Measure

Step-4

Pareto Chart of Potential Causes of Failure Mod

2000
100
1500 80

Percent
Count

1000 60
40
500
20
0 0
Potential Causes of Failure Mod e y t x l x r
u um tu r ti t r ke f l u an o fl u CM th e
c a a n a r e h e
r by S O
r v a per q u t m in met ng
l a s r i n
de t em n o ty los y o
f
du giv
e
u n on t ha bil i ol t ly s
A ti M e a ila a n g q pe r ec
TE ac v t h n o s p
ig ng R
e
al a M e Wro pr ng
ar ri ed o
h ate a in Wr
C M
a int
o tm
n
p
m
Te

Count 600 420 400 240 32 32 21 16 14

Percent 33.8 23.7 22.5 13.5 1.8 1.8 1.2 0.9 0.8
Cum % 33.8 57.5 80.0 93.5 95.3 97.1 98.3 99.2100.0

The most significant factors can be seen from the

FMEA table and the pareto chart
 Analyze
Passive Data Analysis Step-1
I Chart of Yieldbefore process improvement

UCL=0.7599
0.75

0.70
Individual Value

_
X=0.6633 Target yield: 0.75
0.65

0.60

LCL=0.5666
0.55
2 4 6 8 10 12 14 16
Observation

Past data analysis shows that the average yield in the plant was
0.6633 with base - methanol route batches as against a minimum
yield of 0.75 with Base IPA route.
 DOE: First set of Improve
Step-1
experiments
StdOrder RunOrder MeOH Vol Reflux temp yield purity
•Design – Multilevel full
6 1 2.5 65-70 0.515 85.03
factorial design
2 2 1.5 65-70 0.57 84.5
4 3 2 65-70 0.624 90.82 •Number of factors – 2
1 4 1.5 60-65 0.586 83.9
•Total number runs - 12
5 5 2.5 60-65 0.52 81
3 6 2 60-65 0.628 86.5
11 7 2.5 60-65 0.548 84.6
7 8 1.5 60-65 0.56 85.5
8 9 1.5 65-70 0.55 86
9 10 2 60-65 0.624 86.8
12 11 2.5 65-70 0.53 87
10 12 2 65-70 0.65 89.5

Responses
(Y’s)
 DOE:Analysis of first set of Improve

experiments
Main Effects Plot (data means) for yield
Step-2

MeOH Vol Reflux temp

0.64

0.62

0.60
Mean of yield

Main effects of the individual factors

0.58 clearly shows that : i) yield is maximum
at 2 volume of methanol and ii) Almost
0.56
constant at 65-70 deg C
Define 0.54

Measure
0.52
Analyze 1.5 2.0 2.5 60-65 65-70
Improve
•DOE
Interaction Plot (data means) for yield
•Control 60-65 65- 70
0.65
M eO H
Vol
1.5
0.60 2.0
2.5
Me OH Vol

0.55 The interaction of the two

0.65
factors(MeOH vol and Temp) shows
Reflux
temp that the yield is maximum at 2 vol of
60-65
0.60 65-70 methanol when the temperature is
Reflux temp maintained at 65-70 deg C
0.55

1.5 2.0 2. 5
 DOE:Analysis of first set of Improve

experiments
Main Effects Plot (data means) for purity
Step-2

MeOH V ol Reflux temp

89

88
Mean of purity

87

86

85
Define
Measure 84
Analyze 1.5 2.0 2.5 60-65 65-70 Main effects and interaction effects
Improve shows that the purity is higher when the
•DOE setting is kept at 2 vol methanol with 65-
Interaction Plot (data means) for purity
•Control 60-65 65-70
70 deg C
90 MeOH
Vo l
1.5
88
2.0
2.5
MeOH Vol 86

84

82
90 Reflux
temp
88 60-65
65-70

86 Reflux temp

84

82
1.5 2.0 2.5
 DOE:Analysis of first set of Improve
experiments Step-2
Factor Type Levels Values
MeOH Vol fixed 3 1.5, 2.0, 2.5
Reflux temp fixed 2 60-65, 65-70

Analysis of Variance for yield, using Adjusted SS for Tests

Source DF Seq SS Adj SS Adj MS F P

MeOH Vol 2 0.0217982 0.0217982 0.0108991 47.10 0.000
Reflux temp 1 0.0000608 0.0000608 0.0000608 0.26 0.627
MeOH Vol*Reflux temp 2 0.0003615 0.0003615 0.0001808 0.78 0.499
Error 6 0.0013885 0.0013885 0.0002314
Total 11 0.0236089
Define R-Sq = 94.12% R-Sq(adj) = 89.22%
S = 0.0152124
Measure
Analyze Analysis of Variance for purity, using Adjusted SS for Tests

Improve Source DF Seq SS Adj SS Adj MS F P

•DOE MeOH Vol 2 37.423 37.423 18.711 9.56 0.014
Reflux temp 1 17.642 17.642 17.642 9.02 0.024
•Control MeOH Vol*Reflux temp 2 5.317 5.317 2.658 1.36 0.326
Error 6 11.742 11.742 1.957
Total 11 72.123

S = 1.39891 R-Sq = 83.72% R-Sq(adj) = 70.15%

Results : As p value is less than0.05 for methanol vol and

reflux temp, the factors are important for the responses i.e.
yield and purity
 DOE:Analysis of first set of Improve
experiments Step-2

Contour Plot of purity vs Reflux temp, MeOH Vol

purity
< 83
67
83 - 84
84 - 85
85 - 86
86 - 87
66 87 - 88
88 - 89
Reflux temp > 89
Define
65
Measure
Analyze
Improve 64

•DOE
MeOH Vol = 2.02363
•Control 63 Reflux temp = 67.4690
purity = 89.6119

1.50 1.75 2.00 2.25 2.50

MeOH Vol

The contour plot also shows that purity of oxime is more at 2.023
vol of methanol at 67.5 deg C temperature (65-70)
 DOE: First set of Improve
Step-3
experiments
Learning
•From the first set of DOE it is clear that methanol setting at 2 volume
and temperature setting at 65-70 deg C (reflux) gives the maximum
yield and purity.
•From earlier plant/R&D trials kit is clear that with more volume of
methanol yields are low.

Path forward
•Based on the result of first set of DOE it is decided to have a
confirmatory runs at the critical values to firm up the process as CCD is
not possible for temp range settings of 65-70 deg C.
•Experiments planned with both TiOC Methanol and Base Methanol at
R&D with new process parameter obtained from DOE
 Improve
Actions taken Step 6
•First 6 batches demo given to plant with different batch sizes over a period of
time (TiOC : MeOH Rt)
•Next 10 batches were done by plant independently

TiOC Potency Output

Sl. No Batch No. Input kg Methanol TEA kg Yield HPLC purity
Batch No. mcg/mg kg
1 050 004 50 821 80 21.2 30 0.6 87.45
2 057 007 50 810 80 21.2 29.5 0.59 87.88
3 067 009 125 813 200 53 75.89 0.60712 89.01
4 096 010 250 800 400 106 151 0.604 85.03
5 097 010 125 800 200 53 74.9 0.5992 90.82
6 099 010 250 800 400 106 153.4 0.6136 89.47
7 100 010 125 800 200 53 73.7 0.5896 89.232
8 101 010, 011 125 800,796 200 53 75.4 0.6032 86.547
9 102 011 250 796 400 106 148.9 0.5956 82.34
10 103 011 125 796 200 53 73.9 0.5912 86
11 107 011 125 796 200 53 76.3 0.610 90.82
12 108 011 250 796 400 106 149.8 0.5992 89.47
13 109 012 125 796 200 53 70 0.56 89.4
14 110 012 250 800 400 106 144.6 0.5784 86
15 111 012 125 800 200 53 71.5 0.572 89.232
16 112 012 125 800 200 53 71.3 0.5704 88
 Improve
Actions taken Step 6
I Chart of Y ield
0.63
UCL=0.62716
0.62

0.61
Individual Value
0.60
_
X=0.59272
0.59

0.58

Define 0.57
Measure 0.56 LCL=0.55828
Analyze
0.55
Improve 2 4 6 8 10 12 14 16
Observation The plant demo batches ( TiOC
MeOH) shows that the mean yield is
I Chart of HPLC purity 0.592 with a average purity of
Control 96 87.92%
UCL=94.58
94

92
Individual Value

90
_
88 X =87.92

86

84

82
LCL=81.26
80
2 4 6 8 10 12 14 16
Observation
 Improve
Actions taken Step 6
S ummar y for Y ield at plantTiOC Methanol
A nde rson -D arlin g N orm alit y T est
A -S q uared 0. 47
P -V a lue 0.2 14

M ea n 0. 592 72
S tD e v 0. 015 38
V aria nce 0. 000 24
S kew ne ss -0.7 804 60
K urto sis -0.1 844 92
N 16

M inim um 0. 560 00
1 st Q ua rtile 0. 581 20
Define M ed ian 0. 597 40
3 rd Q ua rtile 0. 603 80
Measure 0.56 0.57 0.58 0.59 0.60 0.61
M axi mu m 0. 613 60
Analyze 95 % C on fide nce In terv al f or M ea n
0 .58 453 0. 600 91
Improve 95% C onf iden ce Inte rv a l fo r M edi an
0 .58 694 0. 603 39

9 5% C onfidence I nte rv als 95 % C on fide nce Int erv al f or S tD e v

0 .01 136 0. 023 80
Me an
Control
M edi an

0.585 0.590 0.595 0.600 0.605

The graphical summary shows that with 95% confidence interval the
average yields will be between 0.584 to 0.601
 Improve
Actions taken Step 6
Following batches were from Base MeOH route in the plant
AZD1
AZD1 Out put In Purity by
SL.NO Batch Size Potency Methanol TEA HAH Yield
Batch No Kg Hplc
Kg
1 078 100 954 200 53 47.5 77.5 0.775 90.94
2 082 100 954,951 200 53 47.5 75.2 0.752 93.95
5 091 100 967 200 53 47.5 72.2 0.722 92.79
6 092 200 967 400 106 95 152 0.76 91.25
7 104 100 967 200 53 47.5 77 0.77 90.78
8 105 200 967 400 106 95 154 0.77 92.3
Define
Measure Summary for Y ield Base MeOH Plant
A nderson-D arling N orm ality T est
Analyze A -S quared 0.50
P -V alue 0.123
Improve M ean 0.75817
S tD ev 0.01956
V ariance 0.00038
S kew ness -1.58170
K urtosis 2.51166
Control N 6
M inim um 0.72200
1st Q uartile 0.74450
M edian 0.76500
3rd Q uartile 0.77125
0.72 0.73 0.74 0.75 0.76 0.77 M axim um 0.77500
95% C onfidence I nterv al for M ean
0.73764 0.77869
95% C onfidence I nterv al for M edian
0.73271 0.77321

9 5 % Confidence Intervals 95% C onfidence I nterv al for S tD ev

0.01221 0.04797
Mean

Median

0.73 0.74 0.75 0.76 0.77 0.78

Average yield obtained for 6 batches is o.758 over a period

of time
 Improve
Actions taken Step 6

Two-Sample T-Test and CI: AZD I yield, Stage

Two-sample T for AZD I yield

Stage N Mean StDev SE Mean

After 6 0.7582 0.0196 0.0080
Before 16 0.6633 0.0345 0.0086

Difference = mu (After) - mu (Before)

Estimate for difference: 0.094917
95% lower bound for difference: 0.068931
T-Test of difference = 0 (vs >): T-Value = 6.30 P-Value = 0.000 DF = 20
Both use Pooled StDev = 0.0315

•Two-Sample T-Test clearly shows the difference of the yields Before and after
modification of the process.
•After modification of process the yield is more than before modification of the
process
 Improve
Actions taken Step 6

Boxplot of AZD I yield by Case

0.80

AZD I yield 0.75

0.70

0.65

0.60

Before After
Case

The box plot shows the yield improvement after the process
change in the Base-Methanol Rt. and also the reduction in
yield variation
 Control
Control Plan Step-1

Month Batch No Input Output yield Month Batch No Input Output yield Month Batch No Input Output yield
Oct-05 238 125 75 0.600 Nov-05 277 125 73.75 0.59 Dec-05 285 125 75 0.600
Oct-05 239 250 145 0.580 Nov-05 278 125 75 0.6 Dec-05 286 125 74 0.592
Oct-05 240 125 75 0.600 Nov-05 279 125 74 0.592 Dec-05 287 250 147 0.588
Oct-05 241 125 74 0.592 Nov-05 280 250 150 0.6 Dec-05 288 125 73 0.584
Oct-05 242 250 145 0.580 Nov-05 281 125 75 0.6 Dec-05 290 125 75 0.600
Oct-05 243 125 76 0.608 Nov-05 282 125 73.75 0.59 Dec-05 291 125 75 0.600
Oct-05 244 125 75 0.600 Nov-05 283 125 76 0.608 Dec-05 293 125 73 0.584
Oct-05 245 250 145 0.580 Nov-05 284 250 152 0.608 Dec-05 294 125 74 0.592
Oct-05 246 125 75 0.600 1250 749.5 0.600 Dec-05 298 125 75 0.600
Oct-05 247 125 76 0.608 Dec-05 299 125 75 0.600
Oct-05 248 250 145 0.580 Dec-05 301 125 75 0.600
Oct-05 249 125 75 0.600 Dec-05 302 125 75 0.600
Oct-05 250 125 75 0.600 Dec-05 304 125 75 0.600
Oct-05 251 250 145 0.580 Dec-05 305 125 77 0.616
Oct-05 252 125 75 0.600 Dec-05 310 125 77 0.616
Oct-05 253 125 75 0.600 Dec-05 311 125 76.6 0.613
Oct-05 254 250 150 0.600 2125 1271.6 0.598
Oct-05 255 125 75 0.600
Oct-05 257 250 150 0.600
Oct-05 263 125 74 0.592
Oct-05 264 125 76 0.608
Oct-05 265 250 152 0.608
Oct-05 266 250 151 0.604
4000 2379 0.595

The above data shows the yield of Q3 taken after three months of the
completion of the project for TiOC-MeOH
 Control
Control plan Step-1

I Chart of AZD I yield for Q3

UCL=0.62195
0.62

0.61
Define
Individual Value

Measure
0.60 _
Analyze X=0.59772
Improve
0.59

Control
Control plan 0.58

LCL=0.57350
0.57
5 10 15 20 25 30 35 40 45
Observation

The I Chart shows the yield of Q-3 (TiOC-methanol)

matching exactly with the demonstration batches as per
modified process in the plant
 Control
Control plan
Step-1
Process Capability Sixpack of AZD I yield
I C ha r t C apa bility H isto gr a m
0.62 UCL=0.62195

Individual Va lue
_
0.60 X=0.59772

0.58
LC L=0.57350
5 10 15 20 25 30 35 40 45 0.58 0.59 0.60 0.61 0.62

Mov ing Range C har t Nor ma l P r ob Plot

0.030 UCL=0.02976
A D: 2.250, P: < 0.005
Moving Range

0.015
__
MR=0.00911

0.000 LC L=0
5 10 15 20 25 30 35 40 45 0.58 0.60 0.62

La st 25 O bse r va tio ns C apa bility P lot

0.62 Within
Within O v e rall
StDe v 0.00808 StD ev 0.00939
Values

0.60
Cp 1.44 Overall
Pp 1.24
C pk 1.14 Ppk 0.98
C C pk 1.44 C pm *
0.58 Specs

25 30 35 40 45
Observation

The I Chart shows the yield of Q-3 (TiOC-methanol)

matching exactly with the demonstration batches as per
modified process in the plant