Filling of Capsules and Blister with Powder for …tuftad.org.tr/folders/TUFTAD_Seyfang_DPI_filling...2015/03/05 · Filling of Capsules and Blister with Powder for Inhalation: Dosing

© 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

2

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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Introduction

Dosing Technology

MachineIntegration


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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Introduction

Dosing Technology

MachineIntegration


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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Introduction

Dosing Technology

MachineIntegration


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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Introduction

Dosing Technology

MachineIntegration


Standard powder dosing system: Dosator

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Introduction

Dosing Technology

MachineIntegration



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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Introduction

Dosing Technology

MachineIntegration



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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Introduction

Dosing Technology

MachineIntegration



Special dosator with small ID can improve dosing accuracy

1 mm Ø

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Introduction

Dosing Technology

MachineIntegration



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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Introduction

Dosing Technology

MachineIntegration


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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Introduction

Dosing Technology

MachineIntegration


Powder dosing system: Dosator

20- upDosing head

RotatingPowder bowl

RotaryDisk support

Filling ofinjection-moulded disks

with 5mg powderfor inhalation

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Introduction

Dosing Technology

MachineIntegration



Common problems: Sticking, clogging, limited dosing accuracy, …

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Introduction

Dosing Technology

MachineIntegration


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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Introduction

Dosing Technology

MachineIntegration



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Introduction

Dosing Technology

MachineIntegration


Powder hopper

Scraper blade fixture

Cleaning nozzles

Stirrer

12 dosingcavities


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Introduction

Dosing Technology

MachineIntegration



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Introduction

Dosing Technology

MachineIntegration


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)


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Introduction

Dosing Technology

MachineIntegration


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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Introduction

Dosing Technology

MachineIntegration



1 powder reservoir 2 powder feeder3 vacuum chamber 4 gasket5 membrane 6 filled blister cavity

Membrane filling technology

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Introduction

Dosing Technology

MachineIntegration



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Introduction

Dosing Technology

MachineIntegration



Membrane filling technology

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Introduction

Dosing Technology

MachineIntegration



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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Introduction

Dosing Technology

MachineIntegration


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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Introduction

Dosing Technology

MachineIntegration


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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Introduction

Dosing Technology

MachineIntegration



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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Introduction

Dosing Technology

MachineIntegration



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Introduction

Dosing Technology

MachineIntegration



Production machine SSP2 with membrane filler

Harro Höfliger

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Introduction

Dosing Technology

MachineIntegration



Production machine MSP with vacuum drum filler

Harro Höfliger

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Introduction

Dosing Technology

MachineIntegration


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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Introduction

Dosing Technology

MachineIntegration


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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Introduction

Dosing Technology

MachineIntegration



Bridging of powder could lead to stochastic underfilling of units, which are not detected by statistical IPC.

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Introduction

Dosing Technology

MachineIntegration



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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Introduction

Dosing Technology

MachineIntegration



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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Introduction

Dosing Technology

MachineIntegration



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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Introduction

Dosing Technology

MachineIntegration


Verification of dosed mass: VisioAMV Sensor

Functional principle: Capacitive sensor in high frequency mode with high data acquisition rate

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Introduction

Dosing Technology

MachineIntegration


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


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Introduction

Dosing Technology

MachineIntegration



Powder container

Drum dosing system

VisioAMV sensor plate

Capsule bushings

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Introduction

Dosing Technology

MachineIntegration



6-up Vacuum drum system, 14 lanes, integrated into blister line

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Introduction

Dosing Technology

MachineIntegration



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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Introduction

Dosing Technology

MachineIntegration


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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Introduction

Dosing Technology

MachineIntegration


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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Introduction

Dosing Technology

MachineIntegration


DPI Formulations: Comparison of dosing methods

Lactose monohydrate powder blends used in the dosing study

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Introduction

Dosing Technology

MachineIntegration



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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Introduction

Dosing Technology

MachineIntegration



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:

Documents

Filling of Capsules and Blister with Powder for …tuftad.org.tr/folders/TUFTAD_Seyfang_DPI_filling...2015/03/05 · Filling of Capsules and Blister with Powder for Inhalation: Dosing