Technology selection methodologies for addressing

Technology selection methodologies

for addressing bioavailability

challenges

Michael Grass | Principal Scientist, Lonza – Bend

Jenifer Mains |Formulation R&D Manager - Edinburgh

• a

Lonza Pharma & Biotech | Michael Grass & Jenifer Mains | AAPS PharmSci 360 | 2018 NOV

2

Our business model

Feasibility

Studies

Product

Annuities

Drug Substance

Intermediates

Drug substances Drug Product

Intermediates

Drug Products

DesignSmall / Lab-Scale (non-GMP)

DevelopClinical Scale

ManufactureCommercial Scale


3

Flexible Model Across the Product Development Cycle

Small Molecule Technologies

DESIGNSmall / Lab-Scale (non-GMP)

DEVELOPClinical Scale

MANUFACTURECommercial Scale

Drug Substance Intermediates – early and GMP intermediates

Drug substances – full range of API inclusive of HPAPI, cytotoxic payloads for ADC’s

Drug Product Intermediates – multiparticulates (MP), micronized API, spray dried dispersions

Drug Products - tablets (IR and MR), encapsulated powder and MP, soft gels, liquid-fill hard caps

> 300Projects

> 200Products


4

Our Global Development & Manufacturing Network

3 Regions | 8 Sites

• Full Chemistry Capability

• Integrated Drug Product Development

APAC

Nansha, China

Europe

Edinburgh, UK

Ploermel, France

Molinazzo, Switzerland

Visp, Switzerland

North America

Bend, OR

Quakertown, PA

Tampa, FL

DPI and Drug Product

API


5

Our specialized focus areas

Design Develop Manufacture

Drug Substance

and Intermediates

Drug Product Concepts

Early –stage Clinical Trial Materials

Clinical Trial Materials

Commercial

Supply

• Customized API Development

• Highly Potent API & Drug Products

• Addressing Bioavailability Challenges

• Particle Engineering

• Modifying Pharmacokinetics

• Multi-particulate Formulations

Product Options

API / HAPIDrug Product Intermediate

Soft Gelatin Capsules

Tablets – IR, Osmotic, Matrix, Orally Dissolving

Powder Multi-particulate Filled Capsules

Liquid-filled Hard Capsules


Problem Statement DefinitionFormulation Selection


7

70-80% of drugs in pharmaceutical pipeline are low solubility

Biopharmaceutical classification system

Our BA enhancement toolkit is geared towards addressing BCS II compound challenges

Depth in all enabling technologies used in addressing either BCS IIA or IIB compounds

• phase-appropriate equipment

• extensive track record

• predictive modeling & tools for tech selection

2008;7:255–270

IIA Dissolution Rate Limited

IIB Solubility Limited

Butler, J., Dressman, J. J. Pharm. Sci., 2010


8

Important Considerations for Pre-formulation Assessment

Solubility1. Crystalline Aqueous

2. Amorphous Aqueous3. Crystalline Organic

Aqueous Solubility Challenge1. Lipophilicity/Micelle partitioning

2. Melting point/Crystal lattice energy (i.e. “brick dust”)

Permeability1. Molecular Descriptors

(e.g. MW, rotatable bonds, charge state)

2. Caco-23. Perfusion

Metabolism/Efflux

Pharmacokinetics Absolute BA

1.BA dose dependence2.Food effect

3. Gastric pH effect

Target Product Profile1. Dose

2. Dosing Frequency3. In vivo model (e.g. rat,

dog, monkey, human, etc.)

Chemical Stability1. Labile functional groups

2. Forced degradation

Physical Stability1. Thermal Properties

(e.g. Tm, Tc, Tg)2. Water Uptake


9

Goal: efficiently arrive at product development with certainty of approach

Problem Statement Definition Guides Technology Choice

SDD

LIPIDIC

NXSTAL

Product Concept

Molecular Properties

Predictions

Technology & Formulation

In vitro, in silico, & in vivo testing

Problem Statement

HME


10

Many Enabling Technologies Are Available

H.D. Williams et al. “Strategies to Address Low Solubility in Discovery and Development,” Pharmacol. Rev., 65(2013)315-499

Amorphous

• Solid dispersions

• SDD

• HME

• Lyophiles

• Drug/polymer nanoparticles

• Pure amorphous drug

Size Reduction

•Micronization

• Sub-micron crystals (100 to 800 nm)

• Nanocrystals (<100 nm)

• Cosolvents

• Surfactants

• Cyclodextrins

• Lipids:

• Oils

• SEDDS/SMEDDS

• Lipid Multiparticulates

Solvation

• Polymorphs

• Cocrystals

• Salts

Crystal Form

•Molecular modification

• Pro-drugs

Molecular Design


11

Conceptual bioavailability enhancement technology applicability map

H.D. Williams et al. “Strategies to Address Low Solubility in Discovery and Development,” Pharmacol. Rev., 65(2013), 315-499

Solu

bili

ty (

mg

/mL)

LogP


12

Performance

ManufactureStability

Formulation Selection Criteria

Performance:• Prediction of in vivo performance• Can the technology achieve required PK

performance?• Dose, dosage form, etc.

Stability• Chemical stability• Physical/performance

stability• Stability risk (ability to

model with accelerated studies)

Manufacturability• Scale-up considerations• Cost of goods• Required batch size


Amorphous Dispersions


Lonza Pharma & Biotech | Michael Grass & Jenifer Mains | AAPS PharmSci 360 | 2018 NOV 14

Increased Solubility and Dissolution Rate by Eliminating the Crystal Lattice Energy

15Lonza Pharma & Biotech | Michael Grass & Jenifer Mains | AAPS PharmSci 360 | 2018 NOV

In vitro Performance Characterization Should be in vivo Relevant


In vitro Performance Characterization Should be in vivo Relevant

• Amorphous “solubility”

• Precipitation risk

• Polymer selection

• Drug/polymer interaction

Dissolution FluxAmorphous Solubility Stomach → Duodenum

A robust set of bioperformance in vitro tools improves the capability to understand formulation performance mechanistically

• Amorphous “solubility”• Precipitation risk • Polymer selection• Drug/polymer interaction

• Dissolution rate• Precipitation rate• Maximum apparent

concentration• Speciation

• Clean measurement of “effective” concentration

• Able to properly account for micelle, colloid, and particle contribution to boundary layer diffusion and dissolution rate

• Dissolution rate• Precipitation rate vs.

emptying rate• Gastric precipitation • “Book-end” for

formulation performance


Amorphous Dispersions Stability Prediction is Critical

Thermodynamics Kinetics Experience

Solv

ent

Excipients API

SolventTank

SolutionTank

Process Heater

Condenser

Baghouse / Police Filter

System Gas Blower

Cyclone

ProductCollection

System Gas Blower

Feed Pump

DryingChamber

Atomizer

Secondary Dryer

Closed Loop / Recycle Equipment

0 1 2 3 40%

1%

2%

3%

4%

Drying Time [hours]

Wt%

So

lve

nt

SolventPolymer

Active

Solution TankSolvent Tank

Feed Pump

Cyclone BaghouseDrying

Chamber

Process Heater

Condenser

Product

Collection

System Gas

Blower

System Gas

Blower

Atomization

Drying Kinetics

18

Spray-Dried Dispersion Equipment and Process Schematic


http://www.google.com/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&docid=g98hYbPgvs2ukM&tbnid=oP-B8A4dDu0g_M:&ved=0CAUQjRw&url=http://www.pro-sonix.com/boilerFeedWaterHeatingInfo.asp?article=AP-90+Boiler+Feedwater+Heater&aid=35&id=14&ei=0-77UbrlGuH5igKkuYFI&bvm=bv.50165853,d.cGE&psig=AFQjCNF5lmOFGibdC5pS321JVdkT2a9L4A&ust=1375551556392780

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&docid=g98hYbPgvs2ukM&tbnid=oP-B8A4dDu0g_M:&ved=0CAUQjRw&url=http://www.pro-sonix.com/boilerFeedWaterHeatingInfo.asp?article=AP-90+Boiler+Feedwater+Heater&aid=35&id=14&ei=0-77UbrlGuH5igKkuYFI&bvm=bv.50165853,d.cGE&psig=AFQjCNF5lmOFGibdC5pS321JVdkT2a9L4A&ust=1375551556392780

19

A Spray dryer is a spray dryer……

Spray Dryer Scalability – Why is it important?

• Feasibility and formulation screening dryers often have limited operating space (Small particles and fast drying)

• Ideally the manufacturability assessment happens as close to discovery as practical and may be strongly coupled with the formulation selection process• Understanding limitations early can reduce scale-up surprises later• Custom equipment designed for feasibility to keep properties in same ball park of future

clinical/commercial expectations• Offline tools and models for scale-up for larger scale spray dryers


20

Spray-Dried Dispersion (SDD): Equipment Scale Range

Late Stage Clinical/CommercialProcess DevelopmentToxicology and Early-Phase Clinical Supplies

FormulationIdentification

Mini Spray Dryer25 mg → 1 g

Lab Spray Dryer(<35 kg drying gas/hr)

0.5 g → 100 g

Lab to Pilot Scale (“PSD-1” <150 kg drying gas/hr)

5 g → 5 kg

Pilot to Commercial (“PSD-2” < 750 kg drying gas/hr)

kgs → tons

Pilot to Commercial (NGD <200 kg drying gas/hr)

kgs → tons

Confidential | 28 August 2018

High On-timeSmall Footprint

Continuous Solution Prep


Case Study #1Amorphous Itraconazole Formulations: Room

for Improvement?


22

Amorphous Itraconazole (ITZ) is well absorbed relative to

crystalline ITZ

Amorphous RFP – Sporanox® (HPMC SLD)

Amorphous Dispersion (Soluplus HME)

Nanocrystals

Bulk Crystals

Is there room at the top?

Zhang et al. Eur J Pharmaceutics Biopharmaceutics (2013) 85 (3), 1285-1292

Itraconazole pH 6.5 Solubility (µg/mL)

Buffer FaSSIF

Crystalline < 10-3 0.07

Amorphous < 1 7 - 10

100x Amorphous Enhancement


23

Dimensionless numbers can predict impact of solubility, permeability or dissolution rate in vivo

FaCS Ref: Sugano, K., et al., J Pharm Sci. (2015), 104, 2777-2788

Solubility-permeability limited

Τ𝑃𝑛 𝐷𝑜 < 𝐷𝑛 & 𝐷𝑜 > 1

𝑃𝑛 < 𝐷𝑛 & 𝐷𝑜 < 1

Permeability-limited

𝐷𝑛 < 𝑃𝑛/𝐷𝑜

Dissolution-limited

Amorphous Itraconazole

ItraconazoleBCS II basepKa = 3.7cLogP = 6.3


24

Can a “better” amorphous dispersion be made via formation of nanoparticles?

Room at the Top?

Itraconazole pH 6.5 Solubility (µg/mL)

Buffer FaSSIF

Crystalline < 10-3 0.07

Amorphous < 1 7 - 10

100x Amorphous Enhancement

Mucus layer diffusion α r-1

100 nm

5 nm

1 nm

Dissolved drug


25

Amorphous spray dried dispersions (SDDs) of Itraconazole (ITZ):

+ItraconazoleBCS II basepKa = 3.7cLogP = 6.3

OH

H

CH2OR

H

ORH

OR H

OH

H

H

ORH

OR

CH2OR

H

O

O

n

R= -H-CH3-COCH3

-COCH2CH2CO2H-CH2CH(OH)CH3

-CH2CHCH3

OCOCH3

-CH2CHCH3

OCOCH2CH2CO2H

Hydroxypropyl MethylcelluloseAcetate Succinate (HPMCAS)

Stewart, A.M., et al. Mol Pharmaceutics (2017), 14 (7), 2437-2449

25% activeHydrophilic SDDAffinisol 716HP

25% activeHydrophobic SDDAffinisol 126HP

or


Hydroxypropyl Methylcellulose(HPMC)

“Novel”Formulations

ReferenceFormulation

Spray Dry

+Itraconazole

Spray Layer on Sugar Cores

26

Material sparing in vitro membrane flux test can assess solubility-permeability limited absorption

Accurel PP 1E membrane (55% porous, 100 µm thickness)

50 µL lipid (20% phospholipid in dodecane)

Feed Volume: 5 mLReceiver Volume: 10 mL

SA: 4.9 cm2

SA/V = 1.0 cm-1


27

Hydrophilic SDD has the highest flux in vitro

Flux (µg/min/cm2) Colloid (µg/ml)

1.18 602

0.85 150

0.53 0

No. Formulation Dispersion polymer

1 25% ITZ/75% HPMCAS SDD AFFINISOL 716HP

2 25% ITZ/75% HPMCAS SDD AFFINISOL 126HP

3 Sporanox® spray layered dispersion HPMC


28

Hydrophilic SDD shows the fastest absorption in rats – rank orders with in vitro performance


Case Study #2Spray Drying Poly(methyl methacrylate-co-

methacrylic acid), PMMAMA [Eudragit L and S]Dr. Kim Shepard


30

Enabling improved physical stability and higher loading amorphous formulations

Eudragit L100: A high Tg enteric polymer

Improved Physical Stability Higher Loading, Improved Performance


31

Enteric Polymers with different properties and applications

PMMAMA HPMCAS

Structure

Trade Name(s)Eudragit® L100, S100, L100-55 (Evonik

Industries)

Affinisol® 912, 716, 126 (DOW)AQOAT® HPMCAS-L, M, H (Shin Etsu)

AquaSolve™ (Ashland)

Tg (°C) 190 115 – 120

Acid Substitution (mmol/g) 4.2 – 5.6 0.7 – 1.5

MW (kg/mol) 125 50

Comparison of PMMAMA and HPMCAS

OH

H

CH2OR

H

ORH

OR H

OH

H

H

ORH

OR

CH2OR

H

O

O

n

R= -H-CH3-COCH3

-COCH2CH2CO2H-CH2CH(OH)CH3

-CH2CHCH3

OCOCH3

-CH2CHCH3

OCOCH2CH2CO2H


32

Strings form during spray drying using typical spray drying conditions, leading to poor flow and powder properties

Spray Drying Eudragit L100 Using “Standard Conditions”

Lefebvre model for atomization

Sheets Filaments Droplets

◼ High MW ◼ High Tg

◼ “Skinning” occurs at a lower concentration than typical spray drying polymers

λL = 5-10 µm


33

Two characteristic times govern string formation

Model-based parameters to control string formation

Droplet skinning time

Solution concentration

Drying gas temperature

Solvent Volatility

Solution Temperature

Recycle (% RS)

Droplet break-up time

Atomization pressure

Nozzle geometry

Solution viscosity

Experimental “Handles”

Strings form when tskinning < tbreakup

Droplet skinning time

Droplet break-up time


34

Process Space for Eudragit L100 Spray Drying on a PSD-1

Constant parameters: PSD-1, Methanol, 1850 g/min gas, SK80-16 nozzle, 400psi, single-pass


Lipid Formulations at Lonza


Bioavailability EnhancementLipid Formulations classification system (LFCS)

36

Type I

Oils

Type II

SEDDS

Type IIIA and IIIB

SEDDS/SMEDDS

Type IV

Lipid-free

Lipids, no

surfactant

No water-soluble

components

Includes lipids and water-soluble

surfactants and possibly co-

solvents

Comprises only water-

soluble surfactants and

co-solvents

No/limited

dispersion Emulsion

IIIA: Fine emulsion

IIIB: Transparent dispersionMicellar solution

Requires

digestionWill be digested Digestion may not be necessary Limited digestion

• Proposed by Professor Pouton Monash University

• Widely accepted and used by the wider lipid community

• Provided much needed clarity in classifying different types of formulation

Pouton, Eur J Pharm Sci 2006, 29, 278–287

In vitro lipid digestion Test

for performance assessment

0

20

40

60

80

100

120

0 20 40 60

% A

ctiv

e in

gred

ien

t in

aq

ueo

us

ph

ase

Time (min)

Surfactant/Co-surfactant(80/20)




37

Lipid Digestion

1. Reduce gastric emptying

2. Increase bile salts, + other biliary/pancreatic

secretion

3. Generate digested lipids

4. Supersaturation

5. Interacting with metabolic process

6. Directing drug transportation to lymphatic

system

Feeney et al., 2016, Adv Drug Dev RevLonza Pharma & Biotech | Michael Grass & Jenifer Mains | AAPS PharmSci 360 | 2018 NOV

38

Addressing solubility issues with LBF

LBFs provide rapid onset of action, as no dissolution is required. They:

increase drug solubilization and disposition

inhibit efflux and/or metabolic processes

leverage lymphatic absorption pathway

In addition to enhanced exposure, LBFs have been clinically shown to reduce food effects and food effect variability


39

Lymphatic absorption

1. Flow Rates of Lymph are 500 time lower than those of the systemic blood system

2. Lipid Concentration in the Lymph is around 1%

3. Lymphatic Uptake requires the presence of Long Chain Triglyceride, in order for the TG rich lipoproteins to be assembled.

4. API Log P > 4.7 (LogD) is required for the partitioning into TG at a ration of 50000:1

5. API Solubility > 50 mg/g is also normally required to ensure appropriate update of the API into the Lipoproteins

6. Capacity for protein binding


Excipient effects on efflux transporters

40

Tween® 20Span® 20

Cremophor® ELBrij® 30

Pluronic® P85

Tween® 80Cremophor® RH40

Myrj® 52Vitamin E TPGSGelucire® 44/14

Span® 40Span® 80

Propylene glycolGlyceryl triacetate

Ethyl oleate

P-gpinhibition

BCRPinhibition

No significant changes in intracellular ATP levels

Yamagata et al., J Cont Release 2007, 124, 1- 5 Yamagata et al., Int J Pharm 2009, 370, 216–219


Development and Characterization and manufacture of lipid formulations


42

Formulation design

• Experienced formulators

• A library of experimentally generated phase diagrams

• Software based formulation design

Pre-formulation kinetic solubility findings

Lipid expert software

Phase separation

Coarse

Emulsion

Microemulsion


43

Phase diagram construction

Formulation design

Water

Oil

Surfactant/Co-solvent

Coarse emulsion

SEDDS oily dispersion

Micro-emulsion


• Selected formulations determined and assessed by serial dilution in water

• Optimal composition determined through phase diagram production

Self Microemulsion

Characterisation and manufacture of lipid formulations


45

LBF development – in vitro testing: dispersion

90 nm 375 nm

• On capsule opening, self-micro / emulsifying formulations undergo dispersion into homogenous systems in the stomach

• Such systems maintain the drug in a solubilized manner, then undergo consistent gastric emptying similarly to aqueous solutions

• Oil-rich formulations are more poorly dispersing, and sometimes rely on digestion to increase drug disposition

In vitro dispersion is evaluated in e.g. aqueous, gastric media to understand the fate of the drug, determine formulation robustness, and discriminate among formulation candidates

Adapted from Porter et al., Nature Reviews 07, 6, 231-248


46

Dispersion testing

Active compared to placebo over time in the beaker and by microscopy

Small particle size, not visible by microscopy


47

In-vitro digestion testing


0

10

20

30

40

50

60

70

80

90

100

1 2 3 4

% R

eco

very

Formulation Number

Pellet

Aqueous

Lipid

Lipid

Aqueous

Pellet

48

In-vitro digestion testing

• High aqueous solubility and stability presence desirable for bioavailability enhancement

• Lipid layer may be absorbed

• Pellet layer suggests API precipitation and is unlikely to be absorbed


Time (min)

0 10 20 30 40 50 60

% D

rug

in

aqu

eo

us p

hase

0

20

40

60

80

100

120

F4

F3

F2

F1

49

Digestion results and in-vivo performance

Time (min)

0 10 20 30 40 50 60

% D

rug in a

queous p

hase

0

20

40

60

80

100

120

Time (hr)

0 2 4 6 8 10

Dan

azo

l p

lasm

a c

once

ntr

atio

n (

ng

/mL

)

0

20

40

60

80

100

120

140

F4

F3F2

F1

In vitro dispersion and digestion enable selection of lead and back-up formulations, provide fair prediction of in vivo performance

•Effective in vitro discrimination reduces reliance on in vivo testing

•Rank order correlated with preclinical study results

•Standardized in vitro tests help identify best LBF for pre/clinical


50

Two dosage format options

Lipid / liquid filled capsules

• Liquid

• Suspension

• Uncoated, coated

LIQUID FILLED HARD CAPSULES

• Liquid

• Suspension

• Semi-solid

• Solid

• Uncoated, Coated

• Sealed/Banded

SOFT GELATIN CAPSULES (SOFTGEL)

Common formulation approaches and

applications


Pharma Liquid Fill Hard Capsules

51

Three commercial scale general manufacturing lines

Mixing vessels up to 300L size, designed for heating and vacuum

• Liquid filling of hard capsules, to temperature of approx. 70°C

• Filling of hard capsules at speeds up to 120,000caps/hour

• Banding speeds to match filling machines

• Tooling sizes from 4 to 00

• Hot form film and foil blister, with leafleting and cartooning

• Serialisation

Two equivalent high containment cleanrooms

• Single product line per suite

• Negative pressure isolators, designed to also run inert or dry using

Nitrogen

• Secondary Change on all powder possible rooms

• Vacuum, or powder pumped, transfer of powder directly from

isolator to high shear mixing head

• Suites all full air extract

• Currently qualified to 0.05µg/m3

High Containment Compounding, Filling & Banding of Liquid Filled Hard Gel Capsules

Clinical and Commercial Blister Packaging & Cartoning

Clinical & Commercial Supply Chain Management

Packaging Serialisation


Pharma Soft Gelatine capsules

52

About 5000 m2 cGMP clinical and commercial manufacturing for Soft gelatine capsules

• Mixing vessels up to 800 kg, designed for heating, high shear mixing and vacuum

• Over 2 billion softgel capsules produced in 2016 (four commercial scale manufacturing lines)

• Hormones capsules produced in dedicated facility

• HPAPI powder Handling up to OEL <1µg/m3 using isolator and closed processes

• Commercial offset printing capability with camera inspection system on site

• Customized capsule size and shapes (oval, oblong, round, …)


Case studies


54

Cyclosporine formulation

300 mg Sandimmune®Coarse emulsion

Significant variability in BAStrong food effects

180 mg Neoral® Self-emulsifying LBF

Greater BA, less variabilityReduced food effects


55

Cyclosporine formulation dispersion

Neoral SandImmune

Start

6 hours


56

Cyclosporine formulation digestion

7.1 3.4 3.6 2.6 3.4

6.6 9.3 7.0 10.821.0

78.4 82.680.1

85.0

79.7

0.0

20.0

40.0

60.0

80.0

100.0

120.0

0 5 10 30 60

Time (mins)

Lipid

Aqueous

Pellet

4.0 3.9 4.2 7.5 8.3

105.0 103.2 102.1 98.7 96.4

0.0

20.0

40.0

60.0

80.0

100.0

120.0

0 5 10 30 60

Cyc

losp

ori

ne

Per

cen

tage

in e

ach

ph

ase

(%)

Time (mins)

Neoral SandImmune

Note the kinetics of the drug dispersion during digestion may partially explain the variability and possible food effects


57

Improvement of existing formulations

• Formulation 1 and 2 were developed elsewhere, formulations 3, 4 and 5 were developed at Lonza

• The three formulations demonstrated formulation stability on dispersion, and increased drug solubilisation in the aqueous phase during digestion

• They also showed superior performance in an animal in-vivo study


Q & AWant more information?

https://pharma.lonza.com/contact


https://pharma.lonza.com/contact

Documents

Technology selection methodologies for addressing