Using Control Charts to Evaluate

Process Variability

Daniel Y. Peng, Ph.D.

Quality Assessment Lead
Office of Process and Facility (OPF)
OPQ/CDER/FDA
PQRI 2015 Annual Meeting
North Bethesda, Maryland
October 5, 2015
1

Walter Andrew Shewhart (1891-1967)

A physicist, engineer and statistician
Father of statistical quality control
Statistical method from the viewpoint
of quality control (1939)

Creator of PDSA (Plan, Do, Study and

Act) cycle
Creator of control chart
Originator of the Chance and
Assignable variation concept

Uncontrolled variation is
the enemy of quality
Dr. W. Edwards Deming (1900-1993)

Sources of Variation
Variation exists in all processes.
Variation can be categorized as either:
Chance or Common causes of variation
Inherent to a system, random, always present and
hence predictable within statistical limits
Eliminate inherent variability (noise) is difficult

Assignable or Special causes of variation

Exterior to a system, non-random, not always present
(intermittent)
can cause changes in the output level, such as a spike,
shift, drift, or non-random distribution of the output.
Are usually easier to be detected, controlled or
eliminated

Control Chart
6.0
USL

UCL

Quality 5.0
attribute
(unit)

CL

LCL
LSL

4.0
30

40

Sample #

50

60

Definition: a graphical display of a product quality characteristic that

has been measured or computed periodically from a process at a
defined frequency
Every control chart consists of:
A set of data
A central line (CL) (mean)
Two statistical process control limits (UCL and LCL) (Is the process Stable?)

Upper and Lower Specification Limits (USL and LSL)

Patients need ( Safety and Efficacy) (Is the process Capable?)

Potential Applications
To proactively monitor and trend a process
To detect the presence of special cause variation
To identify continual improvement opportunities
To maintain the process in a state of statistical
control
Using science and risk-based approach
Take action in a timely manner
6

Key Considerations for

Constructing a Control Chart

Choice of Product Quality Characteristics

Critical Quality Attributes (CQA)
A physical, chemical, biological or microbiological property or
characteristic of an output material including finished drug
product that should be within an appropriate limit, range, or
distribution to ensure the desired product quality (ICH Q8)
Identification of CQA: primarily based upon the severity of harm
to the patient (safety and efficacy)

Critical (input) material attributes and critical

process parameters (CMAs/CPPs)
Other relevant process characteristics that can
assist in process monitoring and controlling 8

Types of Control Chart

Variable Control Chart

Characteristics that can be measured (continuous numeric data) e.g. Assay,

Dissolution, % of Impurity
The average and variability charts are usually prepared and analyzed in pairs
Average Range chart (Xbar-R chart, subgroup size 2-10)
Average Standard Deviation chart (Xbar-S chart, subgroup size >10)
Individual Moving Range chart (I-MR chart, n=1)

Attribute Control Chart

Characteristics that have discrete values and can be counted, e.g. % defective, #
of failed batches in a month
p chart / np Chart: for fraction of occurrence of an event- Binominal distribution
e.g. % of unsuccessful batch at a facility every month
c chart / nc Chart: for counts of occurrence in a defined time or space increment
-Poisson distribution
e.g. number of particulate matter in an injection vial

Other types of control chart:

cumulative sum control chart (CUSUM)

exponentially weighted moving average control charts (EWMA)
9

Subgroup Size and Sampling Frequency

Subgroup: the observations sampled at a particular
time point
Subgroup Size and Sampling Frequency (N x K)

The number of observations in each subgroup: 1 n

the objective of the monitoring (detect large or small shift)
how quickly the output responds to upsets
consequences of not reacting promptly to a process upset
time and cost of an observation

Rational Subgroup:

Minimize the variation of observations within a subgroup

Maximize variation between subgroups
10

Statistical Process Control Limits

UCL and LCL:
the thresholds at which the process output
is considered statistically unlikely
typically, 3 SD (Shewhart limits)

Rationale: to balance the two risks:

Failing to signal the presence of a special
cause when one occurs;
False alarm of an out-of-control signal when
the process is actually in a state of statistical
control
11

How out-of-control points are identified?

Rule No.1

any point falls

outside UCL/LCL

Other Rules

certain nonrandom
patterns of the
plotted data
Use it judiciously

Risk of false alarm

8 Western Electric Rules

12

Over-Reaction vs. No-Reaction

Procedures should describe how trending and
calculations are to be performed and should
guard against overreaction to individual events as
well as against failure to detect unintended process
variability (2011 FDA Process Validation Guidance)

Control chart and process capability analysis often go hand-in-hand

13

Illustrative Examples

14

Within Batch Variability Example

Xbar-R Chart of Disso@240min

Sample Mean

45

40
1

35

UCL=31.75
_
_
X=29.25

30
25

Not Stable
&
Not Capable

LCL=26.75
1

1
1

1054

1233

1309

1338

1356

1429
1452
Time

1515

1539

1602

1625

UCL=10.36

Sample Range

10.0
7.5

_
R=5.17

5.0
2.5

LCL=0

0.0
1054

1233

1309

1338

1356

1429
1452
Time

1515

1539

1602

1625

ER coated beads, mixed with extra-granular cushioning excipients and compressed into tablets
Compression: ~ 5h, sample frequency: every 8-10 min (total 33 subgroups), subgroup size= 6

15

Between Batch Variability Example

Process Capability Analysis of Tablet Assay (first 25 batches, subgroup size =3)
Capability Histogram

Subgroup Mean

Xbar Chart
UCL=102.108

102

S pecifications
96
LS L
U S L 104

_
_
X=100.287

100

LCL=98.466

98
1

11 13 15
Batch No.

17

19

21

23

25

96

Subgroup Range

100

102

Cpk: 2.95

104

A D: 0.636, P : 0.094

UCL=4.582

_
R=1.78

LCL=0

0
1

11 13 15
Batch No.

17

19

21

23

25

96

Within
StDev 1.051
Cp
1.27
Cpk
1.18
PPM
229.14

102
100
98
5

10

15
Batch No.

99

102

105

Stable
&
Capable

Capability Plot

Run Chart
104

Assay (%)

98

USP: 90-110

Normal Prob Plot

R Chart

96

USL

LSL

20

25

Within
Ov erall

Overall
StDev 1.079
Pp
1.24
1.15
Ppk
Cpm
*
PPM
323.15

Specs

Data source: Chopra, V., Bairagi, M., Trivedi, P., et al., A case study: application of statistical process control tool for
determining process capability and sigma level, PDA J Pharm Sci and Tech, 66 (2), 2012, pp. 98-115
16

Between Batch Variability Example

Process Capability Analysis of Tablet X Content Uniformity (AV)
I Chart

Capability Histogram

Individual Value

5.0

Specifications
USL 15

_
X=3.137

2.5

0.0

USL

UCL=5.558

LCL=0.716
28

31

34

37

40

43

46

49

52

55

Moving Range Chart

Moving Range

10

12

14

Normal Prob Plot

1 1

AD: 0.637, P: 0.088

3.0

UCL=2.974

1.5

__
MR=0.910
LCL=0

0.0
28

31

34

37

40

43

46

49

52

55

Last 30 Observations
Within
S tDev 0.8070
Cp
*
C pk
4.90
PPM
0.00

4
2
28

31

34

37

40
43
46
Batch No.

49

Capability Plot

AV

Not Stable
but
Capable

52

55

Within
Overall

O v erall
S tDev 0.9460
Pp
*
P pk
4.18
C pm
*
PPM
0.00

Specs

Tablet content uniformity (AV) of last 30 commercial batches of Tablet X manufactured by Firm Y
(subgroup size =1, I-MR chart)

17

Site Performance Monitoring Example

% of unsuccessful batch/month at Site A (# of lots attempted: 20-30/month)
Binomial Process Capability Analysis of Unsuccess Batch
P C har t

Unsuccess Rate
% Unsuccess Rate

0.10
0.05

_
P =0.0437

0.00

LC L=0
1

20
10
0

Stable
but
Not Capable

20
25
30
T otal Batch M anufactur ed/M onth

11 13 15 17 19 21 23 25
M onth

Tests performed w ith unequal sample sizes

H istogr am

C umulative Unsuccess Rate

Tar

S ummary S tats

10.0

(95.0% confidence)

% D efectiv e:
Low er C I:
U pper C I:
Target:
P P M D ef:

5
4
3
2
5

10

15
M onth

20

25

Low er C I:
U pper C I:
P rocess Z:
Low er C I:
U pper C I:

4.37
2.79
6.49
0.00
43726
27917
64891
1.7090
1.5150
1.9123

Fr equency

C umulative Unsuccess Rate

P r opor tion

U C L=0.1809
0.15

7.5

Binomial process
capability index:
0.569

5.0
2.5
0.0

3
6
9
12
% Unsuccess Rate

18

Paradigm Shift Culture of Quality

Manufacturers take full responsibility for
quality of their products

Focus on meeting patients expectations

Regulators expectations considered minimal
approach

Strive for continual improvement

Management and organizational commitment
to prioritizing quality
Each person in organization understands and
embraces their role in quality

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Summary
Brief introduction of control chart: history, definition, types
Key considerations for constructing a control chart:
Choice of drug product quality characteristics
Subgroup size and sampling frequency
Statistical process control limits (UCL and LCL)

Illustrative examples for process monitoring and control:

Within batch variability
Between batch variability
Site performance monitoring
Control Chart can be a valuable tool to:
Proactively monitor and trend a process
Detect the presence of special cause variation
Identify continual improvement opportunities
Maintain the process in a state of statistical control

20

Acknowledgements
Dr. Christine Moore
Dr. Naiqi Ya
Dr. Ubrani Venkataram

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