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28 Pharmaceutical Technology REGULATORY SOURCEBOOK MARCH 2021 P h a r mTe c h . c o m Quality Collaboration S ince 2018, when N-nitrosamine (NA) contamination was detected in commonly prescribed medications, the formation, reaction, removal, and mutagenicity of NAs have come under increased scrutiny by regulators, patients, and the bio/pharmaceutical industry. Working groups within the IQ Consortium (IQ) engaged the expertise of member companies to determine how established industry standards might be applied to better understand the risk that NAs pose to the pharma supply chain, and to provide guidance on develop- ing acceptable limits for these potentially genotoxic compounds. These efforts focused on the following: • The formation of NAs during small-molecule synthesis and drug-product manufacturing • The subsequent reaction or removal of NAs when formed • The complexity of measuring NAs at very low levels • The risk of NA forming during drug product packaging. Assessing the scope of problem Pharmaceutical companies and regulators are most concerned about the potential for NAs to be present as low-level contam- inants in drug products (1–3). They were first detected in sar- tans, and their source was traced to the chemical synthesis of the tetrazole ring system, specifically to the reaction of trace 2° amine contamination with sodium nitrite, used as a quenching agent under acidic conditions, in the manufacturing process. NA contamination has also been detected in pioglitazone, ranit- idine, nizatidine, and metformin. International Council for Harmonisation (ICH) M7(R1) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk considers NA compounds to be part of the cohort of concern, which means that NAs can be highly potent animal carcinogens (1–2). The standard limits set by ICH M7 for mutagenic impurities, such as the threshold of toxicological concern, may require tight- ening for certain nitrosamines. Since NA contamination was first found in medicines, mul- tiple regulatory agencies have begun to require risk assessments for the presence of NAs in marketed products. These assess- ments must be completed in extremely short time-periods. The Timothy Curran and J.P. Bercu; both authors are members of the IQ Consortium. PAULISTA - STOCK.ADOBE.COM Managing the Risk of Nitrosamine Impurities Collaborative industry efforts have shed light on ways industry standards can help pharma companies better understand the risks nitrosamines pose to the supply chain. IQ Consortium working groups have engaged in ongoing efforts to evalute risk models and guidance documents to help increase pharma industry knowledge about these impurites.