U.S. FDA Slams Warning Letter On Dr. Reddy's For GMP Violations At Mexico API And Steroids Site

MUMBAI - U.S. FDA issued a warning letter to India's Dr. Reddy's Laboratories Ltd. following investigations that detected adulterated APIs at its Cuernavaca, Mexico site. The regulatory agency noted "significant deviations" from current good manufactuirng practices at the site. The FDA probe centers around unvalidated analytical methods, deficiencies in handling out-of-specification investigations and parameters used to ensure cGMP compliance.

Dr. Reddy's acquired the Mexico plant in 2005 from Roche for total investments of $59 million, including working capital outlays. The acquisition also included ongoing, long-term supply contracts for products manufactured at the site. Roche and other innovator companies are the main customers for the Mexican site. The acquired portfolio comprised about 18 products that the Hyderabad-headquartered firm defined as "mature APIs," including a range of intermediates and steroids.

Serious Matter For Dr. Reddy's

FDA issued Form 483 observations following a November 2010 inspection of the Mexico facility, and the agency was not satisfied with the response the company submitted Dec. 1. In a statement, Dr. Reddy's said it felt it responded to the 483 observations by implementing a number of corrective actions, but FDA has asked for additional data and corrective actions. The firm said it would work collaboratively with FDA to resolve the issues.

FDA investigators noted, among other deviations, an unvalidated high-performance liquid chromatography method for assay and related substances. "This is just an example of numerous methods used by your firm that had not been validated according to approved procedures," FDA said in a letter addressed to Dr. Reddy's CEO G.V. Prasad.

The agency also criticized the company's plan to rectify incomplete method validations, which did not adequately address how to deal with unvalidated products already on the market or in the process of reaching the market. "Your proposal to verify key parameters for the first API batch produced does not provide the same level of assurance as method validation," the June 3 FDA letter said, and the agency requested the company submit a plan to ensure "that adulterated API will not reach the U.S. market."

Likewise, the agency raised concerns that the company's cleaning validation for equipment that was incomplete and asked how the company would ensure that marketed product is not cross-contaminated.

Dr. Reddy's was also faulted for its handling of out-of-specification issues at the Mexico site. FDA sought clarifications on shortfalls like the timeliness of closing OOS investigations, delays - up to eight months - in reporting failed stability batches and failure to follow written procedures.

No Internal Consumption, All Global Clients

A Dr. Reddy's official told PharmAsia News that the manufacturing unit had mostly served outside demand from large multinational firms and the APIs were not consumed for the company's global generics business, including the U.S. The site contributed nearly $60 million to the overall top line and employed more than 350 people.

Until the company meets the agency's requests, FDA can choose to withhold approval of any products that lists Dr. Reddy's as an API manufacturer, or the agency can prevent importation of any product manufactured at the Mexico facility. Dr. Reddy's has until June 18 to respond to the warning letter.

At the time of acquiring the unit, Dr. Reddy's said it planned to emerge as a leading player in the custom pharmaceutical services business and position itself as a partner of choice for innovator companies. The company had planned to build service offerings across the value chain. "The strategic acquisition provides an opportunity for our CPS business to grow from the current base of $10 million to $100 million over the next 18 months," Prasad had said.

However, a downturn in the prices of key ingredients and raw materials coupled with rationalization of vendors and suppliers by global companies in the last few years impacted the business prospects of many contract manufacturers.

At the time of the buyout, the Roche plant had figured as a "gold standard facility" among Roche's global facilities, a former official with Dr. Reddy's said.

For the last few years, FDA has detected manufacturing deviations at several local and overseas sites owned by Indian companies like Ranbaxy Laboratories Ltd., Cipla Ltd., Sun Pharmaceuticals Industries Ltd. and Claris Lifesciences Ltd.

During the last year, FDA turned aggressive in enforcement of GMP standards (Also see "FDA Continues Aggressive Enforcement as Drug GMP Warning Letters Mount" - Pink Sheet, 1 Apr, 2011.).

Meanwhile, in a site safety related issue, two contract laborers were reported dead after a nitrogen gas leakage at a Dr. Reddy's chemicals unit near Hyderabad last December.

- Vikas Dandekar ([email protected])