Trend Analysis in the

Biopharma Manufacturing
Presentado por
Business Excellence Consulting

Pepe Rodríguez-Pérez, PhD

.www.calidadpr.com
 787.525.3014

2008
 Trend Definitions
• Trend: A sequence o pattern of data (Short term and
Long term)
• Trend: A statistical term referring to the direction or rate
of change of a variable. ICH 9
• Adverse Trend: A general drift or tendency in a set of
data over an established period of time, which exceeds
established limits. Adverse trending can be upward or
downward depending upon the type of performance
metric.
• Tendencia: secuencia o patrón mostrado por un grupo
de datos que se desvían de un valor esperado (ej.: valor
histórico)
Trend Analysis – © BEC 2008 2
 Run Charts
A run chart is a line graph of data points plotted in chronological
order that helps detect special causes of variation.

Run charts allow us to:

• Understand process variation
• Analyze data for patterns
• Monitor process performance
• Communicate process performance
99.9

99.4

98.9
Run Chart: %Assay

98.4
Mean: 98.64

97.9

97.4

96.9

96.4

95.9
14 n
r

ar

ar

10 r
ar

ar

ar

17 r
ar

ar

ar

ar

ar

27 r
ar

29 r

30 r
ar

pr

pr

pr

pr

pr

pr

pr

pr

pr

pr

pr

pr

r
a

p
a

Ja

Ap

Ap

Ap

Ap
-M

-M

-M

-M

-M

-M

-M

-M

-M

-M

-M

-A

-A

-A

-A

-A

-A

-A

-A

-A

-A
M

-M

3-

0-

3-
1-

2-

6-

7-

8-

6-

3-

4-

1-

2-

3-

4-

5-

8-

9-
12

19

22

26

28

11

12

14

16

18

20

26

27

28

29
4

1
Trend Analysis – © BEC 2008 3
 FDA’s Expectations of Trending
• Trending is an important tool in reporting the state of environmental
control
• Daily, Weekly, Monthly,
• Long term: up to three years
• Parametric Release
• Main requirements of a Quality Management System (QMS)
• Each firm must define what is an adverse trend
• When an adverse trend is identified, an investigation should be
initiated to identify the root cause(s)
• Implement effective corrective and preventive actions (CAPA)
• FDA suggests that three (3) years of historical data be kept for the
purpose of long-term trending.

Trend Analysis – © BEC 2008 4

 FDA Regulations
• Medical Device QSR. Sec. 820.100 Corrective and preventive
action.
• (a) Each manufacturer shall establish and maintain procedures
for implementing corrective and preventive action. The
procedures shall include requirements for: (1) Analyzing
processes, work operations, concessions, quality audit reports, quality
records, service records, complaints, returned product, and other
sources of quality data to identify existing and potential causes of
nonconforming product, or other quality problems. Appropriate
statistical methodology shall be employed where necessary to detect
recurring quality problems;
• 2004 FDA Sterile Product Guidance
• The QCU should provide routine oversight of near-term and long-term
trends in environmental and personnel monitoring data
• 2006 FDA Guidance for Industry: Quality Systems Approach to
Pharmaceutical Current Good Manufacturing Practice Regulations

Trend Analysis – © BEC 2008 5

 FDA Guidance for Industry (2006):
Quality Systems Approach to Pharmaceutical
Current Good Manufacturing Practice Regulations.
Analyze Data for Trends
• Quality systems call for continually monitoring trends and improving systems. This can
be achieved by monitoring data and information, identifying and resolving problems,
and anticipating and preventing problems.
• Quality systems procedures involve collecting data from monitoring, measurement,
complaint handling, or other activities, and tracking this data over time, as appropriate.
Analysis of data can provide indications that controls are losing effectiveness. The
information generated will be essential to achieving problem resolution or problem
prevention.
• Although the CGMP regulations (§ 211.180(e))require product review on at least an
annual basis, a quality systems approach calls for trending on a more frequent basis as
determined by risk. Trending enables the detection of potential problems as early as
possible to plan corrective and preventive actions. Another important concept of
modern quality systems is the use of trending to examine processes as a whole; this is
consistent with the annual review approach. Trending analyses can help focus internal
audits.
Trend Analysis – © BEC 2008 6
 Process Performance =
“Voice of the Process”

-3σ +3σ

Shape: Normal
Center: μ= 50
Spread: 6σ= 30 (1σ= 5)
Process Spread

35 40 45 50 55 60 65

Trend Analysis – © BEC 2008 7

 Process Specifications =
“Voice of the Customer ”
LSL USL

Process
Specifications

20 25 30 35 40 45 50 55 60 65 70 75 80

Trend Analysis – © BEC 2008 8

Process Capability: Marriage of the
“Voice of the Process ”
with the
“Voice of the Customer ”

Trend Analysis – © BEC 2008 9

 Trending vs. Product Specifications
(Process Stability vs. Process Capability)
•Trending relates to the process behavior (Process Stability)
•It is the voice of the process
•SPC (Statistical Process Control)
•Run Charts and Control Charts
•Scatter & Regression
•Trending should not be confused with statistical significance
•Process Capability relates to the ability of the process to meet the
(customer) specifications
32

30

28
Run Chart: value

26

24

22

20

18
1

12

13

14

15

16

17
1

Trend Analysis – © BEC 2008 10

Properties of Normal Distribution

68.2%
+/- 1.0 σ 90.0%
+/- 1.65 σ
95.0%
+/- 1.96 σ
95.45%
+/- 2.0 σ 99.0%
+/- 2.58 σ
99.73%

+/- 3.0 σ
Trend Analysis – © BEC 2008 11
 Trend Analysis Basic Questions

Do you see any trend or pattern that deserve further

investigation?

Common Mistakes:
You conclude that there is a trend when all you are
“detecting” is common variation (present in all processes).
You are unable to detect a real trend or pattern (you’re
trend-blind, a very common eye disease in the
Biopharmaceutical industry).

Trend Analysis – © BEC 2008 12

 Trending 101
 Be sure to evaluate enough datapoints (no less than 15-20
in any case) to cover normal variation of the process under
analysis.
 First of all, verify if the most recent datapoints are within
expected range of variation.
 Do you see any pattern? or any daily trend? Weekly?
Monthly? Seasonal?.
3.40

1.40
Run C hart - Trends

Median: 0.00

-0.60

-2.60

-4.60

-6.60
1

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30
Trend Analysis – © BEC 2008 13
 Run Charts & Control Charts
7.00
6.00
5.00
4.00
Run Chart - Clustering

3.00
2.00
1.00
0.00 Median: -1.00
-1.00
-2.00
-3.00
-4.00
-5.00
-6.00
-7.00
1

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30
6.500
6.006
6.000
Individual s: Overal l S atisfaction

5.500

5.000 6
6
4.500
Mean CL: 3.80
4.000

3.500

3.000

2.500
5
2.000 1.596

1.500
1
3
5
7
9
11
13
15
17
19
21
23
25
27
29
31
33
35
37
39
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53
55
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59
61
63
65
67
69
71
73
75
77
79
81
83
85
87
89
91
93
95
97
99
Trend Analysis – © BEC 2008 14
 The “prototype”: The Run Chart
•What is a “Run”?
•A run is defined as one or more consecutive data points on the same
side of the center line (mean or median).
•A run can be of any length, from one point to many points. A run ends
anytime the connecting line crosses the center line.
•The number of runs you should expected to see in a stable process
depends on the number of data points.
•If the line touches the center line and then returns to the same side,
do not count it as crossing.
7.00
6.00
5.00
4.00
Run Chart - Clustering

3.00
2.00

Points on the 1.00

0.00 Median: -1.00
Seven
line are -1.00
-2.00

ignored -3.00
-4.00 Runs
-5.00
-6.00
-7.00
1

10

11

12

13

14

15

17

18

19

21

22

23

24

25

26

27

28

29

30
1

Trend Analysis – © BEC 2008 15

 Expected Numbers of Runs
with only common-cause variation
Number of Data Lower Limit for Upper Limit for
Points not on Median Numbers of Runs Numbers of Runs
10 3 8
11 3 9
12 3 10
13 4 10
14 4 11
15 4 12
16 5 12
17 5 13
18 6 13
19 6 14
20 6 14
21 7 15
22 7 16
Trend Analysis – © BEC 2008 16
 Run Chart: Test for Special Causes
Test #1: The presence of too much or too little
variability
•Too many runs (too much variation)
•Too few runs (not enough variation)
•It the number of runs you seen in the process is within
those limits, you can conclude that only common-cause
variability is present  your process is stable.
•It is best to have at least 16 points in a run chart,
excluding those on the median, to have adequate
statistical power to identify a special cause.
Trend Analysis – © BEC 2008 17
 Test #1: The presence of
too little variability
16

14

12
Run Chart: values

Median: 10.00
10

4
1

10

11

12

13

14

15

16

17

18

19

20

21

22
• Too few runs generally indicates that something cyclic
is systematically shifting the process average

Trend Analysis – © BEC 2008 18

 Test #1: The presence of
too much variability
• Too many runs could point to a problem of
consecutive, over-compensating process adjustments
or indicate that the data points actually came from two
sources with different process averages.

14

12
Median: 11.00
Run Chart: values

10

4
1

10

11

12

13

14

15

16

17

18

19

20

21
Trend Analysis – © BEC 2008 19
 Run Chart: Test for Special Causes
•How many runs?
•Is the process stable?
109

104
Median: 102.00
Run Chart: Data

99

94

89
1

11

13

15

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25

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35

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49

51
Trend Analysis – © BEC 2008 20
 Run Chart: Test for Special Causes
Test #2: The presence of a shift in the process
• A special cause exists if a run contains too many
data points (the run is too long)
• With less than 20 points, a run of seven (7) is
considered too long
• With more than 20 points, a run of eight (8) or more
data points is too long.
• Note: When counting runs on the same side of de
center line, ignore any points on the center line.
Trend Analysis – © BEC 2008 21
 Test #2:
The presence of a shift in the process

16

14
Run Chart: val ues

12 Median: 11.00

10

4
1

10

11

12

13

14

15

16

17

18

19

20

21

22

24

25
2
Trend Analysis – © BEC 2008 22
 Run Chart: Test for Special Causes
Test #2: The presence of a shift in the process
• Some authors add the following as other indicators of a
shift:
• 10 points on one side out of 11 in a row.
• 12 points on one side out of 14 in a row.
• 16 points on one side out of 20 in a row
18

16
Run Chart: values

14

12
Median: 10.00
10

6
1

10

11

12

13

14

16

17

18

20

21

23

24

25

27

28

30
1

2
Trend Analysis – © BEC 2008 23
 Run Chart: Test for Special Causes
Test #3: The presence of a trend in the process
• A trend is defined as an unusually long series of
consecutives increases or decreases in the data.
• At least six or seven (no agreement with the exact
number).
• Note 1: do not be “trend-happy”
• Note 2: count any point on the center line but
ignore points that repeat the preceding value.

Trend Analysis – © BEC 2008 24

 Test #3:
The presence of a trend in the process
27

26

25
Run Chart: values

24

23

22

21

20

19

18
1

10

11

12

13
21

20

19

18
Run Chart: values

17

16

15

14

13

12

11
1

10

11

12

13
Trend Analysis – © BEC 2008 25
 Test #3:
The presence of a trend in the process
•Any trend?
•Is the process stable?
22

20

18
Run Chart: values

16

14

12 Median: 11.00

10

8
1

10

11

12

13

14

15

16

17

18

19

20
Trend Analysis – © BEC 2008 26
 Test # 4:
Alternating Points
•Fourteen or more points in a row alternating up and down.
•When counting up and down, ignore any points that repeat
the preceding value (if two points in a row have the same
value, ignore the second points).

25

24

23
Run Chart: value

22

21

20

19

18

17
1

10

11

12

13

14

15

16

17

18
Trend Analysis – © BEC 2008 27
 Control Charts:
Is adequate the use of sigma zones?
• Create a “red alert” zone between 2 and 3 sigma
• It’s not statistically sounded!
3σ

2σ

1σ

1σ

2σ

3σ

Trend Analysis – © BEC 2008 28

 Control Charts:
Is adequate the use of sigma zones?
•Using the 2 Sigma (95.5%) rule: five flags would be noticed.
•However, the process is perfectly under statistical control.
50.00 47.53

45.00

40.00

35.00
Ind ividu als: Days

30.00
Mean CL: 25.29
25.00

20.00

15.00

10.00
3.05
5.00

0.00
1

11

13

15

17

19

21

23

25

27

29

31

33

35

37

39

41

43

45

47

49

51

53

55

57

59
Trend Analysis – © BEC 2008 29
 Run Chart: % Assay

95.9
96.4
96.9
97.4
97.9
98.4
98.9
99.4
99.9
1-
M
a
2- r
M
a
4- r
M
a
6- r
M
a
7- r
M
a
8- r
M
10 a r
-M
12 ar
-M

Nice trend??:
a
13 r
-J
14 n a
-M
16 ar
-M
17 ar
-M
19 ar
-M
22 ar
-M
23 ar
-M
24 ar
-M
26 ar
-M
27 ar
-M
28 ar
-M
29 ar
-M
30 ar

the pill manufacturing process!!

-M
ar
1-
Ap
r
2-
Ap
3- r
Ap

Trend Analysis – © BEC 2008

4- r
Ap
5- r
Ap
8- r
Ap
r
Additional tools:

9-
Ap
10 r
-A
11 pr
Regression Analysis

-A
12 pr
-A
13 pr
-A
p
14 r
-A
p
16 r
-A
18 pr
-A
20 pr
-A
26 pr
-A
27 pr
-A
p
28 r
-A
p
29 r
-A
Regression line demonstrates a very good improvement to

pr
Mean: 98.64

30
 Run Chart: % Assay

95.9
96.4
96.9
97.4
97.9
98.4
98.9
99.4
99.9
1-
M
a
2- r
M
a
4- r
M
a
6- r
M
a
7- r
M
a
The true:
8- r
M
10 a r
-M
12 ar
-M
a
13 r
-J
14 a n
-M
16 ar
-M
17 ar
-M
19 ar
-M
22 ar
-M
23 ar
-M
24 ar
-M
26 ar
-M
27 ar
-M
28 ar
-M
29 ar
-M
30 ar
-M
ar
1-
Ap
r
2-
Ap
3- r
Ap

Trend Analysis – © BEC 2008

4- r
Ap
5- r
Ap
8- r
Ap
r
9-
Additional tools:

Ap
10 r
-A
11 pr
-A
Regression Analysis

12 pr
-A
13 pr
-A
p
14 r
-A
p
16 r
-A
18 pr
-A
20 pr
-A
26 pr
-A
27 pr
-A
p
28 r
-A
p
29 r
-A
pr
the only factor affecting % assay was the API lot being used

Mean: 98.64

31