In this webinar, you will learn: - The key issues in continuous manufacturing concerning excipients - How those issues can be addressed Detailed description: Continuous manufacturing is a major trend in solid dose formulation. It shows economic and quality benefits, however, hurdles and challenges need to be tackled before getting there. This webinar will address these hurdles and challenges as they relate to excipients. We will present how continuous manufacturing lines are set up and the benefits users have experienced from them. Feeding of especially small components of formulation combined with bad flow is a major challenge, as well as having a high number of components leading to many feeders. Our answer to these challenges are threefold: betting on multifunctional excipients, and on premixes, either as finished products or as customized projects.

1. The life science business of Merck KGaA,
Darmstadt, Germany operates as
MilliporeSigma in the U.S. and Canada.
Continuous
Manufacturing
Dr. Leo Ohrem
Issues and Answers

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

3. 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 & breakthrough R&D
3
3D-
Printing
Research
Development

4. Poll Question
4

5. 1. Are you currently working on continuous
manufacturing in solid dose?
a. No
b. No but in the near future
c. Yes, with focus on direct compression
d. Yes, with focus on wet granulation
e. Yes, with all above and will include dry granulation
f. Yes, for immediate release
g. Yes for controlled release
h. Yes, for ODT formulations
i. Yes, for low soluble drugs

6. Whats new?
Continuous Manufacturing | Sept 2021
6
Single Unit operations (UO) have been continuous:
• Tablet compression
• Roller compaction
• Hot melt extrusion
New is the interconnection of several
UO without intermediate handling,
storage, analytics

7. 7
From powder to tablet
in <5 minutes
API
Excipients
Blending
Lubricant
Blending
Tabletting
Excipients
Excipients
Coating
Final analytics
Continuous direct compression

8. 8
From powder
to tablet
in < 25 minutes
in continuous
wet granulation
API
Excipients
Blending
Excipients
Excipients
Lubricant
Blending
Tabletting
Coating
Final analytics
Granulation & drying
API Excipients
Blending
Excipients
Excipients
Including wet granulation or
roller compaction

9. 9
Why Continuous Manufacturing in solid dose?
Quantifiable evidence for increased efficiency demonstrated

10. Pharma companies in the market with
registered drugs using CM
Vertex Okambi (lumocaftor/Ivacaftor)
Jansen, Prezista (darunavir)
Eli Lilly, Versenio (abemaciclib)
Vertex Symdeko (Tezecaftor)
Pfizer Daurismo (glasdegib)
10
Who is actively working on Continuous manufacturing?
Actively supported
by authorities:
US-FDA, EMA,
PMDA

11. Consequences on excipients?
Quality constraints?
New products?
Flow!
Dosability!
Number of components!
Content Uniformity!
Batch-Batch Consistency!
What‘s in it for us?
11

12. Poll Questions
12

13. 2. How many components will you
have to feed into a proposed
continuous process?
a. 2-3
b. 3-5
c. 5-10
d. more

14. 3. which components do you expect to
be difficult to be fed to the process?
a. API
b. Filler
c. Binder
d. Disintegrant
e. Lubricant
f. Glidant
g. sweetener
h. Flavors

15. Impressions from the real world
15
Hopper Emptying Test (Coarse Concave Screw)
M200 PMIC
MT-S not possible
MgSt
Wrong initial fill weight
KT20
ZD12FB
CF
CF_adp
MT-S
For poorly flowing µ-APAP in small scale feeders
almost immediate flow stagnation observed
Mass
flow
[kg/h]
Mass
flow
[kg/h]
Mass
flow
[kg/h]
15

16. Our Answer

17. Excipient challenges in CM
Our Concept
17
1 DC Mannitol Parteck® M as multifunctional
excipient
2 Binary Premixes off the shelf ready to use
3 Customized premixes as individual projects
17

18. Parteck® M as
Multifuctional
Excipient

19. Why Mannitol?
Vegetable origin
Acceptance by authorities & customers
Lowest water content & hygroscopicity
Inert to APIs & humans
No impurities
4
19

20. Moisture
content and
hygroscopicity

21. Substance Water content
Starch < 15 %
MCC < 7 %
Isomalt < 7 %
Excipient System A < 5.75 %
Excipient System B < 3.5 %
Excipient System C < 3 %
Lactose monohydrate < 1 %
DC-Mannitol < 0.3 %
Excipients systems A-C
are ready-to-use
systems of the
following composition:
 A: lactose
monohydrate,
povidone,
crospovidone
 B: lactose
monohydrate,
cellulose
 C: lactose
monohydrate, maize
starch
Moisture Content
Water content of excipients matters
21
Mannitol is the best choice to use with moisture sensitive APIs
Rowe, R. C., P. J. Sheskey, et al., Eds. (2009). Handbook of Pharmaceutical Excipients.
6th Edition. London, Washington DC, Pharmaceutical Press and American Pharmacists
Association or manufacturer’s information.
21

22. Hygroscopicity
Comparison of filler excipients
22
Least hygroscopicity for mannitol
Even sorbitol may work well, if humidity can be controlled
22

23. Inertness
Impurities

24. Keep it simple!
What you leave out, you do not need to worry about
Impurities
Excipients and their impurities
24
 MCC Water, glucose (reducing sugar), hydrogen bonding
(-> retardation), aldehydes, free radicals/peroxides
 Glucose, Lactose Water, aldehydes, formic acid, reducing sugar
 Starch Water, reducing sugar, aldehydes
 HPMC Water, reducing sugar, retardation, aldehydes
 PEG, Tween Aldehydes, peroxides
 Povidone Peroxides, aldehydes, retardation
 Crospovidone Peroxides, aldehydes
Wu Y, Levons J, Narang AS, Raghavan K, Rao VM. Reactive Impurities in Excipients: Profiling, Identification and Mitigation of Drug–Excipient Incompatibility. AAPS
PharmSciTech. 2011;12(4):1248-1263. doi:10.1208/s12249-011-9677-z.

25. Impurities
Reducing sugars are cause for instability and browning
(Maillard reaction)
25
How to minimize:
Commercial standard according to pharmacopoeia limits for
polyols (mannitol, sorbitol)
Ph. Eur.  max. 0.10 %
USP  max. 0.30 %
Is this limit sufficient for API stability?

26. Unwanted related substance from the reaction of API impurity (amine) and the reducing
sugars in the mannitol
Mannitol A with API, tested after storage (60°C, 7 days),
The content of the target impurity is 1.91%
Mannitol A & API, tested after blending
Mannitol B & API, tested after blending
Mannitol B with API, tested after storage (60°C, 7 days),
The content of the target impurity is 0.57%
min
signal
Impurities
Reaction of API impurity with reducing sugars in mannitol
26
Impurity levels can be different between suppliers of the
same type of excipient

27. Impurities
Formulation of mannitols from different suppliers using direct
compression
27
DC Formulation with
Mannitol A
• Unwanted degradation
product of API: 6.5%
DC Formulation with Mannitol B
• Unwanted API degradation
product of API: 1.5%
• Many fewer types of
impurities identified
The choice of excipient and the respective level of
impurities are critical factors influencing API stability
27

28. Impurities
Example: Reducing sugars in Parteck® M batch to
batch
28
Typical Values of an impurity are never the same as the
specification limits
28

29. Why Parteck® M?
Large & structured surface area
leads to good content uniformity
Perfect flow
No aerosil® needed
Perfect compressibility
No binder needed
good disintegration
No disintegrant needed
29
4

30. 30
Granulation process
Statistical mixture vs ordered mixture
Common
knowledge:
Homogenous
mixtures only
possible for similar
particle sizes
30

31. Granulation process
Statistical mixture vs ordered mixture
31
31

32. Spray-dried Mannitol A
+ 1% Ascorbic Acid < 10µm
Spray-dried Mannitol B
+ 1% Ascorbic Acid < 10µm
Granulation process
Statistical mixture vs ordered mixture
32
Large structured surface enables ordered mixtures by adsorption of
the API
32

33. Compression force
Evaluation of different excipients for direct compression
33
0
100
200
300
400
500
600
0 5 10 15 20 25 30 35
Tablet
hardness
[N]
Compaction force [kN]
Calcium diphosphate anhydrate
Calcium diphosphate dihydrate
Lactose monohydrate
Mannitol, granulated
Mannitol, spray-dried A
Microcrystalline cellulose
Sorbitol
Sorbitol, spray-dried
Sorbitol and spray-dried mannitol deliver superior compressibility
33

34. Compression force
Particle Engineering creates compressibility
34
SEM of DC-Mannitol SEM of Parteck® M
Large surface areas show great compressibility
34

35. 35
Polymorph and BET-surface
Parteck™ M 100 beta 3
Parteck™ M 200 beta 3
Mannitol 100 (SD) alpha 0.6
Mannitol 200 (SD) alpha 0.5
Mannitol 300 beta 0.5
Mannitol 400 beta 0.4
Mannitol 500 beta 0.3
Mannitol SD EZ alpha 0.5
Mannitol DC Granul. A beta 0.3
Mannitol DC Granul. B 2080 beta 0.5
Mannitol DC granul. C 3215 beta 0.4

36. 36
Compressibility of mannitols
tablet
hardness[N]
0
100
200
300
400
0 5 10 15 20 25 30 35
compression force [kN]
Parteck® M 200
Mannitol SD
Gran. Mannitol
Method
Formulation:
99% test material + 1%
magnesium stearate; 5 min.
mixing
Compression:
single punch press (Korsch
EK0 DMS, rpm:54, punch:
11mm, flat, facetted)
Tablet weight:
500 mg (rel. S.D.:0.5)
Mannitol A and B are
commercially available
mannitol grades for direct
compression.

37. 37
0
20
40
60
80
Parteck® M DC-Mannitol Lactose/starch-
granules
Tablettose
tablet
hardness
(N)
Parteck® M: High compressibility
Formulation:
98,5% Mannit; 1,5% Mg-Stearat, Compr. Force 15 KN
99% Lactose, 1% Mg-Stearat, Compr. Force 15 KN

38. 38
0
10
20
30
Parteck® M DC-Mannitol Lactose/starch-
granules
Tablettose
Disintegration
time
(min)
Parteck® M: Fast Disintegration
Formulation:
98,5% Mannit; 1,5% Mg-Stearat, Compr. Force 15 KN
99% Lactose, 1% Mg-Stearat, Compr. Force 15 KN

39. What type of granulation shall be used?
39
Direct
compression
Wet
granulation
Dry
Granulation
Roller
compaction
All shall be possible!
Parteck® M fits all purposes

40. 40
Direct
compression
Parteck® SRP 80
Parteck® ODT
Parteck® PLX
188
Parteck® M
Parteck® L M

41. 41
Wet
Granulation
Parteck®
Delta M Parteck® M

42. 42
Wet Granulation vs Direct Compression
How to select an enabling technology?
Wet
Granulation
(beta
Mannitol)
Wet
Granulation
(delta
Mannitol)
Parteck® M
for Direct
Compression
After
Granulation
Beta form
mannitol
Beta form
mannitol
After
Granulation
Beta form
mannitol
Beta form
mannitol
Delta form
mannitol

43. Wet Granulation vs Direct Compression
Results: Select the best enabling technology
43
Wet Granulation
Crystalline
Beta Mannitol
Wet Granulation
Parteck® Delta
Mannitol
Direct
Compression
Parteck® M 200
Results:
Wet Granulation
Results:
Direct Compression
Punching
Pressure:
29 kN
Tablet weight: 541 mg
Tablet
hardness
34 N
Friability: bad
Disintegration: 9 Min
50Sec
Punching
Pressure:
12 kN
Tablet weight: 505 mg
Tablet hardness 210 N
Friability: 0,20
Disintegration: 4 Min 23
Sec
Punching
Pressure:
12 kN
Tablet weight: 484 mg
Tablet hardness 111 N
Friability: 0,29
Disintegration: 4 Min
15 Sec



Important
Important

44. Poll Question
44

45. 4. How do you appreciate premixes
and or coprocessed excipients?
a. No, not at all – only straight pharmacopoeia
materials
b. Premixes most likely but coprocessed not
c. Coprocessed preferred

46. Binary premixes
off the shelf
ready to use

47. Excipent System
New concept
47
DC-Mannitol
Lubricant
Mg Stearate
Parteck® LM
2 grades

48. 48
• No need for dosage of small bad flowing component Mg-Stearate
• Guaranteed content uniformity
• Proven flow and processing performance
• Proven lubrication functionality
Advantages
Results published at AAPS 2020
(Poster available)

49. 49
• No need for dosage of small bad flowing component Na-
croscarmellose
• proven content uniformity & stability over long haul supplychain
• Proven flow and processing performance
• Proven disintegration functionality
• Registered in EU as pediatric drug
Parteck® ODT
Established 2009 good track record

50. Customized
premixes

51. 51
Individual customized premixes
Project business case
Open for any excipients of customers choice – no API
Analyt. Methods to be developed (& validated)
3
2
1
Content uniformity & stability to be proven
(segregation?)
Exclusivity – no off the shelf product, made to
order
4
5

52. 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.
© 2021 Merck KGaA, Darmstadt, Germany and/or its affiliates. All Rights Reserved.

53. Q&A