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

The U.S. Food and Drug Administration (FDA) has updated (Revision 1) its Guidance for Industry on Out-of-Specification (OOS) Results. The first version of the document was dated October 2006.

The guide follows a step-by-step approach consisting of three main phases for investigating OOS test results


The process outlined in the text follows quite closely the requirements laid out in 21 CFR part 211.


The definition of “OOS” has not changed.

«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

The revision of the guideline contains some formal adjustments from the previous version, and also focuses on updating references to other FDA relevant guidelines and regulatory requirements (USP chapters, CFR paragraphs, etc.)

In addition, the new text contains some clarifications or rewordings from the 2006 edition, the following changes are worth mentioning:

  • 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.”
  • Section V.B. – Cautions: has been divided into three subsections:
  1. Averaging results from multiple sample preparations from the original sample
  2. Averaging results from same final sample preparation
  3. Borderline results that are within specification

Both versions of the guideline can be downloaded from the FDA homepage.