Approaches and Considerations for the Investigation and Synthesis of N-Nitrosamine Drug Substance-Related Impurities (NDSRIs)

Abstract

N-Nitrosamine risk assessment of pharmaceuticals has moved from an initial focus on the potential presence of known small-molecule N-nitrosamines such as N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) in active substances toward the potential for generation of more complex nitrosamine drug substance-related impurities (NDSRIs) in drug products. While N-nitrosation of simple secondary amines is well-understood, more complex amines can undergo alternative reaction pathways that can be more challenging to predict. A number of such complex amines are known not to undergo N-nitrosation but are either unreactive or react by alternative pathways such as C-nitrosation or nitration to generate non-N-nitrosamine products. This article proposes a standard set of three orthogonal nitrosation forced degradation type reaction conditions that can be used to investigate the potential for generation of novel N-nitrosamines by nitrosation of complex amines. These complementary reaction conditions are considered to provide a thorough evaluation of the potential for N-nitrosamine formation from complex amines with respect to risk factors within pharmaceutical manufacturing. If, after investigation of nitrosation under the proposed conditions, formation and isolation of an N-nitrosamine is not possible, the resultant understanding of chemical reactivity and stability can be used to justify that the N-nitrosamine in question would not be expected to be generated from the complex amine in the drug substance or product. If an N-nitrosamine is formed under these reaction conditions, the information gained can be used as part of the risk assessment and also provides a starting point for the development of a process to synthesize a discrete sample for further testing. Additionally, synthetic and analytical considerations that should be taken into account during preparation of novel N-nitrosamines for use in analytical or toxicological studies are discussed.

Risk Assessment and Control of N-Nitrosamines in Antibody–Drug Conjugates: Current Industry Practices

“…The cases where risks were identified in the drug-linker synthesis were associated with simple N -nitrosamines. However, given the increased attention now being paid to NDSRIs and efforts to increase the structural diversity of drug payloads in ADCs, it can be anticipated that scrutiny of NDLRIs may become more prominent in the future.…”

Synthesis and Trace-Level Quantification of Mutagenic and Cohort-of-Concern Ciprofloxacin Nitroso Drug Substance-Related Impurities (NDSRIs) and Other Nitroso Impurities Using UPLC-ESI-MS/MS─Method Optimization Using I-Optimal Mixture Design

“…Due to the increase in business opportunities and demand for commercial standards, suppliers have been covering more commercial standards over the past few months. However, the list of NDSRIs is quite large; therefore, it requires a lot more time to cover all of them . Hence, we synthesized the COX-NDSRI- and COX-related N-nitrosamine impurities from the COX drug substance.…”

Nitrosamine impurities in pharmaceutical dosage forms: Current challenges and mitigation strategies

“…Regularly test raw materials, in-process samples and finished products to ensure compliance with regulatory limits and identify any potential sources of contamination. [40] Optimization of process: Modifying manufacturing processes to minimize or eliminate the formation of nitrosamine impurities is a critical mitigation strategy. This may involve adjusting reaction conditions, using alternative reagents optimizing the process to minimize the potential for nitrosamine formation.…”