Early Developability Assessment, Key to Success for...

Early Developability Assessment, Key to Success for Development Phases

Dr. Philippe LIENARD

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What’s Developability Assessment?

• Blanket term used to define the process of assessment for development candidates

• based on their physicochemical and biopharmaceutical properties

• Selection of new chemical entities (NCEs)

• Decisive parameter according to developability during pre-candidate profiling.

• Early prediction & comparison of properties critical in selecting suitable physical form (salt, polymorph, etc.) of the future candidate.

• Based on pharmacokinetic and efficacy/toxicity studies, suitable formulation for Phase I clinical studies have to be anticipated.

• Streamline efficacy/toxicology evaluation

• Allowing pharmacologically effective and developable molecules to reach the clinic and eventually to the market.

9th Annual Global Drug Delivery and Formulation Summit - March 2017 2

Target ID & Validation

Lead Identifi-cation

LeadOptimiza

-tion

Pre-clinical

Phase 1Phase

2aPhase

2bPhase 3 Filing LCM

Research Early Development Late DevelopmentManu-

facturing

9th Annual Global Drug Delivery and Formulation Summit - March 2017

FDA : Record NME filling in 2017

3

(Chemical &Engineering News 03/01/2018)

Small Molecules Come Back in 2017

•Highest number since 1996• cancer treatments, anti-infectives

• rare diseases

• beneficiaries of breakthrough status/rare disease• BTD is significantly shortening drug development timelines Application—asking FDA to

begin clinical trials—to approval letter was 65 months for the 17 BTD

4

FDA : Record NME filling in 2017(Chemical &Engineering News 03/01/2018)


46 New molecular entities in 2017

63% Small molecules approved

Increase chemical complexity

40%Of current small molecule required advanced formulation

science


From Lead Compounds to Development Candidat

Low selectivity

PK variability

DDI (CYP 3A4 inhibition)

Low solubility/stability…etc

High selectivity

Metabolic stability

Low PK variability

Low DDI risk

Improved solubility/stability

CANDIDATE

RescaffoldingLead

optimization

HIT molecule LEAD molecule

CAN 1&2Two molecules with defined R1, 2, 3, 4, 5 to be evaluated in

parallel up for selection/nomination for development

TPPDosing &

Admin

- Oral administration

- One capsules daily, on top of SoC.

- Low starting dose (5mg) then individual dose adjustment

Presentation Goals

1. How to scientifically select a new molecular

entities (NMEs) in a research leads portfolio

2. How to characterize physico-chemical

properties as function of the expected Target

Product Profile (TPP)

3. Rationally select polymorph before

development

4. How and when do you need to utilize enabling

technologies to streamline drug development

of molecule presenting limitations/weaknesses.

6

Early Developability Assessment, Key to Success in Development Phases

,

x HCl

yMsOH

,

BTEAC, DMF

Br2, AcOH

AcONa

HNO3, H

2SO

4

AcOH

Et3N, MeOH

H2 / Pd-C

Ac2O, AcOH

1- NCS, AcOH

2- NaOH

1- CH3C(OCH

3)

3,Toluène

2- TMSCl

3- MeONa

Chlorure de

Pivaloyle

HCl aq, EtOH

Ms-

HCl aq.

Assessment of Chemical Synthesis Route

7

S. M. A. R. T. synthesis

Short

More efficient

Amenable to scale up

Robust

In a Timely manner

Route scouting (IP, FTO, Cost of Good)

Forecasted quantities,

Complexity of the chemistry

Risk

Timeline

Yes/No

Process development,

Scale-up feasibility

Safety consideration

Optimization

Yes/No

Clinical batch

production

Scientifically Select a Candidate NMEStability in Solution under Stress Conditions

8

Chemical stability in

solutionResults Condition Comments

Strong acidic

conditions pH1Stable

2w at 40°C and

protected from light degradation +0.4%

Strong basic

conditions pH12Stable

2 w at 40°C and

protected from light degradation + 0.3%

Indoorlight

exposureStable

2w at 40°C no degradation

Strong oxidizing

conditions H2O2

(0.3%)Unstable

24h at RT and protected

from light

Degradation + 15.4%

Main oxidation product :

9.7%

Intense light

exposureUnstable

10h at 2.1mil lux hour Degradation +93.2%

Major impurities: 58.5% and

15.3%

< 2% stable

2%< <10% slight

degradation

>10% degradation

In solution CAN2 is chemically stable at least 2w in strong acidic (pH1) and

strong basic conditions (pH12)

Sensitive to oxidant agents and at intense light exposure

▪ Formulation with limited oxygen exposure or antioxidant recommended.


Early Solid Phase Selection

• Assessment solid form with small quantity

• Avoid amorphous

• Prefer form demonstrated with well defined polymorph

• Anhydrous better than solvate

• Pre CLiN solid form should have following properties

1. Physically/chemically stable in a wide range of temperature

2. Reproducibility in crystallization

3. Micronization feasibility (if need for oral formulation)

9

Challenges/Implications

Early Solid Phase Assessment/Selection

Solid state, solubility, Biopharm are key contributors for early development challenges

9th Annual Global Drug Delivery and Formulation Summit – March 2017 - Berlin 10

•Solubility/particle

size/dissolution properties in

regards to the clinical dose

foreseen

•Pharmacology

•Tox formulation

Well defined and stable

Yes/No

Solid State

Solubility

Early Biopharmaceutical

Assessment vs clinical anticipated doses

Standard

Formulation

Pre-clinical

Standard

formulation

Pre-clinical

Enabling

Formulation

•Clinical formulation

anticipated

Enabling

Formulation

Salt, co-crystal

•Avoid amorphous

•Prefer form demonstrated with

well defined polymorph/crystallin

form

•Anhydrous better than solvate

PAGE

To rapidly evaluate the polymorphism tendency

of a compound

Early Polymorphism Screening

• 200mg API distributed in solution within the 96 wells

• Evaporation of the distribution solvent

• Distribution of crystallization solvents in the 96 wells

45 pure solvents and 51 solvent mixtures (water/organic or organic/organic)

Volume of solvent selected from calculation of API solubility in the different

classes of solvent

▪ In-Silico Solubility Solvent Screening (QM – Cosmo RS)

• Optimized T-program to induce crystallization of materials

Slow cooling

Then slow evaporation

• Analyses of 96-wells plate

High throughput XRPD Crystallinity of materials

High throughput Raman microscopy if necessary (salt)

Early Polymorphism Screening – 1 µPlate (Request : 300mg of API : Free Form or salt) – 1 week

11

PAGE

Results of the Early Polymorphism Screening

12

CAN2

• 11 crystalline forms identified on the same plate !

➢Evidence of non cross contamination

➢High Polymorphism Tendency of API

➢Form IV detected in majority of case

• Manual Confirmation of New crystalline Forms using the 100mg

remaining API quantity

➢ Confirmation of New crystalline Forms

➢ Development of the first crystallization protocol using filtration

and not evaporation

AAcetone 194 Cyclohexane 194 Isopropyl acetate 194 1-pentanol 194 MethylButyl Cetone 194 1,2-Dimethoxyethane 194 Acetone 174 Acetone 174 Water 174 Water 175 Water 174 Water 174

- - - - - - - - - - - - Ethyl acetate 19 Ethanol 19 1,4-Dioxane 19 2-Propanol 19 Acetonitrile 19 Ethanol 19

BAcetonitrile 194 Dichloromethane 194 Methanol 194 2-Propanol 194 p-Xylene 194 CPME 194 Acetone 97 Acetone 97 Water 157 Water 97 Water 167 Water 97


CMethyl THF 194 1,4-Dioxane 194 Methyl acetate 194 1-Propanol 194 Pentane 194 Ether ethylique 194 Acetone 19 Acetone 19 Water 97 Water 19 Water 97 Water 19


D1-Butanol 194 Ethanol 194 Methyl-t-butyl ether 194 Tetrahydrofuran 194 n-Heptane 194 Propyl Acetate 194 Dichloromethane 174 Ethyl acetate 174 Water 19 Water 174 Water 19 Water 174

- - - - - - - - - - - - Ethanol 19 Cyclohexane 19 1,4-Dioxane 174 1-Propanol 19 Acetonitrile 174 Methanol 19

E2-butanol 194 Ethyl acetate 194 ChloroButane 194 Trichloroethylene 194 1,2 Dichloroéthane 194 DIPE 194 Dichloromethane 97 Ethyl acetate 96 Water 174 Water 147 Water 174 Water 97

- - - - - - - - - - - - Ethanol 97 Cyclohexane 97 Tetrahydrofuran 19 1-Propanol 46 Acetone 19 Methanol 97

F2-Butanone 194 Ethyl formate 194 Methylcyclohexane 194 Toluene 194 ChloroBenzene 194 Ethyl acetate 144 Dichloromethane 19 Ethyl acetate 19 Water 97 Water 97 Water 97 Water 19

- - - - - - - - - - Acetonitrile 50 Ethanol 174 Cyclohexane 174 Tetrahydrofuran 97 1-Propanol 97 Acetone 97 Methanol 174

GButyl acetate 194 Hexane 194

4-Methyl-2-

pentanone194 Water 194 Anisol 194 Cyclohexane 138 Ethanol 111 2-Butanone 127 Water 19 Water 19 Water 19 Ethanol 97

- - - - - - - - - - 1-Butanol 55 Acetonitrile 82 Ethanol 66 Tetrahydrofuran 174 1-Propanol 174 Acetone 174 n-Heptane 97

HCyclopentanone 194 Isobutyl acetate 194 2-methyl-1-propanol 194 3-Methyl -1-butanol 194 Nitrométhane 194 Ethyl acetate 127 Toluene 138 Methanol 144 2-Propanol 117 1-Propanol 99 Ethanol 136 2-butanol 141

- - - - - - - - - - Ethanol 67 1-Butanol 55 Toluene 50 Toluene 76 Toluene 95 Toluene 58 Water 53

5 6 1131 2 127 8 9 104

Crystalline Form IV

Crystalline Form V

Amorphous FormCrystalline Form I (XRPD1)

Crystalline Form II (XRPD2)

Crystalline Form III (XRPD3)

Crystalline Form VI

Crystalline Form VII

Crystalline Form VIII

Crystalline Form IX

Crystalline Form X

Crystalline Form XI

Operations: Y Scale Add 6250 | Import

RA14845376 plate 185 well H02 - File: 17675.raw - Type: 2Th/Th lo

Operations: Y Scale Add 5729 | Y Scale Mul 0.542 | Import

RA14845376 plate 185 well F05 - File: 17663.raw - Type: 2Th/Th lo


RA14845376 plate 185 well A05 - File: 17662.raw - Type: 2Th/Th lo

Operations: Y Scale Add -208 | Y Scale Add -3500 | Y Scale Mul 1.

RA14845376 plate 185 well H01 - File: 17660.raw - Type: 2Th/Th lo


RA14845376 plate 185 well C03 - File: 17659.raw - Type: 2Th/Th lo


RA14845376 plate 185 well G09 - File: 17666.raw - Type: 2Th/Th lo

Operations: Y Scale Add 875 | Y Scale Mul 0.417 | Y Scale Add 16

RA14845376 plate 185 well G12 - File: 17672.raw - Type: 2Th/Th lo

Operations: Y Scale Add -292 | Y Scale Add 375 | Y Scale Add 100

RA14845376 plate 185 well B12 - File: 17670.raw - Type: 2Th/Th lo

Operations: Y Scale Mul 0.583 | Import

RA14845376 batch VAT.HCM1.046.1 - File: 17654.raw - Type: 2Th/

Lin

(C

ounts

)

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

2-Theta - Scale

3 10 20 30 40

FI

FII

FIII

FIV

FV

FVI

FVII

FVIII

FIX

• Forced degradation conditions

13

Scientifically Select a Candidate NMESolid State Stability CAN2 - XRPD1

Conditions Results Comments

80°C and 80% RH

2 w

Physically and

Chemically stableDegradation <0.1%

80°C dry

2 wChemically and

physically stableDegradation <0.1%

Intense light exposure

1.2mil lux hour 10 h

Chemically and

physically stableDegradation <0.1%

In solid state CAN2 is chemically and physically stable at least 2w

under forced degradation conditions (high dry temperature, high

temperature and humidity and intense light exposure)


Solid State – Crystal Engineering - Solubility

Scientifically Select a Candidate NME

CAN1 crystallized

Birefringent rod

CAN1 micronized

BY SONICATION

CAN1 micronized

BY JET-MILLING

Homogenous size distribution

0

10

20

30

40

50pH1

pH3

Fessif pH5.1

Fassif pH6.6

pH7.4

Micronized solubility profile (mg/ml)

1 h

2 h

4 h

24 h

0

5

10

15

20

25

30pH1

pH3

Fessif pH 5.1Fassif pH 6.6

pH7.4

Crystallized solubility profile (mg/ml)

1 h

2 h

4 h

24 h

| 15

Both CAN1 & 2 are potential BCS II

Key Data for EarlyBiopharmaceutical Assessment

CAN1 CAN2

Mw ~400 ~400

logD 2.5 3

pKa None None

P Caco2 10.10-7cm.s-1 30.10-7cm.s-1

Sol Water mg/mL

(pH=7.4)

0.01 0.02

Sol FaSSIF mg/mL 0.02 0.03

Sol FeSSIF mg/mL 0.04 0.06

| 16

Evaluation in silicoGastroPlus input in models version 1.0

Human

Parameters Units Main value range comment

MW g/mole 377,4

logP 2,97 in silico method - consensus

LogD @ pH7.4 2,97

S0 mg/mL 0,01700 exp XRPD1

pKa >8 no effect of pka on solubility profile

CLint µL/min/mg

mL/h/106cells

Bile salts solubilization ratio 27µG/mL

Ptotal Caco-2 TC-7 10-7 cm.s-1 26

Peff 10-4 cm.s-1 1,3 internal correlation including references in study

P-gp probable Pcaco with elacridar is 6x higher

(main biorelevant solubility) mg/mL 0,027 good fit of good quality in vitro data

Particle size µm 15 2,5-50

Diffusion coefficient 10-5 cm2.s-1 0,72 calc by Gastroplus

precipitation time (s) s - nd (formulation dependent) not expected for base

Blood to plasma ratio 0,99

Protein binding %

fu % 5

Intestinal water %

CL L/h/kg

Vss L/kg

t1/2 h

F %

S HCl pH1 µg/mL

S citrate pH3 µg/mL 18 experimental

S phosphate pH7.4 µg/mL 17 experimental - 50mM buffer

S FaSSIF pH6.5 µg/mL 27 experimental

S FeSSIF pH5.0 µg/mL 64 experimental

S GUSP pH1.2 µg/mL

S FeSSGF pH3.0 µg/mL

Fraction absorbed in animal &

human

• At various doses considered

• With scenarios on particle size-

● GastroPlus is one important Biopharm tool for human estimation ● Allows a bottom up approach to anticipate bioavailability and absorption in human based on good quality in vitro

● Model can be checked on available preclinical data (IV, oral solution and standard suspension available for Rat)

● Predicts Fa and F in human

Inputs

output

| 17

● In silico evaluation in Fasted human with GastroPlus v9.0 based on in vitro data

DV50=30µm

anticipated max

active dose

CAN 1 & 2 GastroPlusPreliminary assessment in Human

Fraction absorbed should remain >50% up to 100mg for CAN1 & 200mg for

CAN2, but higher dose may be needed to cover phase I

probable non linearity of Fa with dose, partially mitigated by micronization

CAN 2

CAN 1

CAN 2

CAN 1

| 18

DCS applied to CAN 1&2

IIb

IVIII

Developability area

Standard vs DDS

Standard size controlMicronized

Nano

ASD

Micronized

zone

CAN2

CAN1

● Based on arbitrary maximum dose per administration of 100mg, with current physical forms

CAN 1 & 2 are classified as class IIb,

● Standard formulation with small size recommended

IIa

| 19

CAN1 vs CAN2 Biopharm evaluationPreliminary assessment in Human summary

● CAN 1&2 are DCSIIb compounds and both potential BCS2 (preliminary classification

depending on future real therapeutic dose in human and observed PK), with potential need for

micronization (depending on dose) as evidenced by benchmark

● Due to their differences in solubility and permeability, and as confirmed by current Rat PK

data, CAN 2 has better potential to achieve good exposure for doses of 100mg or higher as a

standard formulation.

● Influence of DS size could be assessed in preclinical models to confirm or not the need

for small size

CAN1 CAN2

G+% Fa est.@ 100mg (15µm) 50 85

Assessment for clinical Estimated standard formulationup to 100 mg with XRPD1

Estimated standard formulation up to 200 mg with XRPD1

DCS IIb IIb

CMC Preliminary Developability AssessmentHead to Head Comparison CAN1 vs CAN2

CAN#1 CAN#2

Chemical

development

7+2 steps

Overall yield ~ 17% up to 500 g

Slight optimization needed for

CER/GMP1

7+2 steps

Overall yield ~ 17% up to 500 g

Slight optimization needed for

CER/GMP1

Micronization Particle size > 10 mm Particle size < 10 mm

Solubility (water,

pH=7.4)Low Low

Chemical & Physical

stability solid

2 W 80°C dry stable2 W 80°C dry stable

2 W 80°C/80%RH

Suntest stable

2 W 80°C/80%RH slightly unstable

Suntest stable

Chemical Stability

Solution

Stable versus pH and ambient light Stable versus pH and ambient light

Unstable versus oxidation/intense

lightUnstable versus oxidation/intense light

Physical

form/PolymorphismOnly 1 pattern form Several pattern

Tox formulation Enabling (PEG/Solutol 95/5) Suspension

Biopharm

assessment for

Clinical formulation

Estimated standard formulation up to

100 mg with XRPD1

Estimated standard formulation up to

200 mg with XRPD1

20

0

1

2

3

4

5

6

7

8

9

10

Chemical development

Micronization feasibilility

Solubility (water pH =7.4) mM (50 mMmax)

Permeability

Chemical & Physical Stability SolidChemical Stability Solution

Physical Form/Polymorphism

Tox Formulation

Biopharm Assessment

CAN#1

CAN#2

Based on knowledge acquired so far, from CMC/Biopharm point of view

✓ CAN2 preferred versus CAN1

✓ CAN2 deemed developable up to 200 mg in Human

Early Clinical Formulation PlanKey objective: early selection of formulation strategy for CAN3

API Structural properties Results

pKa 2.3

log D 7.45.5

Solid-State related properties Results

Polymorphism tendency across batches2

Chemical Stability Solidstable

Physical Stability Solidstable

Acceptable general physico-chemical properties, except very

low aqueous solubility.

0

20

40

60

80Gastric USP pH=1

pH = 3

Fessif pH 5.1Fassif pH 6.6

pH = 7.4

Crystallized solubility profile

(mg/ml)

Material Screening flow chart

NoYes 1 - Free compound

Aqueous equilibrated solubility

pH 4 and 7.4 > 50 mM

Polymorphism screening

2- If ionizable cpd : Salt Screening

(pka)

No

3- Enabling formulation

4 - Co-Cristal Screening

No

*dissolution in human model (fasted/fed)

will allow comparing formulation options

Aqueous equilibrated solubility

pH 4 and 7.4 (> 50µM) and biorelevant media

on most stable polymorphic form

Yes

Yes

Yes

Yes

No

✓ Anticipated clinical formulation covers

predicted human active

Formulation feasible ?

Biopharm assessment vs clinical doseYes

| 23

CAN3 Early Biopharmaceutical Assessment

● Anhydrous form II of CAN3 tested in formulation:• aqueous suspension (Solutol/water 20/80)

• lipidic solution Labrasol/Labrafil 60/40 (up to 100 mg/ml) & suspension V

• Very poor dissolution with aqueous standard suspension

✓ High solubilized end fractions but rapid precipitation observed in both lipidic formulations

in-vitro static dissolution

Labrasol/Labrafil 60/40 selected for early toxicological studies,

solution up to 100 mg/mL

By courtesy of Louis. Henrion

Dissolution of CAN3 lipid based formulation vs

standard formulation

| 24

Amorphous Solid Dispersion (ASD)Dissolution of ASD based on crystalline drug and amorphous

Fast Dissolution of ASD versus crystalline form

Parachute effect to improve dissolution time

Need an early technology assessment for ASD of CAN3

●Key Factors

influencing the

dissolution rate

● Physical state

● Particle Sizes

● Technologies

1. Film technic

2. Milling

3. Spray-drying

Amorphous Solid Dispersion (ASD)

9th Annual Global Drug Delivery and Formulation Summit – March 2017 - Berlin 25

Crystallization generally considered as main risk for ASD development

Drug

Polymer

Need an stability assessment for ASD of CAN3

Evaluation of physical stability versus technology

ASD Stability testing 20% drug loading in Soluplus®X-Ray profils of CAN3 as function of technology and time

Milling

Film

Spray Drying

Cristalline

All sample do not present any peak of diffraction in X-Ray,

although microscopy analysis revealed presence small crystals

Optimization needed

Technology influencing the dissolution profile

Dissolution of CAN3 in human fasted (first intention for clinical phase I)

conditions as function of technology

Milling

Spray-Drying

Film

Crystalline

Gastric + intestinal media

Time (min)

Dis

solv

ed f

raction (

% H

PLC

)

All ASD samples present improvement of dissolution profile,

including parachute effect – significant gain as compared to lipid

formulation - Milling could be preferred - Optimization needed

| 28

Developability Assessment for Early Clinical Formulation Plan

Free compound/standard formulation

100 mg/dose to keep above Fa % > 50 %

Lipid Based formulation

200 mg/dose based on maximum tolerated lipids in Human

Amorphous Solid Dispersion300 mg/dose based on based on maximum tolerated excipients Soluplus ®

DATEPresentation title

Key conclusion for CMC : select strategy for FIM for anticipated active clinical doses – need PK dog.

Free compound/standard formulation preferred for CMC standpoint

100 mg 200 mg 300 mg

Take Home Message

• Head to head comparison (CAN 1 & 2)1. Chemical development plays a critical role

2. Solid state, solubility, dissolution, biopharm assessment are key contributors for the early development challenges

3. High throughput polymorphism screening is essential

4. Gastro-plus, with solubility data in bio-relevant media is of great interest to help relevant choice of candidate to push in development phases.

• Early formulation and technology assessment made for pre-clinical studies are essential to assess feasibility in clinical phase (CAN 3).

Developability Assessment


Growing importance of developability assessment in

pharmaceutical early development to make the right choice

for development phases

Acknowledgments

• Tsiala Benard• for precious presentation advices

• Antony Bigot

• Astrid Mallet

• Guillaume Louit

• Louis Henrion• For head to head CAN 1vs 2 comparison results and interpretation

• Eric Serruau

• Brigitte Sabine Essimbi

• Mostafa Nakach• For early technology choice, results and interpretation CAN 3

• External partners : Jerome Menegotto (Evotec)


THANK YOU

Date post:	27-Feb-2021
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