Drug “X”
Drug “X”
Drug “X”
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Accelerating CMC timelines in early<br />
development<br />
Patricia Hurter<br />
Vice President, Pharmaceutical Development
New approach<br />
© 2008 Vertex Pharmaceuticals Incorporated 2
Topics<br />
�When is CMC on the critical path?<br />
�What is hard to find in existing CRO’s?<br />
�“The Dream CRO”<br />
© 2008 Vertex Pharmaceuticals Incorporated 3
Supplying clinical material for FIM – on critical path<br />
© 2008 Vertex Pharmaceuticals Incorporated 4
BC studies for formulation changes on critical path<br />
Phase 1 POC Phase 3/Commercial<br />
<strong>Drug</strong><br />
<strong>“X”</strong><br />
� 10 months from<br />
formulation definition<br />
to next efficacy study<br />
Vertex R&D<br />
© 2008 Vertex Pharmaceuticals Incorporated 5
“Hard to Find” Capabilities in Existing CROs<br />
Bioavailability<br />
Enhancing Technologies<br />
DS<br />
(small-scale) Scaleable Equipment<br />
Local<br />
Analytics<br />
Clinical<br />
Integrated<br />
Services<br />
Scientific<br />
Excellence<br />
© 2008 Vertex Pharmaceuticals Incorporated 6<br />
DP<br />
Sophisticated<br />
clinical tools
Fast-into-man approaches<br />
Neat drug in capsule Solution or suspension<br />
Xcelodose<br />
� For that rare, soluble<br />
drug!<br />
� Homegeneity, stability,<br />
prep issues<br />
� Taste issues<br />
� Avoid “drain cleaner”<br />
© 2008 Vertex Pharmaceuticals Incorporated 7
Nanomilling can increase exposure<br />
Nanoparticles Stabilized in Suspension<br />
Translation to Solid Dosage Form<br />
300μ<br />
800μ<br />
Celphere<br />
Bead<br />
© 2008 Vertex Pharmaceuticals Incorporated 8<br />
C plasma (ng/mL)<br />
ng/mL MK-0869<br />
1400<br />
1200<br />
1000<br />
800<br />
600<br />
400<br />
200<br />
0<br />
Wet 0.5μ<br />
5μ<br />
Nano (120nm)<br />
NanoCrystal, 0.12 um<br />
Wet-Milled, 0.48 um<br />
Jet-Milled, 1.85 um<br />
004H004, 5.49 um<br />
0 4 8 12 16 20 24<br />
Hours (Expanded View, 0-24 Hours)<br />
1.5μ<br />
Time (hrs)<br />
Jet 2μ
Enthalpy<br />
Disrupting crystal structure increases<br />
dissolution rate<br />
Cocrystal<br />
Supercooled<br />
Liquid<br />
Amorphous<br />
Crystalline<br />
T g<br />
T m<br />
Temperature<br />
Liquid<br />
Higher energy<br />
metastable<br />
Amorphous<br />
Anhydro spray dryer<br />
© 2008 Vertex Pharmaceuticals Incorporated 9
Liquid Filled Capsules/Emulsifying Formulations<br />
Liquid Capsule Filling Machine<br />
Reduced Food Effect with<br />
Lipidic Formulation of Halofantrin<br />
Time (hrs)<br />
Khoo et al, Pharm Res, 20, 1460, 2003<br />
Trevaskis et al, JPET, 316, 881, 2006<br />
© 2008 Vertex Pharmaceuticals Incorporated 10
Piccola Minipress<br />
Compaction Simulator<br />
Need scaleable technologies<br />
Gerteis Minipaktor<br />
50<br />
0 10 20 30 40 50 60 70<br />
© 2008 Vertex Pharmaceuticals Incorporated 11<br />
Dissolution (%)<br />
Dissolution affected by Equipment<br />
110<br />
100<br />
90<br />
80<br />
70<br />
60<br />
Slugged<br />
TF Mini<br />
"Old" Gerteis<br />
Time (minutes)
The Human GI is a Murky, Globulous Place<br />
(not a clean glass beaker)<br />
Movie by Given Imaging<br />
http://www.givenimaging.com<br />
© 2008 Vertex Pharmaceuticals Incorporated 12
Plasma Concentration (ng/ml)<br />
PSWC Kyoto, 2004<br />
Regional absorption studies<br />
Plasma Concentration (ng/ml)<br />
© 2008 Vertex Pharmaceuticals Incorporated 13<br />
Plasma Concentration (ng/ml)
Scintigraphy to determine fate of dosage form<br />
Images courtesy of Ian Wilding<br />
© 2008 Vertex Pharmaceuticals Incorporated 14
DS Manuf.<br />
Phase 1 Unit<br />
Ideal state<br />
Quality<br />
Complex DP Manufacturing<br />
Analytical<br />
Communication Scintigraphy Bioanalysis<br />
© 2008 Vertex Pharmaceuticals Incorporated 15
Conclusions<br />
�Opportunities to revolutionize delivery of clinical materials<br />
� Drastic change in timelines<br />
� More scientifically optimized formulations for FIM<br />
� Simpler supply chain, less room for failure, ownership<br />
of the entire chain<br />
� More knowledge gained from Phase 1 studies<br />
© 2008 Vertex Pharmaceuticals Incorporated 16
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