An FDA inspection of the Zhejiang Huahai Pharmaceutical plant a year ahead of its global recall of tainted heart drug valsartan found a plant with little regard for quality control and which blamed out-of-specification test results on “ghost peaks,” lab errors and environmental pollution.
The plant repeatedly reanalyzed API batches to achieve passing results, even when tests showed a “large differential,” then shipped them to the U.S. without ever investigating why the out-of-spec results occurred in the first place. The problems were laid out in a highly redacted FDA Form 483 just posted by the FDA which stemmed from a May 15, 2017, inspection.
In July, the European Medicines Agency announced that Huahai had informed it had identified N-nitrosodimethylamine (NDMA), a chemical that might lead to cancer, in the valsartan provided to the European market.
The drugmaker instigated a voluntary recall in Europe and Asia of affected API batches as did drugmakers like Teva’s Actavis, Stada and Dexcel Pharma, which has used the ingredient in their finished products. It said the impurity appeared to be the result of a manufacturing change.
Since then the the FDA has identified more than a dozen products in the U.S. with the impurity that are being recalled. It updated the list today, adding Hetero Labs, labeled as Camber Pharmaceuticals. In a previous update, the FDA said its investigation into the situation found the tainted ingredient may have been on the market for years.
“Based on records from the manufacturer of the recalled valsartan, some levels of the impurity may have been in the valsartan-containing products for as long as four years,” the agency said.
But it also pointed out that FDA scientists estimate that if 8,000 people took the highest valsartan dose (320 mg) from the recalled batches every day for the full four years, there may be one additional case of cancer over the lifetimes of those 8,000 people. "This assessment led to FDA’s decision to have these batches recalled," the agency said.
Among other issues reported in the Form 483, the FDA said that the Chinese company was not consistently quantifying or documenting impurities found in analytical testing. It also said equipment was not thoroughly cleaned, with paint pieces found on some.