Slide 1

High-Concentration Monoclonal Antibody Powder Suspension

in Non-aqueous Vehicle for Subcutaneous Injection

Mayumi Bowen

Pharmaceutical Processing & Technology Development

Genentech, Inc

AAPS Annual Meeting and Expositions

11/04/2014

Slide 2 Subcutaneous Administration for mAb Therapy

Many monoclonal antibodies (mAb) require high dose (≥100 mg/dose) due to

the low potency

Many of the indications especially Oncology are successfully administered intravenously,

however frequent or chronic administration requires more convenient subcutaneous

(SC) home administration

SC administration poses a volume restriction, typically ≤2 mL, which necessitates

high mAb concentration

Typical needle size used for SC administration is 25G or higher.

Slide 3 Challenges for mAb SC Administration

1 80 3000

SC Injection

≤ 20-25

MAb concentration dependent high solution viscosity impacts

manufacturing and injection administration capabilities.

Long-term mAb stability at high mAb concentration

in a aqueous solution can be limited.

Acceptable injection is considered to be ≤ 20-25 N injection

glide force, preferably using smaller needles (i.e. ≥ 27G).

Smaller needles will pose less pain sensation to patients

and may potentially impact pain perception leading to

an advantage in patient compliance.

Viscosity (cP)

M. Adler, American Pharm Review, Feb 2012

S. Yadav, J of Pharm Sci., Vol. 99, No. 12, Dec 2010

0 50 100 150 200 250

MAb concentration (mg/mL

Vis

cosity

(cP

)

70

60

50

40

30

20

10

0

MAb-H

Mab-A

Mab-G

Mab-E

27G

26G

Slide 4

Due to limitation of liquid formulation at high mAb concentration even formulating

with viscosity reducing agents (i.e. salts, amino acids, solvents), we explored

feasibility of non-aqueous high concentration mAb powder suspensions for

subcutaneous injection.

Study Objectives

Identify feasible powder forming process, suspension vehicles and formulation

Formulate suspension with ≥150 mg/mL mAb, which enables acceptable injection

(i.e. injection force ≤ 20 N through a ≥ 27G Thin Wall needle)

Understand the mechanisms of suspension physical performance

Slide 5

Liquid Formulation

Powder Forming

Powder / Vehicle

Weigh Out

Suspension

Homogenization

Syringe Filling

Moisture Particle

Size Density

Scanning

Electron

Microscope

Particle

Size Viscosity

Injection

Glide Force

Suspension Preparation Analysis

Suspension Preparation and Analysis Process Flow

Suspension

Physical Stability

mAb

Stability

Slide 6 Study Outline

Select powder forming method and analyze mAb powder characteristics

Select non-aqueous vehicles and prepare mAb powder suspensions

Analyze suspension characteristics

• Suspension viscosity

• Injection glide force (injectability) via 27G Thin Wall needle

• Suspension particle size using Laser Diffraction analysis

• Suspension physical stability

• Particle-particle interaction and particle-vehicle interaction determination

using Inverse Gas Chromatography

• MAb stability in suspension formulation

Slide 7 Powder Criteria

Process / Powder Properties Rational

Scalable high-efficiency powder-forming process Enhance manufacturability

Spherical particles Minimize particle contact for better suspension

Low water content • Increase unit volume mAb load

• Enhance long-term mAb stability

Minimize excipients

(target weight ratio: mAb:sugar = 2:1)

(target molar ratio: mAb:sugar = 1:220)

Increase unit volume mAb load while maintaining

mAb stability

Small particle size (target: ~10 mm) Increase unit volume mAb load

High particle bulk density Increase unit volume mAb load

Spray drying is a potentially viable method for powder preparation

Slide 8 Spray Drying

Well-established, scalable, rapid powder forming methodology.

Key process parameters; air flow rate, liquid flow rate, inlet temperature, liquid formulation

Easy scalability, tons/day, and continuous process possible

Large-scale dryers being used in wide range of industries (chemical, food, pharmaceuticals).

Liquid Feed

Spray Nozzle

Drying Chamber

Cyclone

Gas (Out)

Exhaust

System

Powder Receiving

Vessel

Gas (In) Heating

Slide 9 Tested Spray Dryers

Buchi

B-290 (Bench-top scale)

SPX Anhydro

MS-35 (Pilot scale) MS-150 (Mfg scale)

• Made of glass (electrically insulator) • Made of stainless steel (electrically conductive)

• Insulated drying chamber & cyclone

• High-efficiency cyclone

• 00 Specifications B-290 MS-35 MS-150

Max. Inlet Temperature (oC) 220 220 350

Max. Drying Output (kg water/h) 1.6 (Toutlet=60oC) 2.0 (Toutlet=60oC) 14 (Toutlet=70oC)

Drying Chamber Diameter (cm) 10 30 90

Drying Chamber Height (cm) 56 60 83

Drying Chamber Surface Area (m2) 0.15 0.77 4.25

Theoretical powder residence time (sec) 1.2 4.7 19.5

Slide 10

mAb type mAb A mAb B mAb C

Spray-dryer B-191 MS-35 B-191 MS-35 B-191 MS-35

Inlet Temp. (ºC) 134 182 138 182 136 182

Otlet Temp. (ºC) 88 87 89 87 88 87

Atomizing Gas (kg/hr) 1 4 1 4 1 4

Liq Feed Rate (mL/min) 3 12 3 12 3 13

Liq vol dried (mL) 50 250 50 250 50 250

Collection Yield (%) 60 99 65 100 59 98

Particle Size D50 (mm) 2.5 9.6 2.8 8.8 5.1 10.6

Water Content (%) 7.6 4.0 6.9 4.7 8.8 5.0

SEC Monomer (%) No change No change No change No change No change No change

Morphology

(SEM images)

10 mm (x2000)

10 mm (x2000)

20 mm (x1000)

10 mm (x2000)

Powder Characteristics dried by 2 Types of Spray-dryers

Slide 11 Suspension Vehicle Criteria

Suspension Vehicle Properties Rational

Low viscosity (Target: ≤10 cp at 25ºC) Enhance manufacturability, injectability

Hydrophobic mAb powder should not be soluble

Safe Potentially parentally acceptable/approved

Slide 12

Miglyol 840

(Propylene Glycol Dicaprylate /

Dicaprate)

Ethyl Lactate Benzo Benzoate

Structure

Viscosity (cP) at 25ºC 9 2 9

Pharmaceutical

Applications

Not currently approved for

parenteral use, but some

animal tox data available for

transdermal application

Used as pharmaceutical

preparation, flavor

enhancer for oral dose

medications.

Not approved for parenteral

use but acute toxicity data

in mice by SC and IV are

available

Use as a preservative in

liquid dosage form for

parenteral administration

in quantities < 10%

Proposed Vehicles for Study

Slide 13 No Effect of mAb Types or Powder Properties on Suspension Viscosity

Similar to liquid, suspension viscosity increased as a function of mAb concentration

Suspension viscosity was higher than the corresponding liquid solution at ≤200 mg/mL

Viscosity of 3 different mAb suspensions was comparable

Suspension (Vehicle: Miglyol 840)

Liquid

Slide 14 Similar Surface Energy among tested mAbs Types

50 : Non-polar, dispersive surface energy (mJ/m2)

G50 : Polar, acid-base Gibbs free energy (mJ/m2)

- : Not tested

Solvent

(gaseous probe)

mAb A mAb B mAb C

50 (mJ/m2)

G50 (mJ/m2)

50 (mJ/m2)

G50 (mJ/m2)

50 (mJ/m2)

G50 (mJ/m2)

Decane, Nonane, Octane, Heptane 37.5 - 36.8 - 38.3 -

Acetone - 8.4 - 8.2 - 8.4

Ethyl acetate - 6.2 - 6.6 - 7.3

Ethanol - 14.8 - 14.5 - 14.9

Acetonitrile - 12.9 - 12.7 - 12.8

Comparable surface energy distribution among the three mAb powders could explain;

similar particle-vehicle interaction

similar particle-particle interaction

comparable suspension viscosity

To determine the interaction between suspension vehicle and mAb powder,

Surface Energy was tested using Inverse Gas Chromatography

Slide 15 Suspension Viscosity Depends on Vehicle Type

Viscosity at ≤200 mg/mL: Ethyl lactate < Liquid < Miglyol 840 = Benzo benzoate

Ethyl lactate suspension demonstrated <80 cP at 333 mg/mL mAb C

Miglyyol 840 suspension

Benzo benzoate suspension

Ethyl lacate suspension

Liquid

Vis

co

sit

y (

cP

) a

t 2

5ºC

Slide 16

mAb C

Miglyyol 840 suspension

Benzo benzoate suspension

Ethyl lacate suspension

Predicted Liquid extracted from Fig (D. Overcasher)

Suspension Viscosity Depends on Vehicle Type

Slide 17 Lower Glide Force in Suspension than Liquid formulation

Glide force of three types of suspensions was lower than predicted liquid formulation

Ethyl lactate suspension demonstrated <15 N at 333 mg/mL mAb C

D. Overcashier, Am Pharm Rev 9:77–83, 2006

Hagen-Poiseuille equation

mAb C

Miglyyol 840 suspension

Benzo benzoate suspension

Ethyl lacate suspension

Predicted Liquid extracted from Fig (D. Overcasher)

Slide 18 Higher Heat of Sorption in Ethyl Lactate Suspension

To measure the strength of the interaction between mAb particle and suspension vehicle,

Heat of Sorption (kJ/mole) was determined using Inverse Gas Chromatography

Suspension Vehicle mAb A mAb C

Miglyol 840 39.9 ±0.5 43.4± 0.5

Benzyl benzoate 36.5 ±0.7 42.8± 0.6

Ethyl lactate 51.5 ±0.3 58.5 ±0.4

Higher heat of sorption in ethyl lactate than Miglyol 840 or Benzyl benzoate may imply;

in Ethyl lactate, higher particle-vehicle interaction than particle-particle interaction

in Ethyl lactate, lower degree of particle self association

Slide 19 Vehicle impacts suspension particle size

0

2

4

6

8

10

12

14

16

0.1 1 10 100 1000

Fre

qu

en

cy (

%)

Diameter (mm)

Benzyl Benzoate

Ethyl Lactate

Miglyol 840

Particle Size Distribution determined by Laser Diffraction

Higher heat of sorption may cause a lower level of particle agglomeration

(smaller suspension particle), which may correspond to lower viscosity

and glide force.

25 28

7

Slide 20

Ethyl lactate Miglyol 840

Suspension Physical Stability (Sedimentation)

Note the blue tape was not part of the suspension but used for optical focusing during photo taking

150 mg/mL mAb C suspension after 2 week ambient storage

Sedimentation rate of mAb C in Ethyl lactate was greater than that in Miglyol 840

Stoke’s law

V = velocity

rp = particle density

rs = solvent density

h = solvent viscosity

d = particle diameter

g = force of gravity

Slide 21

0

2

4

6

8

10

12

14

0.1 1 10 100 1000

Fre

qu

en

cy

(%

)

Diameter (mm)

100:0

75:25

50:50

25:75

0:100

Vehicle Mixture modulates Suspension Particle Size

Particle Size determined by Laser Diffraction

0

5

10

15

20

25

30

35

Volume Ration of Vehicle Mixture (Ethyl lactate : Miglyol 840)

100:0 75:25 50:50 25:75 0:100 Me

an

Pa

rtic

le S

ize

(m

m)

Ethyl lactate : Miglyol 840

0:100

25:75

50:50

75:25

100:0

Slide 22 Vehicle mixture optimizes suspension physical stability

Vehicle mixture (Ethyl lactate:Miglyol 840 = 75:25) rendered good suspension physical stability

Vehicle Volume Ratio (Ethyl lactate : Miglyol 840)

100:0 75:25 50:50 25:75 0:100

150 mg/mL mAb C in suspension after 2 week ambient storage

Slide 23

Data suggested suspension vehicle type was a key factor for suspension performance.

• Ethyl lactate suspension displayed lower viscosity, lower glide force and

smaller particle size than Miglyol 840 and Benzo benzoate, which may be due to

a strong particle-vehicle interaction that prevents particle agglomeration in suspension.

• Ethyl lactate suspension at 333 mg/mL mAb demonstrated a low glide force of <15N

via a 27G TW needle, however physical suspension stability was worse than

other vehicles tested.

• Suspension vehicle mixture (Ethyl lactate : Miglyol 840 = 75:25) improved suspension

performance at 150 mg/mL mAb.

Non-aqueous mAb powder suspensions is feasible for SC administration at high mAb

concentration (>300 mg/mL mAb).

Summary

Slide 24

Acknowlegements

Genentech

Nick Armstrong

Yuh-Fun Maa

Edwin Chan

Aaron Hubbard

SPX Flow Technology Systems, Inc. formerly Anhydro (Elkridge, MD)