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Detecting and Managing of OOT or OOE Results


The terms “Out of Specification Result” and “Out of Trend Result” are well defined in pharmaceutica industry. As per UK MHRA -

  • 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).
  • Out of Trend (OOT) Result – 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, 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.

This definition is extremely focused on stability studies, however, mentioning environmental trend analysis indicates that OOT results may also be observed during trend analysis for statistical process control.

To be considered an "Out of Expectation Result” or to be "discordant" there must be an expectation based on some evidence what would be the most likely outcome of the analytical process performed. This excludes any unusual result derived from analysing a sample with a totally unknown assay or content of the analyte in question. 

Two different cases might therefore be considered "Out of Expectation Results”:

1. Unexpected Variation in Replicate Determinations

Usual analytical practice will use a specific number of replicates - that is several discrete measurements to provide more accurate results. These may be either replicate injections from the same HPLC sample preparation, replicate readings or other multiple determinations. This procedure has to be specified in the written, approved test procedure together with the limits for variability (range and/or RSD) among the replicates. 

These could be based upon the process capability of the method as determined during the method development and its subsequent validation. However, usually companies use a general limit of the range of Δ ≤ 2.0 % for assays. In case of replicate series of complete tests (full run-throughs of the test procedure) wider limits for variability among the replicates may be defined.

Any unexpected variation in replicate determinations - either derived by multiple measurements of one sample preparation or replicate series of complete tests - disqualifies this data set from being used for further result calculation.

E.g. if the range between replicates is limited to Δ ≤ 2.0 % and the two replicates differ by 2.2 %, data generated from the analysis cannot be used. It is very important that the documentation accompanying the analysis is very clear about why the data sets have been rejected.

When unexpected variation in replicate determinations occurs, investigation into the cause is required similar to an investigation in the case of a non-compliant system suitability (SST) test. Usually this is reported as a laboratory deviation. The flow of the investigation may follow the proven approach of investigating an OOS result on a lab scale.

Repeating the test or measurement- preferable using the same sample preparation if appropriate - should not be performed prior to identifying a hypothesis why the replicates range was higher than expected and having taken corresponding actions.

2. Unexpected Results in a Single Test or a Small Set of Tests

Analytical results from one single performance of one test or from a small number of tests obtained over a short period of time may be considered "Out of Expectation" if -

  • The test result does not fit into the other results of that series, but the number of tests and data points is not comprehensive enough to allow statistical calculation whether the result belongs to a population to be expected from the mean and the variability of the overall data set.
  • The result does not violate a given specification.
  • There is enough evidence and information allowing to anticipate the "expected" result and thus to allow judgement that the result does not represent the expectations. 

This anticipation may be based on
  • Analytical results of the same sample or the same material using another, validated analytical procedure (e.g. IPC testing of a compounded bulk product, using an UV assay procedure and a later testing of the filled product using HPLC).
  • Knowing the theoretical composition of the sample (e.g. samples prepared during galenic development)
  • Results of tests of other samples/batches within a campaign or series of experiments(e.g. results of three out of four batches in one campaign are close to the theoretical assay, one is close to a specification limit) 
To decide, whether a result is really out of expectation or may be considered representing the typical variability of the procedure applied, data of the analytical validation of the procedure used should be used. 

According to the concept of analytical uncertainty usually applied in chemical analysis, the combined standard uncertainty of the result would be the appropriate performance indicator to help deciding, whether the result in question really is "unexpected" or simply represents a rare, but still probable value. 

As analytical uncertainties of pharmaceutical test procedures are rarely established, a common way to estimate this range may be used.
  • Expanded analytical uncertainty = 1.5 x RSD intermediate precision

In case an assay procedure based on HPLC has a reported (and correctly determined) intermediate precision of 0.8 %, the expanded analytical uncertainty to be expected in later routine application of the procedure is 1.2 % RSD.

To determine the limits (based on a 95 % confidence level) within which analytical results are representing the analytical variability of the procedure to be expected and accepted, the following calculation has to be performed; 
  • 95 % confidence interval = 2 x expanded analytical uncertainty 
In the example, any analytical result falling within a range of ± 2 x 1.2 % = ± 2.4 % of the anticipated result are representing analytical variability of the procedure on a 95 % confidence level and have to be accepted as is. 

Only results falling outside this range are to be considered "Out of Expectation".

In this case, data should not be used and accepted without previous investigation to determine the cause for the unexpected discrepancy from the anticipated result. This investigation should follow the well established process of laboratory investigations in case of OOS results. 

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Tags in: handling of OOE and OOT results, investigation of OOS, OOT or OOE limit.

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