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