TUFTAD_Seyfang_DPI_filling_20150305_draft1.pdf

© 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 Days
February 23-24, 2015

2
Selection of
Dosing System
Dosed Mass
Verification
Introduction
Dosing
Technology
Machine
Integration
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
Stability
Industrialisation
Validation
Assembly
Technology

3
Selection of
Dosing System
Dosed Mass
Verification
Introduction
Dosing
Technology
Machine
Integration
DPI Formulations: Powder to be Handled
„Ordered mixtures“ with
coarse carrier particles,
e.g. lactose monohydrate
Example: 4% Beclomethasone-
proprionate / Lactose Monohydrate
Spray-dried products Hollow spheres „Nanocluster“

4
Selection of
Dosing System
Dosed Mass
Verification
Introduction
Dosing
Technology
Machine
Integration
Dosing Real Powders for Inhalation
► Most powders for inhalation are poor flowing and
tend to agglomerate when being agitated.
► Gravitational forces are not sufficient to achieve
uniform filling of dosing chambers
► All current volumetric powder dosing systems therefore
apply 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)

5
Selection of
Dosing System
Dosed Mass
Verification
Introduction
Dosing
Technology
Machine
Integration
DPI: Filling Technology at a Glance
Filling
Technology
Dosator Vacuum Drum Membrane Screw Auger PiD Filler
Dry
Powder
Inhaler
classification
Capsule Capsule
Cartridge
/ Disk
Cartridge /
Disk
Disk
Blister Blister
Reservoir Reservoir

6
Selection of
Dosing System
Dosed Mass
Verification
Introduction
Dosing
Technology
Machine
Integration
Standard powder dosing system: Dosator

7
Selection of
Dosing System
Dosed Mass
Verification
Introduction
Dosing
Technology
Machine
Integration
 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 plate
of powder bowl.
 Lowering of dosator pin to
slightly compact powder plug
inside dosator tube for transfer
Rotating
powder bowl

8
Selection of
Dosing System
Dosed Mass
Verification
Introduction
Dosing
Technology
Machine
Integration
 Horizontal movement of
dosator tube to shear off
confined dose from
powder reservoir.
 Transfer of powder plug
inside dosator tube to
target receptacle.
Ejection of powder plug.

9
Selection of
Dosing System
Dosed Mass
Verification
Introduction
Dosing
Technology
Machine
Integration
Special dosator with small ID can improve dosing accuracy
1 mm Ø

10
Selection of
Dosing System
Dosed Mass
Verification
Introduction
Dosing
Technology
Machine
Integration
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)

11
Selection of
Dosing System
Dosed Mass
Verification
Introduction
Dosing
Technology
Machine
Integration
Special dosator unit to fill injection-moulded disks:
20-up dosing head to dose approx. 5mg powder for inhalation
Powder dosing system: Dosator

12
Selection of
Dosing System
Dosed Mass
Verification
Introduction
Dosing
Technology
Machine
Integration
Powder dosing system: Dosator
20- up
Dosing head
Rotating
Powder bowl
Rotary
Disk support
Filling of
injection-moulded disks
with 5mg powder
for inhalation

13
Selection of
Dosing System
Dosed Mass
Verification
Introduction
Dosing
Technology
Machine
Integration
Common problems: Sticking, clogging, limited dosing accuracy, …

14
Selection of
Dosing System
Dosed Mass
Verification
Introduction
Dosing
Technology
Machine
Integration
Powder Microdosing System: Vacuum Drum
Filling powder into dosing bore by assistance of vacuum;
confinement of the dose by a scraper blade

15
Selection of
Dosing System
Dosed Mass
Verification
Introduction
Dosing
Technology
Machine
Integration

16
Selection of
Dosing System
Dosed Mass
Verification
Introduction
Dosing
Technology
Machine
Integration
Powder hopper
Scraper blade fixture
Cleaning nozzles
Stirrer
12 dosing
cavities

17
Selection of
Dosing System
Dosed Mass
Verification
Introduction
Dosing
Technology
Machine
Integration

18
Selection of
Dosing System
Dosed Mass
Verification
Introduction
Dosing
Technology
Machine
Integration
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)

19
Selection of
Dosing System
Dosed Mass
Verification
Introduction
Dosing
Technology
Machine
Integration
Powder Microdosing System: Membrane Filler
 The Accuhaler / Diskus device contains a blister strip
with multiple cavities.
 During manufacturing the powder is filled into
the 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:

20
Selection of
Dosing System
Dosed Mass
Verification
Introduction
Dosing
Technology
Machine
Integration
1 powder reservoir 2 powder feeder
3 vacuum chamber 4 gasket
5 membrane 6 filled blister cavity
Membrane filling technology

21
Selection of
Dosing System
Dosed Mass
Verification
Introduction
Dosing
Technology
Machine
Integration

22
Selection of
Dosing System
Dosed Mass
Verification
Introduction
Dosing
Technology
Machine
Integration
Membrane filling technology

23
Selection of
Dosing System
Dosed Mass
Verification
Introduction
Dosing
Technology
Machine
Integration
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)

24
Selection of
Dosing System
Dosed Mass
Verification
Introduction
Dosing
Technology
Machine
Integration
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

25
Selection of
Dosing System
Dosed Mass
Verification
Introduction
Dosing
Technology
Machine
Integration
Dosing System Integration / Scale up
Omnidose TT
300 C / h
Omnidose
3500 C / h
ModuC LS
25.000 C / h
ModuC MS
100.000 C / h
From developmental work to
high speed production:
- Upscalable
- Flexible
- Modular

26
Selection of
Dosing System
Dosed Mass
Verification
Introduction
Dosing
Technology
Machine
Integration
 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 / Vacuum
Connectors
3 Dosing head
4 Filling position

27
Selection of
Dosing System
Dosed Mass
Verification
Introduction
Dosing
Technology
Machine
Integration

28
Selection of
Dosing System
Dosed Mass
Verification
Introduction
Dosing
Technology
Machine
Integration
Production machine SSP2
with membrane filler
Harro Höfliger

29
Selection of
Dosing System
Dosed Mass
Verification
Introduction
Dosing
Technology
Machine
Integration
Production machine MSP
with vacuum drum filler
Harro Höfliger

30
Selection of
Dosing System
Dosed Mass
Verification
Introduction
Dosing
Technology
Machine
Integration
Regarding the critical powder properties a 100% verification
of the dosed mass is a highly desirable feature !
Verification of dosed mass: Statistical IPC ?

31
Selection of
Dosing System
Dosed Mass
Verification
Introduction
Dosing
Technology
Machine
Integration
Verification of dosed mass: 100% in-line
Reasons for integration of 100% in-line verification
of dosed mass
► Process safety
► Avoidance of DPI units not corresponding to
pharmacopoeial requirements
► Better control during start / end of filling process
(no steady state) , improved yield
► Avoidance of OOS-events due to erratic powder flow
in feeding / conveying systems (bridging, sticking)
► increased data volume available
► accelerates formulation development

32
Selection of
Dosing System
Dosed Mass
Verification
Introduction
Dosing
Technology
Machine
Integration
Bridging of powder could lead to stochastic underfilling of units,
which are not detected by statistical IPC.

33
Selection of
Dosing System
Dosed Mass
Verification
Introduction
Dosing
Technology
Machine
Integration
When the dosed mass is very low, the variance of the empty
capsule shell will be in the same range !
Therefore we need tare– / gross - weighing !
5,5 mg fill

34
Selection of
Dosing System
Dosed Mass
Verification
Introduction
Dosing
Technology
Machine
Integration
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 !

35
Selection of
Dosing System
Dosed Mass
Verification
Introduction
Dosing
Technology
Machine
Integration
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.

36
Selection of
Dosing System
Dosed Mass
Verification
Introduction
Dosing
Technology
Machine
Integration
Verification of dosed mass: VisioAMV Sensor
Functional principle: Capacitive sensor in high frequency mode
with high data acquisition rate

37
Selection of
Dosing System
Dosed Mass
Verification
Introduction
Dosing
Technology
Machine
Integration
Calculation of
dosed mass
PLC
13.456 mg
Powder
dose
Change of capacitance
over time
Signal x mass factor
= recorded mass
Send mass
data to PLC
Process
control
VisioAMV-Sensor

38
Selection of
Dosing System
Dosed Mass
Verification
Introduction
Dosing
Technology
Machine
Integration
Powder container
Drum dosing system
VisioAMV sensor plate
Capsule bushings

39
Selection of
Dosing System
Dosed Mass
Verification
Introduction
Dosing
Technology
Machine
Integration
6-up Vacuum drum system, 14 lanes, integrated into blister line

40
Selection of
Dosing System
Dosed Mass
Verification
Introduction
Dosing
Technology
Machine
Integration
Determination of accuracy and linearity of VisioAMV – sensor
using a triple-row drum
(additional weight variation by change of vacuum setting)
Sensor vs. Load Cell Deviation of Sensor [%]

41
Selection of
Dosing System
Dosed Mass
Verification
Introduction
Dosing
Technology
Machine
Integration
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)

42
Selection of
Dosing System
Dosed Mass
Verification
Introduction
Dosing
Technology
Machine
Integration
Dry Powder Inhaler: Selection of Filling Method
Dynamic characterisation methods
Measure response of powder to various simulated process conditions
Measure directly response to aeration, consolidation, moisture, flow rate
Measure bulk properties of density, compressibility and permeability

43
Selection of
Dosing System
Dosed Mass
Verification
Introduction
Dosing
Technology
Machine
Integration
DPI Formulations: Comparison of dosing methods
Lactose monohydrate powder blends used in the dosing study

44
Selection of
Dosing System
Dosed Mass
Verification
Introduction
Dosing
Technology
Machine
Integration
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
FT4
Powder
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 study
Seyfang 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

45
Selection of
Dosing System
Dosed Mass
Verification
Introduction
Dosing
Technology
Machine
Integration
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
Dosator
Powder 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 ---
Standard
procedure
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 ---
Dosator
Powder 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 ---
Standard
procedure
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 Blister
with Powder for Inhalation:

TUFTAD_Seyfang_DPI_filling_20150305_draft1.pdf

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