Trend Data

Lynn Torbeck
Torbeck and Assoc.
Evanston, IL

June 28, 2007 1

Overview
OOT vs. OOS
Why trend?
How to get started
Types of trends with examples
OOT is relative
Graphical tools
Tend limits
June 28, 2007 2
Why Trend Data?
Good business practice.
Early warning of possible Out Of
Specification (OOS) results.
Gain process understanding.
Minimize risk of potential failures
of product in the market.
Find the gold in the hills for
process improvements.
June 28, 2007 3
Regulatory Basis for
Trending
No specific regulation requirement
211.180(e) Annual Reviews
FDA Form 483 for observations
Establishment Inspection Reports
Warning letters
FDA presentations at conferences

June 28, 2007 4

OOS Guidance Footnote
Although the subject of this
document is OOS results, much of
the guidance may be useful for
examining results that are out of
trend (OOT).

How is OOT different than OOS?

How is OOT the same as OOS?
June 28, 2007 5
Out Of Specification - OOS
OOS is the comparison of one
result versus a predetermined
specification criteria.
OOS investigations focus on
determining the truth about that
one value.
Is the OOS result confirmed or not?

June 28, 2007 6

Out Of Trend - OOT
OOT is the comparison of many
historical data values versus time.
OOT investigations focus on
understanding non-random
changes.
Is the non-random change
confirmed or not?

June 28, 2007 7

OOS Guidance
Taking into account the differences
between OOS and OOT, the
guidance does provide a
framework for OOT investigations:
Responsibilities
Philosophical basis
General principles of investigations

June 28, 2007 8

1. How to get started
Select the variable to be studied:
Potency
Yield
Impurities
Hardness
Bioburden

June 28, 2007 9

2. How to get started
Select a time period:
At least one year if possible.
More than two preferred.
Do not go past a major change in
the process. Use process knowledge
to advantage.
Use the reportable result, the value
compared to the specifications.

June 28, 2007 10

3. How to get started
Enter the data into analysis software:
Excel
Minitab
Sigma Plot
JMP
StatGraphics
Northwest Analytical
SAS

June 28, 2007 11

4. How to get started
Plot the data vs. time or lot sequence.
Look for non-random changes over
time.
Determine if they are of practical
importance.
Statistical significance is insufficient.
Do an impact and risk assessment.

June 28, 2007 12

What is Trending?
The several activities of:
Collecting data,
Recording it,
Documenting it,
Storing it,
Monitoring it,
Fitting models to it
Evaluating it, and
Reporting it.

June 28, 2007 13

What is a trend?
Any non-random pattern.

Short and long term patterns in

data over time that are of practical
importance.

June 28, 2007 14

Beneficial Trends
Desirable patterns in the data
series.
Examples:
A move toward the target or center of
the specification.
More consistent with less variation.
Less likelihood of an OOS value.
A benefit to SSQuIP.

June 28, 2007 15

Beneficial Trend
1.2

0.8
mg/mL

0.6

0.4

0.2

0
12/10/200 6/28/2003 1/14/2004 8/1/2004 2/17/2005 9/5/2005 3/24/2006 10/10/200
2 6

Date
June 28, 2007 16
No Trend
Easier to define
what a trend is not. 104

103
Random data 102

Noise 101

Normal
Stationary 100

99
No ups, no downs 98

No cycles 97

No outliers Index 100 200 300 400 500

June 28, 2007 17

Neutral or No Trend
Neither beneficial or adverse
Examples:
Results that are always the same.
Stability data with a slope of zero.
Data in a state of statistical control
on a control chart.

June 28, 2007 18

Process Control
Statistical Process Control, SPC
Normal random data over time
Due to common causes only
Engineering Process Control, EPC
Estimate departures from target
Feedback to control point
Physical changes to the process

June 28, 2007 19

Adverse Trends
Undesirable patterns in the data
series.
Examples:
A movement away from the target.
Increased variability.
Increased probability of OOS.
An unexplained change to a beneficial
trend.
A challenge to SSQuIP.

June 28, 2007 20

Out-of-Trend (OOT)
A change from an established
pattern that has the potential of an
adverse effect on SSQuIP or of
becoming OOS.
Must be large enough to be of
practical significance.
Statistical significance is insufficient
to determine OOT.
June 28, 2007 21
Long Term Change
Not stationary Increasing Trend
.1 per step after 50
around a fixed value 107

Increasing or 106
105

decreasing average. 104

103

Yields
Apparently will 102

continue to get
101
100

worse (or better) 99

98
unless action is Index 10 20 30 40 50 60 70 80 90 100

taken.

June 28, 2007 22

The Aberrant Outlier
Stationary and An outlier
Mu=100, Sigma=1.0
random but with 105

one very large 104

value that could be 103

102
a statistical outlier.

Yield%
101

Generally assumed
100

99

to be due to a 98

special cause.
97
Index 10 20 30 40 50 60 70 80 90 100

June 28, 2007 23

Shift in the Average
Here the mean Mean Shift
Mu=100 to 104 Sigma=1.0
has increased 106
from 100 to 104
at sample 51.
No other changes

Yield
101

were made.
Variability is the 96

same. Index 10 20 30 40 50 60 70 80 90 100

June 28, 2007 24

Variation Change
This is stationary Increasing Variability
Mu=100, Sigma=1.0, 2.0, 3.0 & 4.0
around a fixed 110

mean of 100%.
But, the standard

Yield %
100
deviation
increased from
1.0 to 4.0. 90

Index 10 20 30 40 50 60 70 80 90 100

June 28, 2007 25

Cycles
A reoccurring Cycles

cycle. 104

Stationary about 103

102

a fixed mean. 101

Cycles
100

The data are not 99

independent.
98

97
96

Index 10 20 30 40 50 60 70 80 90 100

June 28, 2007 26

Autocorrelated
Data are Autocorrelated

correlated with
105
the previous data. 104

Not stationary. 103

AutoCorr
102

Check different 101

time lags, 1,2, .

100

99

98
Index 10 20 30 40 50 60 70 80 90 100

June 28, 2007 27

OOT is Relative
Stationary White Noise
mu=100%, S=1%
110
Yield %

100

90
Index 10 20 30 40 50 60 70 80 90 100

June 28, 2007 28

OOT is Relative
The importance of a trend is its size
relative to the specification criteria.
A state of Statistical Control is
desired but not necessary.
A state of Engineering Control is
necessary to meet specifications.
Success is a marriage of the two.

June 28, 2007 29

A Little Humor (Very Little)
Lottery: A tax on the statistically-
challenged.
If you want three opinions, just
ask two statisticians.
Statistics means never having to
say you're certain.
http://www.keypress.com/x2815.xml

June 28, 2007 30

Trend Fitting
The general process of representing
the trend component of a time series.
A Dictionary of Statistical Terms. Marriott

Depends very much on the type of data

and the subject matter being studied.
Need to adapt the tools and techniques
to our specific data and issues.

June 28, 2007 31

Tools of Trending
Summary statistics
Averages, Medians
Ranges, Standard Deviations, %RSD
Graphical plots
Distribution analysis - Histograms
Outlier determination
Regression analysis

June 28, 2007 32

Graphic Tools
Line Plots vs. time.
Shewhart Control Charts.
Histograms.
Sector chart

June 28, 2007 33

Line Plots vs. Time
Stationary Time Series
Mu=100, Sigma=1.0
Response on the 102

vertical axis.
101

Time or batch #

Yield %
100

on the horizontal 99

axis. 98

Usually connect Index 10 20 30 40 50 60 70 80 90 100

the data points

with a line, but
optional.

June 28, 2007 34

Control Chart
I and MR Chart for Yield %

Add natural 103.5

UCL=103

Individual Value
102.5
101.5

process limits to 100.5

99.5
98.5
Mean=100

the line plot. Subgroup

97.5
96.5
0 50 100
LCL=97

3 4
UCL=3.686

Moving Range
3

A chart for the

2

1 R=1.128

response.
0 LCL=0

A chart for the

variability.

June 28, 2007 35

Control Chart Family
Individuals
Averages
Medians
Standard deviations
Ranges
Number of defectives
Fraction defectives
Defects per units
Number of defects

June 28, 2007 36

Variation Change
I and MR Chart for Yield %

A control chart 110

1

Individual Value
will detect change 1
1
1
1 11 1
1
UCL=103

in the variation.
100 Mean=100
LCL=97
11 11 1 1
1 1 1 1
1 1 1
90 1
1 1
Subgroup 0 50 100

1
1

Moving Range
1 1
10 1
11
1 1
1 1 11
1 1 1 11 111 11
1 1 11 1 1
5 1 111 1 1
UCL=3.686
R=1.128
0 LCL=0

June 28, 2007 37

The Outlier
I Chart for Yield%
A control chart
finds values 106
105
1

outside the 104

Individual Value
103 UCL=103
natural limits of 102

the data. 101

100 Mean=100

The value is 99
98
larger than would 97 LCL=97

be expected by 96
0 50 100
chance alone. Observation Number

June 28, 2007 38

Western Electric Rules
1. One value outside 3 S limits.
2. Nine values in a row on one side
of the average.
3. Six values in a row all increasing
or decreasing.
4. 14 values in a row alternating up
and down.

June 28, 2007 39

Western Electric Rules
5. Two of three values greater than 2
S from the average.
6. Four of five values greater than 1 S
from the average.
7. 15 values in a row within 1 S of the
average.
8. Eight values in a row greater than 1
S.
June 28, 2007 40
Histogram
Show the shape
of the distribution 20

of data.

Frequency
In this case it is 10

Normally
distributed. 0

96 97 98 99 100 101 102 103 104

Yield %

June 28, 2007 41

The Outlier
The outlier is Variation Change
clearly seen in the 20

histogram.

Frequency
10

97 98 99 100 101 102 103 104 105 106

Yield%

June 28, 2007 42

Outlier Determination
Reference:
USP 30 NF 25
Chapter <1010>
Analytical Data Interpretation and
Treatment
Page 392 Outlying Results
Appendix C: Examples of Outlier Tests
for Analytical Data.

June 28, 2007 43

Regression Analysis
99%PredictionInterval

220000

200000

180000
Value

160000

140000

120000

100000
0 5 10 15 20
Months
June 28, 2007 44
Trend Limits
Numeric (or non-numeric) criteria, that if
exceeded, indicates that an out-of-
trend change has occurred.
Usually the natural process variation
AKA Alert limits
Use Statistical Tolerance Limits
See USP <1010> Appendix E

June 28, 2007 45

Here, Trend This

40
Var 1

30

20

Index 100 200 300

June 28, 2007 46

A New Engineering Chart
Brings together for the first time :
Comparison to the specification limits in
place of the probability limits
Divides the specification range into equal
zones in place of 1, 2, & 3 sigma areas
Uses cumulative scores
Pharmaceutical Technology, April
2005

June 28, 2007 47

 The New Sector Chart
SIALIC ACID EXAMPLE
Fail
3.915 3.695 3.298 4.04 3.87 4.147 3.938 4.167 3.9 3.927 3.81 3.9 4.033 3.853 4.142 3.958 3.77
Sector Weight Low High
F 10
D 2 4.1 4.2 2 2 2
C 1 4 4.099 1 1
B 0 3.9 3.999 0 0 0 0 0 0
A 0 3.8 3.899 0 0 0
A 0 3.7 3.799 0
B 0 3.6 3.699 0
C 1 3.5 3.599
D 2 3.4 3.499
F 10 10

Batch
June 28, 2007 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 4816 17
The New Sector Chart
Rules
The first batch tally takes the weight of
the sector it is in.
Subsequent batches have a cumulative
tally of the previous tally plus the
current sector weight.
If the tally reaches a value of, say, 10,
an alert is given.
If the batch enters the A or B sectors,
the tally is reset to zero.

June 28, 2007 49

The New Sector Chart
Rules
Sectors A and B cover the center
50% of the specification range.
Sector F is outside the current
specification.
Other weights can be set to fit the
process and the degree of
sensitivity needed.

June 28, 2007 50

Advantages of Sector
Chart
No minimum sample size. Can start with
one data point.
No assumptions about the data at all.
Identifies beneficial and adverse trends.
Weights and tally total are selected by
scientific and empirical knowledge.
A decision is made with each new point.
Alerts quickly if a problem exists.

June 28, 2007 51

Justification for Sector
Chart
If the process is well inside the
specification, it need not be in a
state of statistical control.
The focus is on OOT and SSQuIP not
being out of statistical control.
Sensitivity of the chart is adjustable.
Can be use in parallel with other
charts.
June 28, 2007 52
Thats All Folks
Summary Points:
1. OOT is not OOS
2. OOT is non-random changes over time
3. OOT is a statistical and graphical issue
4. OOT is relative. Statistical significance
is not sufficient.
5. Trend limits = Natural Limits

June 28, 2007 53

References
Graphics:
http://www.edwardtufte.com/tufte/
http://www.itl.nist.gov/div898/handbo
ok/eda/section3/eda34.htm
Statistics
http://www.itl.nist.gov/div898/handbo
ok/index.htm

June 28, 2007 54

Software References
http://www.minitab.com/
http://www.systat.com/products/si
gmaplot/
http://www.nwasoft.com/
http://www.jmp.com/
http://www.statgraphics.com/
http://www.sas.com/

June 28, 2007 55