HANDLING OUT OF TREND (OOT) RESULTS

Along with application of statistical methods for identifying out of trend (OOT) results such as
the regression control chart method, by time point method and slope control chart method that
are based on defining tolerance intervals from historical estimates of average and standard
deviations for various parameters, another important aspect of handling OOT results is to
understand the possible causes of deviation from the expected trend(s). A thorough
understanding of the causative factors leading to OOT results and remediation of the causes can
lead to better process control, less wastage of resources and more informed decisions regarding
handling of results.
Therefore along with developing statistical tools to identify OOT, classification of the
process and decisions regarding batch monitoring will benefit from risk analysis of the
manufacturing process.
Risk assessment helps to identify and classify possible hazards that can arise and lead to
aberrant values for various attributes of the product such as, dissolution, impurities, assay and
blend/content uniformity. Processes in unit operations that are assigned as high risk are likely to
cause OOT results and should be scrutinized further when OOT results are obtained in practice.
At AlphaMD LifeSciences we are able to conduct a thorough risk assessment of
manufacturing processes for various dosage forms ranging from liquids (solutions, suspensions,
parenterals) to solid dosage forms such as tablets and capsules. Failure mode and Effects
Analysis (FMEA) will be used to identify and classify potential causes of failure at each unit
operation of the manufacturing process and assign a Risk Priority Number (RPN). The potential
causes behind Process Sigma values for various product attributes based on central tendency and
standard deviation of the process will be identified which allows a more thorough understanding
of the process and helps minimize the occurrence of OOT results in the future.

Example:
Blend uniformity was measured for four batches at different time points during the blending
operation. Blend uniformity (BU) was determined by withdrawing random samples of the
powder blend from each batch and measuring the API content using a validated HPLC assay
method. Blend uniformity is reported as % relative standard deviation (% RSD). Upper and

lower tolerance limits were determined for each time point and the test batch data was compared
using the by time point method.

3.2

Blend uniformity (% RSD)

3.1
3
Batch 1

2.9

Batch 2

2.8

Batch 3
2.7

Batch 4
Upper limit

2.6

Lower limit

2.5

Test batch
2.4
2.3
0

10

15
20
Time (mins)

25

30

35

Conclusion: The by time point method was used to identify if the test batch was OOT based on
comparison with three previous test batches. Although statistical analysis showed that the test
batch was OOT, it is important to understand the Root Cause and propose Corrective and
Preventive Action (CAPA) as well.
The following is a FMEA risk assessment tool used to identify potential risks that may
have led to the aberrant test batch results. This will help ascertain the cause of OOT data and
suggest measures to correct this in future batches.

CQA

Unit Op

Failure
Cause 1
Mode
BU
Blending Segregation Particle
shape/size
differences:
potential
change in
raw
material
supplier or
excipient
grade
S: Severity

Cause 2

Change in 3
blending
time
or
equipment
failure

RPN

45

Action
Use
NIR
spectroscopy
to monitor
blend
uniformity,
mill API and
excipients
prior to use

O: Occurrence
D: Detection
RPN: Risk Priority Number = S*O*D
OOT result could have been caused by changes in API/excipient(s) supplier and/or
equipment maintenance issues and therefore future batches should be closely monitored to avoid
these problems.

Conclusion:
Statistical analyses to determine OOT results are more valuable when supported with a thorough
understanding of the risks associated with the manufacturing process.
Along with tools such as control charts that can help to identify problematic production
batches that deviate from historical data, it is important to understand the cause of failure and
suggest corrective measures that can help reduce OOT results. Risk assessment is a suitable tool
that can be used in conjunction with statistical analysis of OOT data.