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FDA Cracks Down on Indian Manufacturers, Citing New FDASIA Authority and Egregious Violations

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By Alexander Gaffney, RF News Editor

In the wake of a disturbing regulatory investigation against Indian manufacturer Ranbaxy, in which regulators determined that the company had routinely falsified and altered testing results—determinations that later resulted in a massive $500 million fine against the company, the largest in history—the US Food and Drug Administration appears to be cracking down hard on other Indian manufacturers for similar discrepancies.

The Start of a Crackdown?

The first hint of that crackdown came on Wednesday in the form of two Warning Letters, both extensive in nature and detailing extensive violations.

The first, a Warning Letter to Wockhardt regarding its Waluj, India plant, detailed a wide range of disturbing allegations, including bathrooms that allowed for the collection of standing urine on floors, products contaminated with glass and unknown "black particles," staff that repeatedly lied to FDA on multiple occasions, and manufacturing lines that were kept hidden from investigators.

But the most egregious of all deficiencies alleged against the company regarded its testing practices. FDA said the company used "unofficial batch record forms" to conduct testing, allowing it to re-conduct tests that did not meet specifications and discard the original forms. The letter notes one instance in which an FDA investigator observed piles of discarded forms, which he requested be brought to him for inspection. A Wockhardt employee then reportedly tried to hide the forms, substituting them for a stack of alternate documents while placing the other ones in a bag in another location. The FDA investigator later discovered the documents, and found that they were batch reports regarding batches that did not meet visual inspection criteria.

The examples provided in the Warning Letter "raise serious concerns regarding the integrity, reliability and accuracy of the data generated and available at your facility," FDA wrote, demanding that the company provide an "independent and comprehensive evaluation of the extent and the deletion and destruction of records, a risk assessment regarding the potential impact on the quality of products, and a comprehensive corrective and preventive action plan."

Similarities Rampant Between Wockhardt and Fresenius

But Wockhardt wasn't the only Indian company to receive a Warning Letter this week, and neither was it the only one to have allegations of data fraud levied against it.

Another letter released on 23 July 2013 to Fresenius Kabi—no stranger to Warning Letters as of late—references a January 2013 inspection in which FDA investigators discovered "significant deviations" from current good manufacturing practices (CGMPs) for active pharmaceutical ingredients.

Like Wockhardt, the company was accused of having "kept some samples, data and results outside of the local systems for assessing quality."

In other words, it was conducting off-the-record testing and not reporting all of the results it obtained, FDA said. Only the "final" results were recorded, with the implication being that undesirable tests were discarded in favor of ones showing the drugs to be in compliance with standards.

"Samples were retested without a record of the reason for the retest or an investigation," FDA added. "Only passing results were considered valid, and were used to release batches of APIs intended for US distribution."

Even the company's electronic data management software, typically used to ensure accountability in the quality system, permitted "unauthorized changes," FDA charged, allowing files to be "easily altered or deleted."

As with Wockhardt, FDA said Fresenius' "inability to detect and prevent poor data integrity practices raises serious concerns about the lack of quality system effectiveness" at the facility. Senior management at Kresenius, including those at the corporate level, appeared to be "unaware" of the deficiencies found at the plant, FDA added. "Your senior management, at the local and corporate levels, is responsible for assuring that strict corporate standards, procedures, resources, and communication processes are in place to detect and prevent breaches in data integrity, and that such significant issues are identified, escalated, and addressed in a timely manner," the letter adds.

Indeed, the letter goes on to paint a disturbing picture of a plant that apparently acted outside the knowledge of Fresenius' corporate leaders. In one notable instance, the facility reportedly combined two batches of API, with one having failed specifications testing and the other having passed. The new batch was then certified as having passed, the letter said. In subsequent interviews with Fresenius, FDA said management employees "found no evidence that a request to blend batches of API came from management."

This, FDA said, "raises additional concerns, as it shows that your organization operates outside of the framework of a robust quality system. When your employees are able to decide that a failing API can be blended with a passing API batch to obtain a final passing result, this indicates that there is poor quality governance."

Inspection Authority and an Attempted Magic Trick

As with the Wockhardt letter, the Fresenius Warning Letter also references FDA's new inspection authority, granted to it under the FDA Safety and Innovation Act (FDASIA). In particular, if FDA determines that a company has delayed or otherwise disrupted its investigation, it can declare a drug "misbranded"—an authority clarified in a recently released guidance document.

This authority was cited in both letters, with FDA highlighting cases in both where employees had outright lied to investigators regarding certain conduct. In the case of Fresenius, one employee had reportedly "denied several times that he had performed sample trial injections and performed injections other than those reported in the quality control release testing records." FDA later determined these statements to be false once the firm admitted otherwise.

In another case, the company told FDA investigators that all files were automatically uploaded to a central server, and that no files would be found elsewhere. Investigators later found raw data testing files not contained on the server to be contained in desktop file folders.

In a third instance, FDA observed "foreign material" inside an unspecified piece of manufacturing equipment. An immediate request to inspect the material was denied, and when clearance was finally granted, the investigator found that the area had been cleaned. A facility employee then claimed the observed material had just been a "reflection of the light," but a subsequent deviation report observed by FDA confirmed the presence of the foreign material and an instruction to clear the equipment.

And—the cherry on top—an employee was observed "attempting to hide manufacturing-related records in his pocket from the FDA investigator," an act which he was apparently unsuccessful in completing.

If there seems to be one takeaway from both letters, it's that FDA is moving aggressively against companies where it determined that under-the-table testing is taking place, and is also referencing its new authority under FDASIA—in this case before it had even been explained in a guidance document—liberally. Companies would do well to get compliant, it seems.


FDA's Warning Letter to Fresenius

Warning Letter to Wockhardt

Inspection of Ranbaxy




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