High-Concentration Monoclonal Antibody Powder Suspension ... · High-Concentration Monoclonal...
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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