A new Warning Letter from the US Food and Drug Administration (FDA) has called out yet another Indian pharmaceutical manufacturing facility for allegedly tampering with or falsifying its data-the 10th letter to an Indian company in the last year making similar allegations.
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 eight Warning Letters to Indian companies alleging improper data controls:
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. Many 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.
A New Warning Letter
Now FDA has sent a new Warning Letter to Smruthi Organics, an Indian manufacturer of active pharmaceutical ingredients (API) that was inspected by the agency in October 2013.
During that inspection, FDA contends that its inspectors found numerous violations of acceptable current good manufacturing practices (cGMPs), most of which were related to data integrity.
For example, FDA said it was unable to determine why some recorded events had been deleted, and found that the company lacked any standard operating procedures to govern the retention of electronic raw data, such as laboratory testing data.
In another troubling finding, FDA said it had found evidence of "trial" analyses being used. Such practices could be used to hide problems or re-run analyses without there ever being an official record. While the company indicated that the practice had been stopped, FDA pressed it for a retrospective analysis to determine how it might have affected operations. The inspection also uncovered a "duplicate logbook" used to record results that had differed from the official logbook without explanation.
In other instances, FDA found "incomplete raw data" used to validate and verify APIs and "calibration and media preparation records that were not authentic." FDA said a review of employee records had determined that the persons who had allegedly signed off on the records "were not at work on the day the work was accomplished."
The Warning Letter also features an extremely rare reference to the European Directorate for the Quality of Medicines (EDQM), which had inspected Smruthi Organics in February 2013. FDA explained that the EDQM inspection had found that out-of-specification APIs were being blended in with in-specification APIs.
FDA, it seems, was curious to dig into this issue more itself, but the company maintained that the "relevant records had been destroyed." Later, the company reversed course, saying that there had been a miscommunication, and that the records had not been destroyed. In its Warning Letter, FDA requested access to these records as well as a "full accounting" of which batches had been blended.
FDA has never before referenced EDQM in a Warning Letter, a review of FDA's Warning Letter database confirmed.
The company's products are currently subject to an import alert, and FDA has said it will not approve any applications or supplements listing the company as an API manufacturer.
Warning Letter to Smruthi Organics