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1
NIPTE-FDA Collaborative Case StudyOn Model-based Design Space Development
Across Scales & with Stability Considerations
Design Space Integration
2
Design Space Integration
• Considered– Degradation
• NMT 0.4 mole % lactam– Hardness
• NLT 3 kP– Weight variation
• 90 % - 110%• % RSD NMT 6%
– Dissolution• NLT 40% @ 5 min
– Disintegration• NMT 10 min
3
Shelf Life Design Space
Probability of lactam < 0.4 mole % after 2 years @
22°C
Low Moisture max p=0.7Medium Moisture max p=0.71
0
~
a
obs
o
ERT
obs
o
dLk
dtL L
k Ae
A D
4
Tabletting Design Space
20
30
40
50
60
70
Mea
n D
isso
lutio
n 1
5
Leve
rage
Re
sid
uals
0 50 100 150 200 250
Hydrophobicity
Leverage, P=0.0271
20
30
40
50
60
70
Mea
n D
isso
lutio
n 1
5
Leve
rage
Re
sid
uals
0 5 10 15
Mean Tablet Hardness
Leverage, P<.0001
0
5
10
15
20
25
Ave
rag
e di
sin
tegr
atio
n
time
Lev
era
ge
Res
idu
als
50 100 150 200 250
Hydrophobicity
Leverage, P<.0001
0
5
10
15
20
25
Ave
rag
e di
sin
tegr
atio
n
time
Lev
era
ge
Res
idu
als
0 2 4 6 8 10 12 14 16 18
Mean Tablet Hardness
Leverage, P<.0001
disintegration time =-4.54 + 0.86 * hydrophobicity+ 0.06 * hardness
Hydrophobicity Hardness
% dissolved @5 min =78.1 – 0.1 * hydrophobicity– 3.0 * hardness
5
Tabletting Design Space
Disintegration
Dissolution
Hydrophobicity = -26 + 36 * Blend Time
=># of rotations are limited
50
100
150
200
250
Hyd
rop
hobi
city
Act
ual
50 100 150 200 250
Hydrophobicity Predicted
P<.0001 RSq=0.64 RMSE=37.617
6
Dissolution Data (provided by FDA)
0 5 10 15 20 25 30 35 40 45 500
20
40
60
80
100
120
96251-2 #1
96251-3 #1
96251-4
96251-5
96251-6
96251-7
96251-8
96251-9
96251-10
96251-11
96251-12 #1
96251-13
96251-14
96251-15
Time (h)
% d
isso
lved
7
Dissolution
20
30
40
50
60
70M
ean
Diss
olut
ion
15
0 5 10 15 20 25
Average disintegration time
% dissolved @5 min = 63.3 – 2.4 * disintegration time
Disintegration is often limiting step for highly soluble drugs
12
Design Space Integration
• Tablet weight variation = f (spray rate, impeller speed)– within USP limit
• In-process lactam is well below 0.4 mole %– a meaningful limit may be established only after
accelerated stability studies
13
Model Building
20 25 30 35 40 45 500.01
0.015
0.02
0.025
0.0300000000000001
f(x) = 0.000330905350366283 x + 0.00668066973408026R² = 0.975504874980725
Temperature (C)
In-p
roce
ss la
ctam
(mo
le %
)
In-process lactam ~ max. product temperatureLab scale
14
Model Validation (Lab Scale)
0 242.7 485.4 728.1 970.8 1213.5 1456.2 1698.9 1941.6 2184.3 2427
16.4728
24.7093
32.9457
41.1821
49.4185
57.6549
65.8914
74.1278
82.3642
Fluidized bed drying
Time (s)
Tem
pera
ture
(C
)
Inlet air temperature
Inlet air temperature, smoothed
Granule temperature
Predicted granule temperature
15
Model Prediction
EEF EMT0.175 0.50.175 10.45 1
0.45 0.5
No need to run full factorial!!!
Single experiment to calibrate model parametersSecond experiment to verify model predictions
16
Model Prediction (Intermediate Scale)
0 250 500 750 1000 1250 1500 1750 2000 2250 2500
10.1
20.2
30.3
40.4
50.5
60.6
70.7
80.8
90.9
101
Fluidized bed drying
Time (s)
Tem
pera
ture
(C
)
Inlet air temperature
Predicted granule temperature