Few prescription medications MADE IN THE USA

Heart-Drug Suppliers for Millions Faulted Over Data, Bugs and Dirt

https://www.supplychainbrain.com/articles/29738-heart-drug-suppliers-for-millions-faulted-over-data-bugs-dirt

A pair of drugmakers in India that the U.S. is counting on to produce generic blood-pressure pills after a far-reaching recall have been faulted by regulators for quality-control issues.

Cadila Healthcare Ltd. and Alkem Laboratories Ltd. both won approvals in March from the Food and Drug Administration to make generic versions of valsartan for the U.S. market. Neither company made any of the recalled valsartan, but both companies have recently been cited by agency inspectors for quality-control failures that echo problems at other drugmakers — renewing questions about the safety of some of the world’s most widely prescribed medicines.

Workers ignored testing data showing product flaws; destroyed records indicating that drugs were failing key quality measures; and didn’t properly clean equipment, FDA inspection reports stated. Inside one factory, inspectors said they saw swarms of insects.

Millions of Americans take valsartan for high blood pressure and heart failure. Since last year, pharmacies have pulled many formulations of it, as well as other medications in the same class of drugs, after some were found to contain potential cancer-causing contaminants. Some versions of valsartan are now in short supply.

Most of the tainted drugs originated in India and China, which have become popular sources of generic medications and active-drug ingredients as producers and health-care providers try to hold down costs.

Those forces have left regulators scrambling to police an expanding global supply chain. Some of the plants that made the contaminated drugs were flagged by FDA inspectors prior to the valsartan recalls for attempting to cover up manufacturing problems, as reported by Bloomberg News earlier this year.

But the generic drugmakers cleared by the FDA to make versions of valsartan since the recall have many of the same red flags.

No Control

Records obtained through a public-information request show that a year before the FDA cleared Alkem on March 12 to sell generic valsartan in the U.S., agency inspectors noted numerous issues at one of the company’s two main manufacturing plants in India.

At a plant in Daman, India, inspectors found that workers destroyed logbooks or deleted data on quality testing and ignored signs that drugs made there contained impurities. In less than a month, workers deleted 2,000 files that appeared to include failing quality-test results, according to the inspection records. Data issues were so widespread that inspectors wrote that “there is no quality control unit” at the plant.

Inspectors also observed flying insects, including mosquitoes and gnats, that were “too numerous to count,’’ according to the reports.

Despite the array of problems described in the inspection, Alkem’s plant received a clean bill of health. The FDA revisited Daman in January, nine months after its initial, troubling inspection and gave the plant a pass. Two months later, the agency approved Alkem’s valsartan.

Alkem said its version of the drug was made in India but wouldn’t confirm at which plant. The company said the January visit from the FDA didn’t produce a list of any problems at the factory, an indication that the matter is closed.

It’s almost unheard-of for the agency to sign off so quickly on fixes by a plant with extensive problems, according to Massoud Motamed, a former FDA inspector who conducted inspections in China and India and now works in the drug industry.

“That’s not realistic to fix that in nine months,” said Motamed, who left the agency in 2017 and had no role in the Alkem inspection. “Working for industry, I can tell you it’s impossible.’’

An FDA spokesman, Jeremy Kahn, said in an email that the agency can inspect a facility at any time and does so based on risk factors including when the last inspection took place and the prior inspection history. The FDA also considers the need to maintain sufficient supply of a particular drug, he said.

“The agency followed an appropriate timeline given the factors relevant to this firm,” he said. “Generally, FDA can expedite inspection of facilities and assessment of drug applications for drugmakers that want to produce drugs in short supply so they can become operational as soon as possible.”

Quality Concerns

Cadila received approval from the FDA on March 16 to sell valsartan combined with another blood-pressure drug, hydrochlorothiazide. About a month later, records show, FDA inspectors tallied a lengthy list of quality concerns at a plant in Ahmedabad, India, that is making that drug combination.

Inspectors found in April and May that equipment at Cadila’s facility wasn’t cleaned appropriately to prevent contamination and that workers ignored signs of impurities.

A representative for Cadila didn’t respond to a request for comment.

Those issues are similar to problems FDA inspectors flagged at the company in China that’s at the center of the recall. Zhejiang Huahai Pharmaceutical Co. Ltd. was found to have ignored impurity indications in its valsartan. In a November warning letter, the FDA said that if the company had investigated further, it might have been alerted to the presence of the carcinogen NDMA sooner than the original recall, in July 2018.

The NDMA may have been in the valsartan as long as four years, the FDA said at the start of the recall. The agency is looking into whether the manufacturing process may have led to the contamination.

The FDA has estimated that for every 8,000 people who took the highest dose of valsartan, there would be one additional case of cancer.

China Echoes

In 2017, Motamed, the former inspector, discovered that Zhejiang Huahai workers omitted from official records quality-test failures, including ones that flagged impurities in unnamed drugs the company didn’t attempt to identify.

Motamed wanted to impose strict penalties on Zhejiang Huahai but was overruled by senior FDA officials, who allowed the company to attempt to address the problems. A year later, another generic drugmaker that bought valsartan from the manufacturer found an impurity that was determined to be potential carcinogen NDMA — kicking off the wave of recalls, which continues to expand.

The recall has heightened scrutiny of the safety of generic drugs, which are used to fill nine of every 10 prescriptions in the U.S., according to the FDA. Competition from generics has been a key part of the Trump administration’s push to lower drug costs.

Last month, the FDA posted a list of 43 versions of valsartan and similar drugs that don’t contain carcinogens. The FDA hasn’t updated the list, which names another 386 drugs that still need to be evaluated.

Alkem’s valsartan and Cadila’s combination pill aren’t listed in either category. The list will be updated on a periodic basis, said Kahn, the FDA spokesman.

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