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The present work addresses the systematic development, enhancement and application of highly sensitive analytical methods for the investigation of nitrosamine impurities in drug substances and drug products. It is demonstrated how these can be effectively brought to the point of application in the interaction of science and regulatory compliance in order to meet the highest standards of scientific and technical knowledge. As a first step, quality-by-design (QbD) principles are used to rapidly and systematically develop a robust and sensitive method. Due to the unique properties of supercritical fluid chromatography (SFC), this method is not only capable of separating ten pertinent nitrosamines and achieving detectability at trace levels, but also enables simultaneous analysis of the drug substances losartan, valsartan and their monographed related substances. Based on this work, it is demonstrated which advantages result from the high adaptability of the QbD development approach for the lifecycle of an analytical method. Thus analytical progression within the existing framework and design space is possible without a complete new development. For this purpose, accepted lifecycle management (LCM) principles are used to evolve the existing compound-specific method into a universally applicable method for nitrosamine determination. The published method is the only validated method to date that can simultaneously separate and detect at least 16 nitrosamines, regardless of the sample matrix. Based on this method, analytical results are subsequently presented from hundreds of marketed drug substance and drug product samples collected over a period of four years as part of the "nitrosamine crisis". In addition, a more sophisticated and standardized testing methodology is presented. It can be used not only to test for the presence of known nitrosamines, but also to investigate the formation of novel, drug-substance-related nitrosamines. These have recently become an increasing concern of the regulatory risk assessment process and hereby the dominant issue for pharmaceutical manufacturers and authorization holders. The present work essentially contributes to the detection and elucidation of known and novel potentially carcinogenic nitrosamines in drugs. It thus protects the health of patients, by enabling contaminated drugs to be withdrawn from the market and prevents novel nitrosamines to occur without knowledge of the responsible manufacturer. It therefore enhances the quality and safety of existing and new drugs. However, the outlined principles of method development, analytical lifecycle management and method application can also be applied to areas outside the trace analysis of nitrosamines or pharmaceutical quality control (e.g. in forensics, bio- and environmental analysis) and are generally applicable.