Warning Letter of the Week: non-uniformity edition

A love note for the CEO of Mylan Pharmaceuticals from the Center for Drug Evaluation and Research:

2. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192). 

Your investigations into out-of-specification (OOS) results and process deviations were inadequate. Root causes did not consistently include scientifically supported conclusions.... 

B. Your firm opened two manufacturing investigation reports, No. 1071629 on December 12, 2016, and No. 1106258 on January 25, 2017, to investigate atypically high assay and high variability content uniformity results for three batches of prednisolone sodium phosphate 10 mg orally disintegrating tablets (ODT). The investigations identified a root cause of untrained or inexperienced operators [redacted]. The investigation did not fully evaluate the processing factors that contribute to variability in your finished tablets. In particular, it did not evaluate the inherent variability of the [redacted] method used for charging [redacted], and identify more robust methods for performing this critical transfer that could prevent blend segregation and tablet dose non-uniformity. It also did not ensure improvements were adequately specified in batch records to enable an ongoing state of control. We acknowledge your firm’s market recall on April 30, 2018, of all batches of prednisolone sodium phosphate ODT within expiry from the U.S. market. 

C. Your firm opened multiple manufacturing investigation reports and trending assessments from July 2016 to October 2017 related to out-of-trend and OOS content uniformity results for metolazone 2.5 mg tablets. A scientifically justified root cause had not been identified, and effective CAPA plans had not been implemented. Despite substantial non-uniformity observed in multiple batches of metolazone 2.5 mg tablets, you continued to manufacture and release this drug product up to the time of the inspection.

I don't know anything about tableting, but I bet that non-uniformity isn't a fun problem to solve.