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Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)
Craig Davies-Cutting, Ph.D.Catalent Pharma Solutions
Management Forum – Dry Powder InhalersLondon30 June – 1 July 2010
© 2010 Catalent Pharma Solutions. All rights reserved
Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)Management Forum, London, July 1 2010
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Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)
Considerations for Filling DPIs• Quality by Design (QbD) Considerations
— Development Philosophy— Impact of Device — Impact of Powder
• Mechanisms for Dosing Inhalation PowdersApproaches for Filling DPIs• Compare and Contrast Data
— Auger Filling— Dosator Filling— Drum Filling
Concluding remarks
2
Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)Management Forum, London, July 1 2010
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Quality by Design (QbD)
QbD
Product Profile
Control Strategy
Life Cycle Management, Continuous
Improvement
Critical Quality
Attributes (CQAs)
KeyParametersAssociated with CQAsand Risk
AssessmentDesign Space
Control Strategy
Life Cycle Management, Continuous Improvement
ICH Q8(R2) Pharmaceutical Development; ICH Q9 Quality Risk Management
Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)Management Forum, London, July 1 2010
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Product Development & DPI FillingProject Scope
Pre-IND/IMPD
PhIIb PhIII/NDA/MAA
CommercialManufacture
PhI to IIaClinical Product
Commercial Product
•Manual/Semi-auto
•100 – 5,000 doses
•Low/moderate throughput
•Semi-auto/automated
•5,000 – 100,000 doses
•Moderate throughput
•Fully automated
•100,000+ doses
•High throughput
•In-line process verification
3
Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)Management Forum, London, July 1 2010
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Product Development & DPI FillingProject Scope
Pre-IND/IMPD
PhIIb PhIII/NDA/MAA
CommercialManufacture
PhI to IIaClinical Product
Commercial Product
•Manual/Semi-auto
•100 – 5,000 doses
•Low/moderate throughput
•Semi-auto/automated
•5,000 – 100,000 doses
•Moderate throughput
•Fully automated
•100,000+ doses
•High throughput
•In-line process verification
Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)Management Forum, London, July 1 2010
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Define the GoalsProduct Profile
Product profile
Performance•Delivered dose uniformity
•Aerodyn particle size distribution
Fit for pupose•Clinical
•Commercial
Therapeutic target•Local vs systemic
Target patient population, region, etc.
Input Materials, eg. API, Carrier Lactose
Formulation/Process
Powder Filling/Device Assembling
Device Selection/ PackageFormulation/Device Interaction
StabilityStorage vs. in Use
MethodologyQC Release vs. Real Patient Use
Process Analytical Technology (PAT)
Understand the CQAs; Associate attributes/parameters to CQAs and assess the risk; Develop design space; Implement control and Manage the product lifecycle
4
Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)Management Forum, London, July 1 2010
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Product Profile, Critical Quality Attributes (CQAs) and Design Space
DDU and APSD
Dry Powder Inhaler Specifications: Delivered dose uniformity (DDU) and Aerodynamic Particle Size Distribution (APSD) Appearance, Identification, Microbial Limits, Water/Moisture content, Net Content, Drug Content, Impurities and Degradation Products, Microscopic Evaluation
FormulationFlowability
Formulation
FormulationContent
Uniformity
FormulationPhysical/Chemical Stability
Device Metering/
Dispersion Mechanism
Formulation Aerosolization
Properties
Process- Mixing
Process- Device
Filling
Input Materials-
API/Carrier Lactose
Device / Package
Key Product Attributes
CQAs
Design Space
Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)Management Forum, London, July 1 2010
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QbD and DPIs
Dry Powder Formulation
Inhaler Device
Active and passive devices
Factory metered and device metered device
Quantos™
Xcelodose®
Omnidose ™
Other
Size reduced API (< 5µm)
Pure API size reduced by micronization, spray dry or other technology
Loose agglomerates of pure API/API diluent
API/Carrier (Lactose monohydrate) blend
Blending/blender
Low shear- Turbula® shake mixer, Pharmatech® blender
“High shear” (high impact)Pharmx®, KG5,Glatt®, Hosakawa® GEA NiroPharma (PMA), DIOSNA
Quantos is a trademark of Mettler-Toledo AG Corp., Turbula is a registered trademark of Willy A. Bachofen AG Corp. ,Pharmx is a registered trademark of Spraying Systems Co. ,Glatt is a registered trademark of Glatt GmbH. , Hosokowa is a registered trademark of Hosokawa Micron Corp., Xcelodose is a registered trademark of Capsugel Belgium BVBA Corp, Omnidose is a trademark of Harro Hoefliger
Dry Powder
Formulation
Inhaler Device
Powder Filling and
Packing
Dry Powder Inhaler
Product Process
QbD and DPIs
•Delivery of dry powder aerosol to the lungs for local or systemic treatment•Dry Powder Inhaler = Dry powder formulation + Inhaler device
5
Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)Management Forum, London, July 1 2010
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Introduction to Dry Powder Inhalers (DPIs)Devices
Pre-Metered
Multi Unit Dose
Reservoir
Dry Powder Inhalers
Active
Unit Dose Multi-Unit Dose
Passive
Unit Dose Multi-Unit Dose
Compressed air
Vibration (piezo-electric)
Capsule Foil blister
Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)Management Forum, London, July 1 2010
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Introduction to Dry Powder Inhalers (DPIs)Devices
Pre-Metered
Multi Unit Dose
Reservoir
Dry Powder Inhalers
Active
Unit Dose Multi-Unit Dose
Passive
Unit Dose Multi-Unit Dose
Compressed air
Vibration (piezo-electric)
Capsule Foil blister
6
Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)Management Forum, London, July 1 2010
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Micro-dosing Inhalation Powders
What do we mean by micro-dosing?• Pre-metered powder aliquots• Fill weight in the range < 1 – 50 mg
Inhalation powder formulations• Highly potent drugs
— low drug concentration• Formulations
— Pure API without any further excipients— Spherical aggregates— Spray-dried or micronized actives— Ordered mixtures
• API/carrier• API/excipient/carrier blends
— Lyophilized, • proteins/peptides
Ordered mixtures, eg. API/carrier
particles
Low density, porous particles
Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)Management Forum, London, July 1 2010
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Micro-dosing Inhalation PowdersPowder Characteristics – Design Space
Ideal World
Low cohesive forces
• Formulation
• Packaging
Low tendency to agglomerate
No compaction
Uniform powders
Excellent flow
Real WorldParticle size/shapeSurface textureDensity/porosityHygroscopicityOxygen/light sensitivityElectrostaticPowder packing/compactionAge/historyPoor flow properties
Powder segregation (blends)
Particle-particle interactions dominateAPI processing & product performance
7
Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)Management Forum, London, July 1 2010
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Micro-dosing Inhalation PowdersControl Strategies
Develop “Fit for purpose” products & processes• Clinical product – limit number of input lots (Control)• Commercial product – full chemical & physical
characterization across many lots (Understand)
Device Filling• Develop scaleable filling processes
— Where possible, same filling mechanism from development through to commercial process
Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)Management Forum, London, July 1 2010
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Dosing Pharmaceutical Powders
Inhalation Capable
Micro-dosingVibratory
Micro-dosing
Large powder vols
Bottle/sachet
Reservoir DPI
Micro-dosing
Oral capsules
Tablets
Micro-dosing
Large powder vols
Bottle/sachet
Reservoir DPI
Micro-dosing
Typical Applications
Drum
DosatorFixed Powder Volume
Dosing Disk/Tamping
Dosing Disk/Dr Blade
Electrostatic deposition
Flowing Powder Volume (novel)
Auger ScrewFlowing Powder Volume
Mechanism of Dosing
Dosing Principle
8
Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)Management Forum, London, July 1 2010
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Early/Clinical Development
Pre-IND/IMPD PhI to IIaClinical Product
•Manual/Semi-automatic
•100 – 5,000 doses
•Low/moderate throughput
Micro-dosing Equipment Fills Niche in R&D, Clinical Trial Materials
Tablets & Capsules March 2009
Powdernium™
Symyx Technologies
Quantos ™Mettler-Toledo
Xcelodose®Capsugel
Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)Management Forum, London, July 1 2010
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Quantos – “Perfect Dosing”
Case StudyMicro-dosing system eases clinical manufacturing at Catalent
– a solution for inhalation drug delivery
Catalent Pharma Solutions, Somerset, NJ, operates a facility in Research TrianglePark, NC, that offers expertise and a full range of services for pulmonary and nasal drug delivery.
In 2008, the company was conducting development work on behalf of a client who sought help with a new chemical entity to be delivered via a dry powder inhaler (DPI). Part of development included characterizing the aerosols and the performance of the DPI. "We were working on inhalation drug delivery, and one issue with dry powder inhalers is filling the powder into the dose unit assembly," said Lei Mao, the senior scientist at Catalent who led the formulation development team working on the project……….
New inhalation drug development
Weighing micronized API
Traceable data management
9
Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)Management Forum, London, July 1 2010
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Product Registration & Commercialisation
Pre-IND/IMPD
PhIIb PhIII/NDA/MAA
CommercialManufacture
PhI to IIaClinical Product
Commercial Product
•Manual/Semi-auto
•100 – 5,000 doses
•Low/moderate throughput
•Semi-auto/automated
•5,000 – 100,000 doses
•Moderate throughput
•Fully automated
•100,000+ doses
•High throughput
•In-line process verification
Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)Management Forum, London, July 1 2010
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Bridging Process ScaleOne Approach
Pre-IND/IMPD PhI to IIaClinical Product
Commercial Product
10
Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)Management Forum, London, July 1 2010
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Scaleable Dosing for Inhalation Powders
Inhalation Capable
Micro-dosingVibratory
Micro-dosing
Large powder vols
Bottle/sachet
Reservoir DPI
Micro-dosing
Oral capsules
Tablets
Micro-dosing
Large powder vols
Bottle/sachet
Reservoir DPI
Micro-dosing
Typical Applications
?
(Reservoir?)
Scaleable
Drum
DosatorFixed Powder Volume
Dosing Disk/Tamping
Dosing Disk/Dr Blade
Electrostatic deposition
Flowing Powder Volume (novel)
Auger ScrewFlowing Powder Volume
Mechanism of Dosing
Dosing Principle
Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)Management Forum, London, July 1 2010
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Bridging Filling Process ScalePreferred Approach
Pre-IND/IMPD PhI to IIaClinical Product
Repeatable unit processes (scaleable)
Integrated modules/unit functions
• Form, fill, seal, cut, assemble
Moderate to high throughput
In-process verification
Robustness
11
Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)Management Forum, London, July 1 2010
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Integrated Scale up Path
Pre-IND/IMPD
PhIIb PhIII/NDA/MAA
CommercialManufacture
PhI to IIaClinical Product
Commercial Product
•Manual/Semi-auto
•100 – 5,000 doses
•Low/moderate throughput
•Semi-auto/automated
•5,000 – 100,000 doses
•Moderate throughput
•Customized line
•High throughput
•In-line blister form/fill/seal/cut
•In-line fill/fill weight verification
Omnidose ™ TT
•Manual/Semi-auto
Omnidose™
• Semi-auto/auto
Omnidose ™ Integtrated Line
•Fully auto
Images reproduced courtesy of Harro Höfliger AG
Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)Management Forum, London, July 1 2010
22
Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)
Considerations for Filling DPIs• Quality by Design (QbD) Considerations
— Development Philosophy— Impact of Device — Impact of Powder
• Mechanisms for Dosing Inhalation PowdersApproaches for Filling DPIs• Compare and Contrast Data
— Auger Filling— Dosator Filling— Drum Filling
Concluding remarks
12
Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)Management Forum, London, July 1 2010
23
Auger Filling MechanismsReservoir Device
Chiesi NEXT™ DPIFixed dose combination formulation• Mic BDP 100 μg/FF 6 μg• Lactose Monohydrate/Ternary agent
(European Patent EP1274406).Fully automated Auger filling system• M.A.R. s.r.l., Milan, Italy
Key findings• Powder flowability was critical• Auger Speed, # of revolutions & hopper
loading frequency were all significant wrtfill weight
• Auger Speed, # of revolutions & hopper loading frequency had no impact on DDU & FPM— Auger filling was “gentle” on powders
Auger Filling Optimization of a Multidose DPI Using Quality by Design (QbD)Cantarelli et al, RDD 2010, Vol 2, pp 503-508
Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)Management Forum, London, July 1 2010
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Auger Filling MechanismsMicro-dosing: Quantos MicroDosing System ™
Quantos MicroDosing System ™• Flexibility for use in both R&D laboratory
and small scale GMP manufacturing allows direct process transfer
• 100% fill weight verification ensures traceability in the GMP manufacturing
• Up to 12,000 capsules were manufactured with minimal rejects
• Significant manual interventionProduct Profile• 25 mg capsule fill weight• API/lactose blend• Delivered Dose (mean = 85-115 % and
individual = 75-125% of target dose) • Fine Particle Fraction (<5µm, >25%)
and Fine Particle Dose corresponds to > 25% of Delivered Dose
13
Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)Management Forum, London, July 1 2010
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Quantos MicroDosing System ™Fill Weight Accuracy & Precision
0.30.3-RSD
25.03525.04825Mean
0.50.5-RSD
10.02010.04010Mean
0.830.9-RSD
4.7934.9795Mean
1.92.0-RSD
2.4362.4292.5Mean
2.82.4-RSD
1.0040.9811Mean
ConfirmatoryActual Fill Weight (mg)
QuantosActual Fill Weight (mg)
Target Fill Weight (mg)
Low dose dry powder filling with excellent accuracy & precision demonstrated using the Quantos MicroDosing System
Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)Management Forum, London, July 1 2010
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Quantos MicroDosing System ™No Segregation
Excellent correlation between fill weight and assay by HPLC demonstrated no powder segregation occurs during filling
0.0
100.0
200.0
300.0
400.0
500.0
600.0
700.0
800.0
0.0 5.0 10.0 15.0 20.0 25.0
Weight measured by Quantos (mg)
Cap
sule
ass
ay v
alue
s (u
g)
14
Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)Management Forum, London, July 1 2010
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Quantos MicroDosing System ™No Compaction
Cumula tive APSD
0 .0
10 .0
2 0 .0
3 0 .0
4 0 .0
50 .0
6 0 .0
70 .0
8 0 .0
9 0 .0
10 0 .0
0 .0 5.0
C ut o f f d iamet er (µ m)
R &D B at ch (n=3 )
C linical B at ch (n=3 )
Delivered Dose (µg)
0
100
200
300
400
500
600
700
800
0 R&D Batch Clinical Batch
Fine Particle Dose, Aerodynamic Particle Size Distribution, Delivered Dose Comparison for R&D confirmation and cGMP clinical batches
NGI Deposition Pattern
0.0
50.0
100.0
150.0
200.0
250.0
300.0
350.0
400.0
R&D Confirmation Batch (n=3)Clinical Batch (n=3)
>50% FPD
Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)Management Forum, London, July 1 2010
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Dosator Filling Mechanisms
Image reproduced courtesy of Harro Höfliger AG
Dosator with compactionFor processing compactable powders with reproducible fill volume• Dosing range 10 - 600 mg• Fill volume given by plunger height• For powders with a Carr‘s index
between 15 and 25 %• Particle size ideally in the range of
50 to 150 μm• Residual powder volume approx.
200 mlHigh speed filling• Capsule• Disk
15
Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)Management Forum, London, July 1 2010
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MG PlanetaCapsule Filling
25 mg fill weight3 inhalation grade lactoses (DMV Fonterra)• Respitose® ML001
— Milled, broad particle size distribution— ‘Mid’ particle size— %<45μm 40 – 60, %<100μm 75 – 100,
%< 150μm 90 – 100, %<315μm 99.5 – 100
• Respitose® ML002— Milled, broad particle size distribution— ‘Finer’ particle size— %<45μm 65-85, %<100μm >96,
%<250μm 100
• Respitose® SV005 — Sieved, broad particle size distribution— ‘Coarse’ particle size— %<63μm 0 – 20, %<100μm 30 – 60,
%<150μm 75 – 90, %<250μm 99 – 100, %<315μm 100
Fill weight monitored with time
Excellent fill weight accuracy and precision
Filling Accuracy
22.00
23.00
24.00
25.00
26.00
27.00
28.00
0 10 20 30 40 50 60 70
Filling Time, Minutes
Fill
Wei
ght,
mg
Respitose SV005Respitose ML001Respitose ML002
Filling Precision
0.00
1.00
2.00
3.00
4.00
5.00
0 10 20 30 40 50 60 70
Filling Time, Minutes
%R
SD
Respitose SV005Respitose ML001Respitose ML002
Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)Management Forum, London, July 1 2010
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Images reproduced courtesy of Harro Höfliger AG
Drum Filling Mechanism
Drum filler with vacuum
Suitable for powders with poor flow properties• Dosing range 1 - 50 mg• Fill quantity determined by volume
of dosing cavities in the drum
• For extremely cohesive powders
• Particle size from 1 μm upwards• Residual volume approx. 50 ml
16
Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)Management Forum, London, July 1 2010
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Drum Filling MechanismMaterial Characteristics & Fill Weight Accuracy/Precision
2.40.81960.05D10 3.7
D50 4.5
1.8Spray-dried API
2.491.26961.8
2.021.27961.4
2.90.691400.22D10 2.3
D50 2.9
1.4Spray-dried API
1.348.0960.52D10 2.3
D50 11.3
10.8Milled Lactose, fine
0.918.521120.68D10 4.0
D50 50
10.8Milled Lactose, medium
%RSDMean Fill Weight,
mg
Sample Number
Bulk Density,
gcm-3
Particle Size,
μm
Cavity Size/Vol,
mm3
Material
Data courtesy of Harro Höfliger AG
Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)Management Forum, London, July 1 2010
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Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)
Considerations for Filling DPIs• Quality by Design (QbD) Considerations
— Development Philosophy— Impact of Device — Impact of Powder
• Mechanisms for Dosing Inhalation PowdersApproaches for Filling DPIs• Compare and Contrast Data
— Auger Filling— Dosator Filling— Drum Filling
Concluding remarks
17
Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)Management Forum, London, July 1 2010
33
Concluding Remarks
Robust options are available for micro-dosing inhalation powders, however;
• Device, powder characteristics & mode of filling are critical indriving final product performance
• Adopt “fit for purpose” filling solutions aligned with the ultimate project goals
• Platform approaches can be applied to early development processes, however define potential scale-up path as early as possible in the project lifecycle
• Customised device & powder specific equipment is required for high speed commercial filling operations
© 2009 Catalent Pharma Solutions. All rights reserved