The agency is getting tougher with the generic drugmaker, which is already cited by federal prosecutors for allegedly falsifying records that resulted in the production and sale of meds failing to meet FDA standards. Now, the FDA has issued warnings letters and an import alert for more than 30 meds made at two plants in Dewas and Paonta Sahib in India.

The agency, which has been investigating Ranbaxy since 2005, cites deviations from Good Manufacturing Practices and, as a result, federal authorities have the right to detain at US borders any Ranbaxy drugs and active pharmaceutical ingredients made at those facilities (this is the list of products).

In explaining the action, FDA officials call the move “proactive,” but stressed they are not removing Ranbaxy products from the market and there is no evidence, to date, Ranbaxy has shipped defective drugs. The actions don’t apply to products made at Ranbaxy’s other plants, which have so far met manufacturing requirements. Whether that warms heart at Daiichi Sankyo, which recently agreed to buy Ranbaxy for $4.6 billion, is unclear. The House Energy & Commerce Committee, however, says the FDA should have acted sooner (see comments below).

“Today’s actions are clearly warranted by the serious violations established by FDA’s investigations at these two sites,” Deborah Autor, who heads the FDA CDER Office of Compliance, says in a statement. “Until the company addresses these deficiencies, APIs and finished drug products from these plants will remain on the Import Alert, and we will not approve any Abbreviated New Drug Applications or New Drug Applications that list either of the two facilities as the manufacturer of APIs or finished drug products.”

The feds, you may recall, alleged officials at Ranbaxy’s plant in northern India used raw chemicals from unapproved sources, fabricated in-house test data to meet FDA standards and attempted to conceal the ruse from FDA inspectors, according to court documents. Those allegations included fabricating bioequivalence and stability data to support AIDS drugs to be paid for by the President’s Emergency Plan for AIDS Relief program (PEPFAR) and distributed to foreign countries (back story).

The FDA Import Alert covers more than 30 different generic drug products (Drug List) produced in multiple dosage forms and dosage amounts ( i.e., 25 mg, 50 mg, and 100 mg) at these two locations. The FDA says it evaluated whether its move would create any potential drug shortages in the US, and has determined that other suppliers can meet market demand, with one exception.

Because Ranbaxy is the sole supplier in the US of Ganciclovir oral capsules, which is an antiviral, to avoid creating a shortage of the drug, FDA generally will not detain shipments of this product, and plans to arrange for additional oversight and controls until the company resolves these manufacturing issues.

One Warning Letter addressed problems at Ranbaxy’s Dewas facility found during an inspection conducted by FDA in early 2008. During that inspection, FDA investigators documented significant cGMP deviations in the manufacture of sterile and non-sterile finished products and violations with respect to the manufacture and control of APIs.

Specific areas of concern included the following aspects of the firm’s quality control program: The facility’s beta-lactam containment program (measures taken to control cross-contamination), which appeared inadequate to prevent the potential for cross-contamination of pharmaceuticals; inadequate batch production and control records; inadequate failure investigations; (a failure investigation is done to address any manufacturing control or product rejection to determine the root cause and prevent recurrence); and inadequate sterile processing operations.

The second Warning Letter addressed the Paonta Sahib facility following an inspection at its Batamandi unit, also in early 2008. This inspection documented various cGMP deficiencies, including the lack of assurance responsible individuals were present to determine the firm was taking necessary steps under cGMP; inaccurate written records of the cleaning and use of major equipment; incomplete batch production and control records; and inadequate procedures for the review and approval of production and control records for drug products.

Following the two inspections, FDA provided Ranbaxy with a separate list of inspectional findings for each of the facilities. In mid-April and May, Ranbaxy responded in writing to these findings in lengthy submissions to FDA. The agency then evaluated its findings, Ranbaxy’s responses, and the firm’s overall inspectional history, an evaluation that required substantial time due to the complex scientific and technical nature of both the identified deficiencies, particularly at the Dewas site, and the firm’s responses. Ultimately, the agency says it concluded Ranbaxy’s responses were not adequate and that the warning letters were appropriate.

This represents the second time in less than three years FDA has issued a Warning Letter to Ranbaxy. In 2006, FDA cited Ranbaxy for violations of US manufacturing requirements at its Paonta Sahib facility.

The House Energy & Commerce Committee, which itself is investigating the FDA and its investigation, issued a statement saying: “The FDA has refused to take meaningful regulatory action despite the fact that, for the past three years, it possessed credible information that Ranbaxy had engaged in a pattern of fraudulent behavior regarding its generic drug applications and records pertaining to good manufacturing practices.

“The FDA, for example, conducted preapproval inspections for only 17 percent of the Ranbaxy applications approved since January 2005. It also allowed Ranbaxy to perform the key bioequivalence studies for generic drug approvals in facilities owned by the firm and conducted by clinicians employed by the firm.”

Says John Dingell, who chairs the committee: “The heparin fiasco made it clear that the FDA had compromised the policies that were put in place during the last generic drug scandal to protect the public from fraud. This latest Ranbaxy announcement further confirms that those protective policies are in shambles. The FDA is not doing its best to protect the medicines that Americans depend on for their health.”