The FDA Guidance for Industry, Investigating Out‑of-Specification (OOS) Test Results for Pharmaceutical Production, was published in October 2006 (here).  The pharmaceutical industry has had about 14 years to learn how to comply to this guidance.  A quick survey of recent Form 483s and Warning Letters would indicate that there is still much to be learned on how to comply with the current regulatory expectations for OOS investigations.  What is the “root cause” for this slow learning progress?  It is my belief that it is likely performing investigations with the wrong goal in mind.  If the main goal of the investigation is to simply complete the SOP-mandated OOS investigation, then a truly thorough investigation is an unlikely result.

The goal of the investigation should focus on the conclusive identification of the root cause for the OOS result.  The identification of the root cause will likely require “critical thinking” skills and appropriate hypothesis testing.  Although a well-written compliant OOS SOP is vital to the investigation process, it by no means ensures an adequate investigation.  An OOS investigation must be timely, and, to be adequate, contain  three main elements:  conclusive root cause identification, thorough impact assessments, and identification of effective CAPAs.

Impact assessment and effective CAPAs are contingent on the conclusive root cause identification.  So again, the focus must be on “root cause”.  Every effort and the best subject matter experts should be applied to establishing the true root cause for OOS results.  Once the focus is on root cause identification and not batch disposition, the lessons learned will lead to effective CAPAs and fewer future OOS events.

Until the concept of learning from OOS investigations and engaging in continuous improvement activities is embraced, regulatory observations for OOS investigations will continue.  Just what have we learned in the past 14 years?

“By seeking and blundering we learn.” ― Johann Wolfgang von Goethe

For further information and assistance on the topic of thorough OOS investigations, please contact either Ron George, Ph.D. at or Mary Oates, Ph.D. at