During the height of the monsoon in 2011, a technician at a laboratory in a village in India hit a delete button, a keystroke that would have consequences three years later.
The quality-control employee of Sun Pharmaceutical had run high-powered chemical analyses on a drug sample to check for impurities. A certain level of impurity means a whole batch is supposed to be thrown out.
But that’s not what happened. Instead, the results of the failed tests were deleted, according to a previously undisclosed account detailed in a November 2013 US Food and Drug Administration (FDA) document obtained by Bloomberg News. The following day, workers used another sample from the same batch, which passed the test. That result was entered and the entire batch was declared clean and ready to be shipped abroad, eventually to be used by patients in the US.
The US FDA’s computer forensics experts eventually found 5,301 additional results from chromatography tests at the facility were deleted. “Our review found analysts regularly deleted undesirable chromatographic results, and products were retested without initiating an investigation, as required,” inspectors wrote in the document. The incident “raises concern about the integrity of all data generated by your firm,” the FDA wrote in a separate warning letter to Sun in May.
Two months earlier, the agency had banned imports from the plant, near Vadodara. The name of the drug or the ingredient the company was testing was redacted in the documents Bloomberg obtained from the FDA under a Freedom of Information Act request.
Frederick Castro, a spokesman for Sun Pharma, declined to comment.
The incident wasn’t restricted to Sun. A review of FDA documents by Bloomberg News found similar action on quality tests had taken place at dozens of other companies’ plants in India that make drug ingredients and pills for export to the US. While not as visible as the dead frogs and flies inspectors have found at other pharmaceutical laboratories in India, the pattern of data integrity breaches worries doctors in the US and other countries. They say they fear prescribing generic drugs that might not do what they’re supposed to.
“If they make multiple batches, does it come out the same, with the same amount of drug in it? And, when you give it to a patient, can you assume it will work consistently?” asked Harry Lever, a cardiologist at the Cleveland Clinic in the US.
A review of inspection documents and warning letters shows at least 12 drug companies with Indian facilities that have been banned from sending pharmaceutical products to the US since last year are accused of failing to report data from tests to confirm the drugs were safe and would work. India is the second-largest drug exporter to the US. Indian pharmaceutical companies primarily produce generic drugs and active ingredients for medicine. The top 10 pharmaceutical companies based in the country generate $ 15 billion in annual sales, according to data compiled by Bloomberg. The US doesn’t require tests of imported drugs as they cross the border; the FDA relies on factories conducting quality tests and reporting accurate results, only carrying out its own studies if it receives several complaints about a medicine. In India, the agency has about a dozen staff members to police about 600 factories registered with the US. This year, the FDA had conducted 97 inspections of drug manufacturers, as of October-end, said Tara Goodin, a US FDA spokeswoman.
Sun Pharma has 25 manufacturing facilities globally, including 11 in India and seven in the US. The plant near Vadodara was approved to make generic cephalosporin, a class of a popular antibiotic. Three years after the incident highlighted by the FDA, Sun’s Caraco Pharmaceutical Laboratories in Detroit recalled 450,000 bottles of cephalexin, a type of cephalosporin. The active ingredient made by Sun wasn’t produced using good manufacturing practices, the FDA said in an enforcement report in August, without providing details. It’s unclear whether the Detroit plant and the one in India processed the same products. Caraco representatives didn’t respond to phone messages.
The FDA told Bloomberg it could only handle requests for four inspection documents, known as Form 483s, at a time without making the process lengthier and more complicated. With about 600 FDA-registered factories in India, it is difficult to get a snapshot of data integrity across the entire sector. Warning letters are public and don’t require a Freedom of Information Act request. However, not every red flag in an inspection results in a warning letter, meaning the full extent of violations might not be publicly available.
Sun’s plant was banned four months after its inspection. A senior quality control officer told FDA investigators laboratory employees there frequently pre-tested samples before recording a final result, according to the agency’s warning letter to Sun. The practice was unacceptable, the FDA said. The missing results were in an obscure “default” folder in a software programme called Empower, according to a Form 483.
Last year, Gurgaon-based Ranbaxy pleaded guilty to felony charges for similar violations and paid $ 500 million in fines. A spokesman for Ranbaxy, which is being acquired by Sun, declined to comment.
Pattern of conduct
“There’s a pattern of conduct at other companies that is similar, if not identical, to the Ranbaxy problems,” said Andrew Beato, a Washington-based lawyer who helped a whistleblower expose Ranbaxy. Reporting on product safety and effectiveness was only valuable “when it is reliable, truthful and accurate”, Goodin, the FDA spokeswoman, said in an e-mail. When it wasn’t, “those manufacturers’ practices raise questions about the accuracy, reliability, and truthfulness of all the data and information they collect and report”, she added.
Asked whether felony prosecutions were possible for any of the 12 companies with plants in India on the banned list, she said: “Firms unable to show control over their processes and testing might not be producing safe, high-quality products and, therefore, might be subject to enforcement action.” Data-integrity breaches weren’t limited to plants in India banned from exporting to the US.
In a document, the FDA said at a Hospira plant in India in December 2013, workers didn’t make available records on drug production. Investigators saw two boxes of what appeared to be paper records locked in a janitor room, they said in their report. Key in hand an hour later, investigators found one of the boxes removed, and when it was returned from the “waste area”, papers were missing, according to the Form 483. The document didn’t say how investigators first spotted the boxes in the locked room. The Hospira plant had already received a warning letter in May 2013, following an October 2012 inspection. It’s not clear whether any new action resulted from the December 2013 inspection. Hospira representatives didn’t respond to phone messages.
In 2012, the Indian government had introduced laboratory norms to manufacturers and, last year, made it a requirement to comply with those, he added.
Many companies in India on the FDA’s banned list supplied vital therapies or ingredients. For instance, India-based Smruthi Organics supplied the active ingredient in the antibiotic Noroxin to Merck & Co, the second-largest drugmaker in the US, according to the US National Library of Medicine. In June 2013, a Smruthi plant was banned from sending product to the US. In March this year, the company was formally warned by the FDA on its facility, where the agency said workers blended failed batches of active ingredients with those that passed tests and destroyed related documentation.
Merck confirmed it “no longer sources” ingredients from Smruthi, and the company discontinued Noroxin in April. Mylan, the largest generic drugmaker in the US, also suspended a relationship with Smruthi, which supplied ingredients for 12 Mylan products, all of which Mylan recalled. The plant remains closed. Neither Merck nor Mylan were found to be in violation of FDA rules. Eaga Purushotham, managing director of Smruthi Organics, didn’t respond to e-mails and calls seeking comment. Smruthi “is making every attempt to resolve regulatory issues”, which contributed to a loss in the quarter ended September, the company said in a filing last month. In February, FDA Commissioner Margaret Hamburg visited India and vowed to step up efforts to help companies overcome hurdles on compliance.
Besides Sun, Ranbaxy and Smruthi, nine other companies own factories whose exports were prohibited by the FDA. Here’s a list of the companies, with their comments or with Bloomberg’s attempts to reach them.
Amsal Chem Pvt Ltd: The company had sent a response to the FDA and was awaiting feedback, Director Subhash Majithia said in an e-mail. The company had “a continuous process of upgrading in all areas”.
Apotex Inc: “We are actively working with the agency and independent consultants to implement measures that will enhance our quality assurance protocol,” it stated.
Canton Laboratories Pvt Ltd: No response.
Amanta Healthcare Ltd: No response.
Micro Labs Ltd: No response.
RPG Life Sciences Ltd: No response.
Sentiss Pharma Pvt Ltd: “We received an import alert from the FDA and since then, have been working diligently to comply with all its requirements,” it said in a statement.
JB Chemicals & Pharmaceuticals Ltd: The company closed its Unique Chemicals facility in Rabale in 2010, Secretary Mayur Mehta said. The company hadn’t received communication from the FDA about an import alert for the facility, Mehta added. The FDA said its 2013 inspection was to verify the facility was no longer operating, and the agency put the plant on import alert to make sure its previously manufactured products weren’t exported to the US.
Wockhardt Ltd: No response.