Warning Letter for systematic invalidating of OOS Results

Warning Letters are bothersome for the companies receiving them and usually force them to make elaborate adjustments to their GMP relevant processes. Thanks to the Freedom of Information Act, the publicly available Warning Letters provide outsiders with a wealth of information regarding the issues FDA inspectors pay special attention to and show what traces they pursue in order to uncover GMP deficiencies. The Warning Letter issued to Lupin Limited, an Indian pharmaceutical manufacturer, is particularly instructive in that respect.

The inspection took place at two different production sites. Inspectors found violations of GMP regulations at both facilities, concerning the handling of OOS results and bulk hold times. The individual deficiencies are described as follows:

Invalidating of OOS results

The release testing of an active pharmaceutical ingredient (API) intended for further processing showed the assay result to be out of specification. Instead of declaring this an OOS result and initiating a root cause analysis, the analyses were repeated with new samples, the improved values were used as release criteria and the original OOS result was declared an outlier result. After the inspector looked at the individual values, he concluded that such invalidating of an OOS result and its reinterpretation as an "outlier result" by dubious statistical methods is to be considered a GMP violation.

This procedure was practiced at the QK laboratories of both facilities.

The test for content uniformity of tablets delivered an OOS result, due to which an investigation in the laboratory had been initiated. It was clear after this investigation that the reason for the OOS result could not be found in the laboratory, since they apparently operated correctly there. The OOS results were still annulled with a reference to "laboratory errors", on the grounds that another set of tablets had passed the content uniformity test and therefore, the original OOS result had to have been due to a laboratory error.

The inspector's assessment was unmistakeable in this case: if an error in quality control can be ruled out, a root cause analysis must be conducted in the production area. Such indirect reasoning for eliminating (bothersome) OOS results is not permissible from a GMP point of view.

Exceeded bulk hold times

The bulk hold time for tablets intended for further processing was exceeded considerably with no corresponding data from stability studies. Samples of the end product were only occasionally tested for stability, if at all. The storing conditions for bulk samples were not representative for the conditions under which the bulk ware was stored in the production area. This clearly contradicted an SOP on "Hold Time Study", which was not followed.

Due to the risk of physical properties (moisture levels, aggregation of particles, etc.) changing and quality deficiencies emerging as a result, the inspector rated the bulk storage as critical.

This procedure was also criticised at both facilities.

The practice of invalidating OOS results is not new at Lupin Limited. The most recent Warning Letter makes a reference to this in a separate paragraph ("repeat observations at multiple sites") and cites two earlier Warning Letters describing the very same GMP violations.

For further information please see the FDA Warning Letter to Lupin Limited.

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