The Viscosity Reduction Platform: Enabling Subcutaneous (subQ) Delivery

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

The life science business
of Merck KGaA, Darmstadt,
Germany operates as
MilliporeSigma in the U.S.
and Canada

Challenges arising from
elevated protein viscosity
Additional applications
Our solution: The Viscosity
Reduction Platform
What we offer

Challenges arising from
protein viscosity

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
5

Effect of viscosity in highly concentrated antibody formulations
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
6
Injection force is
dependent on
solution viscosity

7 Webinar - The Viscosity Reduction Platform: Enabling Subcutaneous Delivery | October 7, 2021
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 !

Several mAbs show a critical viscosity vs. concentration profile
In-house mAbs and marketed mAbs identified as models with viscosity issues
8

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
Fab
Fc

Single excipients often not sufficiently able to reduce protein viscosity
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

High single excipient concentrations can destabilize the protein
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

Our solution: Viscosity
reducing Excipients

Use of excipient combinations to reduce protein viscosity efficiently
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
13

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
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
14
Aspiration time Injection Force Aspiration time Injection Force

Combinations of excipients enable SC delivery
Several useful combinations depending on the properties of the
protein under the formulation conditions
15

Infliximab
Aspiration Time: 42 s - 44%
Injection Force: 15 N - 21%
16
Aspiration time Injection Force

Infliximab
Evolocumab
17

Excipient combinations can reduce viscosity even beyond
the purely additive level
• Excipient interactions are
not purely additive
• Several excipient
combinations can
achieve an over
additive viscosity
reduction
18

Formulation pH affects excipient performance
 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
19
Evolocumab

Excipient combinations show an improved stability
Use of excipient combinations can counteract the destabilizing effect of
strong viscosity reducing excipients !
20
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

Storage and accelerated storage study:
• At 2-8°C high degree of stability for the relevant excipient combinations
21

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
22

Benefit of our platform of synergistic excipient combinations
Viscosity reduction
Improved administration
• Reduced injection volume / less frequent injections
• Switch to more convenient route of administration (SC)
Increased patient
convenience and compliance
23
Protein stability

Plasma proteins can be concentrated to a higher concentration
• 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%
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
25

A lower viscosity improves process economics in TFF
• 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
26

Enable
subcutaneous
delivery
Increase
dose per volume
ratio
Improve
process
economics
27

How to evaluate our
technology
• Test-Kit available on request
(technical grade)
• Detailed user guide describing
proof-of-concept screening
available
29

Formal Paper
Toxicological Profile
and
Safety Evaluation
by European
Registered Toxicologist
In-vitro
skin irritancy test
(HET-CAM)
No irritancy
detected
Available on request
30
Regulatory and toxicological considerations positive
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

Excipient launch roadmap
31
Product Item code Product name Launch timeline
Ornithine HCl 137118
L-Ornithine
monohydrochloride
EMPROVE® EXPERT DAB
Already available
L-Phenylalanine 107267
L-Phenylalanine EMPROVE®
EXPERT Ph Eur,USP
Already available
Benzenesulfonic
acid
103893
Benzenesulfonic Acid
EMPROVE® EXPERT
Q1 2022
Thiamine
Phosphoric Acid
Ester
500667
Thiamine phosphoric acid
ester chloride dihydrate
EMPROVE® API
Sampling quantities available,
Commercial quantities: 2023
Pyridoxine HCl tbd tbd Q3 2022

32
Protein viscosity challenge
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

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

Merck, the Vibrant M, Emprove and SAFC are trademarks of Merck KGaA, Darmstadt, Germany or its affiliates. All other trademarks are the property of
their respective owners. Detailed information on trademarks is available via publicly accessible resources.
© 2021 Merck KGaA, Darmstadt, Germany and/or its affiliates. All Rights Reserved.

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