Nitrosamine in drug products: an open discussion

The context


Nitrosamines have become a focus of global regulatory agencies, including FDA, due to the discovery of trace amounts of these compounds in a class of drugs known as angiotensin II receptor blockers (ARB), frequently referred to as “sartans.” The “sartan” molecules involved include valsartan, losartan, irbesartan, azilsartan, olmesartan, eprosartan, candesartan, and telmisartan. Valsartan and losartan were the most severely affected due to their market share when several lots were recalled.

The genotoxic and carcinogenic potential of N-nitrosamines raises a serious safety concern, and in September 2020, the FDA issued guidance for the pharmaceutical industry regarding the control of nitrosamines in drug products.

The FDA database shows that >1400 product lots have been recalled from the market due to the presence of carcinogenic N-nitrosamine impurities at levels beyond the acceptable intake limit of 26.5 ng/day. The drugs that were present in recalled products include valsartan, irbesartan, losartan, metformin, ranitidine, and nizatidine. This perspective provides a critical account of these product recalls with an emphasis on the source and mechanism for the formation of N-nitrosamines in these products.

Many of the global regulatory authorities, including WHO, EMA and Health Canada have provided directives regarding evaluation of nitrosamines in products including complete retrospective analysis of all approved Drug Products (DPs) based on the strong concern of possible carcinogenicity effects on exposed patients and to mitigate such an effect.

Very recently, in February 2021, FDA release a draft guidance for Industry: Click here for the original document

The FDA Guidance for Industry gives suggestion to the industry on how to approach the assessment of the nitrosamine in drug active and drug products including some indication of acceptable limits for some of them as in the following figure:

Recommendation to API manufactures and to Drug Products manufacturers are included to mitigate the impact of nitrosamine impurities in drugs as well as how to control the drug supply chain and how to report changes to reduce their presence.

Since some years, Pharmaceutical Industry activated itself to study such a problem from an analytical point of view and provide toxicological assessment to reach possible acceptable level of nitrosamine species in a variety of drug product.

The industry proposes a streamlined approach to reduce the presence of nitrosamines in their Drug Products is based on better understanding of the source of these impurities. The risk evaluation will take into account all aspects of the development of the DPs throughout its life cycle.

Five sources of nitrosamines formation have been identified:

  • presence of certain process condition and certain raw materials, starting material and intermediates with lack of complete purging methods to avoid the contamination;
  • the use of sodium nitrite or other nitrites in presence of secondary and tertiary amines. They can be present in solvent and reagents or in common bass such as triethylamine;
  • the use of contaminated raw materials such us in the manufacturing process such as recycled solvents, reagents and catalyst that can pose a risk due to the presence of amines in the waste stream;
  • Using third parties to recover the materials (again solvents, reagents and catalysts) which are not addressed to pose attention to the contamination matter and do not use appropriate dedicated equipment;
  • the use of contaminated starting materials including intermediates from providers using chemical processes which produce nitrosamines.

The risk-based approach adopted by pharmaceutical industry is addressed to understand the chemical source of nitrosamines by evaluating the chemical process to manufacture the API (Active Pharmaceutical Ingredients) and any possible co-formulants.

This implies several focused evaluations:

  • a complete analysis of the supply chain/s;
  • a complete analysis of the chemical manufacturing processes;
  • a complete evaluation of the Drug Product, its storage condition, and possible degradation products and consequent reaction products when approaching the nitrosamine contamination in the final DP;
  • the development of suitable analytical methods to detect nitrosamines species with determination of a suitable LOD (Limit of Detection) and LOQ (Limit of Quantification) in correlation with the acceptable limits or absence of nitrosamine in API and DPs.

The discussion at the scientific and regulatory level is never-ending with particular reference to the setting of suitable analytical methods and to understand the huge chemical processes and cross-formation processes which lead to nitrosamines presence and, of course, setting of related acceptable limits.