Mitigation Strategies for Nitrosamine Drug Substance Related Impurities: A Practical Framework for the Pharmaceutical Industry
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Abstract
Background: The regulatory challenge of nitrosamine drug substance related impurities (NDSRIs) has arisen because of the detection of carcinogenic nitrosamines in many well-known drugs, including valsartan, ranitidine and metformin. Such impurities are associated with raw material, excipients, solvents, packaging and formulation and storage conditions. While there is guidance from regulatory authorities like the EMA, FDA and ICH, existing guidelines are broad and lack standardized approaches for manufacturers to implement risk mitigation strategies.
Methods: This study combines a systematic literature review (drug recalls and published case studies, 2018-2023 regulatory guidelines) with analysis of experimental observations regarding risk mitigation of NDSRIs to create a framework suitable for the industry. Four critical factors were recognized to be central elements of NDSRIs formation: amine sources from APIs, nitrite contamination in excipients or solvents, acidic pH, and high temperature during processing or storage (>50 °C). All these were the basis of the design of mitigation strategies that encompassed raw material selection, process control, excipient substitution, packaging design and storage optimization.
Results: A structured framework summarizing contamination sources and mitigation strategies and a stepwise flowchart of implementation. Case studies of the valsartan and ranitidine reformulation efforts show successful and unsuccessful mitigation strategies.
Conclusion: This paper proposes a model which the pharmaceutical industry can draw on to better foresee and control nitrosamine risks throughout the drug life cycle. The method will help companies comply with regulatory requirements as well as reduce patient exposure to risk and the risk of costly recalls.
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