CMC Deficiency Patterns in ANDA Review: A Systematic Review of Regulatory Expectations in Healthcare

With a focus on the underlying causes and the changing regulatory landscape, this systematic review examines the trends of chemical, manufacturing, and controls (CMC) deficiencies in the 2020-2025 ANDA cycles. By examining twelve peer-reviewed studies, the review concludes that chemistry deficiencies account for approximately 34% of total ANDA deficiencies. Root causes of deficiency include manufacturing process controls, drug product, stability data, and bioequivalence. The importance of quality by design, digital manufacturing, and data management is emphasized as key drivers of deficiency patterns and approval efficiency. First-cycle approval rates are still low due to a lack of process understanding, insufficient scientific justification, insufficient documentation, and resource limitations as primary root causes. There is clear evidence that active quality risk management, early regulatory interactions, advanced analytics, and cross-functional collaboration can drive deficiencies down and approval efficiency up. The review also points out seven research gaps that require further research to move the frontiers of regulatory science and generic drug development.