Ranbaxy’s Atorvastatin Recall: Will Glass Shards Nick FDA’s Reputation?

Less than a year after signing a consent decree to resolve compliance problems, the company is forced to stop manufacturing its generic version of the best-selling cholesterol drug. For FDA, the issue poses a public relations challenge since it touches on several areas where the agency has recently been criticized – generic drug quality, manufacturing oversight and drug shortages.

The already tattered triumph of Ranbaxy Laboratories Ltd. in beating its competitors to market with a generic version of Pfizer Inc.’s best-selling cholesterol drug Lipitor (atorvastatin) has suffered further damage with a voluntary recall and production shutdown due to particulate contamination.

For FDA, the situation presents a challenge for how to handle problems related to a high-profile product, but also how to handle potential public relations fallout, since the issue touches on three areas where critics have recently declared the agency’s leadership wanting: generic drug quality, manufacturing oversight and drug shortages.

Ranbaxy started a voluntary nationwide recall Nov. 9 covering 41 lots of 10 mg, 20 mg and 40 mg atorvastatin calcium tablets in 90- and 500-tablet bottles due to the potential presence of “very small glass particles resembling a fine grain of sand (less than 1 mm in size),” the company said in a Nov. 28 press release cross-posted on FDA’s website. The recall does not affect the 80 mg dosage strength.

“Due to this quality issue, Ranbaxy has decided to stop manufacturing atorvastatin until it has thoroughly investigated the cause of the glass particulates and remedied the problem,” FDA said in its own statement on the issue. “Based on the information from Ranbaxy and from the FDA’s initial assessment, the possibility of adverse events related to the recalled product appear to be low, and if any adverse events are experienced, they would be temporary.”

However, “the probability of an adverse event due to consumption of this product is unlikely but cannot be ruled out,” the company said. “Because of the size of the particles which may be present in the affected lots it is unlikely to cause a significant safety concern. However, the possibility of adverse experiences arising primarily due to physical irritation cannot be ruled out. As of this date, Ranbaxy has not received any reports of adverse events related to this recall.”

Is The Consent Decree Working?

It’s been exactly one year since FDA handed Ranbaxy a victory by approving its ANDA for generic Lipitor before any others (Also see "Lipitor Goes Generic, But First-Filer Ranbaxy’s Approval Leaves Plenty Of Questions In Its Wake" - Pink Sheet, 5 Dec, 2011.). But that year has not been a good one for the company. The first-filer status itself was compromised as Ranbaxy reached a revenue-sharing deal with Teva Pharmaceutical Industries Ltd. covering the 180-day exclusivity period.

Then, in January, Ranbaxy agreed to a manufacturing-related consent decree with the U.S. Department of Justice requiring it to withdraw all ANDAs containing data generated at one of its facilities in India and relinquish 180-day marketing exclusivity for three pending ANDAs (Also see "Ranbaxy Consent Decree Includes Strict Requirements For Auditing Drug Applications" - Pink Sheet, 6 Feb, 2012.).

The company stressed at the time that that did not affect its atorvastatin product, since it is not manufactured in the facilities cited in the decree.

But the question for FDA becomes how valuable is this kind of government involvement in improving a company’s manufacturing if a flagship product runs into problems so soon after a firm is legally forced to reboot its compliance efforts.

After the deaths attributed to manufacturing problems at the New England Compounding Center, some critics have questioned why FDA didn’t push more aggressively for action from the firm after the agency found problems years earlier (Also see "Reimbursement Questions Add To Compounding Regulation Debate" - Pink Sheet, 26 Nov, 2012.). And Public Citizen recently called on FDA to re-inspect other suspect pharmacy compounders en masse.

Whatever the merits of the those potential steps, FDA could be called on to explain why even a consent decree (second only to market withdrawal in enforcement) power failed to prevent mis-manufacture in Ranbaxy’s case (Also see "GDUFA Implementation Will Be Overseen By Mylan’s Representative in the House" - Pink Sheet, 4 Dec, 2012.)

Will There Be A Drug Shortage?

With a halt to production comes the worry about an interruption of supply. “FDA does not anticipate a drug shortage,” the agency said. “The FDA has consulted with other manufacturers of approved atorvastatin tablets and these manufacturers have indicated that they will be able to meet market demand.”

The recall and shutdown gives the other generic competitors for atorvastatin, including Sandoz International GMBH, Mylan NV, Apotex Inc. and Dr. Reddy's Laboratories Ltd., a chance to move in on the market share. It also provides FDA a chance to show how well it handles supply interruptions, and it begins to exercise its new powers created under the user fee legislation passed in the summer (Also see "FDA Drug Shortage Staff Gets Higher Profile As New Reporting Requirements Begin" - Pink Sheet, 28 Sep, 2012.).

Can You Trust Generic Drugs?

The final and perhaps most nebulous challenge to FDA’s reputation stemming from Ranbaxy’s most recent manufacturing problems is the damage that the atorvastatin recall might do to the public’s faith in generic drugs in general.

The agency worked hard to get Ranbaxy’s product approved for an on-time launch last year, but the announcement of the recall this year, which seemed almost like it could be a Thanksgiving news dump, generated considerable media attention as well. The resulting focus could leave the public wondering whether the rush to cut the price is worth having sand-like beads of glass in the containers.

Brands aren’t immune from manufacturing problems, but public concerns about quality seem to weigh more heavily on generics. Indeed, even though many brand products have left the market after not living up to their labeled potential for safety or efficacy reasons, the recent first-ever withdrawal of a generic for clinical reasons has prompted some calls for fundamental reform of those reviews (Also see "FDA And Generic Drug Quality: Turning Point, Or Precipice?" - Pink Sheet, 8 Oct, 2012.).