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<p>The rigorous identification, quantification, and control of impurities are fundamental to ensuring the safety, efficacy, and quality of pharmaceutical products throughout the drug development lifecycle. As unavoidable byproducts of complex synthesis and manufacturing processes, impurities span a diverse range of compounds—including organic, inorganic, residual solvent, and genotoxic species—all of which require meticulous characterization using a suite of analytical techniques. This review synthesizes best practices for impurity classification, source mapping, and alignment of control strategies with global regulations (ICH Q3A/B, Q3C, Q3D, and M7), distinguishing phase-appropriate profiling, stress testing, and fully validated, stability-indicating methods. Advanced structural-elucidation tools (LC–MS/MS, HRMS, NMR) are surveyed alongside key strategies for lifecycle change management. Special emphasis is placed on mutagenic impurities, especially nitrosamines, highlighting how recent industry experience and regulatory actions have reshaped risk management and analytical sensitivity requirements. The discussion extends to emerging trends—green analytical chemistry, AI-driven prediction and interpretation, and real-time monitoring via Process Analytical Technology (PAT) and Real-Time Release Testing (RTRT)—that are redefining impurity control from reactive detection to proactive prevention. Collectively, this review provides scientists, regulators, and quality professionals with actionable frameworks for robust impurity management, facilitating compliance and accelerating pharmaceutical development.&#xa0;</p>

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Impurity Characterization Across Drug Development Stages: Analytical Methodologies and Regulatory Perspectives

  • 期刊论文

  • 发表日期：

    2026年3月3日

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  • Subathra Ramamoorthy

摘要

The rigorous identification, quantification, and control of impurities are fundamental to ensuring the safety, efficacy, and quality of pharmaceutical products throughout the drug development lifecycle. As unavoidable byproducts of complex synthesis and manufacturing processes, impurities span a diverse range of compounds—including organic, inorganic, residual solvent, and genotoxic species—all of which require meticulous characterization using a suite of analytical techniques. This review synthesizes best practices for impurity classification, source mapping, and alignment of control strategies with global regulations (ICH Q3A/B, Q3C, Q3D, and M7), distinguishing phase-appropriate profiling, stress testing, and fully validated, stability-indicating methods. Advanced structural-elucidation tools (LC–MS/MS, HRMS, NMR) are surveyed alongside key strategies for lifecycle change management. Special emphasis is placed on mutagenic impurities, especially nitrosamines, highlighting how recent industry experience and regulatory actions have reshaped risk management and analytical sensitivity requirements. The discussion extends to emerging trends—green analytical chemistry, AI-driven prediction and interpretation, and real-time monitoring via Process Analytical Technology (PAT) and Real-Time Release Testing (RTRT)—that are redefining impurity control from reactive detection to proactive prevention. Collectively, this review provides scientists, regulators, and quality professionals with actionable frameworks for robust impurity management, facilitating compliance and accelerating pharmaceutical development.