DPI Filling

Considerations & Approaches for
Filling Dry Powder Inhalers (DPIs)
Craig Davies-Cutting, Ph.D.

Catalent Pharma Solutions
Management Forum Dry Powder Inhalers
London
30 June 1 July 2010
2010 Catalent Pharma Solutions. All rights reserved
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 Powders

Approaches for Filling DPIs
Compare and Contrast Data
Auger Filling
Dosator Filling
Drum Filling
Concluding remarks
Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)

Management Forum, London, July 1 2010
Quality by Design (QbD)
Product
Profile
Life Cycle
LifeManagement,
Cycle
Management,
Continuous
Continuous
Improvement
Improvement
Control
Strategy
Control
Strategy
Critical
Quality
Attributes
(CQAs)
QbD
Key
Parameters
Associated
with CQAs
and Risk
Assessment
Design
Space
ICH Q8(R2) Pharmaceutical Development; ICH Q9 Quality Risk Management

3

Product Development & DPI Filling

Project Scope
Clinical
Product
Pre-IND/IMPD
PhI to IIa
Manual/Semi-auto
100 5,000 doses
Low/moderate throughput
Commercial
Product
PhIIb
PhIII/
NDA/MAA
Commercial
Manufacture
Semi-auto/automated
Fully automated
5,000 100,000 doses
100,000+ doses
Moderate throughput
High throughput
In-line process verification

Product Development & DPI Filling

Project Scope
Clinical
Product
Pre-IND/IMPD
PhI to IIa
Manual/Semi-auto
100 5,000 doses
Commercial
Product
PhIIb
PhIII/
NDA/MAA
Commercial
Manufacture
Semi-auto/automated
Fully automated
5,000 100,000 doses
100,000+ doses
Moderate throughput
High throughput

Define the Goals

Product Profile
Product profile
Performance
Input Materials, eg.

API, Carrier
Lactose
Formulation/
Process
Powder
Filling/Device
Assembling
Delivered dose uniformity

Aerodyn particle size distribution
Fit for pupose

Clinical
Commercial
Therapeutic target
Local vs systemic
Target patient population,

region, etc.
Device
Selection/
Package
Stability
Methodology
Storage vs. in Use
QC Release vs.
Real Patient Use
Formulation/Device
Interaction
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
6

Product Profile, Critical Quality Attributes (CQAs)

and Design Space
DDU and
APSD
Key Product Attributes
CQAs
Formulation
Content
Uniformity
Device
Formulation
Formulation
Metering/
Aerosolization
Flowability
Dispersion
Properties
Mechanism
Design Space
Input
MaterialsAPI/Carrier
Lactose
Formulation
Process
- Mixing
Process
- Device
Filling
Formulation
Physical/
Chemical
Stability
Device /
Package
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
7

QbD and DPIs

Delivery of dry powder aerosol to the lungs for local or systemic treatment
Dry Powder Inhaler = Dry powder formulation + Inhaler device
Product
Size reduced API (< 5m)
Process
Dry Powder
Formulation
micronization,
Pure API size reduced by

spray dry or other technology
Dry
Powder
Formulation
Inhaler Blending/blender
Device Low shear- Turbula shake mixer,
Pharmatech blender
High shear (high impact)
Pharmx, KG5,Glatt,
Hosakawa GEA Niro
Pharma (PMA),
DIOSNA
Loose agglomerates of pure API/API

diluent
API/Carrier (Lactose monohydrate) blend
Active and
passive devices
Factory metered
and device
metered device
Inhaler
Device
Dry
Powder
Inhaler
Powder
Filling and
Packing
Quantos
Xcelodose
Omnidose
Other
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

Introduction to Dry Powder Inhalers (DPIs)

Devices
Dry Powder Inhalers

Pre-Metered
Reservoir
Passive
Active
Multi-Unit Dose
Unit Dose
Multi-Unit Dose
Unit Dose
Multi Unit Dose
Vibration
(piezo-electric)
Compressed air
Capsule
9
Foil blister

Introduction to Dry Powder Inhalers (DPIs)

Devices
Dry Powder Inhalers

Pre-Metered
Reservoir
Passive
Active
Unit Dose
Multi-Unit Dose
Unit Dose
Multi-Unit Dose
Multi Unit Dose
Vibration
(piezo-electric)
Compressed air
Capsule
10
Foil blister

Micro-dosing Inhalation Powders

What do we mean by micro-dosing?
Ordered mixtures,
eg. API/carrier
particles
Pre-metered powder aliquots

Fill weight in the range < 1 50 mg
Inhalation powder formulations
Highly potent drugs
Formulations
low drug concentration

Pure API without any further excipients
Spherical aggregates
Spray-dried or micronized actives
Ordered mixtures
API/carrier
API/excipient/carrier blends
Lyophilized,
proteins/peptides
11
Low density,
porous particles

Powder Characteristics Design Space

Ideal World
Real World
Low cohesive forces
Particle size/shape
Formulation
Packaging
Low tendency to agglomerate

No compaction
Uniform powders
Excellent flow
Surface texture
Density/porosity
Hygroscopicity
Oxygen/light sensitivity
Electrostatic
Powder packing/compaction
Age/history
Poor flow properties
Powder segregation (blends)
Particle-particle interactions dominate

API processing & product performance
12


Control 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
13

Dosing Pharmaceutical Powders

Dosing
Principle
Flowing Powder
Volume
Mechanism of
Dosing
Auger Screw
Typical Applications
Large powder vols
Inhalation
Capable
9
Bottle/sachet
Reservoir DPI
Flowing Powder
Volume (novel)
Fixed Powder
Volume
Micro-dosing
Vibratory
Micro-dosing
Electrostatic
deposition
Micro-dosing
Dosing Disk/Tamping
Oral capsules
Dosing Disk/Dr Blade
Tablets
Dosator
Large powder vols
Bottle/sachet
Reservoir DPI
Drum
14
Micro-dosing
Micro-dosing

Early/Clinical Development
Clinical
Product
Pre-IND/IMPD
PhI to IIa
Micro-dosing Equipment Fills Niche in R&D,

Clinical Trial Materials
Tablets & Capsules March 2009
Manual/Semi-automatic
100 5,000 doses
Powdernium
Quantos
Mettler-Toledo
Symyx Technologies
Xcelodose
Capsugel
15

Quantos Perfect Dosing
Case Study
Micro-dosing system eases clinical manufacturing at Catalent
a solution for inhalation drug delivery
Catalent Pharma Solutions, Somerset, NJ, operates a facility in Research Triangle
Park, 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.
16
New inhalation drug development

Weighing micronized API
Traceable data management

Product Registration & Commercialisation
Clinical
Product
Pre-IND/IMPD
PhI to IIa
Manual/Semi-auto
100 5,000 doses
Commercial
Product
PhIII/
NDA/MAA
PhIIb
Commercial
Manufacture
Semi-auto/automated
Fully automated
5,000 100,000 doses
100,000+ doses
Moderate throughput
High throughput
17

Bridging Process Scale

One Approach
Clinical
Product
Pre-IND/IMPD
PhI to IIa
Commercial
Product
18

Scaleable Dosing for Inhalation Powders

Dosing
Principle
Flowing Powder
Volume
Mechanism of
Dosing
Typical Applications
Inhalation
Capable
Large powder vols
Auger Screw
Scaleable
9
(Reservoir?)
Bottle/sachet
Reservoir DPI
Flowing Powder
Volume (novel)
Fixed Powder
Volume
Micro-dosing
Vibratory
Micro-dosing
Electrostatic
deposition
Micro-dosing
Dosing Disk/Tamping
Oral capsules
Dosing Disk/Dr Blade
Tablets
Dosator
Large powder vols
Micro-dosing
Micro-dosing
Bottle/sachet
Reservoir DPI
Drum
19

Bridging Filling Process Scale

Preferred Approach
Clinical
Product
Pre-IND/IMPD
PhI to IIa
Repeatable unit processes (scaleable)

Integrated modules/unit functions
Form, fill, seal, cut, assemble
Moderate to high throughput

In-process verification
Robustness
20

10
Integrated Scale up Path
Clinical
Product
Pre-IND/IMPD
PhI to IIa
Manual/Semi-auto
Omnidose Integtrated Line
100 5,000 doses
Fully auto
Commercial
PhIIb
Omnidose
Product
PhIII/
NDA/MAA
Commercial
Manufacture
Semi-auto/auto
Omnidose TT
Manual/Semi-auto
Semi-auto/automated
Customized line
5,000 100,000 doses
High throughput
Moderate throughput
In-line blister form/fill/seal/cut

In-line fill/fill weight verification
Images reproduced courtesy of Harro Hfliger AG
21


Impact of Device
Impact of Powder

Auger Filling
Dosator Filling
Drum Filling
Concluding remarks
22

11
Auger Filling Mechanisms

Reservoir Device
Auger Filling Optimization of a Multidose DPI Using Quality by Design (QbD)

Cantarelli et al, RDD 2010, Vol 2, pp 503-508
Chiesi NEXT DPI

Fixed dose combination formulation
Mic BDP 100 g/FF 6 g
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 wrt
fill weight
Auger Speed, # of revolutions & hopper

loading frequency had no impact on DDU
& FPM
23
Auger filling was gentle on powders

Auger Filling Mechanisms
Micro-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 intervention

Product Profile
25 mg capsule fill weight
API/lactose blend
Delivered Dose (mean = 85-115 % and

individual = 75-125% of target dose)
Fine Particle Fraction (<5m, >25%)

and Fine Particle Dose corresponds to >
25% of Delivered Dose
24

12

Fill Weight Accuracy & Precision
Low dose dry powder filling with excellent accuracy & precision demonstrated
using the Quantos MicroDosing System
25
Target Fill Weight (mg)
Quantos
Actual Fill Weight (mg)
Confirmatory
Actual Fill Weight (mg)
Mean
0.981
1.004
RSD
2.4
2.8
Mean
2.5
2.429
2.436
RSD
2.0
1.9
Mean
4.979
4.793
RSD
0.9
0.83
Mean
10
10.040
10.020
RSD
0.5
0.5
Mean
25
25.048
25.035
RSD
0.3
0.3


No Segregation
Excellent correlation between fill weight and assay by HPLC demonstrated

no powder segregation occurs during filling
800.0
Capsule assay values (ug)
700.0
600.0
500.0
400.0
300.0
200.0
100.0
0.0
0.0
5.0
10.0
15.0
20.0
25.0
Weight measured by Quantos (mg)
26

13

No Compaction
Fine Particle Dose, Aerodynamic Particle Size Distribution, Delivered

Dose Comparison for R&D confirmation and cGMP clinical batches
R&D Confirmation Batch (n=3)
R &D B at ch ( n=3 )
Clinical Batch (n=3)
C linical B at ch ( n=3 )
10 0 .0
400.0
800
9 0 .0
350.0
Delivered Dose (g)
C u mu la tive APSD
NGI Deposition Pattern
700
8 0 .0
300.0
>50% FPD
250.0
600
70 .0
500
6 0 .0
200.0
50 .0
400
150.0
4 0 .0
300
100.0
3 0 .0
200
2 0 .0
50.0
100
10 .0
0.0
0 .0
0 .0
0 R&D Bat ch
5.0
Clinical B at ch
C ut o f f d iamet er ( m)
27

Dosator Filling Mechanisms

Dosator with compaction
For processing compactable
powders with reproducible fill
volume
Dosing range 10 - 600 mg

Fill volume given by plunger height
For powders with a Carrs index
between 15 and 25 %
Particle size ideally in the range of
50 to 150 m
Residual powder volume approx.
200 ml
High speed filling
Capsule
Disk
Image reproduced courtesy of Harro Hfliger AG
28

14
MG Planeta
Capsule Filling
Filling Accuracy
25 mg fill weight
3 inhalation grade lactoses (DMV Fonterra)
Respitose ML001
26.00
Respitose SV005
25.00
Respitose ML001
Respitose ML002
24.00
23.00
Respitose ML002
Milled, broad particle size distribution

Mid particle size
%<45m 40 60, %<100m 75 100,
%< 150m 90 100, %<315m 99.5 100
22.00
Milled, broad particle size distribution

Finer particle size
%<45m 65-85, %<100m >96,
%<250m 100
10
20
40
50
60
70
Filling Precision
Respitose SV005
30
Filling Time, Minutes
5.00
Sieved, broad particle size distribution

Coarse particle size
%<63m 0 20, %<100m 30 60,
%<150m 75 90, %<250m 99 100,
%<315m 100
4.00
%RSD
27.00
Fill Weight, mg
28.00
Fill weight monitored with time
3.00
Respitose SV005
Respitose ML001
2.00
Respitose ML002
1.00
Excellent fill weight accuracy and precision
0.00
0
10
20
30
40
50
60
70
Filling Time, Minutes
29

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 m upwards
Residual volume approx. 50 ml
Images reproduced courtesy of Harro Hfliger AG
30

15
Drum Filling Mechanism
Material Characteristics & Fill Weight Accuracy/Precision
Material
Cavity
Size/Vol,
Particle Size,
mm3
Milled Lactose,
medium
10.8
Bulk
Density,
Sample
Number
Mean Fill
Weight,
D10 4.0
0.68
112
8.52
0.91
96
1.27
2.02
96
8.0
1.34
96
1.26
2.49
0.22
140
0.69
2.9
0.05
96
0.81
2.4
gcm-3
mg
D50 50
1.4
Milled Lactose,
fine
%RSD
10.8
D10 2.3
0.52
D50 11.3
1.8
Spray-dried
API
1.4
Spray-dried
API
1.8
D10 2.3
D50 2.9
D10 3.7
D50 4.5
Data courtesy of Harro Hfliger AG
31


Impact of Device
Impact of Powder

Auger Filling
Dosator Filling
Drum Filling
Concluding remarks
32

16
Concluding Remarks
Robust options are available for micro-dosing inhalation
powders, however;
Device, powder characteristics & mode of filling are critical in
driving 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
33

2009 Catalent Pharma Solutions. All rights reserved
17

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Considerations & Approaches for

Filling Dry Powder Inhalers (DPIs)

Craig Davies-Cutting, Ph.D.

Considerations & Approaches for Filling

Mechanisms for Dosing Inhalation Powders

Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)

Quality by Design (QbD)

ICH Q8(R2) Pharmaceutical Development; ICH Q9 Quality Risk Management

Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)

Product Development & DPI Filling

5,000 100,000 doses

Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)

Product Development & DPI Filling

5,000 100,000 doses

Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)

Define the Goals

Input Materials, eg.

Delivered dose uniformity

Fit for pupose

Target patient population,

Storage vs. in Use

Understand the CQAs; Associate attributes/parameters to CQAs and assess

Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)

Product Profile, Critical Quality Attributes (CQAs)

Key Product Attributes

Dry Powder Inhaler Specifications:

Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)

QbD and DPIs

Pure API size reduced by

Loose agglomerates of pure API/API

Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)

Introduction to Dry Powder Inhalers (DPIs)

Dry Powder Inhalers

Multi Unit Dose

Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)

Introduction to Dry Powder Inhalers (DPIs)

Dry Powder Inhalers

Multi Unit Dose

Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)

Micro-dosing Inhalation Powders

Pre-metered powder aliquots

Inhalation powder formulations

Highly potent drugs

low drug concentration

Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)

Micro-dosing Inhalation Powders

Powder Characteristics Design Space

Low cohesive forces

Low tendency to agglomerate

Particle-particle interactions dominate

Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)

Micro-dosing Inhalation Powders

Develop Fit for purpose products & processes

Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)

Dosing Pharmaceutical Powders

Dosing Disk/Dr Blade

Large powder vols

Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)

Micro-dosing Equipment Fills Niche in R&D,

Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)

Quantos Perfect Dosing

New inhalation drug development

Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)

Product Registration & Commercialisation