Watch the presentation of this webinar here: https://bit.ly/3FKGUH6
At the high protein concentrations required for subcutaneous administration, protein formulations often become highly viscous. In this webinar, Dr. Tobias Rosenkranz will introduce a new approach that combines different excipients to reduce viscosity and discuss synergistic effects.
Subcutaneous (subQ) administration can improve patient convenience and reduce healthcare costs by avoiding the need for hospitalization. Yet in some cases, high protein concentrations make formulations far more viscous, prohibiting this route of administration. While viscosity can normally be reduced by using certain excipients, merely adding more and more of a single excipient may not bring sufficient improvement and can even compromise protein stability. This webinar will introduce an excipient platform that makes it possible to combine excipients in ways that can reduce protein viscosity to a greater extent.
In this webinar, you will learn about:
• Challenges arising from high concentrated protein formulations
• The viscosity reduction platform: a portfolio of excipients to manage protein viscosity
• The impact of viscosity reducing excipients on protein stability
• The impact of protein viscosity on syringability
Presented by: Tobias Rosenkranz, Ph.D., Senior Manager, Biomolecule Formulation R&D
The Power of Technology and Collaboration in Research - Rheumatology Research...
The Viscosity Reduction Platform: Enabling Subcutaneous (subQ) Delivery
1. The life science business of Merck KGaA,
Darmstadt, Germany operates as
MilliporeSigma in the U.S. and Canada.
The Viscosity Reduction
Platform:
Enabling Subcutaneous Delivery
Darmstadt, October 7th 2021
Dr. Tobias Rosenkranz
2. The life science business
of Merck KGaA, Darmstadt,
Germany operates as
MilliporeSigma in the U.S.
and Canada
3. Challenges arising from
elevated protein viscosity
Additional applications
Our solution: The Viscosity
Reduction Platform
What we offer
5. Increasing protein concentrations can lead to high viscosity levels
beyond injectability
Viscosity Reduction Platform
Market Need
Most therapeutic mAbs are currently only
available for intravenous (IV) administration
(64%)
Subcutaneous (SC) formulations are the
preferred route, as they offer higher patient
convenience and the opportunity to reduce
healthcare cost
Challenge
SC formulations can only reach volumes in the
range of 1-2 mL
➢Need for high protein concentrations to reach
therapeutic dose
High protein concentrations tend to exhibit
viscosity levels beyond injectability
Webinar - The Viscosity Reduction Platform: Enabling Subcutaneous Delivery | October 7, 2021
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6. Effect of viscosity in highly concentrated antibody formulations
Viscosity Reduction Platform
Numbers
The required injection force depends on various
parameters other than viscosity
η: viscosity [mPa*s]
l: length of needle [mm]
Q: flow rate/injection rate [mL/s]
Rb: radius of syringe/barrel [mm]
Rn: inner radius of needle [mm]
Typically, needles thinner than 27G are used for sc
administration.*
*Garindel & Presser, Lyophilization of High Concentrated Protein Solution, Book
Chapter: Lyophylization of Pharmaceuticals and Biologics, Springer Protocols 2019
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Injection force is
dependent on
solution viscosity
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Viscosity Reduction Platform
Effect of protein viscosity on injection force for mAb vs. water
27 Gauge Needle
Water: 1 N corresponds roughly
to the force of 100 g
27 Gauge Needle
mAb: 80 N corresponds roughly
to the force of 8 kg
A thinner needle would additionally amplify the required
injection force !
8. Viscosity Reduction Platform
Several mAbs show a critical viscosity vs. concentration profile
In-house mAbs and marketed mAbs identified as models with viscosity issues
Webinar - The Viscosity Reduction Platform: Enabling Subcutaneous Delivery | October 7, 2021
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9. Viscosity Reduction Platform
Molecular mechanisms causing viscosity in proteins: Fab-Fab interactions
Antibody regions Viscosity at protein concentrations < 200 mg/ml
Caused by protein-protein interactions (PPI)
PPI can occur between different regions of the protein,
however Fab-Fab interactions seem predominant*
Interactions are specific, but transient
PPI are identical to intra-molecular interactions that stabilize
proteins
*S. Kanai et al. Journal of Pharmaceutical Sciences, Vol. 97, No. 10, October 2008
Antibodies comprise of different regions
Fab: Fragment antigen binding
Fc: Fragment crystallizable
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Fab
Fc
10. Webinar - The Viscosity Reduction Platform: Enabling Subcutaneous Delivery | October 7, 2021
Single excipients often not sufficiently able to reduce protein viscosity
Viscosity Reduction Platform
A single excipient
may not reduce
viscosity
sufficiently well,
even when increasing
the excipient
concentration
10
BM: Benchmark BSAcid: Benzene sulfonic acid
Orn: L-Ornithine HCl Pyr: Pyridoxin
Phe: L-Phenylalanine TMP: Thiamine phosphoric acid ester
11. Webinar - The Viscosity Reduction Platform: Enabling Subcutaneous Delivery | October 7, 2021
High single excipient concentrations can destabilize the protein
Viscosity Reduction Platform
Forced degradation study
• 120 mg/ml Infliximab; 170 mg/ml Evolocumab
• 40°C, 75% rel. hum., 28 days
• Reference formulation vs. formulations with
excipients spiked in
Higher excipient concentrations can
destabilize the antibody
11
13. Use of excipient combinations to reduce protein viscosity efficiently
Viscosity Reduction Platform
Our viscosity reducing excipient platform:
A set of excipients to help you manage protein viscosity
• Numerous excipients for reducing viscosity are already
known and used in marketing formulations, e.g. certain
amino acids
• Known excipients are not always able to reduce protein
viscosity sufficiently well
• Used in combination, excipients may develop synergistic
effects enabling improved viscosity reduction and a better
balance of viscosity vs. stability
Webinar - The Viscosity Reduction Platform: Enabling Subcutaneous Delivery | October 7, 2021
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14. Webinar - The Viscosity Reduction Platform: Enabling Subcutaneous Delivery | October 7, 2021
Viscosity Reduction Platform
Effect of protein viscosity on required injection force for mAb
Infliximab
27 Gauge Needle, 0.2 ml/s flow rate
Aspiration Time: 75 s
Injection Force: 19 N
Evolocumab
27 Gauge Needle, 0.2 ml/s flow rate
Aspiration Time: 116 s
Injection Force: 29 N
Typical flow rates 0.15 ml/s – 0.45 ml/s
Usach, I et al.; Subcutaneous Injection of Drugs: Literature Review of Factors
Influencing Pain Sensation at the Injection Site; Adv Ther (2019) 36:2986–2996
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Aspiration time Injection Force Aspiration time Injection Force
15. Combinations of excipients enable SC delivery
Viscosity Reduction Platform
Webinar - The Viscosity Reduction Platform: Enabling Subcutaneous Delivery | October 7, 2021
Several useful combinations depending on the properties of the
protein under the formulation conditions
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16. Webinar - The Viscosity Reduction Platform: Enabling Subcutaneous Delivery | October 7, 2021
Viscosity Reduction Platform
Effect of protein viscosity on required injection force for mAb
Infliximab
27 Gauge Needle, 0.2 ml/s flow rate
Aspiration Time: 42 s - 44%
Injection Force: 15 N - 21%
Typical flow rates 0.15 ml/s – 0.45 ml/s
Usach, I et al.; Subcutaneous Injection of Drugs: Literature Review of Factors
Influencing Pain Sensation at the Injection Site; Adv Ther (2019) 36:2986–2996
16
Aspiration time Injection Force
17. Webinar - The Viscosity Reduction Platform: Enabling Subcutaneous Delivery | October 7, 2021
Viscosity Reduction Platform
Effect of protein viscosity on required injection force for mAb
Infliximab
27 Gauge Needle, 0.2 ml/s flow rate
Aspiration Time: 42 s - 44%
Injection Force: 15 N - 21%
Evolocumab
27 Gauge Needle, 0.2 ml/s flow rate
Aspiration Time: 37 s - 68%
Injection Force: 15 N - 48%
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Aspiration time Injection Force
Aspiration time Injection Force
Typical flow rates 0.15 ml/s – 0.45 ml/s
Usach, I et al.; Subcutaneous Injection of Drugs: Literature Review of Factors
Influencing Pain Sensation at the Injection Site; Adv Ther (2019) 36:2986–2996
18. Excipient combinations can reduce viscosity even beyond
the purely additive level
Viscosity Reduction Platform
• Excipient interactions are
not purely additive
• Several excipient
combinations can
achieve an over
additive viscosity
reduction
Webinar - The Viscosity Reduction Platform: Enabling Subcutaneous Delivery | October 7, 2021
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19. Webinar - The Viscosity Reduction Platform: Enabling Subcutaneous Delivery | October 7, 2021
Formulation pH affects excipient performance
Viscosity Reduction Platform
Excipient properties are
less affected by pH
Protein becomes more
charged at a lower pH
→ Excipients need to
match the protein
properties at the desired
pH
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Evolocumab
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Viscosity Reduction Platform
Excipient combinations show an improved stability
Use of excipient combinations can counteract the destabilizing effect of
strong viscosity reducing excipients !
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Forced degradation study
• 120 mg/ml Infliximab; 170 mg/ml Evolocumab
• 40°C, 75% rel. hum., 28 days
• Reference formulation vs. formulations with excipients spiked in
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Viscosity Reduction Platform
Excipient combinations show an improved stability
Storage and accelerated storage study:
• At 2-8°C high degree of stability for the relevant excipient combinations
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Viscosity Reduction Platform
Excipient combinations show an improved stability
Storage and accelerated storage study:
• At 2-8°C high degree of stability for the relevant excipient combinations
• At 25°C degradation of protein with TMP observed
• Likely reason is light/temperature sensitivity of excipient
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23. Benefit of our platform of synergistic excipient combinations
Viscosity Reduction Platform
Viscosity reduction
Improved administration
• Reduced injection volume / less frequent injections
• Switch to more convenient route of administration (SC)
Increased patient
convenience and compliance
Webinar - The Viscosity Reduction Platform: Enabling Subcutaneous Delivery | October 7, 2021
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Protein stability
25. Plasma proteins can be concentrated to a higher concentration
Viscosity Reduction Platform
• Viscosity reducing excipients allow
for reaching higher maximal
protein concentrations
• For this plasma protein formulation
the dose per/ml could be
increased by approx. 15-20%
Webinar - The Viscosity Reduction Platform: Enabling Subcutaneous Delivery | October 7, 2021
0 100 200 300
0
50
100
150
200
250
An IgG/IgM/IgA Formulation
Concentration [mg/ml]
Viscosity
[mPa*s]
w/o
Ornithine / BSAcid
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A lower viscosity improves process economics in TFF
Viscosity Reduction Platform
• Viscosity reducing
excipients reduce process
time
• 30% higher protein
concentrations can be
achieved at even lower
transmembrane pressure
Pressure limit
exceeded
Protein concentration was calculated based on the measured tank level.
No loss was assumed. Initial protein concentration was 8 mg/mL.
0 2000 4000 6000 8000
0
30
60
90
120
Concentration of mAbX
in a TFF system
time [s]
protein
conc.
[mg/mL]
w/o
VRP combination
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27. Viscosity Reduction Platform
Webinar - The Viscosity Reduction Platform: Enabling Subcutaneous Delivery | October 7, 2021
Enable
subcutaneous
delivery
Increase
dose per volume
ratio
Improve
process
economics
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How to evaluate our
technology
• Test-Kit available on request
(technical grade)
• Detailed user guide describing
proof-of-concept screening
available
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30. Formal Paper
Toxicological Profile
and
Safety Evaluation
by European
Registered Toxicologist
In-vitro
skin irritancy test
(HET-CAM)
No irritancy
detected
Available on request
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Regulatory and toxicological considerations positive
Viscosity Reduction Platform
Well characterized safety profile
Toxicological evaluation Prior in-human usage
Excipient candidates have all
been used in parenteral
formulations:
• Parenteral nutrition
(here considered
actives)
• Counter ions to APIs
• pH-adjustment
Webinar - The Viscosity Reduction Platform: Enabling Subcutaneous Delivery | October 7, 2021
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Protein viscosity challenge
Viscosity Reduction Platform
Proprietary technology available via license
Proprietary technology available
via license:
• Exclusively protect the best solution for
your protein of interest
• License required for commercial usage
Subsequent launches:
High-quality Emprove® Expert excipients
The technology license is not tied to
the purchase of our excipients
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Summary
Enabling subcutaneous delivery
• Excipient platform can specifically target viscosity challenges
• Use of excipient combinations is more efficient than using single
excipients
• Aspiration time and extraction force can be significantly reduced
• Use of excipient combinations offers additional stability benefits
• Dose concentration can be increased
• A reduced protein viscosity can yield improved process efficiency
For more information, please visit:
sigmaaldrich.com/viscosity-reduction