Long acting injectable microparticle formulation - a new dimension for peptides and proteins

The life science business of Merck KGaA,
Darmstadt, Germany operates as
MilliporeSigma in the U.S. and Canada.
LONG-ACTING INJECTABLE MICROPARTICLE FORMULATIONS
A NEW DIMENSION FOR PROTEINS AND PEPTIDES

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

Need for sustained release drug
delivery systems for Biologics
Long-Acting Injectable Microparticle Formulations
3
Benefits of Sustained Release Drug Delivery
Clinical Benefits
 Longer duration of action / less
frequent injections
 Reduced side effects / toxicity due to
lower systemic levels
 Enhanced therapeutic efficacy
 Improved patient compliance
Applications
 API with low t½ / small therapeutic
window
 Oral incompatibility (proteins)
 Chronic diseases
 Site-specific drug delivery
 Classical PLGA/PLA
formulations are not
suitable for sustained
release of biologicals due
to their rigidity and acidic
microenvironment
formation.
 Currently no PLGA/PLA
polymer-based sustained
release drug delivery
products for protein
therapeutics FDA
approved.

Our Polymer Offering for Sensitive Peptides and Proteins
4
Small Molecules Peptides Proteins
< 1 kDa 1 – 10 kDa > 10 kDa
A versatile portfolio of biodegradable polymers and drug delivery systems to
formulate a fit for purpose drug product
PLGA / PLA (Expansorb®)
SynBiosys®
EXPANSORB® is a registered
trademark of Groupe Seqens,
Longjumeau, France
SynBiosys® is a registered trademark of
Innocore Pharmaceuticals, Groningen,
Netherlands

SynBiosys®
Polymeric microparticle Platform

The SynBiosys® Polymer Platform
Prepolymer blocks Multi-block copolymer with
unique molecular architecture
Polyethylene
glycol
1,4-butanediol
6
(chain-extender)
1,4-butanediisocyanate
OH
HO
ppCP10C20
(amorphous & hydrophilic)
OH
HO
ppLL40
(Crystalline & rigid)
6
Toolkit Synthesis of multi-block copolymers
Initiators
ε-caprolactone
L-Lactide
Monomers
Customized biodegradable polymers designed for delivery of biologicals
Chain extender

The SynBiosys® Polymer Platform
7
Unlike traditional sustained release polymers, SynBiosys® provides a suitable
environment to maintain protein integrity and activity
• Hydrophilic Amorphous Domains
• Absorbs water and swells to form a hydrogel-like
structure
- Diffusion-controlled release
• Hydrophobic Crystalline Domains
• Physical X-link: provides structural integrity
- Control the degree of swelling
• Polymer Matrix Erosion and Degradation
• Degrades through hydrolysis
• No accumulation acidic degradation products
• No acidic microenvironment / in situ pH drop
• Multi-block co-polymers with phase-
separated morphology
• Hydrophilic amorphous domains
• Hydrophobic crystalline domains

Polymer Grade Block 1 Block 2 Block
ratio
PEG
content
SW
10LP10L20-LL40 LP10L20 LL40 10/90 5 wt.% 1.02
20LP10L20-LL40 LP10L20 LL40 20/80 10 wt.% 1.07
30LP10L20-LL40 LP10L20 LL40 30/70 15 wt.% 1.15
50LP10L20-LL40 LP10L20 LL40 50/50 25 wt.% 1.30
• Tools to control drug release
• Polymer
- swelling degree
- degradation rate
• Microencapsulation process
• Variables for Fine-Tuning
• PEG molecular weight
• PEG content
• Co-monomer type
• Co-monomer weight fraction
• Block ratio
• Molecular weight
Block ratio
8
Drug Release Kinetics Controlled by Polymer Composition
LP10L20 = poly(DL-lactide)-b-PEG1000-b-poly(DL-Lactide MW 2000 g/mole);
LL40 = poly(L-Lactide) MW 4000 g/mole

9
Microspheres Solid Implants
Drug Eluting
Coatings
Injectable Gels
SynBiosys® biodegradable polymers are suitable for various long-acting (injectable)
sustained release drug delivery systems
SynBiosys® - Versatile Portfolio of Proprietary Drug Delivery Systems

10
Narrow Particle Size Distribution
SynBiosys® Microspheres
• Uniformly-sized microparticles
• Use of smaller needles (less painful injections)
• High API doses due to highly concentrated MSP
suspensions

From Feasibility Study to Scale-up
11
Feasibility studies
 Small scale formulation development
 0.5 – 25 g
 Batch wise production
GLP tox and ph 1/2 clinical studies
 Scale-up and reproducibility
 25  250 g  kg+
 Semi-continuous production of microspheres followed by
batch wise hardening and drying
Unit operations that control key CQA are operated in continuous mode
resulting in a robust, well scalable process for reproducible production

SynBiosys® multi-block copolymers have amphiphilic character
Polymer chains distributed over Oil / Water interface during emulsification
 Hydrophobic polymer blocks (poly(lactide) or poly(ε-caprolactrone)) dissolved in Oil Phase
 Hydrophilic PEG chains in Water Phase
 PEG-shielded water droplets protect protein from interacting with O/W interface
High Shear
Homogenizer
Polymer dissolved in DCM (O), protein
dissolved in aqueous buffer (W)
W/O (water-in-oil) emulsion with PEG chains in aqueous droplets
and hydrophobic polymer blocks and chains dissolved in DCM
Long Acting Injectable Microparticle Formulations
SynBiosys® Preserves Protein Integrity During Emulsification
12

14
Key Questions
 Are SynBiosys® polymers and the
microparticle process suitable for
long term release of biologics?
 Can biologics be encapsulated and
released structurally intact?
 Can drug release kinetics of
biologics be tuned?
 Are the in vivo released biologics
structurally intact, biologically
active and therapeutically
effective?
2nd
1st
High molecular
weight proteins
Sensitive peptide
Objective
Evaluate the SynBiosys® Technology Platform
of advanced biodegradable drug delivery systems
for sustained release of peptides and
biologicals.
Case Studies
Technical Feasibility Study
* https://s3-us-west-2.amazonaws.com/drugbank/protein_structures/full/DB01276.png?1452829397
*

Case Study I
Sustained release microparticle
formulation for a Sensitive Peptide

Cumulative Exenatide Release
0 1 0 2 0 3 0 4 0 5 0 6 0
0
2 5
5 0
7 5
1 0 0
T im e [ d ]
E
x
e
n
a
t
i
d
e
c
u
m
u
l
a
t
i
v
e
r
e
l
e
a
s
e
[
%
]
t o t a l E X T
i n t a c t E X T
Bydureon® shows a typical release
profile of PLGA microspheres
 low initial burst
 lag-phase
 Bulk drug release between days
25-35
 65% of the released Exenatide
remained intact
Bydureon® was used
 for validation of the analytical
methods
 as a reference formulation
16
Bydureon®: PLGA-based Exenatide Sustained Release Microparticles
Long-Acting Injectable Microparticle Formulation for a Sensitive Peptide - Exenatide

17
0 7 1 4 2 1 2 8 3 5
0
2 5
5 0
7 5
1 0 0
T im e [ d ]
C
u
m
u
l
a
t
i
v
e
R
e
l
e
a
s
e
[
%
]
Formulation Development – Tunability of Release Rate
Exenatide release kinetics
controlled by varying polymer composition
Tools to control drug release
• Polymer
- swelling degree
- degradation rate
• Microencapsulation process
Variables for Fine-Tuning
• PEG molecular weight
• PEG content
• Co-monomer type
• Co-monomer weight fraction
• Block ratio
• Molecular weight

0 7 1 4 2 1 2 8 3 5 4 2
0
2 5
5 0
7 5
1 0 0
T im e [ d ]
E
x
e
n
a
t
i
d
e
c
u
m
u
l
a
t
i
v
e
r
e
l
e
a
s
e
[
%
]
t o t a l E X T
i n t a c t E X T
18
4 weeks Formulation (IC-4wF)
 Exenatide is compatible with
SynBiosys® polymers and the
microparticle preparation
process yielding monodisperse
particles
 Exenatide can be loaded in
microparticles with high EE
(86%)
 Exenatide released from
microparticles remains intact
(70-78%)
Cumulative Drug Release – Animal Trial Material (ATM) Formulation
Mean values of n = 3 are shown ± SD

19
Mean values of n = 6 animals/group are shown ± SEM, LOQ = 0.112 ng/ml
Plasma Pharmacokinetics of 4 weeks Formulation (IC-4wF) (single s.c. administration)
7 1 4 2 1 2 8 3 5 4 2 4 9
0
2 0
4 0
6 0
T im e a f t e r a d m i n i s t r a t io n [ d ]
E
X
T
p
l
a
s
m
a
c
o
n
c
e
n
t
r
a
t
i
o
n
[
n
g
/
m
L
]
0 . 8 m g / k g E X T
4 . 0 m g / k g E X T
8 . 0 m g / k g E X T
B y d u r e o n - 2 . 0 m g / k g E X T
Dose-dependent plasma levels of Exenatide
No lag-phase and sustained release of API for up to 23 days
Plasma Levels after s.c. Injection of ATM Formulations

Continuous glucose-lowering effects and reduced HbA1c values demonstrate that the
steadily released peptide is biologically active and in an intact form
20
Non-fasting blood glucose (NFBG) levels
0 7 1 4 2 1 2 8 3 5 4 2
- 7 5
- 5 0
- 2 5
0
2 5
5 0
T im e a f t e r a d m i n i s t r a t io n [ d ]
C
h
a
n
g
e
i
n
N
F
B
G
[
%
]
B
Y
D
,
P
-
O
,
I
C
-
4
w
F
B
Y
D
B
Y
D
B
Y
D
I C - 4 w F - 1 x 0 . 8 m g / k g E X T
B y d u r e o n - 4 x 2 . 0 m g / k g E X T
P o ly m e r - o n ly
I C - 4 w F - 1 x 8 . 0 m g / k g E X T
*
*
*
*
* *
*
*
* *
* *
* * *
*
* *
In vivo Studies – Pharmacological Efficacy in Diabetic Rats
% Glycated Hemoglobin A (HbA1c)
N
o
t
r
e
a
t
m
e
n
t
P
o
l
y
m
e
r
-
O
n
l
y
B
y
d
u
r
e
o
n

(
4
x
2
.
0
m
g
/
k
g
)
I
C
-
4
w
F
(
1
x
8
.
0
m
g
/
k
g
)
I
C
-
4
w
F
(
1
x
0
.
8
m
g
/
k
g
)
0
5
1 0
1 5
B
l
o
o
d
H
b
A
1
c
[
%
]
d ia b e t ic
n o n - d i a b e t ic
* *

Case Study II
Sustained release microparticle
formulation for a High molecular
Weight Protein

22
Proof of Concept along the Pharma Development Path
Long-Acting Injectable Microparticle Formulation for a Monoclonal Antibody
In vivo
Studies
0 5 1 0 1 5 2 0 2 5 3 0
0
1 0 0
2 0 0
3 0 0
4 0 0
5 0 0
T im e a f t e r a d m in is t r a t io n [ d ]
P
l
a
s
m
a
l
e
v
e
l
m
A
b
X
[
µ
g
/
m
L
]
8 m g m A b X - M S P s s . c .
1 m g m A b X - M S P s s . c .
4 m g m A b X - M S P s s . c .
PK in healthy mice
6
Formulation
Development
@ Innocore
1
In vitro
Release 0 5 1 0 1 5 2 0 2 5
0
2 0
4 0
6 0
8 0
1 0 0
T im e p o in t [ d a y s ]
m
A
b
X
c
u
m
u
l
a
t
i
v
e
r
e
l
e
a
s
e
[
%
]
I n t a c t m A b X
T o ta l m A b X
2
DiFi cells
4 Methods
for Integrity
Testing
3
0 5 1 0 1 5 2 0 2 5
0
2 0 0
4 0 0
6 0 0
8 0 0
0 . 0
0 . 2
0 . 4
0 . 6
0 . 8
1 . 0
m
A
b
X
[
µ
g
/
m
L
]
F
r
a
c
t
i
o
n
f
o
l
d
e
d
T o t a l m A b X ( S E C )
m A b X F r a c t i o n f o ld e d ( F l . S p e c . )
I n t a c t m A b X ( S E C )
I n t a c t m A b X ( E L I S A )
m A b X F r a c t i o n f o ld e d ( C D )
Production
Animal Trial
Material (ATM)
5
Cell-based
Activity Assay
4

Formulation Development – Tunability Drug Release
Sustained release of mAbB from days to weeks is feasible and highly tunable
Release can be steered by
 Blend ratio (fraction PEG3000 relative to PEG1000)
 Composition of crystalline block (poly(L-Lactide) vs
poly(p-dioxanone)
23
Blends of
• 50CP10C20-LL40
• 50CP30C40-LL40
Blends of
• 50CP10C20-D28
• 50CP30C40-D28
mAbB in vitro release kinetics mAbB in vitro release kinetics

Formulation Development – Microparticle Loading
Microspheres can be loaded with at least 25wt% mAbB and still exhibit
sustained release kinetics
Effect of mAbB loading on release rate
Water-free W/O/O Process
 Quick preparation method
 High loading & encapsulation
efficiencies
 Low control over particle size
distribution
 Fast screening
 Fast in vivo
24

25
 mAbX is compatible with
SynBiosys® polymers and
microparticle preparation
process
 mAbX loading in microparticles
is 14.9%
 mAbX released from
microparticles remains intact
(96%)
 Linear release kinetics for up
to 10 days
0 5 1 0 1 5 2 0 2 5
0
2 0
4 0
6 0
8 0
1 0 0
m
A
b
X
c
u
m
u
l
a
t
i
v
e
r
e
l
e
a
s
e
[
%
]
I n t a c t m A b X
T o ta l m A b X
Cumulative mAbX in vitro release (IVR)
Formulation Development – ATM Formulation

5
4
1
2
Functional cell-based
Assay
Ability of mAbX to inhibit
growth of DiFi colorectal
cancer cells
Fluorescence spectroscopy
Tertiarty structure intergrity
of mAbX
Receptor binding ELISA
Quantification of functional
mAbX
SE-HPLC
Quantification and
aggregation/fragmentation of
mAbX
Circular dichroism spectroscopy
Secondary structure integrity of mAbX
3
26
Analysis Strategy of mAbX Integrity after in vitro Release (IVR)

mAbX Integrity: Fluorescence and Circular Dichroism Spectroscopy
27
Calculation of Fraction Folded to simplify comparison between different methods
Fluorescence spectroscopy
Demonstrates the tertiarty structure intergity
Circular dichroism
Demonstrates secondary structure intergity
3 0 0 3 5 0 4 0 0 4 5 0
0 . 0
0 . 5
1 . 0
1 . 5
 / n m
N
o
r
m
a
l
i
z
e
d
f
l
u
o
r
e
s
c
e
n
c
e
i
n
t
e
n
s
i
t
y
/
a
.
u
.
S e t 1 , S a m p l e 1
S e t 1 , S a m p l e 2
S e t 1 , S a m p l e 3
S e t 1 , S a m p l e 4
S e t 1 , S a m p l e 5
S e t 1 , S a m p l e 6
S e t 1 , S a m p l e 7
0 5 1 0 1 5 2 0
3 3 0
3 3 5
3 4 0
3 4 5
3 5 0
3 5 5
T im e / d a y s

M
a
x
/
n
m
n a t iv e m A b X
c o m p le t e ly
u n f o ld e d m A b X
5 1 0 1 5
- 3 0 0 0
- 2 0 0 0
- 1 0 0 0
0
T im e / d a y s

/
d
e
g
c
m
2
d
m
o
l
-
1
c o m p le t e ly
u n f o ld e d m A b X
n a t iv e m A b X
2 2 0 2 4 0 2 6 0 2 8 0
- 4 0 0 0
- 2 0 0 0
0
2 0 0 0
 / n m



d
e
g
c
m
2
d
m
o
l
-
1
S e t 1 , S a m p le 1
𝐹𝑟𝑎𝑐𝑡𝑖𝑜𝑛 𝐹𝑜𝑙𝑑𝑒𝑑 =
𝑥 − 𝜆𝑀𝑎𝑥, 𝑑𝑒𝑛𝑎𝑡.
𝜆𝑀𝑎𝑥, 𝑛𝑎𝑡𝑖𝑣𝑒 − 𝜆𝑀𝑎𝑥, 𝑑𝑒𝑛𝑎𝑡.
𝑥100
𝐹𝑟𝑎𝑐𝑡𝑖𝑜𝑛 𝐹𝑜𝑙𝑑𝑒𝑑 =
𝜃218 𝑛𝑚 − 𝜃218 𝑛𝑚, 𝑑𝑒𝑛𝑎𝑡.
𝜃218 𝑛𝑚, 𝑛𝑎𝑡𝑖𝑣𝑒 − 𝜃218 𝑛𝑚, 𝑑𝑒𝑛𝑎𝑡.
𝑥100

Integrity of mAbX Released from Microparticles
 Preserved integrity & biological activity of released mAbX demonstrated with five
orthogonal analytical methods
mAbX in vitro release mAbX Integrity
0 5 1 0 1 5 2 0 2 5
0
2 0 0
4 0 0
6 0 0
8 0 0
I
V
R
o
f
m
A
b
X
[
µ
g
/
m
L
]
I n t a c t m A b X ( E L I S A )
I n t a c t m A b X ( S E C )
T o t a l m A b X ( S E C )
0 5 1 0 1 5 2 0
5 0
7 5
1 0 0
1 2 5
5 0
7 5
1 0 0
1 2 5
F
r
a
c
t
i
o
n
F
o
l
d
e
d
[
%
]
R
a
t
i
o
t
o
I
C
5
0
o
f
r
e
f
e
r
e
n
c
e
[
%
]
D i f i A s s a y F S C D
28

Pharmacokinetic Study in Healthy NMRI Mice
Plasma Pharmacokinetics of mAbX-MSPs (single s.c. administration)
0 5 1 0 1 5 2 0 2 5 3 0
0
1 0 0
2 0 0
3 0 0
4 0 0
5 0 0
T im e a f t e r a d m in is t r a t io n [ d ]
P
l
a
s
m
a
l
e
v
e
l
m
A
b
X
[
µ
g
/
m
L
]
8 m g m A b X - M S P s s . c .
1 m g m A b X - M S P s s . c .
4 m g m A b X - M S P s s . c .
Mean values of n = 6 animals/group are shown ± SEM
Amount of mAbX released from microparticle formulations is dose-dependent
mAbX can be detected in plasma samples by a functional binding ELISA
29

31
Conclusion
 SynBiosys® polymers and the microsphere encapsulation process are compatible
with sensitive peptides and with high molecular weight proteins such as
monoclonal antibodies.
 Linear release of peptide and monoclonal antibody from weeks to several months
in vitro.
 In vitro released monoclonal antibody with high structural integrity as confirmed
by five orthogonal methods.
 Immunogenic potential of SynBiosys®-based peptide and protein microparticles is
very low.
 Controlled Release of biologically active monoclonal antibody and therapeutically
effective peptide was demonstrated in vivo.
Long-Acting Injectable Microparticle Formulation

Merck, the vibrant M, SAFC and Emprove 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.
© 2020 Merck KGaA, Darmstadt, Germany and/or its affiliates. All rights reserved

34
Source:
EvaluatePharma
 Significant growth of biological
therapeutics
2018 WW sales 243 $bn
2024 WW predicted sales 388 $bn
 Biotech product sales overtake
conventional product sales in the top 100
product by sales in 2018 for 1st time
34%
66% 53%
47% 50%
50%
Biologics
within
Top 100 Sales
Growing importance of biologics drugs drives strong demand for drug delivery systems
for parenteral (sustained) release of protein therapeutics
Worldwide Prescription Drug Sales
Rapidly Increasing Significance of Biologics

Initiators
Polyethyleneglycol 1,4-butanediol
1,4-butanediisocyanate
Chain extender
Catalyst
Tin octanoate
Glycolide Lactide ε-caprolactone p-dioxanone
Monomers
Well-known, clinically-proven safe monomers and chemicals
Excellent track record in regulatory approved and marketed biomedical devices,
combination products and pharmaceutical drug delivery products
35
Monomers and Chemicals

Polyether Ester Urethane multi-block Copolymers
[ ---------------Hydrophilic block-------------]
PCL PEG PCL
[ ---------------Hydrophobic block------------------]
Variables
• Polyester monomer type
• Polyester monomer ratio
• Polyester block length
• PEG Molecular weight
• PEG/Polyester ratio
• Hydrophilic block length
PLA BDO PLA
Variables
• Polyester monomer type
• Polyester monomer ratio
• Polyester block length
• PEG/Polyester ratio
• Hydrophobic block length
UL
H—O-(CH2)5-C—O-(CH2CH2O)n—C-(CH2)5-O—C-N-(CH2)4-N-C—O-CH-C—O-(CH2)4-O—C-CH-O—H
O
=
O
=
O
=
O
=
H
ι
H
ι
I
CH3
O
=
O
=
[ ] ]
[ [ [
] ]
 ---PCL---  ------ PEG ------  ---PCL---  ----- BDI --------PLA----- BDO -- --PLA--
I
CH3
UL UL
36

SynBiosys® Platform - Polymer Nomenclature
37
50 C P10C20-LL40
PEG with molecular
weight 1000 g/mol
Polycaprolactone (PCL)
Weight percentage of
polycaprolactone-PEG
prepolymer
Poly(L-lactide) prepolymer with
molecular weight 4000 g/mol
PCL-PEG prepolymer with
molecular weight 2000 g/mol

1. Combo Dual Therapy stent
 Sirolimus-eluting coronary stent
 Anti CD34 antibody coating
 SynBiosys® polymer coating
 Drug elution in 30 days
 Full and complete polymer resorption
within 90 days
 Proven clinical safety
 Regulatory approval since 2013 (CE)
Clinically Validated Polymer Platform
Combo
®
is
a
registered
trademark
of
OrbusNeich
Proven clinical safety – Combo® sirolimus eluting dual therapy stent:
approved and marketed since 2013 by OrbusNeich
38

• Degradation mechanism and degradation products similar to commonly used biodegradable polyester
used in marketed products
• Extensive ISO-10993 biocompatibility / toxicity data package
• In vivo biocompatibility & degradation (implants, microspheres, coatings)
 Various RoA: subcutaneous, intramuscular, intra-articular, intravitreal, intracardiac
 Multiple species: rats, rabbits, mini-pigs, pigs, horses, primates
Monomer Degr. product Excreted as Route
Lactic acid Pyruvic acid CO2 + H2O Urine, breath
Glycolic acid Pyruvic acid CO2 + H2O Urine, breath
ε-Caprolactone -hydroxy heaxanoic acid -hydroxy heaxanoic acid Urine
p-Dioxanone 2-hydroxy ethoxy acetic acid
2-hydroxy ethoxy acetic
acid
Urine
PEG PEG PEG Urine
1,4-Butanediisocyanate
1,4-Butanediamine
(putrescine)
1,4-Butanediamine Urine, breath
1,4-Butanediol 1,4-Butanediol 1,4-Butanediol Urine
39
• Proven clinical safety – Combo® Dual Therapy Stent approved and marketed since 2013
Biocompatible Polymer Platform and Safe Degradation Products

5 µm SynBiosys® Monospheres concentrated in
macrophages
Phagocytosis = extensive foreign body reaction
SynBiosys® Microspheres after 4 weeks SC (rats, ED-1 staining)
No phagocytosis of monodisperse 30 µm
SynBiosys® Microspheres
40
Reduced Immune Response due to Absence of small Particles

Use of smaller needles (less painful injections)
High API doses due to high MSP concentration
41
Superior Injectability due to uniformly-sized Microspheres

Preclinical Development and cGMP Manufacturing
42
API
&
TPP
Feasibility study
Scale-up for
GLP tox studies
Clinical
Trials
Commercial
Manufacturing
& Sales
Customer
SynBiosys®
DD System
• Optimization
• Scale-up
• Analytical
validation
• GLP tox material
production
• Stability testing
CTM production
(GMP)
• Tech Transfer
• cGMP production
clinical supplies
• QC testing
• Stability studies
• Analytical
development
• Formulation
development
• ATM production
• Stability testing
POC in vivo PK/PD GLP tox studies
Phase I/II clinical
studies

Scale-up Batch Sizes
43
API
&
TPP
Feasibility study
Scale-up for
GLP tox studies
Clinical
Trials
Commercial
Manufacturing
& Sales
Customer
SynBiosys®
DD System
CTM production
(GMP)
POC in vivo PK/PD GLP tox studies
Phase I/II clinical
studies
1-10 g Scale
25 – 250g 50 g - 1 kg
Non-GLP Quality
GLP GMP

Scale-up – Critical Quality Attributes
44
Polymer
solution
Protein
solution
Primary
emulsification
Aq. PVA solution
(Continuous phase)
Membrane
emulsification
Primary solvent
removal
Concentrating, washing
(and drying)
Powder
filling
Secondary solvent
removal
Washing media
Additives: bulking and
wetting agents,
surfactants, etc
Critical quality attributes
• Particle size (distribution)
• Protein content (encapsulation efficiency)
• Release kinetics
• Protein purity / integrity/ activity
• Protein-related impurities
• Internal morphology
• Surface morphology
• Protein distribution in microparticle
• Endotoxins
Critical quality attributes
• Residual solvent
• Residual moisture
• Particle size distribution
• Protein content (encapsulation efficiency)
• Endotoxins, sterility
• Resuspension behaviour
• Syringeability
• Stability
Suspension filling
and lyophilization
Key CQA
Critical process &
formulation
parameters
DoE

Scale-up – Batch-to-Batch Consistency
Particle size distribution (laser diffraction))
Robust, reproducible and well scalable process
45

Drug Type Maximum
microsphere
suspension
concentration
Maximum drug
load in
microsphere
Maximum drug dose (mg)
1 mL SC (≤ 2 mL) IM (≤ 4 mL)
mg MSP/mL mg API/g MSP mg API/mL mg API mg API
SMD 400 400 (40%) 160 ≤ 320 ≤ 640
Peptide 400 200 (20%) 80 ≤ 160 ≤ 320
Protein 400 150 (15%) 60 ≤ 120 ≤ 240
Antibody 300 250 (25%) 75 ≤ 150 ≤ 300
Calculation of maximum API dose of microsphere dosage form
46
Notes
 Microspheres (MSP) are administered as a suspension of microparticles in reconstitution medium (WFI with
aqueous diluent containing CMC)
 The max dose for small molecule drugs (SMD) represents lipophilic SMD. Lipophilic SMD are easy to
encapsulate due to their low aqueous solubility. Hydrophilic SMD are more challenging to encapsulate due
to their high aqueous solubility. As a consequence max doses are significantly lower (10-20% loading 
400 mg/MSP/mL x 10-20% loading  40-80 mg/mL).
 Peptides, proteins and antibodies are well soluble  lower maximum drug load in MSP

Immunogenicity & Toxicology
 IFN-γ
Interferones
 TNF-α
Tumor necrosis
factors
 MIP-1α
 MIP-1β
 RANTES
 MIP-2
 LIX
 MCP-1
 Eotaxin
 IP-10
 KC
Chemokines
 IL-1α
 IL-1β
 IL-2
 IL-3
 IL-4
 IL-5
 IL-6
 IL-7
 IL-9
Interleukins
 M-CSF
 VEGF
 G-CSF
 GM-CSF
Colony stimulating
factors
(Growth factors)
Cytokines
 IL-10
 IL-12 (p40)
 IL-12 (p70)
 LIF
 IL-13
 IL-15
 IL-17
 MIG
After 24h, plasma levels of one (G-CSF) out of 32 cytokines elevated dose-
dependently after administration of formulations containing microparticles
0 1 0 2 0 3 0
0
5
1 0
1 5
2 0
2 5
T im e a f t e r a d m in is t r a t io n [ h ]
P
l
a
s
m
a
c
o
n
c
e
n
t
r
a
t
i
o
n
(
G
-
C
S
F
)
[
n
g
/
m
L
]
u n t r e a t e d
P o ly m e r - o n ly s . c .
8 m g m A b X s o lu t io n s . c .
1 m g m A b X - M S P s s . c .
8 m g m A b X - M S P s s . c .
Mean values are shown ± SD
47

SynBiosys®-based Long Acting Injectables under Development
48
Indication Drug molecule Formulation type RoA
Ocular disease Protein Microparticle Intravitreal
Sexual dysfunction Protein Microparticle SubQ
Ischemic heart disease IGF-1 / HGF Microparticle Intra-arterial
Diabetes GLP-1 analogue Microparticle SubQ
Cancer
Monoclonal
antibody
Microparticle SubQ / IM
Prostate cancer Goserelin Solid implant SubQ
Cancer Peptide Microparticle SubQ / IM
Osteoarthritis Protein Microparticle Intra-articular
Schizophrenia Small molecule Microparticle SubQ / IM

49
The typical technical data above serve to generally characterize the excipient. These values are not
meant as specifications and they do not have binding character. The product specification is available
separately at: www.merckmillipore.com
We provide information and advice to our customers on application technologies and regulatory matters
to the best of our knowledge and ability, but without obligation or liability. Existing laws and regulations
are to be observed in all cases by our customers. This also applies in respect to any rights of third
parties. Our information and advice do not relieve our customers of their own responsibility for checking
the suitability of our products for the envisaged purpose.
Disclaimer

Long acting injectable microparticle formulation - a new dimension for peptides and proteins

Long acting injectable microparticle formulation - a new dimension for peptides and proteins

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