Continuous Granulation using Twin Screw Extruders

Continuous Granulation using Twin Screw Extruders A modular approach to increase your yield in pharmaceutical production. Dirk Leister, TFS, Leader Ap...
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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

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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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