Watch the presentation of this webinar here: https://bit.ly/3A2WcH4 The application of polymer excipients in 3D printing manufacturing is usually limited due to the concerns of filament strength, high processing temperature and large scale manufacturing. Latest technology developments are targeting a direct melt deposition to simplify the process and enable a constant and efficient process. Two different processing approaches will be presented: The advanced melt drop deposition, where individual three dimensional geometries can be created by depostition of polymer droplets and the MED® 3D printing technology which allows by precise layer-by-layer deposition to produce objects with well-designed geometric structures. In this webinar, you will learn: • Latest advancements of melt based 3D printing approaches • Application examples for the individual technologies • Deep dive in the MED® 3D printing technology to design dedicated drug release profiles Presented by: Dr. Thomas Kipping, Head of Drug Carriers Dr. Xianghao Zuo, Deputy Director of R&D, Triastek

1. The life science business of Merck KGaA,
Darmstadt, Germany operates as
MilliporeSigma in the U.S. and Canada.
Latest advancements of
melt-based 3D printing
technologies for oral drug
delivery
Dr. Thomas Kipping, Merck KGaA, Darmstadt, Germany
Dr. Xianghao Zuo, Triastek Inc

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

3. Agenda
1
2
Introduction to pharmaceutical 3D
printing
3
Advanced melt drop deposition
MED® 3D Printing Technology

4. Introduction

5. Overview of 3D printing technologies in the pharmaceutical industry
Introduction
2022-06-23 | Webinar | Latest advancements of melt-based 3D printing technologies for oral drug delivery
Powder based systems
▪ Drop on Powder, Binder Jetting (DOP)
▪ Selective Laser Sintering (SLS)
Extrusion based systems
▪ Solid forms: Fused deposition modeling
(FDM)
▪ Semi-solid forms: Pressure assisted
syringe
Liquid based systems
▪ Drop on Drop deposition (DOD)
▪ Stereolithography (SLA)
1
3
3D Printing in the
Pharmaceutical Industry
2
Liquid binder Laser
UV Laser Temperature
Temperature
Graphic modified from Jamróz et al. 3D Printing in Pharmaceutical
and Medical Applications - Recent Achievements and Challenges.
Pharmaceutical research. 2018;35(9):176
5

6. Potential future applications for 3D printing
Introduction
2022-06-23 | Webinar | Latest advancements of melt-based 3D printing technologies for oral drug delivery
Rx
Diagnosis
Digital prescription
Design of the tablet
3D printing
Personalized medicine
Targeted therapeutic effect
Concept adapted from Lamichhane et al. Complex
formulations, simple techniques: Can 3D printing
technology be the Midas touch in pharmaceutical
industry? Asian Journal of Pharmaceutical
Sciences. 2019;14(5):465-79.
Pharmaceutical
applications
6

7. Future challenges during formulation development
Introduction
2022-06-23 | Webinar | Latest advancements of melt-based 3D printing technologies for oral drug delivery
Permeability
Solubility
BCS
Class I
BCS
Class II
BCS
Class IV
BCS
Class III
35%
30%
25%
10%
5-10%
60 – 70%
5-10%
10-20%
Current distribution of
marketed drug substances
Distribution of drug substances according to their respective BCS
classification modified from Ting et al. Advances in Polymer Design
for Enhancing Oral Drug Solubility and Delivery. Bioconjugate
Chemistry. 2018;29(4):939-52.
Distribution of drug
substances in the pipeline
Bioavailability enhancement is an important topic also for 3D printing applications
7

8. Product characteristics of Parteck® MXP
Introduction
Product Properties
Bulk density (g/mL) 0.53±0.02
Tapped density (g/mL) 0.74±0.02
Particle size (D50) (μm) 60-80
Loss on drying (%) <3.0
Angle of repose (°) 35
Tg
(by DSC)
Tm
(by DSC)
Td
(by TGA)
40-45 °C 170 °C >250 °C
Temperature
Melt Viscosity
D=200 (s-1)
Melt Viscosity
D=1200 (s-1)
210 °C 702 Pa*s 283 Pa*s
230 °C 345 Pa*s 174 Pa*s
Product Properties
Hydrolysis grade (%) 85-89
Solubility (%) (max. in water) 33
Mass average molar mass approx. 32,000
pH-value (4% / water) 5.0-6.5
2022-06-23 | Webinar | Latest advancements of melt-based 3D printing technologies for oral drug delivery
8
Presented values are considered for technical
information only

9. Advanced melt drop
deposition

10. 2022-06-23 | Webinar | Latest advancements of melt-based 3D printing technologies for oral drug delivery
Principle of Arburg Plastic Freeforming (APF)
Advanced melt drop deposition
Process
1. Polymer is melted in a
heated plasticizer barrel
2. Via screw rotation the
material is transported to
the nozzle tip
3. Pressure generation via
translational movement of
the screw
4. Discharge of droplets
controlled via piezo
actuator
Simplified schematic view of the Arburg Plastic Freeforming process (APF)
10

11. Deep dive process development
2022-06-23 | Webinar | Latest advancements of melt-based 3D printing technologies for oral drug delivery
Advanced melt drop deposition
Temperature zones [°C]:
200, 190, 180
Simplified geometry
10mm x 4 mm
biplanar
11

12. 2022-06-23 | Webinar | Latest advancements of melt-based 3D printing technologies for oral drug delivery
SEM images of 3D printed tablets
Melt drop deposition
Infos
▪ SEM Images of 3D
printed tablets
▪ Top- and side view
▪ Strands consist of
individual droplets
▪ High homogeneity of the
process
12

13. Application for tablet developments
2022-06-23 | Webinar | Latest advancements of melt-based 3D printing technologies for oral drug delivery
Melt drop deposition
Info
▪ Variation of infill
volume can be used
to individually
adjust the porosity
of the tablets
30% Infill 40% Infill 50% Infill 60% Infill
70% Infill 80% Infill 90% Infill 100% Infill
SEM images of 3DP tablets created with Parteck® MXP (variation of infillvolume))
13

14. 2022-06-23 | Webinar | Latest advancements of melt-based 3D printing technologies for oral drug delivery
Mass distribution
Advanced melt drop deposition
Mass distribution of 3DP tablets (10% loading), (n=6)
Info
▪ Homogenous mass
distributions can be
achieved
▪ Drug loading affects
homogeneity but still
remains within
targeted limits of
pharmacopoeias
14

15. 2022-06-23 | Webinar | Latest advancements of melt-based 3D printing technologies for oral drug delivery
Mechanical stability
Advanced melt drop deposition
Mechanical strength of 3DP tablets (n=3)
Info
▪ Diametral compression
was assessed with a
Texture Analyzer
▪ 3D printed tablets
based on Parteck® MXP
provide a high
mechanical strength
even at low infill
volumes
15

16. 2022-06-23 | Webinar | Latest advancements of melt-based 3D printing technologies for oral drug delivery
Friability
Advanced melt drop deposition
Mechanical strength of 3DP tablets (n=3)
Info
▪ High mechanical
strength also translates
into low friability values
over the entire process
range
16

17. Solubility enhancement
2022-06-23 | Webinar | Latest advancements of melt-based 3D printing technologies for oral drug delivery
Advanced melt drop deposition
Info
▪ Successful
amorphization of the
drug within the
polymer melt
Weak base
pKa1 = 3.96 (amine); pKa2 = 6.75
(imine) estimated
BCS class II
mW: 531.4
Aqueous solubility: 0.29 mg/L
17

18. Solubility enhancement
2022-06-23 | Webinar | Latest advancements of melt-based 3D printing technologies for oral drug delivery
Advanced melt drop deposition
Info
▪ Solubility enhancement
can be achieved
▪ Fast release kinetics at
lower infill volumes
Modified dissolution conditions to screen for
supersaturation:
100 ml FaSSiF medium, pH 6.5 at 37 °C,
laboratory shaker at 190 rpm
Sample volume 1ml, analysis via HPLC
18

19. The life science business of Merck KGaA,
Darmstadt, Germany operates as
MilliporeSigma in the U.S. and Canada.
Feasibility Study of Parteck® PVA MXP
Using Melt Extrusion Deposition (MED®)
3D Printing Technology
Xianghao Zuo
23rd Jun. 2022, Nanjing, China

20. The R&D and Manufacturing of Triastek
is based in Nanjing, China.
The Business Department of Triastek is
based in Shanghai, China.

21. MED® 3D Printing
Technology

22. MED® 3D Printing Process
Principle of MED® 3D Printing Technology
Melt Extrusion Deposition (MED®) 3D printing is a technology that continuously converts powder
feedstocks into softened/molten states followed by precise layer-by-layer deposition to produce
objects with well-designed geometric structures
• NOT rely on filament
• Lower processing temperature
• NO post-printing process needed
• MED array design enables mass production using multiple materials
to fabricate complex structure
Mixing Melt Extrusion
Deposition
Excipient
API
22 Feasibility Study of Parteck® PVA MXP Using Melt Extrusion Deposition (MED®) 3D Printing Technology| 23rd Jun. 2022

23. Application in Parteck® MXP
Applications of MED® 3D Printing Technology
Feasibility Study of Parteck® PVA MXP Using Melt Extrusion Deposition (MED®) 3D Printing Technology| 23rd Jun. 2022
23
Parteck®
MXP M X P
„Particle technology“-
particle engineered product range
Melt Extrusion PVA
0 100 200 300 400 500 600
0
20
40
60
80
100
Weight
Fraction
(%)
Temperature (C)
MXP
Material PVA MXP
Melting Temperature(℃) 184.72
Glass Transition Temperature(℃) 55.99
Thermal Degradation
Temperature(℃)
247.67
Maximum Daily Exposure(mg) 120

24. Printability Evaluation of PVA MXP
Applications of MED® 3D Printing Technology
Feasibility Study of Parteck® PVA MXP Using Melt Extrusion Deposition (MED®) 3D Printing Technology| 23rd Jun. 2022
24
Material PVA MXP
Printing Temperature(℃) 200
Tablet Dimension(mm) 6×9×0.8
Pilot-Scale MED 3D Printer, hundreds of tablets/day

25. Feasibility Study of Drug-loaded PVA MXP
Applications of MED® 3D Printing Technology
Feasibility Study of Parteck® PVA MXP Using Melt Extrusion Deposition (MED®) 3D Printing Technology| 23rd Jun. 2022
25
Model Drug Felodipine
BCS Class IIb
Log P 3.86
Melting Temperature(℃) 146.94
Glass Transition Temperature(℃) 45.09
Thermal Degradation Temperature(℃) 217.17

26. Amorphous Solid Dispersion of Felodipine in PVA MXP
Applications of MED® 3D Printing Technology
Feasibility Study of Parteck® PVA MXP Using Melt Extrusion Deposition (MED®) 3D Printing Technology| 23rd Jun. 2022
26
Material Weight Ratio Extrusion Temperature(℃) Glass Transition Temperature(℃)
PVA MXP:Felodipine
90:10 200-205-205-205-205-205-205-70 52.24
80:20 200-205-205-205-205-205-205-70 52.59
70:30 190-190-190-190-190-190-190-70 50.70
60:40 190-190-190-190-190-190-190-70 45.53
• The API is amorphous when the content is 40%.
• The API acted as a plasticizer to PVA MXP, lowering the
processing temperature.

27. MED 3D Printing of Felodipine/PVA MXP
Applications of MED® 3D Printing Technology
Feasibility Study of Parteck® PVA MXP Using Melt Extrusion Deposition (MED®) 3D Printing Technology| 23rd Jun. 2022
27
Printing Temperature(℃) 200
Tablet 1 Dimension(mm) 6×9×0.8
Tablet 2 Dimension(mm) 6×9×1.6
Tablet 1
Tablet 2
0
20
40
60
80
100
120
Mass
of
Tablets
(mg)
Tablet 1
Tablet 2

28. Dissolution Study
Applications of MED® 3D Printing Technology
Feasibility Study of Parteck® PVA MXP Using Melt Extrusion Deposition (MED®) 3D Printing Technology| 23rd Jun. 2022
28
900mL at 50rpm, 37 ℃
Tablet 1 Tablet 2
900mL at 50rpm, 37 ℃

29. Product Development: Various Release Units Combined at Will
Applications of MED® 3D Printing Technology
29 Feasibility Study of Parteck® PVA MXP Using Melt Extrusion Deposition (MED®) 3D Printing Technology| 23rd Jun. 2022
0 50 100 150 200 250
0
20
40
60
80
100
%
Drug
Release
Time (min)
Time (min)
0 50 100 150 200 250 300
0
20
40
60
80
100
%
Drug
Release
Time (min)
API 1 API 2
IR ER
0 100 200 300 400 500
0
20
40
60
80
100
%
Drug
Release
Time (min)
0 30 60 90 120 150 180
0
20
40
60
80
100
%
Drug
Release
Time (min)
1
2
3
Control Release Rate Control Release Onset Time Control Release Site
Gastric Retention Immediate Release+ Extended Release Different APIs with Different Release profile

30. Product Development: Combination of APIs/Release Modes/Rates
Applications of MED® 3D Printing Technology
Feasibility Study of Parteck® PVA MXP Using Melt Extrusion Deposition (MED®) 3D Printing Technology| 23rd Jun. 2022
30
Top View
Bottom View
Side View
0
20
40
60
80
100
120
0 1 2 3 4 5 6 7 8
Drug
Release
(%)
Time (h)
Model drug 1
Model drug 2
0
50
100
150
200
250
300
0 6 12 18 24
Concentration
(ng/mL)
Time (h)
Model drug 1
Model drug 2
n=3 beagle dogs, mean + SE
Compartment 2
Compartment 1
Compartment 3
Delay layer
ER Formulation of model
drug 2
IR formulation of model
drug 1
By combining extended release and pulsatile release, multiple APIs with markedly different PK
profiles can be incorporated into a single tablet with once-a-day dosing

31. High-throughput Continuous Manufacturing
Applications of MED® 3D Printing Technology
Feasibility Study of Parteck® PVA MXP Using Melt Extrusion Deposition (MED®) 3D Printing Technology| 23rd Jun. 2022
31
Daily Output (w/packaging): 150-200K tablets (24 hrs CM)
Annual Output: 30-40 million tablets

32. Thank you
for your attention!

33. The vibrant M, Parteck 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.
© 2022 Merck KGaA, Darmstadt, Germany and/or its affiliates. All Rights Reserved.
thomas.kipping@emdgroup.com
Dr. Thomas Kipping
Dr. Xianghao Zuo
xzuo@triastek.com
Eric Tsai
etsai@triastek.com