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Valsartan may have been contaminated since 2011, says FDA warning letter to Huahai
Since July this year, a host of high blood pressure drugs got recalled globally once both the US Food and Drug Administration (FDA) and regulators in Europe learned that the valsartan API made by China’s Zhejiang Huahai Pharmaceuticals contained the cancer-causing impurity N-Nitrosodimethylamine (NDMA).
This week, the FDA posted the warning letter issued to Zhejiang Huahai following an inspection of its valsartan API manufacturing facility from July 23 to August 3, 2018.
According to the FDA warning letter, valsartan API may have been contaminated since November 2011, when Huahai approved a change in its manufacturing process to increase product yield and lower production costs.
FDA
still looking into root cause of NDMA impurity
The discussion on NDMA began after a Huahai customer complained about an unknown peak that was being detected during residual solvent testing of valsartan API in early June. The unknown peak was then identified as NDMA.
An investigation by Huahai determined that the presence of NDMA was caused by the convergence of three process-related factors. As Huahai manufactures valsartan using multiple manufacturing processes, the company’s investigation concluded that only one valsartan manufacturing process was impacted by the presence of NDMA.
However, when the FDA analyzed samples of the API and finished drug product manufactured by Huahai, they found NDMA in multiple batches manufactured with a different process. This made the FDA conclude that Huahai’s “investigation was inadequate and failed to resolve the control and presence of NDMA in valsartan API distributed to customers”.
In a press release following the warning letter, the FDA has stated: “The agency is still looking into the root cause of the impurity”.
Significantly higher amounts of NDMA found in Huahai’s samples
FDA investigators also found other examples where Huahai failed to adequately investigate the presence of unknown peaks observed in chromatograms.
While Huahai had tried to justify its position by saying that NDMA was difficult to detect and that it was not the only firm to identify NDMA in valsartan API, the warning letter clearly states that FDA analysis of samples identified “significantly higher” amounts of NDMA in valsartan API manufactured by Huahai, as opposed to the valsartan API manufactured by other firms.
Moreover, FDA also said it has “grave concerns” as the data indicates “the presence of impurities in API manufactured by multiple processes, and because of the significant inadequacies” in Huahai’s investigation.
The warning letter also reveals that Huahai approved the valsartan API process change in November 2011 with the intention to improve the manufacturing process, increase product yield, and lower production costs. However, Huahai failed to adequately assess the potential formation of mutagenic impurities when it implemented the new process.
No excuses! Huahai’s responsible for quality of its drugs
The company also failed to evaluate the need for additional analytical methods to ensure that unanticipated impurities were appropriately detected and controlled in its valsartan API before it approved the process change.
In its response to the FDA, Huahai had stated that predicting NDMA formation during the valsartan manufacturing process required an extra dimension over the current industry practice, and that its process development study was adequate.
However, the FDA disagreed with this position and said the “common industry practice may not always be consistent with cGMP requirements and that you are responsible for the quality of drugs you produce.”
The facility, which is located in Linhai, was placed on an FDA Import Alert on September 28, 2018.
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Image Credit : Death of a Light Bulb by LASZLO ILYES is licensed under CC BY 2.0 // Modification: Valsartan text was added to the original image.
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