MUMBAI – The latest Import Alert issued by U.S. FDA on the Mohali site of India’s troubled drug manufacturer Ranbaxy Laboratories Ltd. follows inspections in September and December of 2012. Although the company made no details of the inspections public, despite rising concerns from stakeholders, signs were ominous that its newest Mohali site was headed toward an inevitable crisis.

In the earliest revelation, which came through a PharmAsia News report in May 2013, it became clear that issues may have taken very long to rectify ([A#28130516007]).

Even when pressed to disclose the facts, Ranbaxy declined to comment on investigations at Mohali. The management maintained that its much-watched valsartan (Novartis AG’s Diovan) exclusive launch opportunity in the U.S. had been delayed but remained firmly on track ([A#28130808004]).

In a July interview with PharmAsia News, Ranbaxy CEO Arun Sawhney said the company had put in place strong quality systems to avoid future manufacturing lapses ([A#28130703004]).

But as disclosed by FDA in a Sept. 16 release, in September and December 2012, FDA inspections identified significant good manufacturing practices violations at Ranbaxy’s Mohali facility, including failure to adequately investigate manufacturing problems and failure to establish adequate procedures to ensure manufacturing quality.

The failures, as described by FDA, culminated in the more serious action of an Import Alert, a surprising development given Ranbaxy’s public stance over the last several months.

As part of its investigations and disclosure policies, FDA declined to answer questions about its Mohali inspections at the time, saying that it would neither confirm nor deny any inspections it may or may not be conducting on the Mohali site.

The revelations about the Mohali site come at a time when Ranbaxy is implementing provisions of an FDA consent decree on two other manufacturing sites, Paonta Sahib and Dewas, and has caught many stakeholders by surprise ([A#28130513007]).

The agency said it has exercised its authority under the consent decree to extend the terms to other Ranbaxy-owned or operated facilities if an inspection determines that a facility is in violation of Federal Food, Drug, and Cosmetic Act or FDA regulations.

Root Causes Not Found

The U.S. regulatory agency, it is understood, gave sufficient time for the company to comply, but upon failure by Ranbaxy to come up with solutions, FDA took the next step and exercised its authority under the consent decree. The agency made available to the public the two Form 483s (list of inspectional observations) that were issued to the Mohali plant (See: FDA Form 483 September 2012 and FDA Form 483 December 2012 ).

For the Sept. 11-26 inspection, the agency noted “failure to thoroughly review any unexplained discrepancy and the failure of a batch or any of its components to meet any of its specifications whether or not the batch has been already distributed.” The form did not specify the product name.

“Specifically, investigations conducted by your firm from January 2011 through present do not always determine a root cause, do not have adequate data to support the root cause, and/or lack adequate corrective actions and/or follow-up,” FDA investigators Gayle Lawson, Michael Charles and Sarah McMullen noted in the form signed Sept. 26, 2012. In total, the agency found 10 separate deviations in the manufacturing process during its inspections.

For example, the FDA officials found a tablet outside of the specified weight limit during an in-process control check but no investigations by Ranbaxy were made to find the root cause or to develop actions to be taken to prevent the deviations from recurring. “No documented follow up was conducted,” the form said.

The investigators noted in another instance that the root cause for a dissolution failure of a capsule was due to higher alkaline pH in sample collection tubes.

Mystery Of The Black Fiber

In yet another deviation, a black fiber was found embedded in a tablet, which the investigators said was likely either white tape remnants on the nozzle head of the machine or a hair from an employee’s arm that could be exposed on loading the machine. “The firm did not conduct any analysis of the fiber to support these root causes,” the investigators said in the Form 483.

The tone of the Form 483 served to the Mohali plant in its December inspection was similar to the September note. In its observation for the solid oral dosage facility, FDA investigators Muralidhara Gavini and Scott Laufenberg said in their first observation that there was a failure to thoroughly review any unexplained discrepancy, whether or not the batch has already been distributed, and said specifically that the firm’s investigations and corrective and preventive actions were inadequate.

According to the December investigators, site officials knew about API contamination issues, and although significant quantities of API lots were available, the contaminated API was not set aside, nor did Ranbaxy increase sample sizes when contamination was discovered.

In the second observation, FDA found laboratory records did not include complete data derived from all tests, examinations and assays necessary to assure compliance with established specifications and standards.

Ranbaxy said in a Sept. 17 statement it would review details of the Import Alert and would cooperate with FDA to take all necessary steps to resolve the concerns as soon as possible. The company said it has made further improvements at its Mohali facility since the last inspection in 2012.

[Editor’s note: This article also appeared in PharmAsia News Sept. 18, 2013.]

Ranbaxy’s Failure To Strike At Root Cause Triggered U.S. FDA’s Import Alert On Mohali Site

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