KRAS G12C Inhibitors: Analytical Quality Control, HPLC Assay and Related-Substance Profiling, and CMC Regulatory Expectations

This is a narrative review built entirely from public regulatory guidance and published analytical literature. It is written as an educational exercise in regulatory affairs scholarship, illustrating how a careful reviewer distinguishes between different categories of published analytical evidence, bioanalytical, drug-substance, and drug-product, and how each category is properly understood and cited within its own scope. The review treats this careful distinction as the core skill it is demonstrating, rather than as a critique of any single piece of published work. Adagrasib is an oral, small-molecule inhibitor of KRAS G12C used in biomarker-defined oncology settings, and its public scientific record offers a rich case for studying how analytical chemistry, pharmaceutical quality science, and international regulatory frameworks fit together. High-performance liquid chromatography (HPLC) is a central platform in pharmaceutical quality control, and this narrative review discusses how reversed-phase HPLC (RP-HPLC), photodiode-array detection, and orthogonal techniques contribute to a well-constructed analytical strategy for a small-molecule oncology tablet generally, using adagrasib as the illustrative case. It summarizes risk-based analytical procedure development under ICH Q14, validation under ICH Q2(R2), degradation-product control under ICH Q3B(R2), stability principles under ICH Q1A(R2), and the placement of supporting information in CTD Module 3. Published LC-MS/MS methods for measuring adagrasib in biological matrices, together with a published, fully validated stability-indicating HPLC method for adagrasib drug substance with degradation-product characterization, demonstrate a genuinely active and rigorous body of public analytical science on this molecule. This review brings that literature together clearly, distinguishes each study's specific analytical purpose, and models the kind of disciplined, properly cited regulatory affairs writing that the review itself is intended to exemplify.