Continuous Granulation using Twin Screw Extruders A modular approach to increase your yield in pharmaceutical production. Dirk Leister, TFS, Leader Application Group Raoul Pila, Glatt, Product Development Engineer
Combine Expertise for your success
•$ 10+ billions in revenue
• Glatt group 1.500+ employees
• 37.000 employees • 350.000 customers
• represented in 20+ companies worldwide
• Establishing extrusion technologies in thepharmaceutical industry • Hot Melt Extrusion
• Market leader in integrated process solutions for solid dosage forms
• Wet Granulation
• Drying • Granulation • Coating
One stop shop for tablet production 2
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Content • Granulation Technology • Purpose and batch technologies
• Continuous Granulation • From blending to tableting • Modular Approach • Benefits
• Core Technology • Twin Screw Granulator • Continuous Fluid Bed Dryer
• Experimental Data • Achema 2012
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Purpose of Granulation • Granulation is a size enlargement process of particles • To prevent segregation of the constituents of the powder mix • Aid downstream processing by improving the physical characteristics of the mix in terms of: • • • • • 4
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Flow Density Dustiness Compressibility etc.
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Granulation Wet granulation involves the agglomeration of a mix of dry primary powder particles using a granulating fluid. The fluid, which is added during the granulation step, must be pharmaceutically safe and volatile enough so that it can be evaporated by a subsequent drying step. In Melt granulation the binding fluid is created by heating the formulation and causing one or more of the dry ingredients to become molten. Cooling the mix at the end of the granulation step solidifies the molten binder.
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Batch Granulation Technology •
Traditional batch processes • High shear mixers • Roll Compaction • Fluidised bed granulation
•
Risks of Batch to batch variation require careful and complex procedures and controls. • Method and order of charging ingredients • Time and technique for introduction of binders • Definition of end point
•
Large scale equipment needed in development to reduce risk of scale-up. Large quantities of expensive API (Active Pharmaceutical Ingredient) required Difficulty to produce small samples on production scale equipment.
• •
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Comparison of materials – example of batch mixed granules
50 45
characteristic peak @ 90-150 microns
Wt % on sieve
40 35 30 25
Fines variable 2-18% Variable quantities of coarse material Between 2-14% @ 500 micron
20 15 10 5 0 0
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75
90
150
250
355
500
710
850
1000
Sieve size (microns) Source ISPE Conference John Robertson GlaxoSmithkline 7
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Comparison of materials – example of batch mixed granules 35
30
25
20
Lower variability in fines Much lower variability at coarse end
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10
5
0 0
53
75
90
150
250
355
Potential for more consistent process !
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500
710
850
1000
Source ISPE Conference John Robertson GlaxoSmithkline
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Batch vs. Continuous Granulation 3-10 litre
Phase 1
65-150 litre
Phase 2
Phase 3
300-600 litre
Pharmalab 16mm
Phase 1
Phase 2 and Phase 3
Pharmalab 24mm
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Thermo Fisher Pharmaceutical Extruders Phase 0 Preclinical
Chemistry
Medicinal
Available API
Phase 1
Phase 2
Phase 3 Regulatory Approval
Kilogramme Lab
Process Chemistry Development
mg - g
1-10 kg
10 – 100 kg
1,000 kg
1,000 kg
Process Batch
20 g
1 – 5 kg
5 – 50 kg
100 – 500 kg
1,000 kg
Twin screw Extruder
Pharma 11
Pharma 16
Pharma 16 Pharma 24
Pharma 24
Pharma 24 Pharma 36
20 g
1 – 5 kg/h
1 – 5 kg/h 5 – 25 kg/h
5 – 25 kg/h
5 – 25 kg/h 25-100 kg/h
Process Output
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Production Development
Launch
Commercial Manufacturing
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Benefits and Advantages of a Continuous Process • Easier to enclose the whole process • Smaller scale equipment • Small Footprint
• Flexibility of batch size • Small amount of materials in process • Improved control and consistancy
• Elimination of dispensing • Reducing risk of operator error in weighing out ingredients. • Reduced handling of / exposition to all ingredients • Reduce labour cost
• Possibility of implementing PAT • Automation • Process understanding
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How can a continuous, modular approach look like Grav Feeding Grav liquid addition
Twin Screw Granulator
Fluid Bed Dryer
Grav Feeding
Mixing
Tabletting
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Core processes for cont granulation Grav Feeding Grav liquid addition
Twin Screw Granulator
Fluid Bed Dryer
Grav Feeding
Mixing
Tabletting
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Pharma 16 Twin Screw Granulator Gravimetric Screw Feeder
Liquid Feeding Pump
Pharma16 TSG Twin Screw Granulator 14
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Pharma 16 TSG with powder bridge braker
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Pharma 16 TSG showing discharge area
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PharmaLab 16 Barrel Close-Up
117 2
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Flexible Extrusion Equipment 17
Barrel Clamps Removed
118 2
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Flexible Extrusion Equipment 18
Barrel Top Half and Screws Removed
119 2
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Flexible Extrusion Equipment 19
Lower Barrel Front Section Removed
120 2
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Flexible Extrusion Equipment 20
All Lower Barrel Sections Removed
121 2
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Flexible Extrusion Equipment 21
Pharma 16 HME - maximum flexibility… flexible screw configuration
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Pharma 16 HME - Screw Elements: Conveying elements:
Profiles with long helix are used: - in the feeding sections - - for degassing (venting) Profiles with short helix are used: - for high pressure built up - in front of kneading elements
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Pharma 16 HME - Screw Elements: Mixing Elements :
• Mixing Elements are used to introduce shear energy to the extruded materials. • The disks are arranged in different offset angles used for:
- shearing - mixing - dispersing
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Pharma 16 HME - Screw Elements: Distributive Flow Elements :
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Distributive Flow Elements are special mixing elements, used for the distribution of small quantities of additives and shear sensitive materials.
•
Used to break up agglomerated granules.
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Pharma 24 Twin Screw Granulator Gravimetric Screw Feeder Gravimetric Liquid Feeding Pump
Crammer Feeder
Pharma 24 TSG Twin Screw Granulator 26
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Pharma 24 TSG with feeder platforms
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Continuous Fluid Bed Drying • Principle theory of continuous fluid bed drying
wet granules
integrated filter system
expansion chamber processing chamber discharge pipe bottom screen inlet air chambers dry granules
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process air
process air
for fluidization and drying
for fluidization and drying
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Continuous Fluid Bed Drying • Equipment size
throughput
< 15 kg/h
> 10 kg/h
shape
round
rectangular
name
GF 5
GF 25, 50 & 125
Insert for GPCG 2 LabSystem
stand-alone machine
implementation 29
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Continuous Fluid Bed Drying • Principle GF5: ring-shaped process chamber process chamber (annulus) displacement body outer wall divider partition material input
material discharge
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Homogeneous material flow
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Continuous Fluid Bed Drying • Process development with GPCG 2 LabSystem Process overview • Batch drying • Top spray granulation • Wurster coating • CPS Pelletization • Rotor Pelletization • NEU: Continuous Drying
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Continuous Fluid Bed Drying • GPCG 2 LabSystem with GF5
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Experimental Data
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Experimental Data Formulation : Qty (kg)
Proportions (%)*
API
8.0369
80.369
Aerosil
0.0557
0.557
Sodium starch glycolate
1.003
10.030
Cellulose MRK (microcr. Cellulose)
0.5701
5.701
Hypromellose Pharmacoat 603 (HPMC)
2.3400
3.343
Barrel Temperature 35°C Pure water as liquid addition
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Experimental Data
Parameters
X1 Screw speed [rpm]
X2 Spray rate [g/min]
X3 Kneading element config. [°]
-1 low
300
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7x30, 1x60
0 center
450
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5x30, 3x60
+1 high
600
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3x30, 5x60
6 consecutive experiments DoE with Parameters X1, X2 and X3
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Experimental Data 2,0
Verteilungsdichte / distribution density q3 [*1000/µm]
1,8 1,6 1,4 1,2 1,0 0,8 0,6 0,4 0,2 0,0 0
200
400
600
800
1000
1200
1400
1600
1800
2000
Partikelgröße / particle size [µm] Run 1
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Run 2
Run 3
Run 4
Run 5
Run 6
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Achema 2012 Set-Up • Achema • 18th – 22nd July, Frankfurt (Germany) • Hall 3.0 Booth F1 • Pharma 16 TSG • GPCG2 with GF-5
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Thank you for your attention ! Any questions ? Looking forward to see you at Achema !
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