Watch this webinar here: https://bit.ly/351wNw5 This webinar on continuous manufacturing in solid dose will discuss challenges of this new technology, point out critical parameters and show how to tackle these by choice of excipients. Continuous manufacturing in solid dose, more accurately named “continuous tablet manufacturing”, this technology is getting increasing attention in solid dose pharma development. Due to the necessity of profound process stability, this manufacturing mode is very much supported by regulatory authorities. QbD is a must in this case and this reflects the choice of excipients as well. Performance criteria like flow, bulk density and compressibility play an important role. Moreover, this technology shows some specific requirements which are not to achieve by some excipients frequently used before. In this webinar, you will learn: • What are the most challenging issues of continuous manufacturing? • What are the benefits from this technology? • How to tackle the challenges by excipients?

1. The life science business of Merck KGaA,
Darmstadt, Germany operates as
MilliporeSigma in the U.S. and Canada.
Continuous Manufacturing
in Solid Dose
How to Leverage the Opportunities of this new
Technology
Leo Ohrem
October 15, 2020

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

3. Market: Solid formulation is the gold standard for small molecules.
Market need – Fast innovation cycles driven by operational efficiency and individualized
efficacy linked to personalized medicine.
Continuous manufacturing (powder to tablet)
Additive manufacturing (3D pill printing)
Why solid
formulation?
Which are
the
innovation
drivers?
Executive Summary
Solid Formulation for Small Molecules
Continuous Manufacturing in Solid Dose | Oct 15, 20203
$
Additional costs for equipment and development upfront
Significant potential for cost savings, flexibility, quality improvement

4. Drug Manufacturing: From Mass Production to Low Volume/High
Diversity Production
Continuous Manufacturing in Solid Dose | Oct 15, 2020
Moving Ahead
singleproductvolume
product variety
mass production
craft production
mass customization
globalization
regionalization
personalization
(e.g. multiple dosage strengths,
combination drugs, personalized
medicine etc.)
Graph reproduced with modifications
from graphs depicted by J. Womack
et al. (1990), Koren, Y. (2010) and
Bott, M. (2017).
1500 BC
1827
1970
2000
today
Fast, efficient and flexible drug development and manufacturing is needed.
Excipients need to support new manufacturing technologies.
4

5. BAE
Solubility & Bioavailability
Enhancement
Now
Sustaining portfolio development on
excipients for solubility enhancement
(i.e. Parteck® SLC, Parteck® MXP).
Continuous Manufacturing
(powder to tablet)
Medium-term
Incremental evolution of specialty
excipients for the specific needs of
continuous manufacturing technologies
Additive Manufacturing
(3D pill printing)
Long-term
Breakthrough innovation on novel
excipients for existing and future additive
manufacturing technologies
CM
A&F Solid Formulation R&D Activity Focus
The Right Mix of Incremental and Breakthrough R&D
Continuous Manufacturing in Solid Dose | Oct 15, 20205
3D-
Printing
ResearchDevelopment

6. Continuous
Manufacturing

7. Continuous Manufacturing in Solid Dose | Oct 15, 20207
What‘s New?
Single Unit operations (UOs) have been continuous:
 Tablet compression
 Roller compaction
 Hot melt extrusion
New is the interconnection of several UO
without intermediate handling, storage, analytics

8. From Powder to Tablet in <20 Minutes
Continuous Manufacturing in Solid Dose | Oct 15, 2020
Continuous Tableting Line
Feeding &
Mixing
Drying
Transfer &
Milling
Compression
Granulation
Extra-granular
Blending
Lubrication
API (1-50%) +
excipients:
Diluent (5-90%)
Binder (2-10%)
Glidant (0.2-1%)
…more excipients
- Disintegrant (2-5%)
…even more excipients
- Lubricants (0.5-2%)Wet granulation
processing time
Batch: min-hrs.
CM: 15-20 sec
Success factors: Process stability depends on (1) flow, (2) mixability &
(3) wettability
8

9. From Powder to Tablet in <5 Minutes
Continuous Manufacturing in Solid Dose | Oct 15, 2020
Continuous Direct Compression
API (1-50%) +
excipients:
Diluent (5-90%)
Binder (2-10%)
Glidant (0.2-1%)
…more excipients
- Disintegrant (2-5%)
…even more excipients
- Lubricants (0.5-2%)Wet granulation
processing time
Batch: min – hrs.
CM: 15 - 20 sec
Feeding &
Mixing
Drying
Transfer &
Milling
Compression
Granulation
Extra-granular
Blending
Lubrication
Success factors: Process stability depends on (1) flow & (2) mixability
9

10. A Journey to Continuous: Is it Worth the Effort?
Quantifiable Evidence for Increased Efficiency Demonstrated
Continuous Manufacturing in Solid Dose | Oct 15, 202010
Waste
Mfg. Cycle
time
Quality
Control
Process
Knowledge
Footprint
Testing
20 days: In process test
& release test
7 rooms, 6 discrete
pieces of equipment
3%
≤3 days/1000 kg
Ca. 10 out of 265,000 tablets
measured/examined (660 mg)
Based on unit operations and in
process controls (IPCs)
3 days: Real-time
release testing
50% reduction
15% reduction in SLOB
and lot rejection
1.1 days/1000 kg (approx.
70% reduction in man hours)
On/at line measurement
PAT provides real-time information
and advanced process control
Batch Process Continuous Manufacturing
Example from customers

11. Continuous Manufacturing in Solid Dose | Oct 15, 202011
Who is Actively Working on Continuous Manufacturing?
Pharma companies in the market with registered drugs using CM:
 Vertex, Okambi® (Lumocaftor/Ivacaftor)
 Jansen, Prezista® (Darunavir)
 Eli Lilly, Verzenio® (Abemaciclib)
 Vertex, Symdeko® (Tezecaftor)
 Pfizer, Daurismo®(Glasdegib)
Actively supported by authorities:
US-FDA, EMA, JP-FDA

12. Quality Control Feedback Loop
12
Process
Raw
materials
Product
output
Target
product
profile
External input
Comparison
SpecificationsSpecifications
Continuous Manufacturing in Solid Dose | Oct 15, 2020

13. How Can Critical Parameters Be Controlled?
Continuous Manufacturing in Solid Dose | Oct 15, 202013
Batch number
Crit.ParameterXYZ
history future
Upper spec. limit
Lower spec. limit x
x
x
x
x

14. Understanding
the Impact of
excipients

15. Quality constraints?
New products?
1. Flow
2. Dosability
3. Number of components
4. Content uniformity
5. Batch-to-batch consistency
What are the Consequences for Excipients?
Continuous Manufacturing in Solid Dose | Oct 15, 202015

16. Drive to Switch to Continuous Manufacturing
Continuous Manufacturing in Solid Dose | Oct 15, 202016
Issue : Formulations contain up to 12-15 excipients – so many feeders are needed
Solution:
 Use multifunctional excipients
 Use premixes performed under excipient-GMP by Merck KGaA, Darmstadt, Germany

17. Continuous Manufacturing in Solid Dose | Oct 15, 202017
Composition of Formulation
Typical IR formulation
Mannitol
MCC
Povidone
Silicon dioxide
Crospovidone
API
Mg-stearate
Parteck® M
API
Mg-stearate

18. Provides Good Tablet Hardness at Reasonable Compression Forces
Direct Compression of Parteck® M Excipient
Continuous Manufacturing in Solid Dose | Oct 15, 202018
Tablethardness[N]
0
100
200
300
400
0 5 10 15 20 25 30 35
Compression force [kN]
Parteck® M 200
Mannitol A
Mannitol B
Method
Formulation:
99% test material + 1% magnesium stearate;
5 min. mixing
Compression:
single punch press (Korsch EK0 DMS,
54 rpm, 11 mm, flat, faceted punch)
Tablet weight:
500 mg (rel. SD: 0.5)
Mannitol A and B are commercially available
mannitol grades for direct compression.

19. 0
20
40
60
80
Parteck® M DC-Mannitol Lactose/starch-
granules
Tablettose®
Tablethardness[N]
Formulation:
98.5% mannitol; 1.5% Mg-stearate, compr. force 15 kN | 99% lactose, 1% Mg-stearate, compr. force 15 kN
Continuous Manufacturing in Solid Dose | Oct 15, 202019
Tablet Hardness is Improved with Parteck® M Excipient

20. 0
10
20
30
Parteck® M DC-Mannitol Lactose/starch-
granules
Tablettose®
Disintegrationtime[min]
Disintegration Time is Improved with Parteck® M Excipient
Continuous Manufacturing in Solid Dose | Oct 15, 202020
Formulation:
98.5% mannitol; 1.5% Mg-stearate, compr. force 15 kN | 99% lactose, 1% Mg-stearate, compr. force 15 kN

21. Is there a Need
for Sustained
Release in CM?

22. Benefits at a Glance
Parteck® SRP 80 Excipient
Continuous Manufacturing in Solid Dose | Oct 15, 202022
32 Performance
1 Processability QbD / Validation /
Registration
 Suitable for DC processes
 simplified feasibility & development
 rapid & cost-effective manufacturing
 Low hygroscopicity
 advantageous for manufacturing
process
 superior formulation stability
 High compressibility & low
ejection forces with most APIs*
 excellent galenic tablet properties
 high dilution potential
 reduces equipment maintenance
costs
 Constant release behavior over
a broad range of compression
forces & tablet hardnesses **
 robust manufacturing process
 reliable performance and patient
compliance due to reproducible
efficacy of given dose
 Reliable alcohol resistance and
constant release over a broad
pH range
 no alcohol-induced dose
dumping**
 no pH-induced dose dumping**
 improves patient safety
 Compliant with Ph.Eur., USP &
JPE, and is part of the
EMPROVE® ESSENTIAL portfolio
 simplified qualification process,
facilitates regulatory filing &
registration processes, faster time
to market
 Produced in a fully synthetic
way
 no variability in quality or
performance in contrast to
naturally derived raw materials
(e.g. HPMC), facilitates QbD &
validation processes
* Shown in combination with MCC
** Shown in-vitro
A synthetic PVA excipient suitable for matrix-based sustained release formulations

23. 63
150
278
318
0
200
400
600
0
100
200
300
5 10 20 30
Ejectionforce[N]
Tablethardness[N]
Compression force [kN]
Parteck® SRP 80 example formulation
tablet hardness [N]
Parteck® SRP 80 example formulation
ejection force [N]
Propranolol HCl Case Study: Compressibility and Ejection Force
Parteck® SRP 80: Technical Overview
Continuous Manufacturing in Solid Dose | Oct 15, 2020
Tablet hardness was measured n=20
Parteck® SRP 80-based propranolol HCl tablets show high compressibility
and low ejection forces over a vast range of compression forces.
23

24. Propranolol HCl Case Study: No Alcohol-Induced Dose Dumping
Continuous Manufacturing in Solid Dose | Oct 15, 2020
Parteck® SRP 80: Technical Overview
0
10
20
30
40
50
60
70
80
90
100
0 2 4 6 8 10 12
DissolvedpropranololHCl[%]
Time [h]
Parteck® SRP 80 example formulation
HCl 0.1 M
Parteck® SRP 80 example formulation
HCl 0.1 M / Ethanol
95 / 5 % (v/v)
Parteck® SRP 80 example formulation
HCl 0.1 M / Ethanol
80 / 20 % (v/v)
Parteck® SRP 80 example formulation
HCl 0.1 M / Ethanol
60 / 40 % (v/v)
Dissolution procedure:
USP Apparatus 2 (Paddle Apparatus),
900 mL HCl/Ethanol medium, 50 rpm,
37 °C, detection wavelength 214 nm; n=3
Samples used: tablets compressed at 20 kN
Also no pH or food-related dose dumping!
There is no in-vitro dose dumping effect visible over the 12-hour release time, even in a
40% (v/v) alcohol release medium.
24

25. Is There a
Need for ODT
in CM?

26. The following approximate simple formulation has been tested for a variety of
drugs:
Active ingredient (non DC) up to 50%
Parteck® ODT 50 – 99%
Magnesium stearate app. 1.0%
Sucralose for taste optimization 0.2 – 1.0%
Continuous Manufacturing in Solid Dose | Oct 15, 2020
Benefits For the Formulation: High Dilution Potential
Parteck® ODT excipient can incorporate 50% of API in a stable tablet.
26

27. 132
137
120
105
125
104
21 152 46 45 120 39
0
60
120
180
240
300
0
20
40
60
80
100
120
140
160
180
200
Disintegrationtime[s]
Tablethardness[N]
tablet hardness [N] disintegration…
Continuous Manufacturing in Solid Dose | Oct 15, 2020
Benefits for Production: Superior Compressibility
Method: 99%
test material and
1% magnesium
stearate, mixed
and compressed
on 300 mg
tablets, 11 mm,
facetted, single
punch EK 0 DMS
Hardness by
ERWEKA TBH 30
MD
Parteck® ODT shows superior tablet hardness – combined with fastest disintegration.
27

28. Case Study (I) 100 mg Sildenafil (30%)
110
114
52
30
198
48
0
60
120
180
240
0
25
50
75
100
125
150
Parteck® ODT Competitor A Competitor B Competitor C Competitor D Competitor E
Tabletdisintegrationtime[s]
Tablethardness[N]
ODT materials + 100 mg Sildenafil + 1,5 % Parteck® LUB MST
Tablet weight 300 mg; tablet shape Ø 11 mm, Korsch EK0 DMS
Hardness by ERWEKA Multicheck 5.1; Disintegration by Biomation disi 4; Tablet friability by ERWEKA TA420
hardness,
after 1 day [N]
tablet disintegration
time [s]
Manufacturing
not feasible
Manufacturing
not feasible
Manufacturing
not feasible
Only Parteck® ODT excipient shows acceptable DI time at reasonable hardness.
Continuous Manufacturing in Solid Dose | Oct 15, 202028

29. Continuous Manufacturing in Solid Dose | Oct 15, 202029
Benefits for Continuous Production:
Excellent Flowability and Low Friability
Excellent flowability
• Angle of repose: 30°-35°
Low friability
• Parteck® ODT tablets: 0.1-0.4 %

30. Is There a Need for
wet granulation in
CM?

31. Leverages the Optimal Properties of the Delta polymorph to Unlock Wet
Granulation for Mannitol
31
Parteck® Delta M
Mannitol polymorphs
Several polymorphic forms of mannitol have been classified (Walter-Levy, 1968)
Beta polymorph
Most commercially available mannitol is in the beta (β) form, which is the most stable.
Parteck® Delta M
Is crystallized mainly in the delta (δ) polymorph
Applicability to wet granulation
The optimal particle properties of the delta form are compatible with wet granulation.
However, stability is not a concern, as transformation to the stable beta form occurs
during the process.
1
2
3
4
Continuous Manufacturing in Solid Dose | Oct 15, 2020

32. Wet Granulation with Parteck® Delta M
Delta mannitol
before wet granulation
Continuous Manufacturing in Solid Dose | Oct 15, 2020
Parteck® Delta M transforms to the thermodynamically stable beta polymorph during
wet granulation.
Beta mannitol
after wet granulation
32

33. Punching
pressure:
12 kN
Tablet weight: 505 mg
Tablet hardness: 210 N
Friability: 0.20
Disintegration: 4 min 23 s
Punching
pressure:
12 kN
Tablet weight: 484 mg
Tablet hardness: 111 N
Friability: 0.29
Disintegration: 4 min 15 s
Continuous Manufacturing in Solid Dose | Oct 15, 202033
Results: Select the Best Enabling Technology
Wet Granulation
Crystalline
Beta Mannitol
Results:
Wet Granulation
Results:
Direct Compression
Punching
pressure:
29 kN
Tablet weight: 541 mg
Tablet hardness: 34 N
Friability: bad
Disintegration: 9 min 50 s
Wet Granulation
Parteck® Delta
Mannitol
Direct Compression
Parteck® M 200
Punching
pressure:
12 kN
Tablet weight: 505 mg
Tablet hardness: 210 N
Friability: 0.20
Disintegration: 4 min 23 s
Punching
pressure:
12 kN
Tablet weight: 484 mg
Tablet hardness: 111 N
Friability: 0.29
Disintegration: 4 min 15 s



Important Important

34. What if You Want to
omit lubrication in
CM?

35. Combined Excipient System
Continuous Manufacturing in Solid Dose | Oct 15, 202035
New Concept
Parteck® M
+
Mg-Stearate
Lubricant
DC-Mannitol

36. Performance Proven
Continuous Manufacturing in Solid Dose | Oct 15, 2020
Combined Excipient System
0
20
40
60
80
100
0 20 40 60 80 100 120
Propranololrelease[%]
Time [min]
Excipient System LubMannitol+API traditional mix Mannitol+API+MST
-25
25
75
125
175
225
275
325
375
425
0
50
100
150
200
250
300
350
400
5 10 20
Ejectionforce[N]
Tablethardness[N]
Compression force [N]
Hardness
Excipient System LubMannitol+API
Hardness
traditional mix Mannitol+API+ MST
Results to be published at AAPS 2020.
36

37. Advantages
Continuous Manufacturing in Solid Dose | Oct 15, 202037
Combined Excipient System
 No need for dosage of Mg-stearate – a small, poorly flowing component
 Guaranteed content uniformity
 Proven flow and processing performance
 Proven lubrication functionality

38. Email:
hans-leonhard.ohrem@emdgroup.com
Dr. Leo Ohrem
The vibrant M, SAFC, and Parteck 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.