CASSS CMC Strategy Forum Summer 2012
July 16, 2012
Mariana N. Dimitrova, Principal Scientist, Ph. D.
Formulation Sciences Department, MedImmune
Proteins at Interfaces:
Formulation Approaches
Minimizing Device Interface
Incompatibilities
Outline
1 Combination products for protein therapeutics
3 Case study: formulation approaches minimizing interface
incompatibilities
4 Formulation solutions and approaches
2 Challenges with interfacial incompatibilities
2
Combination Products Offer Valuable Advantages
Improved compliance
– Minimizing dosage errors
– Improved patient safety
• Prevent undesirable needle-
sticks
Product differentiation
– User convenience
– Competitive product profile
Device specific advantages
– Improved cost of goods due
to minimal overfill (PFS)
Device Related Challenges Developing
Robust Combination Products
Physical/chemical instabilities
caused by leachables
Interface incompatibilities:
Device specific:
Common Materials in Devices in Direct Contact
with the Protein Therapeutics
• Enable novel primary
container dimensions,
i.e. reservoirs
• Oxygen permeability
• Adsorption to solid
interfaces
• Interfacial
incompatibilities
• Thermoplastic
elastomer
• Interfacial
incompatibilities
• Adsorption to solid
interfaces
• Long term storage
experience
• Glass breakage
• Glass delamination
• Adsorption to the
solid surfaces
• pH shift
Glass Cyclic
polyolefin Polyethylene Polyester
5
• High degree of
thermal expansion
(HDPE)
• Potential for stress
cracking (HDPE)
• Prone to UV
degradation
• Oxidation prone
• Interfacial
incompatibilities
• Adsorption to solid
interfaces
• High degree of
thermal expansion
• Prone to UV
degradation
• Oxidation prone
• Flammable
• Interfacial
incompatibilities
• Adsorption to solid
interfaces
Polypropylene
Formulation and User Requirements
Related Challenges
Formulation development
– High concentration liquid formulations
– Viscosity, tonicity, osmolality, etc.
– Materials of construction compatibility
– Acceptable levels of leachables (silicone
oil, tungsten, etc.)
– Formulation optimization for the specific
device
• Surfactant optimization
User requirements
– Accurate, painless, convenient, fast….
administration
• Small fill volume
• < 10s injections
• <27G needles
Formulation, Device and User Requirements
7
Drug Product
Stability
(Formulation
requirements)
User
Requirements
Device
Requirements
Tug of War
Particle Formation is Most Common Challenge in
Incompatible Devices
Examples of syringes incompatible with a monoclonal antibody
A: incompatible material of the syringe barrel
B: exceeding the defined tolerable levels of silicone oil and tungsten
0
2000
4000
6000
8000
10000
12000
14000
1 6 9 12
Time (months)
SV
Part
icle
s/m
L
≥ 10 um
≥ 25 um
Visible particles after 9 months at 2-8°C
A
USP ≥ 10 m
USP ≥ 25 m 0
2000
4000
6000
8000
10000
12000
14000
1 6 16
Time (months)
SV
Part
icle
s/
mL
≥ 10 um
≥ 25 um
B
Visible particles after 9 months at 2-8°C
USP ≥ 10 m
USP ≥ 25 m
100 µm
Case Study: Formulation Approaches Minimizing
Interface Incompatibilities
Interfacial incompatibility leading to conformational
changes at the interfaces
Impacting product CQAs: visible particle formation,
subvisible particles (SVP), protein concentration loss
Formulation approaches resolving interface
incompatibilities
Interface Incompatibilities
Product
Attributes Glass Polyester* Polyethylene** Polypropylene
Protein
concentration loss No No Yes ( 25%) Yes (5-10%)
Visible particles No No Yes Yes
SVP Low Low High
6 fold increase
High
20 fold increase
Example SVP
images by MFI
Structural changes No No Yes Yes
Interfacial
compatibility Compatible Compatible Incompatible Incompatible
* Polyethylene Terephthalate Glycol (PETG)
** High Density Polyethylene (HDPE)
Trace Elements Analysis by ICP-MS
No significant difference was seen in the trace elemental profile
Calcium was found to be high in compatible and incompatible
containers
Trace Elements
PETG
(ppb)
HDPE
(ppb)
Zinc 13.0 16.0
Copper 2.7 5.3
Iron 3.8 4.4
Calcium 1103.0 1096.0
Magnesium 21.0 21.0
Aluminium 4.1 < LOQ
Particle Composition Analysis by SEM-EDX and FTIR
Majority of particle contained only protein (denatured)
Isolated particles contained leachables
– Polyethylene containers: Ti and Si
– Polypropylene containers: Carboxymethyl cellulose
Interface Incompatibilities Caused Structural
Changes (DSC)
20 30 40 50 60 70 80 90 100-20
0
20
40
60
80
100
120 Glass (compatible)
Polypropylene (incompatible)C
p (
kc
al/
mo
le/o
C)
Temperature (o
C)
Protein structural perturbations/unfolding appear to be the main root
cause for the observed interface incompatibilities
60.1 69.7
83.5
60.1 68.3
83.1
Formulation Approaches Resolving Interface
Incompatibilities
20 30 40 50 60 70 80 90 100
0
50
100
150 Formulation B Polypropylene
Formulation B Glass
Cp
(k
ca
l/m
ole
/oC
)
Temperature (o
C)
20 30 40 50 60 70 80 90 100-50
0
50
100
150 Formulation C Polypropylene
Formulation C Glass
Cp
(k
ca
l/m
ole
/oC
)
Temperature (o
C)
Formulation development preserving protein structure at the interfaces
Two formulations were developed resolving the interfacial incompatibilities
Formulation Excipients Imparted
Colloidal Stabilization
0.00
5.00
10.00
15.00
20.00
25.00
30.00
35.00
40.00
0 2 4 6 8 10 12
[P] mg/ml
Hy
dro
dy
na
mic
Dia
me
ter
(nm
)
High-throughput Dynamic Light Scattering
Self-association as a function of the protein concentration was not observed in
the formulations preventing interfacial incompatibilities (Formulations B and C).
Formulation A
Formulation D
Formulation B
Formulation C
Formulation Excipients Imparted
Colloidal Stabilization
-5.00E-02
-4.50E-02
-4.00E-02
-3.50E-02
-3.00E-02
-2.50E-02
-2.00E-02
-1.50E-02
-1.00E-02
-5.00E-03
0.00E+00
Formulations
kD
Interaction Parameter (Kd)
Interaction parameter (kD) is obtained from plot of diffusion coefficient vs. concentration.
Positive kD indicates repulsive interactions whereas negative values suggest attractive
interactions.
Lower negative kD value are indicative of minimized protein-protein attractive interactions in
the stabilizing formulations B and C.
Formulation A
Formulation D
Formulation B Formulation C
Formulation Compatible Interfaces Incompatible Interfaces
2-10µm ≥ 10µm ≥ 25µm 2-10µm ≥ 10µm ≥ 25µm
Formulation A 897 2 0 29387 7919 2141
Formulation B
Resolving incompatibilities 689 53 17 1162 72 58
Formulation C
Resolving incompatibilities 819 130 46 795 54 34
Formulation Approaches Resolving Interface
Incompatibilities
The two formulations preventing protein perturbation/structural changes at the
interfaces minimized SVP and visible particles formation (SVP analysis by MFI)
Structural perturbations, significant protein concentration loss and particle
formation (visible and SVP) were detected at multiple incompatible
interfaces for a protein therapeutic.
Control and mitigation strategy:
– Developed two formulations preventing interface structural perturbations,
particle formation and protein concentration loss
– Evaluated compatible materials of construction
Case Study Summary and Control Strategy
Formulation Approaches Improving Interface/Device
Compatibility
Extensive evaluation of compatible materials of construction of the device
– Syringe, cartridge, stopper, etc.
Formulation optimization/robustness evaluation with the specific device:
– Real size/surface area (surfactant optimization)
– Real life stresses during transportation, clinical administration, etc.
Acceptable levels of lubrication (silicone oil) in the device
Decoupled evaluation studies to define the acceptable levels of extractables and leachables
– Primary container or device components in direct contact with the product
In partnership with the device engineers evaluate device and patient/user requirements and the potential impact on the formulation.
– E.g. solution viscosity and needle gauge selection
Early compatibility risk assessment input into the design of the device
Summary
Integrating protein therapeutics with devices it is important to
consider:
– Product requirements and characteristics
– Device performance and requirements
– Patient/user interface
We’ve seen, through a case study, the impact of interfacial
incompatibilities on Drug Product CQAs and how to resolve them
utilizing formulation approaches
Combination product risk assessment
Balancing formulation compatibility with device performance and
user requirements considerations
Acknowledgments
Roja Narwal
Chinmay Bakshi
Jared Bee
Vadim Frey
Steven Bishop
Suzanne Kiani
Diane Doughty