Out of Specification Investigations Guidance - What You Need to Know

The US Food and Drug Administration (FDA) and the UK Medicines and Healthcare Regulatory Agency (MHRA) both publish Out of Specification Investigation Guidance documents for the pharmaceutical industry.

Both regulatory bodies' guidances specify investigation processes that are virtually the same, with only minor changes that do not have a significant impact on the common approach being pushed. Following the procedures outlined in either is considered to be compliant with both, though it is helpful to be aware of the minor distinctions.

Sustainable Compliance for Out of Specifications (OOS) Results, Deviations, and Corrective and Preventive Actions (CAPA)

The investigation approach should be the same for analytical results that are OOS, or indeed for any result that is outside the regular pattern of results, according to both US and UK regulations (often referred to as atypical results). It is critical that findings be trended in some form in order to identify OOT and anomalous results. This is usually performed by plotting release test results on a control chart, and for stability program outcomes by plotting the regression line.

FDA Guidance MHRA Guidance
The FDA's "Guidance for Industry Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production - October 2006" may be found at Investigating Out-of-Specification Test Results for Pharmaceutical Production | FDA Click here to access the MHRA "Out of Specification Investigations" Guidance.
Wherever an OOS result is generated, an OOS investigation must be completed. The goal of an investigation like this is to figure out what's the root cause of the OOS. The goal of the entire investigation process is to figure out what is causing the anomaly in the first place.

An OOS/OOT investigation must be conducted for following reasons:

  • Batch release testing and testing of starting materials.
  • If data is used for batch calculations/decisions, and if in the dossier or on the Certificate of Analysis, IPC testing is performed.
  • Stability studies for final products and/or APIs that have been launched.
  • A reference sample is taken from a previously released batch.
  • Batch for clinical trials.

According to the MHRA Guide, the three types of investigations are:

Out-of-Specification (OOS) Result -

  • Test result that does not comply with the pre-determined acceptance criteria (i.e. for example, filed applications, drug master files, approved marketing submissions, or official compendia or internal acceptance criteria).
  • Test results that fall outside of established acceptance criteria which have been established in official compendia and/or by company documentation (i.e., Raw Material Specifications, In-Process/Final Product Testing, etc.).

Out of Trend (OOT) Result -

  • Is generally a stability result that does not follow the expected trend, either in comparison with other stability batches or with respect to previous results collected during a stability study. However, the trends of starting materials and in-process samples may also yield out of trend data.
  • The result is not necessarily OOS but does not look like a typical data point.
  • Should be considered for environmental trend analysis such as for viable and non viable data (action limit or warning limit trends)

Atypical / Aberrant / Anomalous Result -

  • Results that are still within specification but are unexpected, questionable, irregular, deviant or abnormal. Examples would be chromatograms that show unexpected peaks, unexpected results for stability test point, etc.


There are a few exceptions in the guide where OOS/OOT investigations are not required. This is most common with pharmacopoeial tests, which include pre-defined additional testing levels.

  • Dissolution Testing - S1, S2
  • Uniformity of Dose - test additional 20 dosage units
  • In-process testing while trying to achieve a manufacturing process end-point e.g. pH
  • Studies conducted at variable parameters to check impact of drift e.g. process validation exercises

However, authorities advise caution and state that if first-level testing is regularly passed, such tests may need to be investigated as OOT.