pharma in its letter: "Your Senior Quality Control (QC) Officer confirmed that QC laboratory employees had frequently practiced the use of 'trial' injections at your facility. Significantly, in addition to the example above, our inspection found 5,301 deleted chromatograms on a computer used to operate two HLPC instruments in your QC laboratory. Many of these files were 'trial' injections of batches."
In another case, FDA asked the company to re-run tests on a raw material batch that was supposedly within specifications, per "official" test results. When Sun Pharma's employees did so under FDA's supervision, the results of the sample showed that it was out of specification.
This "pervasive practice of deleting files" is unacceptable and requires an investigation, FDA told the company.
Part of the problem, FDA said, was that the computer software used to maintain control over data was not set up properly, allowing data to be "manipulated" to leave no trail for subsequent auditors. "Due to the basic lack of audit trail and data security, an analyst could delete analytical files without traceability of this unacceptable practice," FDA wrote.
FDA: Physical Records Discarded
And even when files weren't deleted digitally, it appeared that Sun was also improperly disposing of physical records, FDA said. "During the inspection, the investigators found approximately 10 waste bags containing torn or partially destroyed raw data CGMP records related to a variety of manufacturing activities," regulators wrote. In some cases, FDA strongly implied that the discarded records may have been thrown away to hide evidence of a problem ever having existed, such as in the case of discarded CAPA records.
FDA's letter demands that Sun Pharmaceutical provide a list of "all the batches of drug products shipped to the US market and APIs intended for use in drugs to be distributed within the US that relied upon missing, inaccurate or unreliable records." That data could be used by the agency to initiate a recall in the future.
The company was also asked to bring on a data integrity consultant, who FDA advised should work to review the company's past practices and bring the company into compliance with US laws and regulations.
Until deviations are corrected, the company will remain under an import alert, FDA said.
FDA Warning Letter to Sun Pharma