Aula -

Towards Process Understanding:
statistical analysis applied to the
manufacturing process of tablets
Nadia Bou-Chacra
Faculty of Pharmaceutical Sciences
University of Sao Paulo, Brazil
Drug Product Development: A QbD Approach

OUTLINES
• FDA´s New Process Validation Guidance;
• Measurement system variability: precision to tolerance ratio;
• Understanding the Cause of Process Variability;
• Control charts: Is your process out of control?
• Nested ANOVA model applied to evaluate variability;
• Estimating process capability indices.

Case Study
• Application of PAT in Captopril (25 mg) tablet process
evaluation using NIR spectroscopy.

FDA´s New Process Validation Guidance
• strongly emphasizes that the pharmaceutical industry has to
understand process variation including all sources and
degrees of variation and ultimately the impact of variation on
any product attributes.

FDA´s New Process Validation Guidance
•Process validation is defined as the collection and evaluation of
data, from the process design stage through commercial
production, which establishes scientific evidence that a process
is capable of consistently delivering quality product.
•“….develop the data collection plan and statistical methods
used in measuring and evaluating process stability and process
capability.”

MEASUREMENT SYSTEM VARIABILITY:
PRECISION TO TOLERANCE RATIO

2
Real (Process) + 2
Measurement System = 2
Total
a
b

100
LSL
USL
6σMS

%P/T =
Precision/Tolerance ratio:
( MS/ total) 100
%RR =
Precision/Total Variation ratio:
(R&R) is the estimate of the combined variation from repeatability and reproducibility.

If %P/T < 10% and %RR < 10% Good!
If 10% < %P/T < 30% and/or 10% < %RR < 30% Ok
If %P/T > 30% or %RR > 30% Bad!!!!

105,0
103,5
102,0
100,5
99,0
97,5
96,0
25
20
15
10
5
0
Frequency
95 105
Mean 100,0
StDev 0,4746
N 100
Normal
Histogram of Dosage-unit uniformity Lamivudine (%w/w)

104
102
100
98
96
94
30
25
20
15
10
5
0
Frequency
95 105
Mean 99,84
StDev 1,800
N 100
Normal

108
105
102
99
96
93
90
30
25
20
15
10
5
0
Frequency
90 110
Mean 99,84
StDev 1,800
N 100
Normal

UNDERSTANDING THE CAUSE OF
PROCESS VARIABILITY

Two causes of variation: common and special
• Common (random) cause variation is inherent in the
manufacturing process as result of the process design,
machinery and activities;
• Special (assignable) cause variation is created by a non-
random event leading to an unexpected change in the process
output. The effects are intermittent and unpredictable. It is
caused by factors that can be clearly identified and possibly
managed.

CONTROL CHARTS: IS YOUR PROCESS
OUT OF CONTROL?

Control chart: Control limits versus Spec limits
Spec limits or tolerances ensure safety, efficacy and quality of medicines.
Control limits:
• Characteristic of the process in question;
• Dependent on sampling
parameters, sample size,
alpha-risk (Type I error);
• Used to identify
presence/absence
of special-cause variation;
• Based on the process mean
and variation.

Special causes
1072
953
834
715
596
477
358
239
120
1
115
110
105
100
95
90
85
Observation
Individual
Value
_
X=101,12
UCL=109,17
LCL=93,07
85 LSL
115 USL
5
3
5
6
3
6
6
6
6
6
6
6
6
2
2
2
2
2
2
2
2
5
2
6
6
5
6
6
5
5
6
5
5
5
5
6
5
4
4
4
4
6
5
6
6
5
6
5
6
6
2
2
2
5
5
5
6
5
5
6
6
8
5
6
6
2
2
2
2
2
2
6
5
5
6
5
5
6
6
2
5
5
5
6
6
2
2
5
6
6
6
6
6
6
6
6
6
5
5
2
2
1
3
3
3
3
3
3
3
3
3
6
5
2
2
2
2
6
I Chart of Dosage-unit Uniformity of Captopril tablets 25 mg

Capability indices: Cp and Cpk
105,0
103,5
102,0
100,5
99,0
97,5
96,0
0,9
0,8
0,7
0,6
0,5
0,4
0,3
0,2
0,1
0,0
95 105
100
Normal
Cp < Cp
+3𝜎

Process Capability Indices: Cp and CpK

Anderson-Darling Normality Test
• The Anderson-Darling test for normality is one of three
general normality tests designed to detect all departures from
normality. The test rejects the hypothesis of normality when
the p-value is less than or equal to 0.05.

APPLICATION OF PROCESS ANALYTICAL
TECHNOLOGY (PAT) AT IN CAPTOPRIL (25 MG)
TABLET PROCESS EVALUATION USING NEAR
INFRA RED (NIR) SPECTROSCOPY

Assays Sample Position Number of samples Total
Blending
uniformity
10 3 samples for each location 30 (1 batch)
90 (3 batches)
Tablet weight* 20 units each 12
minutes
600 units for each side
(left and right)
1,200 (1 batch)
3,600 (3 batches)
Uniformity of
dosage unit
6 units each 12
minutes
198 units for each side
(left and right)
396 (1 batch)
1,188 (3 batches)
% (w/v) release Beginning
Middle
End
6 units for each position
(3 for each side: left and
right)
18 (1 batch)
54 (3 batches)
Batch size: 270.8 kg; aprox.: 2,000000 units (134 mg); cycle time: 360 min.
Table 1. Sample plan for the process validation of Captopril tablets 25 mg

The content homogeneity of the
powder mixture (blend uniformity)
in the process manufacturing of
Captopril tablets 25 mg

3
2
1
100,2
99,9
99,6
Subgr
oup
M
ean
_
X=99,9371
UC L=100,2871
LC L=99,5872
3
2
1
0,4
0,2
0,0
M
R
of
Subgr
oup
M
ean
__
MR=0,1316
UC L=0,4299
LC L=0
3
2
1
1,2
0,9
0,6
Sample
Sample
StDev
_
S=0,9872
UC L=1,3777
LC L=0,5967
I-MR-R/S (Between/Within) Chart of Blend Uniformity Captopril tablets 25 mg

Table 1a. Nested ANOVA: Estimated Variance Component for
Blending Uniformity Captopril 25 mg.
Source Variance Component % of Total Standard Deviation
Batch -0.027 0.00 0.00
Position 0.037 3.71 0.191
Error 0.952 96.29 0.976
Total 0.988 0.994
** Value is negative, and is estimated by zero

Normality test: blend uniformity
103
102
101
100
99
98
97
99,9
99
95
90
80
70
60
50
40
30
20
10
5
1
0,1
Blend Uniformity
Percent
Mean 99,94
StDev 0,9843
N 90
AD 0,198
P-Value 0,884
Probability Plot of Blend Uniformity
Normal
105,0
103,5
102,0
100,5
99,0
97,5
96,0
20
15
10
5
0
Blend Uniformity
Frequency
95 105
Mean 99,94
StDev 0,9843
N 90
Normal
Histogram of Blend Uniformity Captopril tablets 25mg
Variable N N* Mean StDev Median Minimum Maximum
Blend
Uniformity
90 0 99.937 0.984 99.931 97.144 102.101
Table 1b. Descriptive statistics: blend uniformity

105,0
103,5
102,0
100,5
99,0
97,5
96,0
LSL USL
LSL 95
Target *
USL 105
Sample Mean 99,9371
Sample N 90
StDev(Within) 1,04923
StDev(Overall) 0,98434
Process Data
Lower CL 1,44
Upper CL 1,94
PPL 1,67
PPU 1,71
Ppk 1,67
Lower CL 1,42
Upper CL 1,93
Cpm *
Lower CL *
Cp 1,59
Lower CL 1,36
Upper CL 1,82
CPL 1,57
CPU 1,61
Cpk 1,57
Lower CL 1,33
Upper CL 1,81
Pp 1,69
Overall Capability
Potential (Within) Capability
PPM < LSL 0,00
PPM > USL 0,00
PPM Total 0,00
Observed Performance
PPM < LSL 1,27
PPM > USL 0,70
PPM Total 1,97
Exp. Within Performance
PPM < LSL 0,26
PPM > USL 0,13
PPM Total 0,40
Exp. Overall Performance
Within
Overall
Process Capability of Blend Uniformity Captopril tablets 25 mg
(using 95,0% confidence)

Double sided rotary press 3200i
700,000 tablets/hour
Evaluation of the individual
tablet weight (mg) in the
process manufacturing of
Captopril tablet 25 mg

3241
2881
2521
2161
1801
1441
1081
721
361
1
150
140
130
120
Observation
Individual
Value
_
X=133,95
UCL=143,75
LCL=124,14
A B C
126
142
3241
2881
2521
2161
1801
1441
1081
721
361
1
20
15
10
5
0
Observation
Moving
Range
__
MR=3,69
UCL=12,04
LCL=0
A B C
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
I-MR Chart of Captopril Tablet Weight (mg)

3
2
1
135,0
133,5
132,0
Subgr
oup
M
ean
_
X=133,464
UC L=135,261
LC L=131,666
3
2
1
2
1
0
M
R
of
Subgr
oup
M
ean
__
MR=0,676
UC L=2,208
LC L=0
3
2
1
3,6
3,4
3,2
Sample
Sample
StDev
_
S=3,4712
UC L=3,6839
LC L=3,2585
I-MR-R/S (Between/Within) Chart of Tablet Weight by batch

Table 2a. Nested ANOVA: Estimated Variance Component for Tablet Weight
Captopril 25 mg.
Source Variance component % of Total Standard Deviation
Batch 0.551 4.31 0.742
Side (Left and Right) -0.163** 0.00 0.000
Time* 0.537 4.21 0.733
Error 12.245 91.48 3.418
Total 13.057 - 3.574
*B: beginning; M: middle; E: end

Normality test: tablet weight
Variable N N* Mean StDev Median Min Max
Tablet
weight
3600 0 133.46 3.52 133.00 118.00 150.00
Table 2b. Descriptive statistics: tablet weight

150
145
140
135
130
125
120
LSL USL
LSL 126
Target *
USL 142
Sample Mean 133,464
Sample N 3600
Process Data
Lower CL 0,74
Upper CL 0,77
PPL 0,71
PPU 0,81
Ppk 0,71
Lower CL 0,69
Upper CL 0,73
Cpm *
Lower CL *
Cp 0,84
Lower CL 0,82
Upper CL 0,86
CPL 0,78
CPU 0,90
Cpk 0,78
Lower CL 0,76
Upper CL 0,81
Pp 0,76
Overall Capability
PPM < LSL 8055,56
PPM > USL 7777,78
PPM Total 15833,33
PPM < LSL 9285,82
PPM > USL 3549,27
PPM Total 12835,09
PPM < LSL 17109,78
PPM > USL 7724,90
PPM Total 24834,68
Within
Overall
Process Capability of Tablet Weight Captopril 25 mg

Evaluation of the uniformity of dosage
unit in the process manufacturing of
Captopril tablets 25 mg

1072
953
834
715
596
477
358
239
120
1
110
100
90
Observation
Individual
Value
_
X=101,14
UCL=109,36
LCL=92,92
85 LSL
115 USL
1072
953
834
715
596
477
358
239
120
1
10,0
7,5
5,0
2,5
0,0
Observation
Moving
Range
__
MR=3,09
UCL=10,09
LCL=0
1
1
1
1
1
1
1
1
1
1
1
1
1
I-MR Chart of Dosage-unit Uniformity Captopril tablets 25 mg

1072
953
834
715
596
477
358
239
120
1
110
100
90
Observation
Individual
Value
_
X=101,10
UCL=109,22
LCL=92,98
204L 207L 214L
85 LSL
115 USL
1072
953
834
715
596
477
358
239
120
1
10,0
7,5
5,0
2,5
0,0
Observation
Moving
Range
__
MR=3,05
UCL=9,97
LCL=0
204L 207L 214L
1
1
1
1
1
1
1
1
1
1
I-MR Chart of Dosage-unit Uniformity by Batch Captopril tablets 25 mg

3
2
1
105
100
95
Subgr
oup
M
ean
_
X=101,14
UC L=106,03
LC L=96,25
3
2
1
5,0
2,5
0,0
M
R
of
Subgr
oup
M
ean
__
MR=1,840
UC L=6,011
LC L=0
3
2
1
3,3
3,0
2,7
Sample
Sample
StDev
_
S=3,0664
UC L=3,3938
LC L=2,7390
I-MR-R/S (Between/Within) Chart of Dosage-unit Uniformity Captopril tablets 25 mg

Table 3a. Nested ANOVA: Estimated Variance Component for
uniformity of dosage unit (%w/w) Captopril 25 mg.
Source Variance Component % of Total Standard Deviation
Batch 1.493 13.62 1.222
Side -0.016** 0.00 0.00
Position* 0.280 2.55 0.529
Error 9.185 83.82 3.031
Total 10.958 3.310

Normality test: uniformity of dosage unit
115
110
105
100
95
90
99,99
99
95
80
50
20
5
1
0,01
Dosage-unit Uniformity
Percent
Mean 101,1
StDev 3,230
N 1188
AD 5,686
P-Value <0,005
Probability Plot of Dosage-unit Uniformity Captopril tablets 25 mg
Normal
112
108
104
100
96
92
88
80
70
60
50
40
30
20
10
0
Frequency
85 115
Mean 101,1
StDev 3,230
N 1188
Normal
Histogram of Dosage-unit Uniformity Captopril tablets 25 mg
Uniformity of
Dosage unit
1188 0 101.14 3.23 101.50 93.60 110.70
Table 3b. Descriptive statistics: uniformity of dosage unit

112
108
104
100
96
92
88
LSL USL
LSL 85
Target *
USL 115
Sample Mean 101,14
Sample N 1188
Process Data
Lower CL 1,49
Upper CL 1,61
PPL 1,67
PPU 1,43
Ppk 1,43
Lower CL 1,37
Upper CL 1,49
Cpm *
Lower CL *
Cp 1,83
Lower CL 1,75
Upper CL 1,90
CPL 1,96
CPU 1,69
Cpk 1,69
Lower CL 1,62
Upper CL 1,76
Pp 1,55
Overall Capability
PPM < LSL 0,00
PPM > USL 0,00
PPM Total 0,00
PPM < LSL 0,00
PPM > USL 0,21
PPM Total 0,21
PPM < LSL 0,29
PPM > USL 8,89
PPM Total 9,18
Within
Overall
Process Capability of Dosage-unit Uniformity Captopril tablets 25 mg

Evaluation of % (w/v) release of Captopril
in the process manufacturing of Captopril
tablets 25 mg

51
46
41
36
31
26
21
16
11
6
1
120
110
100
90
80
Observation
Individual
Value
_
X=101,69
UCL=112,71
LCL=90,66
80 LSL (Q)
51
46
41
36
31
26
21
16
11
6
1
15
10
5
0
Observation
Moving
Range
__
MR=4,14
UCL=13,54
LCL=0
1
1
1
I-MR Chart of %(w/v) Captopril Release

51
46
41
36
31
26
21
16
11
6
1
114
108
102
96
90
Observation
Individual
Value
_
X=102,84
UCL=113,78
LCL=91,90
204L 207L 214L
51
46
41
36
31
26
21
16
11
6
1
16
12
8
4
0
Observation
Moving
Range
__
MR=4,11
UCL=13,44
LCL=0
204L 207L 214L
I-MR Chart of %(w/v) Captopril Release by Batch

3
2
1
105
100
95
Subgr
oup
M
ean
_
X=101,69
UC L=106,91
LC L=96,46
3
2
1
5,0
2,5
0,0
M
R
of
Subgr
oup
M
ean
__
MR=1,965
UC L=6,419
LC L=0
3
2
1
8
6
4
Sample
Sample
StDev
_
S=5,408
UC L=8,211
LC L=2,606
I-MR-R/S (Between/Within) Chart of %(w/v) Captopril Release

Table 4. Nested ANOVA: Estimated Variance Component for
%(w/v) Captopril Release.
Source Variance component % of Total Standard Deviation
Batch -3.912** 0.00 0.00
Position* 23.170 63.23 4.814
Error 13.474 36.77 3.671
Total 36.644 6.053

Normality test: %(w/v) release
115
110
105
100
95
90
99
95
90
80
70
60
50
40
30
20
10
5
1
Percent
Mean 101,7
StDev 5,639
N 54
AD 0,787
P-Value 0,039
Probability Plot of Captopril %(v/w) Release
Normal
114
108
102
96
90
84
16
14
12
10
8
6
4
2
0
%(v/w) Release
Frequency
80
Mean 101,7
StDev 5,639
N 54
Normal
Histogram of Captopril %(v/w) Release
% (w/w)
Release
54 0 101.69 5.64 102.21 90.37 115.61
Table 4b. Descriptive statistics: % (w/w) Captopril Release

120
114
108
102
96
90
84
LSL USL
LSL 80
Target *
USL 120
Sample Mean 101,686
Sample N 54
Process Data
Lower CL 0,96
Upper CL 1,41
PPL 1,28
PPU 1,08
Ppk 1,08
Lower CL 0,86
Upper CL 1,31
Cpm *
Lower CL *
Cp 1,81
Lower CL 1,47
Upper CL 2,16
CPL 1,97
CPU 1,66
Cpk 1,66
Lower CL 1,33
Upper CL 1,99
Pp 1,18
Overall Capability
PPM < LSL 0,00
PPM > USL 0,00
PPM Total 0,00
PPM < LSL 0,00
PPM > USL 0,31
PPM Total 0,31
PPM < LSL 60,15
PPM > USL 581,81
PPM Total 641,96
Within
Overall
Process Capability of %(w/v) Captopril Release

Conclusion
• The statistical approach used in the process evaluation of
blending, tableting, dosage-unit uniformity, weight variation
and dissolution behavior led to better understanding of the
manufacturing process.
• Although a limited number of batches were investigated, the
statistical methods identified possible approaches for process
improvement in the manufacturing of Captopril tablets.

References
• FDA, Current Good Manufacturing Practices for Drugs: Reports, Guidance and
Additional Information. Pharmaceutical (cGMP) for the 21st century: a risk based
approach. (Rockville, MD, 2002).
• FDA, Guidance for Industry: Process validation: General Principles and Practices,
Jan. 25, 2011.
• ICH, Q8(R1) Pharmaceutical development, ich.org/LOB/media/MEDIA4986.pdf,
accessed Dec. 11, 2009.
• ICH, Q10 Pharmaceutical Quality System, ich.org/LOB/media/MEDIA3917.pdf,
accessed Dec. 11, 2009.
• ICH, Q9 Quality Risk Management, ich.org/LOB/media/MEDIA1957.pdf, accessed
Dec. 11, 2009.

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