Pharma Twin Screw Extruders 2011

Kurt Kortokrax

Sales Account Manager

Kurt.Kortokrax@Thermofisher.com

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Thermo Fisher Scientific – a strong brand

New capabilities acquired from Fisher

Famous catalogs and supply-chain services

+

Thermo’s world-class analytical technologies

All from Thermo Fisher Scientific

• New brand stands for innovation and quality• Thermo instruments plus new reagents,

consumables and equipment• Even better laboratory workflow solutions

• Mark of choice and convenience

• Complete product portfolio of equipment & supplies

• One-stop, total lab supplier

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Pharma Twin Screw Extruders 2011

Hot Melt Extrusion Twin Screw Granulation

Information HME Information TSG

Product Portfolio HME Product Portfolio TSG

Customized Solutions

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Introduction Hot Melt Extrusion

Introduction HME

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HMI – What‘s your challenge today?

Taste maskingPoor solubilit

y

New capsule materialsNew dosage

concepts

Limited by your API

New deliverymethods

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Where is pharmaceutical Hot Melt Extrusion?

“For both the pharmaceutical industry and the academic community HME became an innovative drug delivery technology that is receiving increased attention. HME turned now into highly dynamic, interdisciplinary topics that provide a creative link between engineering and pharmaceutical sciences for the purposes of drug delivery.

Research in these vibrant research areas is making significant advances resulting in innovative, engineered drug delivery systems.”

Source:G. P. Andrews, Phil. Trans. R. Soc. A (2007) 365, 2935–2949

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What is Hot Melt Extrusion?

Processing of polymeric materials above their glass transition temperature (Tg) in order to effect molecular level mixing of thermoplastic binders and/or polymers and active compounds

Melt extrusion is a combination of melting and mechanical energywith advantages like:

• Continuous• Reproducible• Fairly high throughput• Dust reduction• On-line-monitoring

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Biopharmaceutics Classification Scheme

Class II Class I

Class IIIClass IV

Low SolubilityHigh Permeability

High SolubilityHigh Permeability

High SolubilityLow Permeability

Low SolubilityLow Permeability

Per

mea

bilit

y

Solubility

90%

0.1 mg/ml

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Why Hot Melt Extrusion

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Different Types of Solid Dispersions/Solutions

Polymer: amorphous amorphous amorphous

Drug: crystalline amorphous molecularly dissolved

Thermo-dynamic almost stable unstable stable (drug belowStability (kinetically controlled) saturation solubility)

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Pharmaceutical Development Needs

• Consistent, small scale production.• Low consumption of expensive materials • Easy cleaning with simple verification.• Flexibility for new product development.• Reliable and repeatable operating conditions.• Accurate process data for product audit.

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How Extrusion Technology can support you…

Hot melt extrusion supports you by establishing stable solid solutions which increase the availability of poorly soluble ingredients,

A continuous steady state process monitored by process control allows you to minimize failed batches

Extrusion technology allows you to produce new drug dosage forms e.g. mini implants

Melt extrusion allows you to reduce the consumption of solvents - for instance in comparison with the wet granulation process

and many other good reasons …

Extrusion technology is a mature process used in the polymer industry for more than 40 years and in the pharmaceutical for approx. >20 years known.

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Validation Aspects

Regulatory aspects of melt extrusion:

Hot melt extrusion has a comprehensive documentation, which satisfy regulatory authorities

Melt extrusion is a mature technology

Measurable parameters such as feeding rate, equipment temperatures, discharge pressure, vacuum control, etc. can be monitored on-line with local sensors. Data logging provides supporting documentation to ensure the quality of production lots and simplify quality control.

Use of in-line sensors PAT provide a good basis for the FDA – QbD initiative

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Product Portfolio Hot Melt Extrusion

Product Portfolio HME

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Twin Screw Solutions for HME

Mini

16 mm

24 mm

MiniLab Pharma mini HME

EuroLab Pharma 16 HME

Pharma 24 HME

EuroLab Pharma

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Phases of Pharmaceutical Development

Phase 0Preclinical

Phase 1 Phase 2 Phase 3 RegulatoryApproval

Launch

Chemistry Medicinal Kilogramme Lab

Process Chemistry Production Site Production Site

API Batch Size

mg - g 0.2 -10 kg 10 – 100 kg 1,000 kg 1,000 kg

Process Batch

10 g 0.2 - 5 kg 5 – 50 kg 100 – 500 kg 500 kg

Testing In Vitro & Animal

Safety in Human

Safety and Efficacy Market Market

Constraintso Quantity of APIo Quality of APIo Consistent quality of Drug producto Time

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The Solution for your Phase

Phase 0Preclinical

Phase 1 Phase 2 Phase 3 RegulatoryApproval

Launch

Chemistry Medicinal Kilogramme Lab Process Chemistry Production Site Production Site

API Batch Size

mg - g 0.2-10 kg 10 – 100 kg 1,000 kg 1,000 kg

Process Batch

10 g 0.2-5 kg 5 – 50 kg 100 – 500 kg 500 kg

Twin Screw Granulator

Pharma mini HME

Pharma 16Pharma 16Pharma 24

Pharma 24Pharma 24scale out

Process Output

10 g 0.2-5 kg/h 0.2 – 5 kg/h1 – 50 kg/h 1 – 50 kg/h 1 – 50 kg/h

25 – 100 kg/h

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The MiniLab

HAAKE MiniLab – suitable e.g. for

Proof of concept studies

Creating specimen for drug delivery systems

Your advantages of a Micro Compounders

Substantial cost savings for proof of concept studies due to compounding of small quantities of ingredients (5g)

Understanding of material characteristics by documenting structural changes via integrated viscosity measurement

Flexible process conditions for different materials by

Using conical co- or counter-rotating screws

Automatic bypass operation for extrusion/recirculation

Force Feeder especially for continuous powder feeding

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Pharma mini HME for Micro Scale Production

Pharma mini HME

Allows the preparation of small sample batches for clinical trials (e.g. phase 1) when only a few grams of material is needed (minimum 4 grams)

Continuous micro scale production (up to 100 grams per hour) for dedicated Pharma applications (e.g. implants)

Feasibility trials in a very early stage with high potent materials in a Glove Box / Isolator environment (small footprint, easy handling).

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Pharma mini HME FeaturesPharma mini HME

The characteristics of our GMP Version are

All product contact parts made from pharma grade stainless steel

Horizontally split barrel with top and bottom half lifting upwards, with barrel clamps for easy removing, exchanging and cleaning

Cooling block for cooling of feed port with air or water

Minimization of screw threads and focus on easy-to-clean components

Optional available manual feeder and Force Feeder

Replacement barrels available as option (to avoid contamination between different materials and save time because of cleaning between several material runs)

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Pharma mini HME Features

Pharma mini HME

Additional Features

Without backflow channel (available as option)

Straight, easy to clean split extrusion channel

Touch screen control with user levels and password protection, quick data trending (data logging software as option)

Can be used as co- and counter-rotating setup

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EuroLab

EuroLab

Ideal for material and process studies at Universities and R&D centers

Continuous runs with 200 g/hr up to 5 kg/hr

Modular tool to understand and improve process and get knowledge about material behavior and material composition

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EuroLab FeaturesEuroLab

The characteristics of our Eurolab are

Horizontally split barrel with top half lifting upwards for better access to the screws and better process understanding

Modularity: 25:1 extruder with 15:1 extension offers flexibility for several applications

Optional available volumetric and gravimetric single and twin screw feeding systems for solids and liquids with full integration into extruder touch screen (as option)

Segmented upper barrel allows flexibility in feeding and venting

Bench mounted system, small footprint

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EuroLab Features

EuroLab

Additional Features

Touch screen control with quick data trending (data logging software as option)

Wide range of up- and downstream equipment (e.g. strand line, face cut pelletiser etc. Available)

Scales to EuroLab Pharma, Pharma 16 and Pharma 24

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EuroLab Pharma

Eurolab Pharma

Allows the preparation of small sample batches

For material and process studies in Pharma R&D environments

Continuous runs with 200 g/hr up to 5 kg/hr

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EuroLab Pharma Features

EuroLab Pharma

Additional Features

All product contact parts made from Pharma grade stainless steel, material certs and surface roughness measurements avaialable

Stainless steel cover for barrel and bench

Small feeder platform included

Optional barrel cooling

Conversion kit HME -> TSG available

Touch screen control with user levels and password protection, quick data trending (data logging software as option)

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Pharma 16 Hot Melt Extruder

Pharma 16 HMEProcess development studiesProducing samples for Clinical Trials

Advantages of a Pharma HMESubstantial cost savings for process development from compounding of samples (from 200g)

Significant time savings from ability to process multiple samples in succession.

Flexible process configurations for different materials from segmented screws and barrels.

Opportunities for multiple feed streams to minimise use of expensive API.

Special feeding accessories for difficult to handle ingredients.

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Pharma 16 HME Features

• Product contact parts made from pharmagrade steel• Stainless steel housing• Material cerificates available• Full validation documentation available• Removable and segmented top and bottom barrel• Touchscreen control• Integrated feeding solutions• Automated start-up procedure available• Integration of PAT (e.g. NIR) possible• Based on casters, movable

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Pharma 16 HME – Barrel and Screws Removal

Barrel clamps Barrel clamps removed

Upper barrel removed Lower liner and screws removed

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Pharma 16 HME – Barrel and Screws Removal

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Pharma 16 HME – Design Features

Design features

Stainless steel GMP construction.No external painted parts.Sheet metal base is made of stainless steel.

Process contact parts from pharma-grade through-hardened surgical stainless steel

Easily removable screws and barrels for cleaning or reconfiguration.

Adjustment of effective process length to minimise residence time.

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Pharma 16 HME – Segmented Barrel

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Pharma 16 HME – Flexible Screw Design

Distributive Element (narrow)

Dispersive Element (wide)

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Pharma 16 HME – Flexible Screw Design

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Pharma 16 Air Cooled Conveyor Belt

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Pharma 16 – Varicut and Twin Servo Pelletiser

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Pharma 16 – Strand Pelletising Line

PharmaLab16 HMETwin Screw ExtruderPharma 16

Air Cooled ConveyorPharma 16Varicut Pelletiser

Pharma 16 Feeding Systems

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Pharma 24 Hot Melt Extruder

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Pharma 24 HME – Barrel Liners and Screws Removal

Barrel liners and plugs removed

Barrel close-up

All contact parts removed

Barrel open

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Pharma 24 Chill Roll – The Compact Cooling Solution

Flaker parts removed

Belt cartridge removed

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Pharma 24 Chill Roll

Roll opening handles

Flaker removedInterlocked roll guard

Nip gap adjustment

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Pharma 24 Chill Roll Belt Cartridge

Belt Cartridge removed

Pharma 24 Chill RollRemoving the Belt Cartridge.

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Pharma 24 Chill Roll Flaker Cleaning

Flaker parts removed

Pharma 24 Chill Roll (Opening Flaker)

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Pharma 24 Hot Melt Discharge Die Nozzle

Vacuum Vent StackDie Pressure ProbeLong Reach

Die Temperature Probe

Discharge Nozzle

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Pharma 24 Vacuum Venting

Vacuum Vent Stack

Blocked Vent Indicator

Vacuum Gauge

Air Bleed Control

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Pharma 24 Feeding Solutions

Hopper Extension

Load Cell

Discharge Tube,Fitted with

Flexible Bellows

Feeder Controller

Extruder Touch Screen

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Pharma 16 and 24 Feeder Plattforms

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Pharma 16 and 24 Feeder Arrangement

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Pharma 24 HME with Chill Roll

Pharma 24Chill Roll/Flaker

PharmaLab 24 HMETwin Screw Extruder

Gravimetric Screw Feeder

Vacuum VentPressure Probe

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Twin Screw Granulation

Introduction TSG

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Reasons for Granulation

• To prevent segregation of the constituents of the powder mix• Aid downstream processing by improving the physical characteristics of

the mix in terms of:

• 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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Pharmaceutical Batch Granulation

• Traditional batch processes• High speed wet granulation (like APV, GEA, Fielder.)• 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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Continuous Granulation

• Controlled continuous process • Suitable for PAT • No batch to batch variation

• Small inventory of in-process materials• Reduced risk of product loss• Reduced Powder risks

• On demand production• Reduced scale-up risk

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The Clinical Trials Development Cycle

STUDY PHASE Number of Patients Duration Primary Purpose

Phase 1 20 – 100 normal, healthy patients

Up to one year Safety

Phase 2 Up to several hundred patients

One to two years Safety and efficacy

Phase 3 Several hundred to several thousand patients

Two to four years Efficacy and cost benefits

Phase 4(Post Launch)

Several hundred to several thousand patients

Two to ten years Cost benefits and outcomes

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Batch vs. Continuous Granulation

3-10 litre

65-150 litre

300-600 litre

Pharmalab 24mm

Phase 1

Phase 2

Phase 3

Phase 1

Phase 2and

Phase 3

Pharmalab 16mm

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Equivalent Production Capacities

Batch Granulating Equipment

Daily output of Granulate

Continuous Granulating Equipment

65 Litre Batch Mixer15 kg batch

60 kgBased on 4 batches per 12h day

Pharma 16 TSG0.2 – 6 kg/h

300 Litre Batch Mixer75 kg batch

225 kgBased on 3 batches per 12h day

Pharma 24 TSG1 – 60 kg/h

600 Litre Batch Mixer150 kg batch

300 kgBased on 2 batches per 12h day

Pharma 24 TSG1 – 60 kg/h

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Equivalent Production Capacities

Equipment Volume Process Evaluation Samples Daily Production Rates

Batch MixerTotal Tank Volume

Working Volume

Batch Size

Batch Materials Cost

Minimum Sample Size

Number of process

samples per Batch

Sample Materials Cost

Batches per day

Typical Continuous Daily (24h) Output

Mixer Size Litre Litre Kg Kg Kg

3 Litre 3 1.5 0.75 $750 0.750 1 $750 5 3.7510 Litre 10 5 2.5 $2,500 2.500 1 $2,500 5 12.5

65 Litre 65 32.5 16.25 $16,250 16.250 1 $16,250 4 65150 Litre 150 75 37.5 $37,500 37.500 1 $37,500 4 150

300 Litre 300 150 75 $75,000 75.000 1 $75,000 3 225600 Litre 600 300 150 $150,000 150.000 1 $150,000 3 450

Continuous Mixer Extruder

Free Volume

Maximum Inventory

Minimum Batch Size

Batch Materials Cost

Minimum Sample Size

Number of process

samples per Minimum

BatchSingle Sample Materials Cost

Output Kg per Hour

Typical Continuous Daily (24h) Output

Screw Diameter Litre Grammes Grammes Kg Kg Kg

Minilab 0.007 3.5 5 $5 0.005 1 $5 0.1 2.4

Pharmalab 16 25:1 0.068 34 500 $500 0.170 3 $170 4 96

Pharmalab 16 40:1 0.109 54.5 900 $900 0.273 2 $273 4 96

Pharmalab 24 25:1 0.228 114 2000 $2,000 0.570 5 $570 20 480

Pharmalab 24 40:1 0.365 182.5 3000 $3,000 0.913 4 $913 20 480

Based on:-Formulation Density g/ml 0.50 Formulation Cost per Kg $1,000

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Batch Granulation Population Balance

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Comparison of materials – example of batch mixed granules

0

5

10

15

20

25

30

35

40

45

50

0 53 75 90 150 250 355 500 710 850 1000

Sieve size (microns)

Wt

% o

n s

iev

e

Variable quantities of coarse materialBetween 2-14% @ 500 micron

characteristic peak @ 90-150 microns

Fines variable 2-18%

Source ISPE Conference John Robertson GlaxoSmithkline

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Comparison of materials – example of batch mixed granules

0

5

10

15

20

25

30

35

0 53 75 90 150 250 355 500 710 850 1000

Much lower variability at coarse end

Lower variability in fines

Potential for more consistent process ! Source ISPE Conference John Robertson GlaxoSmithkline

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Motivation for adopting continuous granulation

• Financial and business drivers• Reduced footprint

• facilities cost• No or little scale up from development to commercial

• reduced tech transfer costs and risks• reduced FTE requirements• reduction in API requirements through

development• Potential for common platform throughout development

and commercial network• Reduced capital and OPEX costs• Lights out operation• Containment of high actives• Potential for modular construction approach• Reduced inventory – scope for just in time delivery

• Technical Drivers• Implementation of PAT • Scope for improved control and consistency

Source ISPE Conference John Robertson GlaxoSmithKline

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Product Portfolio Twin Screw Granulation

Product Portfolio TSG

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Twin Screw Solutions for TSG

16 mm

24 mm

EuroLab Pharma 16 TSG

Pharma 24 TSG

EuroLab Pharma

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Pharma 16 Twin Screw Granulator

Pharma16 TSGTwin Screw Granulator

Gravimetric Screw Feeder

Liquid Feeding Pump

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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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Pharma 16 TSG dismantled for cleaning

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Pharma 24 Twin Screw Granulator

Pharma 24 TSGTwin Screw Granulator

Gravimetric Screw Feeder

Gravimetric Liquid Feeding Pump

Crammer Feeder

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Pharma 24 TSG with feeder platforms

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Pharma 24 TSG showing barrel clamps

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Pharma 16 and 24 Feeder Platforms

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Customized Solutions

Examples of

Customized Solutions

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EuroLab in Isolator

EuroLab extruder and spheronizer in Isolator (Glove-Box)

Motor EuroLab and Feeder outside

Touchscreen outside

Electronics integrated in isolator-base

Modified extruder base, splash-proof

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Customized Pharma 24 mm Chill Roll

Collection bins

Discharge valve

Clear protection cover

Modified belt take-off

Electronic modification to allow control via 3rd party extruder control

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Special Sheet Layering Application

Twin bore ram feeder to feed sticky or pasty materials

Sheet layering with release tape