The FDA Issues Guidance Addressing Drug Impurities

Why is the FDA Issuing Recommendations?

The U.S. Food and Drug Administration (FDA) issued guidance in September 2020 to help drug manufacturers prevent against unacceptable levels of nitrosamine impurities. These impurities have been linked to cancer and have been found in any popular drugs, including the blood pressure drug Valsartan, and the heartburn drugs Zantac and Ranitidine. The nitrosamine impurity N-nitrosodimethylamine (NDMA) found in each of these medications has been classified as a probable human carcinogen.

Nitrosamine compounds are potent genotoxic agents that are classified as probable or possible human carcinogens by the International Agency for Research on Cancer (IARC).

The FDA has identified 7 nitrosamine impurities that could be present in drug products, including NDMA, NDEA, NMBA, NIPEA, NDIPA, NDBA, AND NMPA. NDMA, NDEA, NMBA, NIPEA and NMPA have already been detected in drug substances or products.

The FDA guidance recommends “a comprehensive risk assessment strategy and other actions that manufacturers can take to reduce or prevent the presence of nitrosamine impurities in their drug.”

How Are Nitrosamines Contaminating Medications?

The FDA guidance stated potential causes for the presence of nitrosamine impurities in active pharmaceutical ingredients (APIs). The formation of nitrosamines is possible in the presence of secondary, tertiary, or quaternary amines and nitrite salts under acidic reaction conditions. When these conditions occur, nitrite salts may form nitrous acid, which can react with an amine to form a nitrosamine. A greater risk of nitrosamine forming occurs if nitrous acid is used to quench residual azide (a reagent) when precursor amines are present.

Amines may appear during the manufacturing process for a multitude of reasons, such as:

  • API (or API degradants), intermediates, or starting materials may contain secondary or tertiary amine functional groups.
  • Tertiary and quaternary amines may also be added intentionally as reagents or catalysts.
  • The amines may react with nitrous acid or other nitrosating agents to form nitrosamines.

Nitrosamine impurities may also be introduced through the contamination of vendor-sourced materials, including raw materials. The FDA suspects that the contamination can arise through:

  • Fresh solvents being contaminated during shipment from vendors
  • Sodium nitrite (a known impurity in some starting materials) being present and reacting with amines under acidic conditions and form nitrosamines. Nitrate-containing raw materials, such as potassium nitrate, may contain nitrite impurities
  • Secondary or tertiary amines (impurities) that have been reported in some raw materials and solvents such as toluene
  • Starting materials or outsourced intermediate materials that could be at risk through cross-contamination if they are manufactured at locations where nitrosamine impurities are produced in other processes

In response to these concerns, the FDA recommended that manufacturers consider potential causes of nitrosamine formation and prioritize the evaluation of APIs and drug products based on factors such as maximum daily dose, duration of treatment, therapeutic indication, and the number of patients treated.

What is the Government’s Response to the Drug Impurities?

The U.S. Department of Justice (DOJ) and the U.S. Attorney’s Office for the Eastern District of Pennsylvania opened an investigation into whether drug manufacturers such as Sanofi SA previously knew about dangerous levels of NDMA contamination found in the popular heartburn drug Zantac and its generic equivalent, ranitidine. The probe is also investigating whether the manufacturers failed to disclose this information to the federal government.

In July 2020, Sanofi and GlaxoSmithKline (GSK) released Securities and Exchange Commission (SEC) filings stating that they received civil investigative demands from the DOJ in June 2020 requesting information on Zantac. GSK stated, “On 18 June 2020, the Group received a Civil Investigative Demand (CID) from the US Department of Justice (DOJ) seeking information related to Zantac pursuant to the False Claims Act…The Group is co-operating with the DOJ to provide this information. Additionally, on 18 June 2020, the New Mexico Attorney General filed a lawsuit against multiple defendants, including GSK, relating to Zantac and other products containing ranitidine.”

The investigation comes after the FDA set the maximum human daily exposure limit to NDMA at 96 nanograms, but testing by the independent pharmacy Valisure in 2019 revealed more than 3 million nanograms of NDMA in 150mg Zantac pills. Subsequently, the FDA announced a global recall for ranitidine-based medications on April 1, 2020.

How GoldenbergLaw Can Help You

GoldenbergLaw is currently representing clients who have been diagnosed with cancer after taking Zantac or ranitidine products. The Zantac Recall Attorneys at GoldenbergLaw have over 30 years of experience delivering justice to victims of corporate negligence. If you are interested in learning more about a Zantac recall lawsuit, contact us today for a free consultation. Let us deliver the Gold standard advocacy you deserve.


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