Out of Specification &Out of Trend Investigations (MHRA)
Investigations of “Out of Specification (OOS) / Out of Trend (OOT)/ Atypical results” have to be done in cases of:
- Batch release
testing and testing of starting materials.
- In-Process Control testing: if data is used for batch calculations/decisions and if in a dossier and on Certificates of Analysis.
- Stability studies on marketed batches of finished products and or active pharmaceutical ingredients, on-going / follow up stability (no stress tests)
- Previous released batch used as reference sample in an OOS investigation showing OOS or suspect results.
- Batches for clinical trials.
All solutions and reagents should be retained until all data has been second person verified as being within the defined acceptance criteria.
Pharmacopoeia have specific criteria for additional analyses of specific tests (i.e. dissolution level specification for S1, S2 & S3 testing; Uniformity of dosage units specification for testing of 20 additional units; Sterility Testing).
However, if the sample test criteria are usually the first level of testing and a sample has to be tested to the next level this should be investigated as it is not following the normal trend.
The OOS process is not applicable for In-process testing while trying to achieve a manufacturing process end-point i.e. adjustment of the manufacturing process. (e.g. pH, viscosity), and for studies conducted at variable parameters to check the impact of drift (e.g. process validation at variable parameters).
Out-of-Specification (OOS) Result –
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 –
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.