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Nitrosamine Impurities: A Regulatory Perspective

In July 2018, the European medicines regulatory network became aware of the presence of nitrosamine impurities in an Active Pharmaceutical Ingredient (API). This was the first time that a nitrosamine impurity had been detected in a pharmaceutical drug. The unexpected delivery of these impurities resulted in voluntary product recalls on a mass scale and led to regulatory warnings and fuelled the need for a proactive approach to risk assessment and mitigation in relation to genotoxic contaminants. Following this, the European Medicines Agency (EMA) had provided guidance to marketing authorization holders to avoid the presence of nitrosamine impurities in human medicines.

What are nitrosamines?

Nitrosamines, also referred to as N-nitrosamines are a family of carcinogen impurities that occur in water and food including cured and grilled meats, dairy products, and vegetables. Technically, nitrosamines refer to any molecule containing the nitroso functional group. They are of concern because nitrosamine impurities are probable human carcinogens. Nitrosamines are common chemicals and everyone is exposed to some level of nitrosamines in daily life and it doesn’t cause any harm when ingested at low levels. But nitrosamine impurities may increase the risk of cancer if people are exposed to them above acceptable levels and over a long period of time. So, the presence of nitrosamines in medicines is nonetheless considered unacceptable.

Discovery of nitrosamine impurities in Active Pharmaceutical Ingredients (API)?

Although nitrosamine impurities were already recognized as environmental contaminants and have been found in water and food in small quantities, their presence in APIs was an unexpected and shocking discovery. In 2018, The European Medicines Agency (EMA), United States Federal Drug Administration (FDA) and Health Canada noted that N-nitrosodimethylamine (NDMA) was found in products containing Valsartan API. Valsartan is an antihypertensive agent belonging to the class of Angiotensin II Receptor Blocker (ARB). This was soon followed by the discovery of a few other nitrosamine impurities such as N-nitrosodiethylamine (NDEA), Nitroso-N-methyl-4-aminobutyric acid (NMBA). The presence of these nitrosamine impurities such as NDMA, NDEA, and NMBA in human drug products is unacceptable because they are all probably human carcinogens and even at low levels in drug products, they pose a serious threat to human health.

Daily intake limits set by regulatory agencies

The threat posed by these nitrosamine impurities that are identified in the Active Pharmaceutical Ingredients (API) made it clear that the manufacturers needed to adopt a proactive approach to mitigate the risk of their presence in drug products. So, regulatory agencies like United States Federal Drug Administration (FDA) have set acceptable limits for nitrosamine impurities in relation to drug products. The United States Federal Drug Administration (FDA) and European Medicines Agency (EMA) published the acceptable daily intake limits for these nitrosamine impurities. They are.

  • N-nitrosodimethylamine (NDMA) – 96 ng/day (nanogram per day)
  • N-nitrosodiethylamine (NDEA) – 26.5 ng/day (nanogram per day)
  • Nitroso-N-methyl-4-aminobutyric acid (NMBA) – 96 ng/day (nanogram per day)

Risk assessment of Presence of nitrosamine impurities in Active Pharmaceutical Ingredients and Drug Products

The European Medicines Agency (EMA) recently finalized the guidelines to marketing authorization holders on how to avoid the presence of nitrosamine impurities in drug products used by humans. The marketing authorization holders should review and assess their manufacturing processes for all drug products containing biologically active or chemically synthesized substances to avoid the presence of nitrosamine impurities in human medicines. 

The European Medicines Agency (EMA) has asked the marketing authorization holders and the manufacturer of drug products to consider these three possible sources of nitrosamine impurities.

  • Active Pharmaceutical Ingredients (API) synthetic route- Formation of nitrosamine impurities during the API synthetic process.
  • The manufacturing process- Formation of nitrosamine impurities during the manufacture of drug products or during shelf life.
  • Contamination- Formation of nitrosamine impurities due to contamination from equipment degradation, recovered materials such as solvents, reagents, catalysts, and intermediates.

Risk assessment process:

Step 1- Risk evaluation

The marketing authorization holders should conduct a risk evaluation that identifies if products are at risk of N-nitrosamine formation. If the risk is identified for an active substance, proceed for Step 2. If no risk is identified for an active substance, the marketing authorization holders or manufacturers should conduct a risk evaluation of the finished product and report these findings to concerned authorities

Step 2- Confirmatory testing 

The marketing authorization holders must perform further confirmatory testing on the products that are identified to be at risk of N-nitrosamine formation or contamination/ cross-contamination and are required to report the confirmed presence of the impurity as soon as possible to the authorities. It is to be noted that the analytical methods for confirming the presence of N-nitrosamine formations are validated and appropriately sensitive to the Active Pharmaceutical Ingredients (API) and all testing is conducted in a GMP compliant facility. The analytical methodology chosen by the marketing authorization holder must be fully validated prior to confirmatory testing. The method validation must be performed using the drug product at the appropriate strength.

If the marketing authorization holders identify the presence of nitrosamines in the drug product, proceed to Step 3. If no nitrosamines are detected report your results to the regulatory authority.

Step 3- Corrective actions 

The marketing authorization holders should inform the concerned authorities (natural competent authorities for nationally authorized products or EMA for centrally authorized products) immediately if the tests confirm the presence of nitrosamine impurities even if it is present in trace amounts. Also assessing the immediate risk to patients and taking appropriate action to avoid the exposure of patients to nitrosamines is crucial.

The marketing authorization holder must apply the necessary changes to the manufacturing process to remove the nitrosamine impurity. If one or more nitrosamine impurities are detected, the manufacturer or the marketing authorization holder should:

  • Determine the origin of the nitrosamine impurity in the drug product.
  • Determine if product recalls are required.
  • Conduct quality investigations.
  • Identify the possible root cause of nitrosamine impurities and Corrective and Preventive Actions (CAPAs).
  • Determine whether potential changes to the process of equipment or facility will reduce the levels or risk of nitrosamine impurities.
  • Devise a risk mitigation plan to ensure levels remain below the acceptable limits.

The WHO, EMA, and national competent authorities continue to monitor and identify the presence of nitrosamine impurities in drug products, in cooperation with regulators from outside the European Union (EU), and work with marketing authorization holders to find rapid solutions to address any adverse findings. 

References:

  1. https://www.ema.europa.eu/en/human-regulatory/post-authorisation/referral-procedures/nitrosamine-impurities#guidance-for-marketing-authorisation-holders-sectionhttps://www.ema.europa.eu/en/human-regulatory/post-authorisation/referral-procedures/article-53-opinions#nitrosamine-impurities-in-human-medicinal-products-containing-chemically-synthesised-active-pharmaceutical-ingredients-(updated-18-october-2019)-section
  2. https://www.fda.gov/drugs/drug-safety-and-availability/information-about-nitrosamine-impurities-medications
  3. https://www.who.int/medicines/publications/drugalerts/InformationNote_Nitrosamine-impurities/en/

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