WP - Filling Cry Powder PDF

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
2 Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)

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

Product Development & DPI Filling

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

•5,000 – 100,000 doses •100,000+ doses
•Moderate throughput •High throughput
•In-line process verification

2
Product Development & DPI Filling
Project Scope
Clinical
Product
•Manual/Semi-auto
•100 – 5,000 doses
Commercial PhIIb
PhIII/ Commercial

•5,000 – 100,000 doses •100,000+ doses

Define the Goals

Product Profile
Product profile Input Materials, eg. Formulation/ Powder

API, Carrier Process Filling/Device
Performance Lactose Assembling
•Delivered dose uniformity
•Aerodyn particle size distribution
Fit for pupose

•Clinical
•Commercial
Therapeutic target Device Stability Methodology

•Local vs systemic Selection/ Storage vs. in Use QC Release vs.
Package Real Patient Use
Target patient population,
region, etc. Formulation/Device Process Analytical
Interaction Technology (PAT)
Understand the CQAs; Associate attributes/parameters to CQAs and assess

the risk; Develop design space; Implement control and Manage the product
lifecycle

3
Product Profile, Critical Quality Attributes (CQAs)
and Design Space
DDU and
Key Product Attributes
APSD
Device Formulation
Formulation Formulation
CQAs Formulation Metering/ Physical/
Content Aerosolization
Flowability Dispersion Chemical
Uniformity Properties
Mechanism Stability
Input
Process
Design Space Materials- Process Device /
Formulation - Device
API/Carrier - Mixing Package
Filling
Lactose
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

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 Process
Dry Powder Dry Inhaler Blending/blender
Size reduced API (< 5µm)
Formulation Powder Device Low shear- Turbula® shake mixer,
Pure API size reduced by micronization, Pharmatech® blender
spray dry or other technology Formulation “High shear” (high impact)
Loose agglomerates of pure API/API Pharmx®, KG5,Glatt®,
diluent Hosakawa® GEA Niro
Pharma (PMA),
API/Carrier (Lactose monohydrate) blend
Dry DIOSNA
Powder
Active and
passive devices Inhaler Powder Quantos™
Inhaler Xcelodose®
Factory metered Filling and
and device Device Omnidose ™
metered device
Packing
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

4
Introduction to Dry Powder Inhalers (DPIs)
Devices
Dry Powder Inhalers
Pre-Metered Reservoir
Active Passive
Unit Dose Multi-Unit Dose Unit Dose Multi-Unit Dose Multi Unit Dose
Vibration
(piezo-electric)
Compressed air
Capsule Foil blister

Introduction to Dry Powder Inhalers (DPIs)

Devices
Dry Powder Inhalers
Pre-Metered Reservoir
Active Passive
Unit Dose Multi-Unit Dose Unit Dose Multi-Unit Dose Multi Unit Dose
Vibration
(piezo-electric)
Compressed air
Capsule Foil blister

5
Micro-dosing Inhalation Powders
What do we mean by micro-dosing?

• Pre-metered powder aliquots Ordered mixtures,
eg. API/carrier
• Fill weight in the range < 1 – 50 mg
particles
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, Low density,
• proteins/peptides porous particles


Powder Characteristics – Design Space
Ideal World Real World

Low cohesive forces Particle size/shape
• Formulation Surface texture
• Packaging Density/porosity
Hygroscopicity
Low tendency to agglomerate
Oxygen/light sensitivity
No compaction
Electrostatic
Uniform powders
Powder packing/compaction
Excellent flow
Age/history
Poor flow properties
Powder segregation (blends)
Particle-particle interactions dominate

API processing & product performance
6
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

Dosing Pharmaceutical Powders
Dosing Mechanism of Typical Applications Inhalation

Principle Dosing Capable
Flowing Powder Auger Screw Large powder vols 9
Volume Bottle/sachet
Reservoir DPI
Micro-dosing 9
Vibratory Micro-dosing 9
Flowing Powder Electrostatic Micro-dosing 9

Volume (novel) deposition
Dosing Disk/Tamping Oral capsules 8

Dosing Disk/Dr Blade Tablets
Fixed Powder Dosator Large powder vols 9

Reservoir DPI
Micro-dosing 9
Drum Micro-dosing 9

7
Early/Clinical Development
Micro-dosing Equipment Fills Niche in R&D,

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

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 New inhalation drug development
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 Weighing micronized API
scientist at Catalent who led the formulation development team working on the
project………. Traceable data management

8
Product Registration & Commercialisation
Clinical
Product
•Manual/Semi-auto
•100 – 5,000 doses
Commercial PhIIb
PhIII/ Commercial

•5,000 – 100,000 doses •100,000+ doses

Bridging Process Scale

One Approach
Clinical
Product
Commercial
8
Product

9
Scaleable Dosing for Inhalation Powders
Dosing Mechanism of Typical Applications Inhalation Scaleable

Principle Dosing Capable
Flowing Powder Auger Screw Large powder vols 9 9
Volume Bottle/sachet (Reservoir?)
Reservoir DPI
Micro-dosing 9 8
Vibratory Micro-dosing 9 8
Flowing Powder Electrostatic Micro-dosing 9 ?

Volume (novel) deposition
Dosing Disk/Tamping Oral capsules 8 8

Dosing Disk/Dr Blade Tablets
Fixed Powder Dosator Large powder vols 9 9

Reservoir DPI
Micro-dosing 9 9
Drum Micro-dosing 9 9

Bridging Filling Process Scale

Preferred Approach
Clinical
Product
Repeatable unit processes (scaleable)

Integrated modules/unit functions
• Form, fill, seal, cut, assemble
Moderate to high throughput
In-process verification
Robustness

10
Integrated Scale up Path
Clinical
Product
•Manual/Semi-auto Omnidose ™ Integtrated Line

•100 – 5,000 doses •Fully auto
Commercial PhIIb
PhIII/ Commercial
Omnidose™ NDA/MAA Manufacture
Product
• Semi-auto/auto
•Semi-auto/automated •Customized line

•5,000 – 100,000 doses •High throughput
Omnidose ™ TT
•Moderate throughput •In-line blister form/fill/seal/cut
•Manual/Semi-auto
•In-line fill/fill weight verification
Images reproduced courtesy of Harro Höfliger AG



— Auger Filling
— Dosator Filling
— Drum Filling
Concluding remarks

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 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 wrt
fill weight
• Auger Speed, # of revolutions & hopper
loading frequency had no impact on DDU
& FPM
— 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 (<5µm, >25%)
and Fine Particle Dose corresponds to >
25% of Delivered Dose

12
Fill Weight Accuracy & Precision
Low dose dry powder filling with excellent accuracy & precision demonstrated
using the Quantos MicroDosing System
Target Fill Weight (mg) Quantos Confirmatory

Actual Fill Weight (mg) Actual Fill Weight (mg)
Mean 1 0.981 1.004

RSD - 2.4 2.8
Mean 2.5 2.429 2.436
RSD - 2.0 1.9
Mean 5 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
700.0
600.0
Capsule assay values (ug)
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)

13
No Compaction
Fine Particle Dose, Aerodynamic Particle Size Distribution, Delivered

Dose Comparison for R&D confirmation and cGMP clinical batches
NGI Deposition Pattern C u mu la tive APSD Delivered Dose (µg)

R&D Confirmation Batch (n=3) R &D B at ch ( n=3 )
Clinical Batch (n=3)
C linical B at ch ( n=3 )
400.0 10 0 .0 800
9 0 .0
350.0 700
8 0 .0
300.0 600
>50% FPD 70 .0
250.0 500
6 0 .0
200.0 50 .0 400
150.0 4 0 .0 300
3 0 .0
100.0 200
2 0 .0
50.0 100
10 .0
0.0 0
0 .0
0 R&D Bat ch Clinical B at ch
0 .0 5.0
C ut o f f d iamet er ( µ m)

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 Carr‘s index
between 15 and 25 %
• Particle size ideally in the range of
50 to 150 μm
• Residual powder volume approx.
200 ml
High speed filling
• Capsule
• Disk
Image reproduced courtesy of Harro Höfliger AG

14
MG Planeta
Capsule Filling
Filling Accuracy
25 mg fill weight
28.00
3 inhalation grade lactoses (DMV Fonterra)
27.00
• Respitose® ML001
Fill Weight, mg
26.00
— Milled, broad particle size distribution Respitose SV005
‘Mid’ particle size

25.00 Respitose ML001
—
Respitose ML002
— %<45μm 40 – 60, %<100μm 75 – 100, 24.00
%< 150μm 90 – 100, %<315μm 99.5 – 100
23.00
• Respitose® ML002 22.00
— Milled, broad particle size distribution 0 10 20 30 40 50 60 70
— ‘Finer’ particle size Filling Time, Minutes
— %<45μm 65-85, %<100μm >96,

%<250μm 100 Filling Precision
• Respitose® SV005
5.00
— Sieved, broad particle size distribution
— ‘Coarse’ particle size 4.00
— %<63μm 0 – 20, %<100μm 30 – 60,

%<150μm 75 – 90, %<250μm 99 – 100, 3.00 Respitose SV005
%RSD
%<315μm 100 Respitose ML001
2.00 Respitose ML002
Fill weight monitored with time
1.00
Excellent fill weight accuracy and precision 0.00

0 10 20 30 40 50 60 70
Filling Time, Minutes

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
Images reproduced courtesy of Harro Höfliger AG

15
Drum Filling Mechanism
Material Characteristics & Fill Weight Accuracy/Precision
Material Cavity Particle Size, Bulk Sample Mean Fill %RSD

Size/Vol, μm Density, Number Weight,
mm3 gcm-3 mg
Milled Lactose, 10.8 D10 4.0 0.68 112 8.52 0.91

medium D50 50
1.4 96 1.27 2.02
Milled Lactose, 10.8 D10 2.3 0.52 96 8.0 1.34

fine D50 11.3
1.8 96 1.26 2.49
Spray-dried 1.4 D10 2.3 0.22 140 0.69 2.9

API D50 2.9
Spray-dried 1.8 D10 3.7 0.05 96 0.81 2.4
API D50 4.5
Data courtesy of Harro Höfliger AG



— Auger Filling
— Dosator Filling
— Drum Filling
Concluding remarks

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

© 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.

Management Forum – Dry Powder Inhalers

Considerations & Approaches for Filling

Considerations for Filling DPIs

2 Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)

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

Product Development & DPI Filling

•Semi-auto/automated •Fully automated

4 Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)

•Semi-auto/automated •Fully automated

5 Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)

Define the Goals

Product profile Input Materials, eg. Formulation/ Powder

Fit for pupose

Therapeutic target Device Stability Methodology

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

6 Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)

Dry Powder Inhaler Specifications:

7 Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)

QbD and DPIs

8 Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)

Dry Powder Inhalers

9 Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)

Introduction to Dry Powder Inhalers (DPIs)

Dry Powder Inhalers

10 Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)

What do we mean by micro-dosing?

Inhalation powder formulations

11 Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)

Micro-dosing Inhalation Powders

Ideal World Real World

Particle-particle interactions dominate

Develop “Fit for purpose” products & processes

13 Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)

Dosing Pharmaceutical Powders

Dosing Mechanism of Typical Applications Inhalation

Flowing Powder Electrostatic Micro-dosing 9

Dosing Disk/Tamping Oral capsules 8

Fixed Powder Dosator Large powder vols 9

14 Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)

Micro-dosing Equipment Fills Niche in R&D,

15 Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)

Quantos – “Perfect Dosing”

16 Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)

•Semi-auto/automated •Fully automated

17 Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)

Bridging Process Scale

18 Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)

Dosing Mechanism of Typical Applications Inhalation Scaleable

Flowing Powder Electrostatic Micro-dosing 9 ?

Dosing Disk/Tamping Oral capsules 8 8

Fixed Powder Dosator Large powder vols 9 9

19 Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)

Bridging Filling Process Scale

Repeatable unit processes (scaleable)

20 Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)

•Manual/Semi-auto Omnidose ™ Integtrated Line

•Semi-auto/automated •Customized line

21 Considerations & Approaches for Filling Dry Powder Inhalers (DPIs)

Considerations & Approaches for Filling

Considerations for Filling DPIs

Flowing Powder Electrostatic Micro-dosing 9

Dosing Disk/Tamping Oral capsules 8

Fixed Powder Dosator Large powder vols 9

Flowing Powder Electrostatic Micro-dosing 9 ?

Dosing Disk/Tamping Oral capsules 8 8

Fixed Powder Dosator Large powder vols 9 9