Out of Specification Results

What happens when a firm obtains out of specification results?

21 CFR 211.192 states:

All drug product production and control records, including those for packaging and labeling, shall be reviewed and approved by the quality control unit to determine compliance with all established, approved written procedures before a batch is released or distributed. Any unexplained discrepancy (including a percentage of theoretical yield exceeding the maximum or minimum percentages established in master production and control records) or the failure of a batch or any of its components to meet any of its specifications shall be thoroughly investigated, whether or not the batch has already been distributed. The investigation shall extend to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy. A written record of the investigation shall be made and shall include the conclusions and followup.

In a recent warning letter – a firm was cited for invalidating out of specification results without adequate investigation and scientific justification.  The warning letter cited several examples where initial results were invalidated based on subsequent passing results without a thorough/scientific investigation.  For example:

The out of specification investigation identified a postulated cause of “poor column efficiency” yet the investigation identified no chromatographic abnormalities were noted and system suitability were met. As noted in the warning letter, “During the inspection, your lab management indicated that retention times, theoretical plates, and tailing factor appeared appropriate and no specific root cause had been demonstrated. You repeated the analyses, obtained passing results, and invalidated the OOS results.” (Para 1.a).

In a second instance it was suspected that the analysis may have incorrectly rinsed the HPLC vials.  As noted in the warning letter, “New samples prepared and tested by a second analyst using both the original column and a new column, as well as old and new vials, also yielded OOS results. Although you lacked sufficient evidence, your investigation concluded that the OOS results were due to sample vial contamination. You invalidated the OOS results after obtaining passing results from testing retain samples.” (para 1.a)

In each of the examples cited in the warning letter the investigation into the out of specification results was not expanded to examine potential manufacturing issues.  Of significant note in the warning letter the FDA states “When an investigation lacks conclusive evidence of laboratory error, a thorough investigation of potential manufacturing causes must be performed. Your acceptance of the passing results from testing a new set of samples based on an unproven hypothesis was insufficient to conclude the investigations.” (para 1.b)

Identification of an out of specification result may be the result of analyst or analysis error and where appropriate the results may be invalidated.  However, when the laboratory investigation infers that the equipment was working properly (first example) or when the analysis are repeated by a second analyst obtaining the same result (second example) the investigation needs to move out of the QC lab and into other areas (manufacturing).  The analytical results in these examples may have identified variation in raw materials, equipment that is no longer operating as expected, shifts in process, or the introduction on a new source of variation – which is a good thing and an expectation of the QC lab’s role.  What this firm observed (but apparently failed to act upon) is the goal of stage 3 of the FDA guide to process validation – through analyzing product and process data that relate to product quality to provide continual assurance that the process remains in a state of control (the validated state) during commercial manufacture, and to analyze this data to detect undesired process variability.

How different might the inspection have gone if the firm would have been able to explain to FDA that we monitored the process, identified an out of specification result, verified the lab resuts were correct, and identified issue X, Y, Z that resulted in superpotent drug content in manufacturing lots A, B, C.

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