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