The document is a presentation about addressing raw material handling challenges in the pharmaceutical industry through dry granulation. It discusses how certain chemicals can cake or clump, making them difficult to weigh, dispense and handle safely and efficiently. The presentation introduces dry granulation as a process to granulate chemicals without using liquids, which can avoid changing the chemical composition. It describes the roller compaction method of dry granulation and explains how it improves properties like flowability and reduces caking and hazards. Test results show granulated materials have comparable dissolution behavior to bulk chemicals while improving other qualities. The presentation promotes MilliporeSigma's line of granulated raw materials for these benefits.

1. The life science business of Merck KGaA,
Darmstadt, Germany operates as
MilliporeSigma in the U.S. and Canada.
Addressing Raw Material Handling
Challenges by Dry Granulation
Dr. Thomas Briel
Strategic Marketing Manager
Webinar – March 2021

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

3. Webinar: Addressing Raw Material Handling Challenges by Dry Granulation | March 2021
3
 Chemical raw materials are used in multi-ton quantities in pharma and biopharma production
 The handling of such quantities can be challenging and is linked to plant schedule and capacity
 Main business drivers in the course of chemical raw material handling are:
Chemical Raw Material Handling – Business Drivers
Business is driven by just-in-time, flexible handling of chemical raw materials
Speed
 Intensified processes, linear volume
growth of chemicals with bioreactor titer
Quality
 Quality control and assurance in line
with raw material flow
Flexibility
 Rapid change-over of chemicals for
next manufacturing process
Cost
 Operators: Lean, robust workflow
 Reduced facility footprint

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Chemical Raw Material Handling – Challenges
Needed: Solutions to address handling challenges
Caking, clumping of
chemicals
Dust formation
Laborious weighing
and dispensing
Implications Operator safety risks Speed
Quality
Flexibility
Cost
Extensive cleaning
Process interruption
Quality deviations
Process delay
Additional floor space
Risk of bioburden

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Caking of Chemicals Increases Risks in Operations
Implications of caking:
Safety risks
Increased probability of operator injury during manual de-caking of solidified blocks
Caking:
 Product property of diverse chemicals
 Complete solidification during storage
 Very difficult to handle at large scale
Total cost of ownership
Increased operating costs due to
 Loss of time needed to break solidified blocks
 Laborious sampling and weighing
 Difficult emptying of primary packaging
 Low predictability of efforts as degree of caking can strongly vary

6. Poll Question

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Addressing Caking by Granulation of Chemicals
Slugging
 Typically uses a tableting machine
or rotary press to form “slugs”
 Slugs are broken by e.g. a
hammer mill to form granules
 High-pressure method
Roller Compaction
 Compression between two rotating
rollers into plates or sheets
 Plates are milled into granules
 In general gentler than slugging
Granulation
Dry Granulation
does not require liquid / binders
-> no change of chemical composition
Wet Granulation
needs binders
-> change of chemical composition

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Addressing Caking by Granulation of Chemicals
Principle of Dry Granulation by Roller Compaction
Compression
to plates
Milling to
granules
Bulk
material

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Addressing Caking by Granulation of Chemicals
Principle of Dry Granulation by Roller Compaction
(1) Bulk material
(2) Funnel with mixer and tamp auger
(3) Temperature-controlled hydraulic compression rolls
(4) Rotor sieve mill
(5) Vibrating sieve
(6) Final granules
(7) Fine particles re-circulation
1
2
3
4
5
6
7

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Addressing Caking by Granulation of Chemicals
Key Process Parameters of Roller Compaction
Pressure
Main parameter to determine hardness and integrity of granules
Generally: The higher the pressure, the harder the granules
Roller Speed
Strongly influences process throughput
Determines retention time of material under pressure
Roller Interspace
Influences pressure, has to be aligned with feeding speed
Fixed for each process, but rollers have certain flexibility (<mm range)

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Addressing Caking by Granulation of Chemicals
Key Process Parameters of Roller Compaction
Milling
Sieve mesh size main parameter determining particle size
General material properties also influence particle size at this step
Material Properties
Not all raw materials are suitable for compaction!
Factors: Crystallinity, plasticity, “stickiness”, age, melting point, etc.
limited cohesion extensive cohesion

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Dry Granulation by Roller Compaction
Addressing Caking by Granulation of Chemicals
Benefits
 Compression force only
 No water or other additives needed
 Ideal for sensitive materials
 Flexible / adjustable process
 High throughput possible
BUT…
 Not a one-fits-all technology!
 Requires deep process understanding

13. Poll Question

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Granulated Raw Materials – Particle Size Distribution
Experimental conditions
 Milling sieve size: 6 mm
 Particle size determined by vibrating sieve tower
 Sieves: 0.5 mm, 1 mm, 2 mm, 2.8 mm, 4 mm
 Weight of fractions recorded: 10, 20 and 30 min
 Mass-% of all fractions determined
0
-
0.5
0.5
-
1
1
-
2
2
-
2.8
2.8
-
4
>
4
0
10
20
30
40
50
Particle size [mm]
Particle
size
distribution
[%]
Granules particle size is always a distribution:
Example:
Urea
Particle size mainly depends on:
• Sieve mesh size
• General material properties
Very low fines!

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Granulated Raw Materials – Appearance (Stability Study)
Granules show significantly less caking, but degree is still material-dependent:
Example:
Urea
t = 0
t = 12 months
25 °C / 60% rH
~70% clumps
Hard to break
~10% clumps
Very easy to break
Granules
Bulk

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Granulated Raw Materials – Appearance (Stability Study)
Granules show significantly less caking, but degree is still material-dependent:
Example:
Potassium
Chloride Granules
Bulk
~40% clumps
Hard to break
No clumps
t = 0
t = 12 months
25 °C / 60% rH

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Granulated Raw Materials – Flowability
 High degree of flowability is key for good processability of raw materials
 Insufficient flowability can lead to additional efforts and process delays
 Flowability of bulk and granulated raw materials were investigated by powder analyzer
Experimental conditions
 Flowability was determined using a powder analyzer
leading to the calculation of the avalanche angle:
Flowability Avalanche Angle [°]
Excellent <45
Good 45 - 55
Average 55 – 62.5
Non-satisfactory > 62.5
Avalanche
angle

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Granulated Raw Materials – Flowability
Granulated raw materials show strongly improved flowability compared to bulk material:
0
25
50
75
1 2 3
Avalanche
angle
[°]
Urea Glycine
non-satisfactory
average
good
excellent
Potassium
Chloride
Flowability of granules
good to excellent
Bulk
Granules
Very comparable results
between different materials

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 Mechanical stress might occur during transport, handling and storage
 Stress conditions have been simulated with a friability tester
Granulated Raw Materials – Mechanical Stability
Experimental conditions
 Granules were placed in the abrasion drum of the friability tester
with ceramic balls (accelerated conditions)
 Rotation for 10 min at 20 rpm
 Determination of mass-% of generated fine particles < 500
µm = Abrasion [%]

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Granulated Raw Materials – Mechanical Stability
 Mechanical stress might occur during transport, handling and storage
 Stress conditions have been simulated with a friability tester
0
2
4
6
8
10
Glycine Urea Potassium Chloride
Abrasion
[%]
Abrasion of Granulated Materials
Granulated products show
excellent material integrity

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Granulated Raw Materials – Dissolution Behavior
 Manufacturing processes require both fast and complete raw material dissolution
 Kinetics of granulated and non-granulated material dissolution have been determined
Experimental conditions
 Dissolution studies were performed with 100 g/L
potassium chloride in 800 ml water; 250 rpm;
room temperature
 Particles were measured by focused beam
reflectance measurement and visual inspection
for up to 10 minutes.
Laser source
Laser return
Optics module
Sapphire window
Focused beam

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Granulated Raw Materials – Dissolution Behavior
Dissolution behavior of granulated raw materials is comparable to bulk material:
Urea Glycine
Potassium
Chloride
Bulk 5.0 min 6.0 min 6.0 min
Granules 8.5 min 8.0 min 6.5 min
Consider:
Few minutes
longer dissolution
vs.
1 - 3 hours additional time
in sampling, weighing and
dispensing of caked materials
Dissolution Time
Dissolution Kinetics (Example: Glycine)
0 2 4 6 8 10
0.0
0.5
1.0
D is s o lu tio n K in e tic - G ly c in e
T im e [m in ]
N
o
r
m
a
l
i
z
e
d
p
a
r
t
i
c
l
e
c
o
u
n
t
B u lk
G ra n u le s
A
d
d
it
io
n
o
f
G
ly
c
in
e
1 0 0 g /L
1 .3 3 m o l/L
B u lk : 0 .3 2 N T U
G ra n u le s : 0 .4 4 N T U
v is u a l
c le a r
v is u a l
c le a r
Visually
clear
Visually
clear

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Product Portfolio Information
 Emprove® Expert grade: Low endotoxin levels for high-risk applications
 Multi-compendial; compliant with major pharmacopoeias
 Available from 3 different batches for qualification purposes and in diverse pack sizes
Glycine Granulated EMPROVE® EXPERT Ph Eur, BP, ChP, JP, USP
Potassium Chloride Granulated EMPROVE® EXPERT Ph Eur, BP, JP, USP
Urea Granulated EMPROVE® EXPERT Ph Eur, BP, JP, USP, ACS
For further information, please visit www.emdmillipore.com/granulated-materials
Currently commercially available raw materials in granulated form:
All granulated products are…
…additional products are currently under development

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The Emprove® Program
Our granulated products are part of the Emprove® Program
The Emprove® Program helps you meet latest regulatory requirements for risk
assessment and offers assistance in developing more robust processes.
Operational Excellence Dossier
Supports process optimization and
safety risk assessment
Quality Management Dossier
Answers questions during quality
risk assessment
Material Qualification Dossier
Information to start a material
qualification
 Product quality report
 Elemental impurity information
 Analytical procedure
 Technically Unavoidable Particle
Profiles (TUPP), if applicable
 Quality self-assessment
 Audit report summary
 Supply chain information
 Stability data
 General information
 Manufacturing flow chart
 Characterization
 Control of drug substance
 Reference standard
 Materials
 Container closure systems
 Stability

25. Poll Question

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Granulated Raw Materials – Summary
Reduced caking
Stable during transport and storage
Better flowability and processability
Good dissolution behavior
Granulated materials
facilitate processability,
speed up manufacturing
processes and increase
operator safety
Part of Emprove® Program
For further information, please visit www.emdmillipore.com/granulated-materials

27. Q&A
Contact:
Dr. Thomas Briel
thomas.briel@emdgroup.com

28. 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.
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