In today’s blog, we want to create awareness that, after sixteen years, in May of 2022, the FDA has finally announced revisions to the 2006 guidance “Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production. (here). Specifically, this revision updates terminology for consistency with current FDA guidance, e.g., the quality control unit “QCU” is changed to the quality unit “QU” and clarifies concepts related to addressing outlier results and practices associated with averaging OOS results.

This guidance provides the FDA’s current thinking on evaluating OOS test results. The FDA recommended three different scenarios outlined in Section V “Concluding the Investigation,” subsection B, “Caution.”

  1. Averaging results from multiple sample preparations from the original sample– Addresses potential sampling or sample preparation variability
  2. Averaging results from the same final sample preparation– Addresses potential instrument variability
  3. Borderline results that are within specification– Addresses potential batch formulation variability

The Agency clarified its current thinking on averaging results from the same final sample preparation for individual OOS results obtained from replicate injections from the same sample preparation vial in QC test methods (such as HPLC). For example, an HPLC test method may specify both acceptance criteria for variability. A single reportable result is determined by averaging the peak response from several consecutive replicate injections from the same test vial. In these cases (and given the acceptance criteria for the variability are met), the result of any individual replicate in and of itself should not cause the reportable result to be OOS. This is the first time the Agency openly recommends reporting average passing result from replicate results where individual replicate result could be OOS.

It can be visualized that the biggest challenge that a company will face are situations where they conceivably will be in more than one scenario; for example, scenarios 1 and 2, and how this new way of thinking will impact the current laboratory investigation system, laboratory information management system “LIMS”, and training.

Finally, in this guidance document, the term “OOS results” includes all test results that fall outside the specifications or acceptance criteria established in drug applications, drug master files, official compendia, or by the manufacturer. The term also applies to all in-process laboratory tests outside of established specifications.