USA TODAY International Edition
FDA flagged factories before drug recalls
Carcinogens found in drugs from China, India
FDA inspections of factories in China and India that made carcinogen-tainted ingredients that forced dozens of recalls of blood pressure drugs in recent months show a history of problems.
Drug companies recalled dozens of lots of the front-line blood pressure and heart medications valsartan, losartan and irbesartan – alone or in combination with other drugs – after testing revealed the drugs had cancer-causing impurities in trace amounts.
The Food and Drug Administration is investigating the underlying causes of the impurities.The federal agency hasn't completed its inquiry, but inspection reports reveal problems at both factories – Zhejiang Huahai Pharmaceutical in China and Hetero Labs in India – before the carcinogen-tainted drugs were discovered.
The recalled products are part of a large class of drugs called angiotensin II receptor blockers, or ARBs, which work by blocking the effects of a hormone that narrows blood vessels. Many of these commonly prescribed drugs are not part of the recall. Consumers can check the FDA's website for a full list of recalled drugs.
Drug companies generally advise affected patients to check with their doctor or pharmacist before they stop taking their medications. Discontinuing a recalled drug could cause more immediate harm than staying on the medication.
The recalls underscore the FDA's enormous challenge in overseeing a global pharmaceutical supply chain in which about 80 percent of drug ingredients and 40 percent of finished drugs sold in the USA are made or handled at more than 3,000 plants overseas.
The FDA has worked through a backlog of unchecked foreign drug plants that has grown over the past decade as the pharmaceutical industry accelerated production overseas. The FDA scrapped its policy of checking all foreign and domestic plants at least once every two years, instead prioritizing checks at facilities based on potential risk to U.S. consumers.
Since 2015, the agency has conducted more inspections overseas than at domestic factories.
Even when inspectors identify issues, it's not always enough to prevent tainted drugs from reaching the USA, where they are prescribed by doctors and taken by patients.
Analysts said the agency struggles to keep pace with a global industry.
Michael Carome, director of the health research group at Public Citizen, said
the FDA works to ensure the quality and safety of the drugs sold in the USA, but it's under pressure to reduce drug shortages.
“There is always that pressure to not cease manufacturing to add to the drugshortage list,” Carome said. “I think we have a federal agency that is overwhelmed in trying to keep up.”
FDA hires more inspectors
Congressional investigators found in 2017 that the FDA was making strides in overseas inspections this decade, but about 1,000 plants had never been inspected as of mid-2016.
The Government Accountability Office, the nonpartisan investigative arm of Congress, reported that 46 percent of the FDA's offshore inspector jobs were unfilled.
In response to the GAO report, the FDA said it hired more inspectors, developed a workforce recruitment and retention plan, offered incentive pay to retain foreign staff and temporarily assigned domestic staff to short-term stints overseas.
Only 15 percent of inspector were unfilled as of July 2018.
The FDA prioritized domestic and overseas inspections based on potential risk, evaluating factors such as a factory's compliance, recall history, date of last inspection and the risk of the drug.
Stepping up inspections and producing detailed findings don't guarantee that drug companies will correct or prevent manufacturing problems that can lead to recalls. jobs
Anomalies go uninvestigated
FDA inspectors who visited the Zhejiang Huahai Pharmaceutical factory in Linhai, China, found that workers repeatedly failed to investigate testing anomalies in drug batches. The FDA did not include the names of the drugs with anomalies in its report.
Inspectors at the factory, the source of the bulk of blood pressure drug recalls, discovered equipment had fraying gaskets, rusted screws and missing pieces.
Despite these findings, factory operations continued uninterrupted. It was not until another company tested the Zhejiang factory's drug ingredients last June and discovered unacceptable levels of the carcinogen nitro so di methyl a mine, or NDMA. The FDA investigated and announced a recall in July.
Follow-up testing revealed a second carcinogen, ni tr os odie thy la mine, or NDEA, in batches of valsartan.
The FDA issued an import alert in September to block products made at the plant from entering the USA. The FDA issued a warning letter in Novemberabout challenges including impurity control, change control and contamination from one manufacturing process line to another.
The FDA said the the Zhejiang factory inadequately investigated the initial report of NDMA.
It's unclear how long the factory had been making the tainted pharmaceutical ingredients first detected by a customer last June.
In November 2011, Zhejiang factory workers changed how they made valsartan to produce more product at lower cost. The factory failed to assess the possibility of forming toxic impurities such as NDMA, the FDA said in a warning letter.
The India plant also had signs of trouble.
In 2016, employees at the Hetero Labs plant in Jadcherla were found shredding documents before inspectors were scheduled to arrive, according to the FDA. The lab failed to keep a log of the documents that were shredded.
One customer complained that a finasteride tablet was twice as thick as others in the bottle, FDA inspectors said in a report. Hetero failed to recall the defective lot, as required, until inspectors pointed it out.
The FDA issued a warning letter to Hetero in August 2017 saying the drugmaker failed to investigate discrepancies found in drug batches and did not regularly clean, sanitize or sterilize equipment to prevent contamination of drug ingredients. The FDA recommended the lab hire a consultant to ensure it followed good manufacturing practices.
The FDA did not issue an import alert against Hetero, as it did for the Zhejiang factory.
Representatives of the Zheijiang factory have issued several statements about the recall through its U.S. subsidiary, Huahai US.
The company noted that the FDA closed inspections in 2016 and 2017 without finding any impurities in valsartan batches. When the factory confirmed the impurities in June, the company said, it initiated a recall.
“A lot of responsibility is on the people who manufacture and offer these drugs for sale.” Janet Woodcock,
director of the FDA’s Center for Drug Evaluation and Research