considerations & approaches for filling dry powder ... · pdf fileconsiderations &...

1

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

2


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


3

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


4

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


5

Product Development & DPI FillingProject Scope

Pre-IND/IMPD

PhIIb PhIII/NDA/MAA



Commercial Product

•Manual/Semi-auto

•100 – 5,000 doses



•5,000 – 100,000 doses


•Fully automated

•100,000+ doses

•High throughput



6

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


7

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


8

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


9

Introduction to Dry Powder Inhalers (DPIs)Devices

Pre-Metered

Multi Unit Dose

Reservoir

Dry Powder Inhalers

Active

Unit Dose Multi-Unit Dose

Passive


Compressed air

Vibration (piezo-electric)

Capsule Foil blister


10

Introduction to Dry Powder Inhalers (DPIs)Devices

Pre-Metered

Multi Unit Dose

Reservoir

Dry Powder Inhalers

Active


Passive


Compressed air

Vibration (piezo-electric)

Capsule Foil blister

6


11

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


12

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


13

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


14

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


15

Early/Clinical Development

Pre-IND/IMPD PhI to IIaClinical Product

•Manual/Semi-automatic

•100 – 5,000 doses


Micro-dosing Equipment Fills Niche in R&D, Clinical Trial Materials

Tablets & Capsules March 2009

Powdernium™

Symyx Technologies

Quantos ™Mettler-Toledo

Xcelodose®Capsugel


16

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


17

Product Registration & Commercialisation

Pre-IND/IMPD

PhIIb PhIII/NDA/MAA



Commercial Product

•Manual/Semi-auto

•100 – 5,000 doses



•5,000 – 100,000 doses


•Fully automated

•100,000+ doses

•High throughput



18

Bridging Process ScaleOne Approach


Commercial Product

10


19

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


20

Bridging Filling Process ScalePreferred Approach


Repeatable unit processes (scaleable)

Integrated modules/unit functions

• Form, fill, seal, cut, assemble

Moderate to high throughput

In-process verification

Robustness

11


21

Integrated Scale up Path

Pre-IND/IMPD

PhIIb PhIII/NDA/MAA



Commercial Product

•Manual/Semi-auto

•100 – 5,000 doses



•5,000 – 100,000 doses


•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


22






Concluding remarks

12


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


24

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


25

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


26

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


27

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


28

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


29

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


30

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


31

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


32






Concluding remarks

17


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

considerations & approaches for filling dry powder ... · pdf fileconsiderations &...

Documents