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© 2015 Harro Höfliger / Sey 04.03.2015
Filling of Capsules and Blister with Powder for Inhalation:
Dosing systems and 100% in-line mass verification
Harro Höfliger/Capsugel Innovation DaysFebruary 23-24, 2015
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Selection ofDosing System
Dosed MassVerification
Introduction
Dosing Technology
MachineIntegration
© 2015 Harro Höfliger / Sey
Inhalation Product Development
Powder Formulation
Excipient selection
API particle size reduction and conditioning
Testing drug product performance
(PSD, ED, FPF, CU)
DPI concept
DPI Prototype Moulded Device (Pilot / Commercial)
Filling Technology /
Packaging Process
Primary Packaging
Proof of Concept
StabilityIndustrialisation
Validation
Assembly Technology
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Selection ofDosing System
Dosed MassVerification
Introduction
Dosing Technology
MachineIntegration
© 2015 Harro Höfliger / Sey
DPI Formulations: Powder to be Handled
„Ordered mixtures“ withcoarse carrier particles, e.g. lactose monohydrateExample: 4% Beclomethasone-proprionate / Lactose Monohydrate
Spray-dried products Hollow spheres „Nanocluster“
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Selection ofDosing System
Dosed MassVerification
Introduction
Dosing Technology
MachineIntegration
© 2015 Harro Höfliger / Sey
Dosing Real Powders for Inhalation
► Most powders for inhalation are poor flowing andtend to agglomerate when being agitated.
► Gravitational forces are not sufficient to achieveuniform filling of dosing chambers
► All current volumetric powder dosing systems thereforeapply additional forces during the dosing step:
► Mechanical deformation / compaction (dosator, screw auger)
► Vacuum or pressure drop (drum filler, membrane filler)
► Energy input to disperse agglomerates (e.g. ultrasonic)
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Selection ofDosing System
Dosed MassVerification
Introduction
Dosing Technology
MachineIntegration
© 2015 Harro Höfliger / Sey
DPI: Filling Technology at a Glance
Filling Technology
Dosator Vacuum Drum Membrane Screw Auger PiD Filler
Dry
Pow
der I
nhal
er c
lass
ifica
tion
Capsule Capsule
Cartridge / Disk
Cartridge / Disk Disk
Blister Blister
Reservoir Reservoir
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Selection ofDosing System
Dosed MassVerification
Introduction
Dosing Technology
MachineIntegration
© 2015 Harro Höfliger / Sey
Standard powder dosing system: Dosator
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Selection ofDosing System
Dosed MassVerification
Introduction
Dosing Technology
MachineIntegration
© 2015 Harro Höfliger / Sey
Standard powder dosing system: Dosator
Immersion of dosator tube into powder bed to confine the dose.
Starting position of dosator pin defines volume of dosing chamber.
Covering of dosator nozzle(= dosing chamber) by base plateof powder bowl.
Lowering of dosator pin toslightly compact powder pluginside dosator tube for transfer
Rotatingpowder bowl
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Selection ofDosing System
Dosed MassVerification
Introduction
Dosing Technology
MachineIntegration
© 2015 Harro Höfliger / Sey
Standard powder dosing system: Dosator
Horizontal movement of dosator tube to shear off confined dose from powder reservoir.
Transfer of powder pluginside dosator tube totarget receptacle.Ejection of powder plug.
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Selection ofDosing System
Dosed MassVerification
Introduction
Dosing Technology
MachineIntegration
© 2015 Harro Höfliger / Sey
Standard powder dosing system: Dosator
Special dosator with small ID can improve dosing accuracy
1 mm Ø
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Selection ofDosing System
Dosed MassVerification
Introduction
Dosing Technology
MachineIntegration
© 2015 Harro Höfliger / Sey
Standard powder dosing system: Dosator
Advantages of Dosator Filling
▪ Flexible and well established dosing technology
▪ Dosators can be build in different form and sizes
▪ Dosed mass can be easily adjusted
▪ Easy up-scaling from lab to large scale
▪ Transfer of process settings from lab to commercial manufacturing
▪ Short time to market due to minimal process development
▪ Available technology
▪ Filling technology is open to originator or generic business
▪ No limitations to commercial volume (niche market vs. mass market)
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Selection ofDosing System
Dosed MassVerification
Introduction
Dosing Technology
MachineIntegration
© 2015 Harro Höfliger / Sey
Special dosator unit to fill injection-moulded disks:20-up dosing head to dose approx. 5mg powder for inhalation
Powder dosing system: Dosator
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Selection ofDosing System
Dosed MassVerification
Introduction
Dosing Technology
MachineIntegration
© 2015 Harro Höfliger / Sey
Powder dosing system: Dosator
20- upDosing head
RotatingPowder bowl
RotaryDisk support
Filling ofinjection-moulded disks
with 5mg powderfor inhalation
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Selection ofDosing System
Dosed MassVerification
Introduction
Dosing Technology
MachineIntegration
© 2015 Harro Höfliger / Sey
Standard powder dosing system: Dosator
Common problems: Sticking, clogging, limited dosing accuracy, …
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Selection ofDosing System
Dosed MassVerification
Introduction
Dosing Technology
MachineIntegration
© 2015 Harro Höfliger / Sey
Powder Microdosing System: Vacuum Drum
Filling powder into dosing bore by assistance of vacuum; confinement of the dose by a scraper blade
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Selection ofDosing System
Dosed MassVerification
Introduction
Dosing Technology
MachineIntegration
© 2015 Harro Höfliger / Sey
Powder Microdosing System: Vacuum Drum
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Selection ofDosing System
Dosed MassVerification
Introduction
Dosing Technology
MachineIntegration
© 2015 Harro Höfliger / Sey
Powder hopper
Scraper blade fixture
Cleaning nozzles
Stirrer
12 dosingcavities
Powder Microdosing System: Vacuum Drum
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Selection ofDosing System
Dosed MassVerification
Introduction
Dosing Technology
MachineIntegration
© 2015 Harro Höfliger / Sey
Powder Microdosing System: Vacuum Drum
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Selection ofDosing System
Dosed MassVerification
Introduction
Dosing Technology
MachineIntegration
© 2015 Harro Höfliger / Sey
Advantages of Vacuum Drum Filling
▪ Exact dosing of very low amounts starting from 0.5 mg▪ Low impact forces leave inhalation powder properties unaffected▪ Even very cohesive powders can be dosed
▪ Easy combination with 100% mass control▪ 100% weight verification with “Advanced Mass Verification”▪ Automatic rejection of overweight or underweight capsules
▪ Easy up-scaling from lab to large scale▪ Transfer of process settings from lab to commercial manufacturing▪ Shortest time to market due to minimal process development
▪ Available technology▪ Filling technology is open to originator or generic business▪ No limitations to commercial volume (niche market vs. mass market)
Powder Microdosing System: Vacuum Drum
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Selection ofDosing System
Dosed MassVerification
Introduction
Dosing Technology
MachineIntegration
© 2015 Harro Höfliger / Sey
Powder Microdosing System: Membrane Filler
The Accuhaler / Diskus device contains a blister strip with multiple cavities.
During manufacturing the powder is filled intothe small blister pockets.
Each cavity is 100% filled up to the rim.
Filled strips are cut apart
Individual strips are coiled, placed inside Diskus / Accuhaler, followed by
Final device assembly
Proprietary filling technology for blister strip:
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Selection ofDosing System
Dosed MassVerification
Introduction
Dosing Technology
MachineIntegration
© 2015 Harro Höfliger / Sey
Powder Microdosing System: Membrane Filler
1 powder reservoir 2 powder feeder3 vacuum chamber 4 gasket5 membrane 6 filled blister cavity
Membrane filling technology
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Selection ofDosing System
Dosed MassVerification
Introduction
Dosing Technology
MachineIntegration
© 2015 Harro Höfliger / Sey
Powder Microdosing System: Membrane Filler
22
Selection ofDosing System
Dosed MassVerification
Introduction
Dosing Technology
MachineIntegration
© 2015 Harro Höfliger / Sey
Powder Microdosing System: Membrane Filler
Membrane filling technology
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Selection ofDosing System
Dosed MassVerification
Introduction
Dosing Technology
MachineIntegration
© 2015 Harro Höfliger / Sey
Powder Microdosing System: Membrane Filler
Basic features of the HH Membrane filler: Can fill cavities of any shape (round, oval, triangular,..)
with powder up to the rim
Can handle a large variety of powders(from free - flowing to cohesive)
Works well with many powders for inhalation(good to poor flow, high content of fines)
Is independent of configuration of cavities(e.g. linear, circular, others)
Easy to upscale from Lab to production
Is based on proprietary technology(M. Weigel, EP2195244 / US8371342, etc)
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Selection ofDosing System
Dosed MassVerification
Introduction
Dosing Technology
MachineIntegration
© 2015 Harro Höfliger / Sey
DPI Capsule Filler: Basic Requirements
► Handling of HPMC capsules and modified gelatin capsules
► Powder dosing range 1mg to approx. 50mg
► Minimum compaction / densification of powder
► Low residual powder volume
► No powder segregation during feeding / filling process
► Integration of 100% verification of dosed mass
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Selection ofDosing System
Dosed MassVerification
Introduction
Dosing Technology
MachineIntegration
© 2015 Harro Höfliger / Sey
Dosing System Integration / Scale up
Omnidose TT300 C / h
Omnidose3500 C / h
ModuC LS25.000 C / h
ModuC MS100.000 C / h
From developmental work tohigh speed production:
- Upscalable- Flexible- Modular
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Selection ofDosing System
Dosed MassVerification
Introduction
Dosing Technology
MachineIntegration
© 2015 Harro Höfliger / Sey
Dosing System Integration / Scale up
Tabletop Membrane filler
Manual operation
Can be run with as little as 20g powder sample
For developmental work
For comparison of different formulations
1 + 2 Pressure / VacuumConnectors
3 Dosing head4 Filling position
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Selection ofDosing System
Dosed MassVerification
Introduction
Dosing Technology
MachineIntegration
© 2015 Harro Höfliger / Sey
Dosing System Integration / Scale up
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Selection ofDosing System
Dosed MassVerification
Introduction
Dosing Technology
MachineIntegration
© 2015 Harro Höfliger / Sey
Dosing System Integration / Scale up
Production machine SSP2 with membrane filler
Harro Höfliger
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Selection ofDosing System
Dosed MassVerification
Introduction
Dosing Technology
MachineIntegration
© 2015 Harro Höfliger / Sey
Dosing System Integration / Scale up
Production machine MSP with vacuum drum filler
Harro Höfliger
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Selection ofDosing System
Dosed MassVerification
Introduction
Dosing Technology
MachineIntegration
© 2015 Harro Höfliger / Sey
Regarding the critical powder properties a 100% verificationof the dosed mass is a highly desirable feature !
Verification of dosed mass: Statistical IPC ?
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Selection ofDosing System
Dosed MassVerification
Introduction
Dosing Technology
MachineIntegration
© 2015 Harro Höfliger / Sey
Verification of dosed mass: 100% in-line
Reasons for integration of 100% in-line verificationof dosed mass
► Process safety
► Avoidance of DPI units not corresponding topharmacopoeial requirements
► Better control during start / end of filling process(no steady state) , improved yield
► Avoidance of OOS-events due to erratic powder flowin feeding / conveying systems (bridging, sticking)
► increased data volume available
► accelerates formulation development
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Selection ofDosing System
Dosed MassVerification
Introduction
Dosing Technology
MachineIntegration
© 2015 Harro Höfliger / Sey
Verification of dosed mass: 100% in-line
Bridging of powder could lead to stochastic underfilling of units, which are not detected by statistical IPC.
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Selection ofDosing System
Dosed MassVerification
Introduction
Dosing Technology
MachineIntegration
© 2015 Harro Höfliger / Sey
Verification of dosed mass: 100% in-line
When the dosed mass is very low, the variance of the emptycapsule shell will be in the same range !
Therefore we need tare– / gross - weighing !
5,5 mg fill
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Selection ofDosing System
Dosed MassVerification
Introduction
Dosing Technology
MachineIntegration
© 2015 Harro Höfliger / Sey
Verification of dosed mass: 100% in-line
Determination of empty capsule weight before filling the capsules, determination of gross weight after closure, calculation of fill weight.
Not applicable for high speed filling !
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Selection ofDosing System
Dosed MassVerification
Introduction
Dosing Technology
MachineIntegration
© 2015 Harro Höfliger / Sey
Verification of dosed mass: 100% in-line
In most volumetric dosing processes the powder dose to be delivered is prepared separately from the target receptacle.
The dose is then transferred to the target (blister pocket, hard capsule or cartridge)
The powder portion can be assessed for verification of mass during the transfer.
Interaction of mass verification system with target receptacle can be minimized.
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Selection ofDosing System
Dosed MassVerification
Introduction
Dosing Technology
MachineIntegration
© 2015 Harro Höfliger / Sey
Verification of dosed mass: VisioAMV Sensor
Functional principle: Capacitive sensor in high frequency mode with high data acquisition rate
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Selection ofDosing System
Dosed MassVerification
Introduction
Dosing Technology
MachineIntegration
© 2015 Harro Höfliger / Sey
Calculation ofdosed mass
PLC
13.456 mg
Powderdose
Change of capacitanceover time
Signal x mass factor= recorded mass
Send massdata to PLC
Processcontrol
VisioAMV-Sensor
Verification of dosed mass: VisioAMV Sensor
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Selection ofDosing System
Dosed MassVerification
Introduction
Dosing Technology
MachineIntegration
© 2015 Harro Höfliger / Sey
Verification of dosed mass: VisioAMV Sensor
Powder container
Drum dosing system
VisioAMV sensor plate
Capsule bushings
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Selection ofDosing System
Dosed MassVerification
Introduction
Dosing Technology
MachineIntegration
© 2015 Harro Höfliger / Sey
Verification of dosed mass: VisioAMV Sensor
6-up Vacuum drum system, 14 lanes, integrated into blister line
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Selection ofDosing System
Dosed MassVerification
Introduction
Dosing Technology
MachineIntegration
© 2015 Harro Höfliger / Sey
Verification of dosed mass: VisioAMV Sensor
Determination of accuracy and linearity of VisioAMV – sensorusing a triple-row drum
(additional weight variation by change of vacuum setting)
Sensor vs. Load Cell Deviation of Sensor [%]
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Selection ofDosing System
Dosed MassVerification
Introduction
Dosing Technology
MachineIntegration
© 2015 Harro Höfliger / Sey
Dry Powder Inhaler: Selection of Filling Method
Common tests to be performed on powders: Determination of corresponding volume to achieve target dose
Particle size distribution
Bulk / tapped density Hausner-Faktor Carr‘s Index Kawakita- equation
Flow properties / Flowability Angle of repose Flow through funnel
- critical orifice- flow speed
Flow factor / Shear cell Powder Rheometer
Particle shape
Cohesivity / sticking tendency
Electrostatic charge (Triboelectric charge)
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Selection ofDosing System
Dosed MassVerification
Introduction
Dosing Technology
MachineIntegration
© 2015 Harro Höfliger / Sey
Dry Powder Inhaler: Selection of Filling Method
Dynamic characterisation methodsMeasure response of powder to various simulated process conditionsMeasure directly response to aeration, consolidation, moisture, flow rateMeasure bulk properties of density, compressibility and permeability
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Selection ofDosing System
Dosed MassVerification
Introduction
Dosing Technology
MachineIntegration
© 2015 Harro Höfliger / Sey
DPI Formulations: Comparison of dosing methods
Lactose monohydrate powder blends used in the dosing study
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Selection ofDosing System
Dosed MassVerification
Introduction
Dosing Technology
MachineIntegration
© 2015 Harro Höfliger / Sey
DPI Formulations: Comparison of dosing methods
Sample (carrier type / % fines) 70/0
70/5
70/20
120/0
120/5
120/20
250/0
250/5
250/20 400
PSD
X10 139 124 5 84 17 4 13 8 4 1,4
X50 224 224 200 131 128 110 51 46 36 7,0
X90 304 318 317 174 177 177 95 89 88 24
Span [(X90-X10)/X50] 0.7 0.9 1.6 0.7 1.2 1.6 1.6 1.8 2.3 3.2
Bulk density [g/l] 630 640 650 730 720 640 590 600 540 320
Tapped density [g/l] 740 760 850 850 890 890 850 880 850 530
CI [%] 15 16 24 14 19 28 31 32 36 40
FT4Powder
Rheometer
Compressed density [mg/mm3]
673 693 762 802 820 828 817 852 832 616
Basic flowability energy [mJ/g]
54 35 24 19 16 12 11 9 7 8
Aerated energy [mJ/g] 45 28 13 9 6 2.5 1.0 1.1 1.8 5.5
Permeability [mbar] 0.2 0.3 1.3 0.6 1.1 5.8 4.0 5.3 10.5 26
Lactose monohydrate powder blends used in the dosing studySeyfang K., Littringer E.-M., Lober M., Schwarz E., Correlation between Properties of Dry Powder Inhaler Model Formulations and their Filling Performance: Comparison of Different Dosing Methods, Respiratory Drug Delivery (RDD) 2014
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Selection ofDosing System
Dosed MassVerification
Introduction
Dosing Technology
MachineIntegration
© 2015 Harro Höfliger / Sey
DPI Formulations: Comparison of dosing methods
Dosing results achieved with different dosing methods:
Dosator and Vacuum drum
Dosing Technology 70/0
70/5
70/20
120/0
120/5
120/20
250/0
250/5
250/20
400
DosatorPowder bed / dosator height
2 : 1
With pre-consolidation
Weight [mg]
--- --- 9,56 --- 11,37 12,40 10,82 10,90 10,01 ---
RSD [%] --- --- 2,11 --- 1,10 2,10 1,10 1,23 1,97 ---
Standardprocedure
Weight [mg]
10,48 11,13 11,60 13,3 13,82 15,06 13,21 13,47 10,78 ---
RSD [%] 2,83 2,38 3,96 6,81 2,45 7,41 7,55 5,02 8,78 ---
DosatorPowder bed / dosator height
3 : 1
With pre-consolidation
Weight [mg]
--- --- 9,85 --- 11,40 11,73 10,77 10,67 10,14 ---
RSD [%] --- --- 2,08 --- 2,81 2,98 1,31 1,35 2,19 ---
Standardprocedure
Weight [mg]
11,20 11,28 12,34 13,43 13,64 15,82 --- 13,75 11,84 ---
RSD [%] 6,07 3,93 3,28 4,12 2,71 4,97 --- 3,09 6,46 ---
Vacuum Drum Filler
Weight [mg] 3,33 3,42 3,83 3,88 4,02 4,12 3,79 3,80 3,76 2,7
RSD [%] 1,42 0,78 1,18 1,00 1,37 1,13 0,74 0,82 0,77 1,3
© 2015 Harro Höfliger / Sey 04.03.2015
Thank You for Your Attention
Filling of Capsules and Blisterwith Powder for Inhalation: