Guidance To Prevent NDMA Contamination Issued By FDA

Guidance To Prevent NDMA Contamination Issued By FDA

Introduction

On September 1, the Food and Drug Administration (FDA) issued guidance recommending the manufacturers of active pharmaceutical ingredients and drug products to implement steps to avoid drug contamination with cancer-causing chemical by-products, such as N-nitrosodimethylamine (NDMA) and other nitrosamine impurities.

Federal drug regulators indicate that the recent unexpected finding of nitrosamine impurities that led to massive Zantac, Valsartan, and Metformin recalls made the need for a risk assessment strategy. The recommendations are not legally binding, but a failure to implement them could result in a liability later.

Zantac (ranitidine hydrochloride) is an antacid and an H2 (histamine-2) receptor blocker used for treating and preventing ulcers in the duodenum, stomach, and intestines. It is also used for treating erosive esophagitis, heartburn, gastroesophageal reflux disease-GERD, Zollinger-Ellison syndrome. In 1983, Glaxo Holdings Ltd, a company which is a part of GlaxoSmithKline PLC, received approval from the FDA to sell Zantac in the U.S. However, owing to patent expiry in 1987 in the United States, Glaxo had to face stiff competition by the generic alternatives launched immediately by competitors. Since 2017, the OTC version of Zantac was marketed by Sanofi in the United States and Canada. In 2004, Pfizer gained FDA approval to sell the Zantac OTC in the United States.

Valsartan belongs to a class of drugs called Angiotensin II Receptor Antagonist and is used to treat high blood pressure (Hypertension), and Congestive heart failure. Diovan (Valsartan) was manufactured by Novartis International AG and was approved by the FDA on August 14, 2002. Diovan lost its patent in September 2014. The launch of the generic drug had been on hold since patent expiry due to regulatory problems with the FDA. In 2014, a US-based Ohm Laboratories (Ohm), a subsidiary of Ranbaxy Laboratories, was the first to get the approval from FDA for generic Valsartan. Thereafter, many generic versions of Valsartan came into the market via many other pharma companies.

The guidance has mentioned many potential root causes of contamination, which include acidic reaction conditions, nitrosamine contamination of raw materials used to make active pharmaceutical ingredients, and contamination through recovered solvents and reagents. The contamination can also be caused due to a lack of process optimization and control or through nitrous acid coming in contact with residual amines during the quenching process, as per the FDA.

In a press release issued on the same day, the FDA indicated that nitrosamines are common in water and foods, but its impurities may increase the risk of cancer when exposed to above acceptable levels over a long period of time.

The FDA is working in collaboration with regulatory counterparts around the world in finding and eliminating the drugs with high levels of nitrosamine impurities that are harmful to humans.