FDA flagged factories before medication recalls

Carcinogens found in drugs from China, India

FDA inspections show a history of problems in factories in China and India that made carcinogen-tainted ingredients that forced dozens of recalls of blood pressure drugs in recent months.

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 FDA hasn’t completed its inquiry, but inspection reports reveal problems at 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.

Even when inspectors identify is- sues, it’s not always enough to prevent tainted drugs from reaching the USA.

Analysts said the agency struggles to keep pace with a global industry.

“As we see when there are widespread recalls and widespread quality questions, there is a tremendous price from a public health standpoint,” said Michael Carome, director of the health research group at Public Citizen.

FDA assigns staff overseas

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 46 percent of the FDA’s offshore inspector jobs were unfilled.

In response to the 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 jobs 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.

“Really, 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, told USA TODAY.

Since 2013, nearly 300 products have been recalled by 65 drug plants within one year of an FDA inspection, according to Kaiser Health News.

FDA inspectors who visited the Zhejiang Huahai Pharmaceutical factory in Linhai 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 nitrosodimethylamine, or NDMA. The FDA investigated and announced a recall in July.

Follow-up testing revealed a second carcinogen, nitrosodiethylamine, 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 November about challenges including impurity control, change control and contamination from one manufacturing process line to another.

The FDA said the Zhejiang factory inadequately investigated the initial report of NDMA.

It’s unclear how long the factory had been making the tainted pharmaceutical ingredients.

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.

Defects, shredded documents

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. 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.

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 notified regulators and initiated a recall.

Hetero Labs representatives shared recall notices with customers and generally advised customers to check with their pharmacists. The company did not respond to USA TODAY about the FDA’s inspections.

“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