Strategic impurity control is pivotal to the safety, efficacy, and regulatory success of next-generation pharmaceutical products. This systematic review underscores the novelty of integrating advanced analytical technologies, toxicological risk assessment paradigms, and global regulatory frameworks into a unified approach. Emphasis is placed on the strategic integration of tools such as liquid chromatography–mass spectrometry (LC-MS), ultra-performance liquid chromatography (UPLC), high-resolution mass spectrometry (HRMS), and inductively coupled plasma mass spectrometry (ICP-MS), which have transformed impurity profiling by enabling highly sensitive detection and structural elucidation—particularly of genotoxic impurities like nitrosamines. Toxicological evaluation has similarly evolved through risk-based models including the threshold of toxicological concern (TTC), quantitative structure–activity relationships (QSAR), read-across, and predictive in silico modeling. The review critically examines the role of regulatory strategies, especially the implementation of Quality by Design (QbD) principles and alignment with ICH guidelines such as Q3A–Q3C and M7, which collectively emphasize the need for integrated, science-driven impurity control. Synthesizing literature from analytical chemistry, regulatory science, and toxicology, this work identifies emerging challenges and opportunities for harmonization. Recommendations include enhancing predictive toxicology databases, fostering alignment of analytical and toxicological workflows, and promoting global regulatory convergence to streamline impurity control practices. By presenting an integrative roadmap, this review advances the concept of strategic impurity control as a cornerstone of innovation and patient safety in pharmaceutical development.
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