FDA Warning Letter: Outlier Test inadequate for OOS Investigation

The FDA's Warning Letter issued to the Chinese API manufacturer Zhuhai United Laboratories Co. Ltd. dated 27 June 2018 underlies an inspection performed by the FDA in September 2017. The FDA particularly criticized the insufficient investigation of the divergent analysis results.

Two initial OOS results of two batches haven't been investigated appropriately. In one case, the result was even significantly below the specification. In both cases, according to the company's brief investigation there were no anomalies and it was stated that possibly the "sample glassware was not thoroughly cleaned". Although Zhuhai United identified no lab error and provided no scientific justification, both OOS results have been invalidated and the batches released due to passing retests.

Furthermore, the initial OOS result of a residual solvent test hasn't been adequately investigated. Another sample preparation has been tested three times. All the three results were very close to the specification upper limit. Zhuhai United invalidated the initial OOS result and declared that the statistical analysis showed a significant difference between the original value and the retest results.

According to the FDA, it is not allowed to use outlier tests to invalidate test results. Such statistical tests cannot identify the cause of an extreme observation. Outlier tests can only be used for informational purposes. The OOS SOP of Zhuhai United has to be accordingly revised with regard to the non-use of outlier tests.

Please also see the FDA's complete Warning Letter to Zhuhai United Laboratories.