preliminary design space
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1
NIPTE-FDA Collaborative Case StudyOn Model-based Design Space Development
Across Scales & with Stability Considerations
Preliminary Design Space
2
QbD process
Define Target Product Profile (TPP)Derive Quality Attributes from TPP
Propose Manufacturing ProcessRisk Analysis (FMEA)
Risk Evaluation (Risk-based Classification)
Propose Parameters to Investigate (e.g., by DOE)
PROCESS DESIGN SPACE
3
Basic Processing SequenceRA Results
CPPs
5
Design Space Definition
• For each unit op establish functional relationships of CPP and CQA of input materials with CQA of output materials– e.g. disintegration time ~ compression force and
hydrophobicity• Establish interactions between unit ops
– e.g. hardness ~ PSD and compression force• Establish design space boundaries by propagating
backwards limits imposed on final product CQAs
6
Design Space Definition
courtesy: Dr. Steef. Boerrighter, Purdue University
7
Preliminary Design Space
• Considered– Degradation
• NMT 0.4 mole % lactam– Hardness
• NLT 3 kP– Weight variation
• 90 % - 110%• % RSD NMT 6%
• DS definition for 15 CPPs• Interactions were established for some CPPs
– one or more slides included to describe those interactions
• There were no significant interactions for few CPPs– ranges for those are shown in slide 18
8
Tablet Hardness ~ Intermediate CQA
Com
pres
sion
For
ce
Bulk density 0.52 kg/m3
1500
2000
2500
3000
Mea
n C
omp.
For
ce
Mean Hardness
280 290 300 310 320 330 340 350Median PS
1.5
2
2.5
3
3.5
4
4.5
5
Mea
n H
ardn
ess
Act
ual
1.5 2 2.5 3 3.5 4 4.5 5Mean Hardness Predicted
P<.0001 RSq=0.98 RMSE=0.1178
1500
2000
2500
3000
Mea
n C
omp.
For
ce
Mean Hardness
280 290 300 310 320 330 340 350Median PS
Bulk density 0.46 kg/m3
Median PSMedian PS
9
Tablet Hardness ~ Intermediate CQA
PAT application:Real time measurement
of bulk density and particle size
10
Tablet Hardness ~ Tabletting CPP
Min
Pun
ch G
ap
Press speed 63360 tab/hr
4.3
4.4
4.5
4.6
4.7
Min
Pun
ch G
ap
Tablet Hardness
3.55 3.6 3.65 3.7 3.75 3.8 3.85Compression height (mm)
4.3
4.4
4.5
4.6
4.7
Min
Pun
ch G
ap
Tablet Hardness
3.55 3.6 3.65 3.7 3.75 3.8 3.85Compression height (mm)
1
2
3
4
5
6
7
Table
tH
ard
ness
Act
ual
1 2 3 4 5 6 7Tablet Hardness Predicted
P<.0001 RSq=0.62 RMSE=0.6823
Press speed 21120 tab/hr
Comp. HeightComp. Height
11
Preliminary Tabletting Design Space
12
Blending
12
15 RPM, 50% 15 RPM, 80% 25 RPM, 50% 25 RPM, 80%0
0.002
0.004
0.006
0.008
0.01
0.012
0.014
0.016
0.018
STS
Significant increase in STS at extreme
conditions
13
Tablet Hardness ~ Drying CPP
EEF
0.2
0.25
0.3
0.35
0.4
0.45
EE
F
1500 2000 2500 3000Mean Comp. Force
0.2
0.25
0.3
0.35
0.4
0.45
EE
F
1500 2000 2500 3000Mean Comp. Force
End Moisture Target = 0.5%
End Moisture Target = 1%
Comp. Force Comp. Force
14
L0, D0 ~ Drying CPP
0.011
0.0115
0.012
0.0125
0.013
0.0135
0.014
0.0145
Gra
n In P
roc
Lacta
m A
ctu
al
0.011 0.012 0.013 0.014Gran In Proc Lactam Predicted
P=0.0816 RSq=0.65 RMSE=0.0007
0.009
0.01
0.011
0.012
0.013
0.014
0.015
Gra
n L
acta
mR
ate
Actu
al
0.009 0.010.011 0.013 0.015Gran Lactam Rate Predicted
P=0.0483 RSq=0.71 RMSE=0.0013
D0,
crys
tal d
amag
e
L 0, i
n-pr
oces
s la
ctam
X – Wet Massing TimeY – Water Content
15
Preliminary Drying Design Space
16
Tablet Hardness ~ Granulation CPP
WMT=60s
Wat
er C
onte
nt
4
4.5
5
5.5
6
Wat
er c
onte
nt
1500 2000 2500 3000Mean Comp. Force
4
4.5
5
5.5
6
Wat
er c
onte
nt
1500 2000 2500 3000Mean Comp. Force
WMT=0s
Comp. ForceComp. Force
17
Preliminary Granulation Design Space
18
Preliminary Design Space
• Granulation– Impeller speed
• 500 RPM• Fr 1.20
– Critical Fr determined for 4 L Gral at 250 RPM = 0.30
• Drying– End Product Target Temperature
• 25°C – 30°C• Blending
– 15 – 25 RPM– 60% – 80% fill ratio– # of rotations: 42-125
19
Summary
• Risk Assessment helps to identify CPP• Preliminary Design Space is defined by backward
propagation• Some PPs identified by RA are not critical in the
explored experimental domain• Preliminary Design Space is constructed for:
– Wet granulation– Fluidized bed drying– Blending– Tabletting
• Some interactions between unit ops were considered– Tabletting and intermediate CQA– Fluidized bed drying and tabletting– Wet granulation and tabletting
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