FDA updates guidance on evaluating out-of-specification results for drugs

The US Food and Drug Administration (FDA) has revised its 16-year-old final guidance on procedures for reviewing out-of-specification (OOS) results in the laboratory, including the responsibilities of the analyst and supervisor in reporting these results.

FDA defines OOS results as “all test results that fall outside the specifications or acceptance criteria established in dug applications, drug master files (DMFs), official compendia, or by the manufacturer. The term also applies to all in-process laboratory tests that are outside of established specifications.”

The update contains minor editorial changes from the 2006 version, clarifies concepts on outlier results, and provides additional information on averaging results from the same final sample preparation. It also replaces the term “quality control unit” to the currently favored terminology “quality unit.”

The original version of the guidance was published 13 years after the 1993 U.S. v. Barr Laboratories decision, which requires companies to investigate any OOS results before conducting any retesting.

On outlier results, the revision states that “occasionally, an outlier test may be of some value in estimating the probability that the OOS result is discordant from a data set, and this information can be used in an auxiliary fashion, along with all other data from the investigation to evaluate the significance of the result.”

The previous version said discordant results “can be used solely in an informational capacity in the course of an investigation to determine the distance of a result from the mean.”

A new subsection of the guidance on averaging results from same final sample preparations explains that “there may be cases where the test method specifies appropriate acceptance criteria for variability and a pre-defined number of replicates from the final diluted sample solution to arrive at a result.”

“For example, an HPLC test method may specify both acceptance criteria for variability and that a single reportable result be determined by averaging the peak response from a number of consecutive, replicate injections from the same test vial. In these cases, and given the acceptance criteria for variability are met, the result of any individual replicate in and of itself should not cause the reportable result to be OOS,” the guidance states.

A firm’s inability to adequately test failing batches has been a recurring theme in many FDA warning letters to pharmaceutical manufacturers. A recent warning letter cited Indian drugmaker Aurobindo for inadequately investigating batch failures. (RELATED: Aurobindo warned for lax investigations, repeated GMP violations, Regulatory Focus 26 January 2022)

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FDA updates guidance on evaluating out-of-specification results for drugs

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