AAPS Presentation 2014
Controlling Powder Properties via Post-Crystallisation Unit Operations: A Case Study Michael Leane November 2014
„Difficult‟ API
“Good” API
Target Material Profiles A guidance from drug product to R&D colleagues clearly stating: What we want API properties to be Why we want these particular properties
What should a TMP include? The property itself, an acceptance range and a rationale or justification. Potential attributes development.
may
change
during
Need to state the impact of a particular property or failure to meet a particular target using riskbased terminology.
What should TMP achieve? Defined mechanism around physical properties.
Consistency. Define Material Selection and Development Team goals. Speed up optimisation of physical parameters. Facilitate formulation
Increase communication.
Introduction: Material A BCS Class 2 compound. Weak base with pH dependent solubility.
pH 2.9: 21.0 mg/mL
pH 7.3: 0.008 mg/mL
Crystallisation can be slow and difficult to control.
Need an efficient process
Roller compacted commercial formulation (10% drug loading).
Material A: “Not optimised”
Particle size justification based on manufacturing efficiency Particle property control enables simpler processing routes. Simpler manufacturing routes are more efficient. In addition, they are less “stressful” on the API.
Variable product can lead to failure. Costs of failure in manufacture are high. Manufacturing Classification System.
9
Particle size justification based on PK performance
1000
10950
Cmax, ng/mL
800
700 600
L AUC(0-T), ng-h/m
500 600 700 800 900 1000
900
10550 10600 10650 10700 10750 10800 10850 10900 10950
10900 10850 10800 10750 10700 10650 10600 10550
cle
et
6
5
140
s
on icr
s
pH
,m
3 2
6
er
on icr
160
4
et
,m er
5
140
60 80 100 120
am Di
am
Di
60 80 100 120
rti
cle rti
Pa
Pa
500
160
4 3 2
Both AUC and Cmax decrease as particle size increases
pH
Particle size justification based on effect on content uniformity
Probability of passing stage one test of content uniformity Density (g/mL) Dose (mg)
1.39 10 Probability of success (%) 60.00 100
100
100
100
55.00 100
100
100
100
100
50.00 100
100
100
100
100
100
45.00 100
100
100
100
100
100
100
99.66 94.67 73.99
40.00 100
100
100
100
100
100
100
99.99 99.57 94.08
35.00 100
100
100
100
100
100
100
100
100
99.67
95-99%
30.00 100
100
100
100
100
100
100
100
100
100
99-99.9%
25.00 100
100
100
100
100
100
100
100
100
100
>99.9%
20.00 100
100
100
100
100
100
100
100
100
100
15.00 100
100
100
100
100
100
100
100
100
100
2.60
2.80
3.00
3.20
3.40
3.60
3.80
4.00
4.20
4.40
Enter density and dose in two yellow cells above
Max:
Enter min and max values for mean diameter and variability in diameter in four yellow cells opposite
Key - Probability of success
„Difficult‟ API
“Good” API
Target Material Profiles A guidance from drug product to R&D colleagues clearly stating: What we want API properties to be Why we want these particular properties
What should a TMP include? The property itself, an acceptance range and a rationale or justification. Potential attributes development.
may
change
during
Need to state the impact of a particular property or failure to meet a particular target using riskbased terminology.
What should TMP achieve? Defined mechanism around physical properties.
Consistency. Define Material Selection and Development Team goals. Speed up optimisation of physical parameters. Facilitate formulation
Increase communication.
Introduction: Material A BCS Class 2 compound. Weak base with pH dependent solubility.
pH 2.9: 21.0 mg/mL
pH 7.3: 0.008 mg/mL
Crystallisation can be slow and difficult to control.
Need an efficient process
Roller compacted commercial formulation (10% drug loading).
Material A: “Not optimised”
Particle size justification based on manufacturing efficiency Particle property control enables simpler processing routes. Simpler manufacturing routes are more efficient. In addition, they are less “stressful” on the API.
Variable product can lead to failure. Costs of failure in manufacture are high. Manufacturing Classification System.
9
Particle size justification based on PK performance
1000
10950
Cmax, ng/mL
800
700 600
L AUC(0-T), ng-h/m
500 600 700 800 900 1000
900
10550 10600 10650 10700 10750 10800 10850 10900 10950
10900 10850 10800 10750 10700 10650 10600 10550
cle
et
6
5
140
s
on icr
s
pH
,m
3 2
6
er
on icr
160
4
et
,m er
5
140
60 80 100 120
am Di
am
Di
60 80 100 120
rti
cle rti
Pa
Pa
500
160
4 3 2
Both AUC and Cmax decrease as particle size increases
pH
Particle size justification based on effect on content uniformity
Probability of passing stage one test of content uniformity Density (g/mL) Dose (mg)
1.39 10 Probability of success (%) 60.00 100
100
100
100
55.00 100
100
100
100
100
50.00 100
100
100
100
100
100
45.00 100
100
100
100
100
100
100
99.66 94.67 73.99
40.00 100
100
100
100
100
100
100
99.99 99.57 94.08
35.00 100
100
100
100
100
100
100
100
100
99.67
95-99%
30.00 100
100
100
100
100
100
100
100
100
100
99-99.9%
25.00 100
100
100
100
100
100
100
100
100
100
>99.9%
20.00 100
100
100
100
100
100
100
100
100
100
15.00 100
100
100
100
100
100
100
100
100
100
2.60
2.80
3.00
3.20
3.40
3.60
3.80
4.00
4.20
4.40
Enter density and dose in two yellow cells above
Max:
Enter min and max values for mean diameter and variability in diameter in four yellow cells opposite
Key - Probability of success
