FDA Releases Nearly 300 Complete Response Letters in 2025 – CMC Issues Found to Be the Main Reason for BLA/NDA Rejection

In the second half of 2025, FDA posted nearly 300 previously unpublished Complete Response Letters (CRLs) from the years 2014 – 2024. An analysis of the first 202 CRLs (published by the FDA in July 2025) showed that CMC deficiencies, (which include QA/QC issues), accounted for the vast majority of market application rejections. Of all rejections, 74% were due wholly or partially to CMC inadequacies. Facility inspection issues were the primary problem, followed by impurity qualification and process control strategy deficiencies.

CMC Regulatory Services will be looking more closely at the CMC causes of FDA’s application rejections since 2014. Keep watch for future articles focusing on CMC strategies to help companies proactively prevent application derailment.

For more details on the analysis of these published CRLs, see “De-Risking Regulatory Submissions – Lessons from 202 FDA CRLs” by Byron Fitzgerald.