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An out-of-trend (OOT) result that does not follow the expected trend, either in
comparison with previous results collected from past history.

This article discusses the possible statistical approaches and implementation challenges
to the identification of OOT results. It is intended to begin a conversation toward
achieving clarity about how to address the identification of out-of-trend results.

It is noted that the identification of OOT results is a complicated issue and that further
research and discussion is needed. This article is not a detailed proposal but is meant to
begin the discussion toward achieving more clarity about how to address the
identification of out-of-trend results.

Regulatory basis

A review of recent Establishment Inspection Reports (EIRs),FDA 483s, and FDA
Warning Letters indicates the identification of OOT data is becoming a regulatory issue
for marketed products. Several companies have received 483 observations requesting
the development of procedures documenting how OOT results will be identified and

It is important to distinguish between OOS and OOT results. FDA issued a OOS
guidance in the scientific literature and discussed at many scientific
conferences about OOS results. Although the FDA guidance indicates in a footnote that
much of the guidance presented for OOS can be used to examine OOT results, there is
no clearly established legal or regulatory basis to require consideration of data within
specification but not following expected trends.

Identification of Out-of-Trend Results

Avoiding potential issues with marketed product, as well as avoid potential regulatory
issues apply of OOT control in the analysis is a best practice in the industry.
In summary, the issue of OOT is an important topic both from a regulatory and
business point of view. Despite this, little has been discussed in the scientific literature
or in regulatory guidance on this topic. This article will introduce some approaches
that might be used to identify OOT data and discuss some issues that companies will
likely need to address before implementation and during use of an OOT identification


Statistical approach


There is a need for efficient and practical statistical approach to identify OOT results to
detect when a batch is not behaving as expected. To judge whether a particular result is
OOT, one must first decide what is expected and in particular what data comparisons
are appropriate.

Methodology [3 sigma approach] :

A minimum of 25 – 30 batches data shall be compiled for fixing the Trend range.

Results that shall be obtained from the 25 batches tabulated, average value,
minimum and maximum values are noted.

Standard deviation will be calculated for these 25 batches. Excel spread sheet
shall be used for Standard deviation calculation.

Standard deviation will be multiplied by 3 to get the 3 sigma (3 σ) value.

Maximum limit will be arrived by adding the 3 σ value to the Average value of
25 batches.

Minimum limit will be arrived by subtracting the 3 σ value from the Average
value of 25 batches. Minimum value may come in negative also at times.

The above maximum and minimum limits in 4.1.5 and 4.1.6 shall be taken as the
Trend range for upper and lower limits.

Any value that shall be out of this range will be considered as Out of Trend
(OOT) value or Outlier value.

Wherever specification has only Not more than, then only Maximum limit for
trend can be considered. Minimum limit should be excluded.

Wherever specification has range then both the Maximum and Minimum limits
for trend should be considered.


One advantage of this approach is that as long as the assumptions are met, the rate of
false positives can be set when one calculates the limits.

However, a disadvantage is the products with limited data, the appropriate limits may
be difficult to determine.This can lead to wrongly centered, too narrow, or toowide
OOT limits.


Implementation challenges

The purpose of developing a criterion for OOT assessments is to identify the
quantitative analytical results during a study that are atypical enough to warrant a
follow-up investigation.

Numerous challenges exist that a company must overcome to implement an OOT
procedure for commercial batches are….

● What statistical approaches are used to determine OOT criterion? What data are used
to determine OOT limits?
● What are the minimum data requirements? What evaluation is performed if the
minimum data requirement is not met?
● What data should be used to update limits?
● The investigation requirements (i.e., who is responsible, what is the timeline, how is it
documented, who should be notified must be clearly defined.
● Who is responsible for comparing the result with the OOT criterion?
● How is an OOT result confirmed? What additional analytical testing or statistical
analyses are appropriate?
● What actions should be taken if an OOT result is confirmed
as an unusual result?
● How are OOT investigations incorporated into the annual product review?

Identifying OOT results is a growing concern for FDA and the pharmaceutical industry.
Ideally, the method to determine an OOT alarm should not be too complex.


1. A.M.Hoinowski et al., “Investigation of Out-of-Specification Results,”
Pharm. Technol. 26 (1), 40–50 (2002).

2. FDA Guidance Document, Investigating Out of Specification (OOS)
Test Results for Pharmaceutical Production.



Managar – Quality Assurance

Symed Labs Limited [Hetero Group]

Hyderabad, India.

E_mail: [email protected]