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

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Considerations & Approaches for Filling Dry Powder Inhalers (DPIs) Management Forum, London, July 1 2010

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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

Considerations & Approaches for Filling Dry Powder Inhalers (DPIs) Management Forum, London, July 1 2010

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

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Considerations & Approaches for Filling Dry Powder Inhalers (DPIs) Management Forum, London, July 1 2010

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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

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Considerations & Approaches for Filling Dry Powder Inhalers (DPIs) Management Forum, London, July 1 2010

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

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

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

Considerations & Approaches for Filling Dry Powder Inhalers (DPIs) Management Forum, London, July 1 2010

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 (< 5µm)

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

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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

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

Considerations & Approaches for Filling Dry Powder Inhalers (DPIs) Management Forum, London, July 1 2010

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

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? • •

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 — — — —

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Low density, porous particles

Considerations & Approaches for Filling Dry Powder Inhalers (DPIs) Management Forum, London, July 1 2010

Micro-dosing Inhalation Powders

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

Considerations & Approaches for Filling Dry Powder Inhalers (DPIs) Management Forum, London, July 1 2010

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Micro-dosing Inhalation Powders 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

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Considerations & Approaches for Filling Dry Powder Inhalers (DPIs) Management Forum, London, July 1 2010

Dosing Pharmaceutical Powders Dosing Principle Flowing Powder Volume

Mechanism of Dosing ƒAuger Screw

Typical Applications ƒLarge powder vols

Inhalation Capable 9

ƒBottle/sachet ƒReservoir DPI

Flowing Powder Volume (novel)

Fixed Powder Volume

ƒMicro-dosing

9

ƒVibratory

ƒMicro-dosing

9

ƒElectrostatic deposition

ƒMicro-dosing

9

ƒDosing Disk/Tamping

ƒOral capsules

8

ƒDosing Disk/Dr Blade

ƒTablets

ƒDosator

ƒLarge powder vols

9

ƒBottle/sachet ƒReservoir DPI ƒDrum

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ƒMicro-dosing

9

ƒMicro-dosing

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Considerations & Approaches for Filling Dry Powder Inhalers (DPIs) Management Forum, London, July 1 2010

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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 •Low/moderate throughput

Powdernium™

Quantos ™ Mettler-Toledo

Symyx Technologies

Xcelodose® Capsugel

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Considerations & Approaches for Filling Dry Powder Inhalers (DPIs) Management Forum, London, July 1 2010

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……….

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New inhalation drug development Weighing micronized API Traceable data management

Considerations & Approaches for Filling Dry Powder Inhalers (DPIs) Management Forum, London, July 1 2010

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Product Registration & Commercialisation

Clinical Product

Pre-IND/IMPD

PhI to IIa

•Manual/Semi-auto •100 – 5,000 doses •Low/moderate throughput

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 •In-line process verification

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Considerations & Approaches for Filling Dry Powder Inhalers (DPIs) Management Forum, London, July 1 2010

Bridging Process Scale One Approach

Clinical Product

Pre-IND/IMPD

PhI to IIa

Commercial Product

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Considerations & Approaches for Filling Dry Powder Inhalers (DPIs) Management Forum, London, July 1 2010

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Scaleable Dosing for Inhalation Powders Dosing Principle Flowing Powder Volume

Mechanism of Dosing

Typical Applications

Inhalation Capable

ƒLarge powder vols

ƒAuger Screw

Scaleable

9

9 (Reservoir?)

ƒBottle/sachet ƒReservoir DPI

Flowing Powder Volume (novel)

Fixed Powder Volume

ƒMicro-dosing

9

8

ƒVibratory

ƒMicro-dosing

9

8

ƒElectrostatic deposition

ƒMicro-dosing

9

?

ƒDosing Disk/Tamping

ƒOral capsules

8

8

ƒDosing Disk/Dr Blade

ƒTablets

ƒDosator

ƒLarge powder vols

9

9

ƒMicro-dosing

9

9

ƒMicro-dosing

9

9

ƒBottle/sachet ƒReservoir DPI ƒDrum

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Considerations & Approaches for Filling Dry Powder Inhalers (DPIs) Management Forum, London, July 1 2010

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

Considerations & Approaches for Filling Dry Powder Inhalers (DPIs) Management Forum, London, July 1 2010

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Integrated Scale up Path

Clinical Product

Pre-IND/IMPD

PhI to IIa

•Manual/Semi-auto

Omnidose ™ Integtrated Line

•100 – 5,000 doses

•Fully auto

•Low/moderate throughput

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 Höfliger AG

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Considerations & Approaches for Filling Dry Powder Inhalers (DPIs) Management Forum, London, July 1 2010

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

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Considerations & Approaches for Filling Dry Powder Inhalers (DPIs) Management Forum, London, July 1 2010

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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 —

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Auger filling was “gentle” on powders

Considerations & Approaches for Filling Dry Powder Inhalers (DPIs) Management Forum, London, July 1 2010

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 (25%) and Fine Particle Dose corresponds to > 25% of Delivered Dose

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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

Low dose dry powder filling with excellent accuracy & precision demonstrated using the Quantos MicroDosing System

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Target Fill Weight (mg)

Quantos Actual Fill Weight (mg)

Confirmatory 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

Considerations & Approaches for Filling Dry Powder Inhalers (DPIs) Management Forum, London, July 1 2010

Quantos MicroDosing System ™ 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)

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Considerations & Approaches for Filling Dry Powder Inhalers (DPIs) Management Forum, London, July 1 2010

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Quantos MicroDosing System ™ 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 (µg)

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

0 R&D Bat ch

5.0

Clinical B at ch

C ut o f f d iamet er ( µ m)

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Considerations & Approaches for Filling Dry Powder Inhalers (DPIs) Management Forum, London, July 1 2010

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

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Considerations & Approaches for Filling Dry Powder Inhalers (DPIs) Management Forum, London, July 1 2010

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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 %