FDA Updates Guidance on Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production

In May 2022, the U.S. Food and Drug Administration (FDA) has published a new version (Revision 1) of its Guidance for Industry on Out-of-Specification (OOS) Results. The original version of the document was published almost 16 years ago, in October 2006.


The definition of "OOS" has not changed.

According to the FDA, "for purposes of this document, the term OOS results includes all test results that fall outside the specifications or acceptance criteria established in drug 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."

Comparison with the 2006 version

Compared to the 2006 version, the following adjustments have been made:

  • Minor editorial changes
  • The term "quality control unit (QCU)" was replaced by "quality unit (QU)"
  • Addition and update of references in the body text and footnotes to refer to the latest version of other relevant guidelines, USP chapters, CFR paragraphs, etc.

In addition, the following changes are worth mentioning:

In section IV.C.2., the wording on "Outlier Tests" has been amended as follows:

  • Version October 2006: "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."
  • Version May 2022: "Occasionally, an outlier test may be of some value in understanding how discordant from a data set a result is, but can be used solely in an informational capacity in the course of an investigation to determine the distance of a result from the mean."

In section V.B., two subheadings

  • 1. Averaging results from multiple sample preparations from the original sample and
  • 3. Borderline results that are within specification)

have been added to the existing text. In between, a new subsection

  • 2. Averaging results from same final sample preparation

was added, stating 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."

Download the Guidance

The final guidance document (Revision 1, May 2022), as well as the original version from 2006, can be downloaded from the FDA homepage. As ECA member you will also find a direct comparison of old and new guidance in the ECA Website members' area.

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