application of high throughput technologies to drug substance...
TRANSCRIPT
1
Application of High Throughput technologies to Drug Substance and Drug Product Development
Colin R. GardnerTransForm Pharmaceuticals Inc.
Lexington, MA 02421www.transformpharma.com
FOCAPO, 12 Jan 2002
Drug Discovery / Development
LifecycleManagement
Development
0.5 - 2 yrs 1 - 2 yrs 1.5 - 3.5 yrs 2.5 - 4 yrs 0.5-2 yrs
$2-4 MM $1-3 MM $5-25 MM $50-250 MM $5-20 MM
R&D takes6.5 - 13.5 years$60- 300 million
Discovery Market
2-5 yrs
Submission&Approval
10-20 yrs
Source: PRTM
Phase 3Phase 2a/bPhase 1Pre-
clinicalDevelopment
TargetsHits
LeadsCandidate
Historic NCE Pipeline SuccessNCE Probability of Success by Phase: 1990s Estimates
10 NCE’sApproved
100 Preclinical Candidates
Preclinical Phase 1 Registration to Approval
Phase 2 Phase 3
Cumulative Success
5 – 16%7 – 20%15 – 35% 6 – 18%25 – 50%
Probability of Successby Phase
25 – 50% 60 – 70% 50 – 60% 80 – 90% 90 – 95%
Source: SDG, London; GW Journal of Innovation, Vol 1, Issue 3, 1995; PRTM estimates
Why Product Candidates Fail
05
1015202530354045
Tox Efficacy Biopharm Business
Global view: Pre-clinical R & D Process
Discovery Development
Target HTS
SyntheticchemistryScale up
100-500mg
Animal modelProbe Tox,
PK, met
2-4 cmpds
GLPTox
F & F
Sample collection
in vitro selectivity
in vitro metabolism
in vitro Tox
Animal modelefficacy
Earl
y D
isco
very
Lead
opt
imiz
atio
n
Pharm.Sci.
Ph I
Genomics Libraries
Hits to Leads
Lead optimization
Process chemistry
Form & Formulation
Active compound
Optimized form
Effective formulation
FORM FORMULATION
Small molecule drugs:•Solubility •Dissolution Rate•Bioavailability•Release profile•Stability
Biologics/Vaccines:•Stability •Solubility•Activity, yield•Efficacy•Delivery profile
Maximize Product Value
Form & Formulation: Traditional
DrugDiscovery
Preclinicaldevelopment
Clinical development Regulatory Manufacture Marketing/
Sales
•Mostly manual experimentation•Low throughput
New R&D Challenges
Resourceconstraints
Pharmaceutical Development
Discoveryrevolution
Timeconstraints
DrugDiscovery
Preclinicaldevelopment
Clinical development
Bringing High Throughput to the Process
DrugDiscovery
Preclinicaldevelopment
Clinical development Regulatory Manufacture Marketing/
Sales
• Bioavailability• Stability• “Bricks”
• Product enhancements
• IP
• Dosage form• Regimen
• COGS • Risk reduction
• Rational process design
• Solubility• Lead selection
•Automated, high throughput experimentation•Microscale•Informatics driven
Optimal
Active pharmaceutical ingredient
Integrated Technology Platforms
CrystalMaxCrystalMaxTMTM
Solid formsSolid forms FormulationsFormulationsInformaticsInformatics
FASTFASTTMTM//SFinXSFinXTMTMINFORMINFORM
Exploration of Solid Forms and Methods
solvent
salt former API / salt ratio
pH
23 1
4
Salts
5
solvent
H2O activity
temperature
2
3
1
Hydratessolvent
process impurityor degradate
process (t,T)
TransForm (CrystalMaxTM)
solvent
process impurity or degradate
process (t,T)
2
1
34
Polymorphs
Traditional
CrystalMax™
•Best solid form
•Efficient• micro-scale (sub-mg)• massively parallel (20,000)
•Comprehensive exploration of ‘space’
•Automatic data capture
Why Use Tubes Rather Than Plates?
30
40
50
60
70
80
90
100
0 5 10 15 20 25 30
Vol
um
e re
mai
nin
g (
%)
T im e (m in )
MeOH/we ll Pentane/w ell MeOH/tube Pentane/tube
100 µL evaporation study
0
500
1000
1500
2000
0.01 0.1 1 101 102
microXRD, acetaminophenRaman, acetam inophenRaman, alendronate sodium
Acqu
isiti
on ti
me
(sec
onds
)
Sample size (mg)
Innovative Approach to Primary Analysis
-0
500
1000
1500
2000
2500
3000
3500
4000
4500
5000
5500
1000 2000
Acetaminophen: Iteration to Find Form III
Micro-XRDstructure solutionof form III
Step 2 Step 3Step 1
I/II95/5
II/I50/50
II/III90/10
• Three polymorphs of acetaminophen identified and characterized using informatics-driven, iterative experimentation
• Different process modes: thermal, evaporative and melt
• Over 10K experiments to explore HT polymorph diversity in < 6 weeks
High Throughput Formulation Discovery
Stability
Solubility
Dissolution rate
Traditional
• Limited experiments• No informatics• “Good enough”
formulation
Stability
Solubility
Dissolution rate
TransForm HT Platforms (FASTTM & SFinXTM)
• Many experiments• Comprehensive
data capture• New knowledge
Informatics-Enhanced Experimental Design
Stability
Solubility
Dissolution rate
• “Smarter” experiments• Data capture & mining• New knowledge• Optimized formulations
FASTTM
Best formulation for specific application • solubility, stability, device compatibity
Efficient• micro-scale (ug range)• massively parallel (>5,000)
Comprehensive exploration of ‘space’
Automated data capture
End-to-end automation
•Small molecules•Biologicals•Vaccines
InformTM: InformaticsDesktop design Relational database Process control
Analysis and Predictive Modeling SoftwareIntegrated data capture, storage and analysisKnowledge-driven discoveryDesigned for U.S. regulatory compliance (CFR 21.part 11)Proprietary design
Discovery Applications
Building in “Developability”Lead
(active molecule)
MetabolismSelectivity
Potency Physical properties
Potency
Selectivity
Metabolism
Best leadsPhysical / chemical
propertiesBiopharmaceuticsLO
(optimized molecule)
Animal Studies: BioavailabilityOral Formulations Intravenous Formulations
Time (hours)0 6 12 18 24
Plas
ma
Con
cent
ratio
n (n
g/m
L)
1
10
100
1000
10000Compound 680463 (0.2 mg/kg)(90% water, 6.9% Polyoxyl 35 Caster oil, 3.1% Propylene Glycol)Compound 647271 (0.5 mg/kg)(60% water, 12.5% of 50% HPBCD, 27.5% Polyoxyl 35 Caster oil)
TPI Formulations
Standard Formulation
TPI Formulations
Improved oral bioavailability demonstrated with TPI formulationsIV dosing enabled by TPI formulations
Applications inPre-Clinical and
Clinical Development
Development Risk: Norvir
PR Newswire July 27, 1998
TransForm Solution: Norvir
Within 4 weeks:Both known forms identified/characterizedThree new forms discoveredNovel, robust methods identified to make each form
MPT 122 °C MPT 125 °C MPT 80 °C MPT 97 °C MPT 116 °C
Form I Form II Form III Form IV Form V
TPI’s analysis required < 2 g of material
TPI 211: Identification of improved formulations
TPI 211: Marketed intravenous anti-cancer drugExcipient-related adverse effects
Challenge
• Eliminate toxicity• Maintain
• solubility • physical stability• chemical stability
TransForm Solution
•4 lead formulations identified from 96,000 experiments•Scale-up •>24 weeks stability•Better animal tolerance
80
100
60
20
40
Applications inLife Cycle Management /
Line Extensions
Oral delivery
High-throughput salt screening
Experimental variables:Salt-forming reagents
pharma acceptable> 40 acids (basic compounds) > 20 bases (acidic compounds)
API/salt former ratiopHionic strengthsolvent composition
Complex system
TPI 745: New Form for Faster Onset and New Delivery Systems
Problem: Potential new indications complicated by slow onset and side effects at high dosage levelsMay require new controlled release delivery system
TransForm SolutionNew form with superior solubility
• Within 2 weeks• 100X more soluble than parent drug
• New IPPotential to reformulate with
controlled release
Solu
bilit
y
New TPI-745 Form Has Faster Onset & Better Bioavailability
30 mpk P.O.
Salt form with “solubility modifier”
Cmax Tmax AUCTPI-A 23.2±6.2 1.3±1.0* 139±26TPI-B 19.6±4.6 2.1±1.1 135±24T-745 21.4±4.0 2.8±1.6 150±43
0
5000
1 104
1.5 104
2 104
0 2 4 6 8
TPI-745ATPI-745BTPI-745
Plas
ma
conc
entra
tions
ng/
ml
time, hours
Transdermal delivery
• Standard Diffusion Cell
• HT Diffusion Cell Array
High throughputLow throughputSlow Fast
SkinSkin
Receptor compartment
Transdermal patch
Skin permeation from HT system
Comparison of Fluxes Comparison of 4 formulations
0.0
5.0
10.0
15.0
20.0
25.0
30.0
0 2 4 6 8 10
Time (hr)
Cum
ulat
ive
Am
ount
Tr
ansp
orte
d (u
g/cm
2)
35
Conclusions• “Developability” is a key factor in finding new drugs
• Potent active compounds are not necessarily drugs – other properties are critical
• HT form and formulation techniques are important
• Discovery: helps medicinal chemists with SAR
•Pre-clinical: optimizes products
• Marketed products: improves product performance and provides new IP
• High throughput technologies do not replace good science and engineering – they provide more data and enable better decisions