Fundamentals of Inhaled

Product Development

Dr Kiren Vyas
Respiratory Technical Manager
Global Manufacturing and Supply
Content

Why deliver drugs by inhalation?

Inhalers and Dry Powder Inhaler
formulations
Secondary unit operations
Drug Product Performance
Advantages of Delivering Drugs to the Lung

Large surface area for rapid

absorption (~ 100m2) – same
surface area as a tennis court
Minimal physical barrier at the
alveolar region
Absence of extremes of pH and
metabolising enzymes
No first pass liver metabolism
Rich blood supply
Applications of pulmonary delivery

Faster onset of action

Lower doses can be used ( side effects)

– e.g. Inhaled Salbutamol

Dose Onset of action
Oral tablet 4 mg 20-30min
Inhaler 0.2mg 1-2 minutes

Local or systemic action

– asthma, COPD, influenza , antibiotics, decongestants, mucolytics
– Diabetes, analgesia

Aerosols or dry powders can be delivered

 The fate of an inhaled drug molecule

10 - 35 % Metabolism or
Deposited in lung absorption
from the lung

Lungs
Mucociliary
clearance Localised action
Systemic
Mouth and pharynx Circulation

Orally bioavailable
fraction

Absorption
from gut Liver
Systemic
side effects
65 - 90 % swallowed
(reduced by spacer First-pass
or mouth rinsing) inactivation
GI tract
Major Factors Affecting Lung Deposition

Particle properties
– Diameter, Density, Shape, Charge, Solubility, Hygroscopicity.

Aerosol properties
– Concentration, particle size range, velocity of spray

Respiratory tract properties

– Geometry, Presence of disease, Humidity

Breathing pattern
– Residence time, Breathing rate, Tidal volume
 International Commission on Radiological
Protection deposition model
Effect of particle size on deposition
100
Alveolar
80 Bronchial
Extra-thoracic
60 Total
Deposition (%)

40

20

0
0.5 1 2 5 10 20
Size (m)

Particles for local delivery: ~3.5 to 6µm; for systemic delivery: <2µm
i.e. very small!!

Kobrich et. al., Inhaled Particles VII, p 15-24, Pergammon Press (1994)
DPIs and their formulation
Twentieth Century Inhalers

Mid
20081990’s MDI’s Powder
(80%)
50% 50%
(20%)

1st Generation

2nd Generation

Lung Deposition * 5-15% 10-20%

Inter/Intra Variability 60-65% 25-35%

* Borgstroem, L. et al 1998 J. Aerosol Med, 11: S59-S64

History of Dry Powder Inhalers
1948 Abbot Antibiotic preparations
1967 Fisons introduce Intal Spinhaler
1972 Glaxo Rotahaler
1978 Rotahaler mark 2
1984 Astra introduce Turbuhaler
1988 Glaxo introduce Diskhaler
1995 Glaxo introduce Accuhaler/ Diskus

Rotahaler/Rotacaps, Diskhaler/ Rotadisk, Accuhaler & Diskus are trade marks of GSK
Spinhaler is a trade mark of Fisons/RPR
Turbuhaler Turbohaler is a trade mark of AstraZeneca
Intal is a trade mark of Fisons
Dry Powder Inhalers

DPIs contain:
–Active drug - particle size range 1-5µm
–Carrier, e.g. lactose
–Other additives (excipients)
Many different designs, but two basic types
–Factory metered dose
–unit dose or multiple unit dose
(e.g. Diskhaler®, Diskus®, Spinhaler®)

–Device metered dose

–reservoir (e.g. Turbuhaler®)
 Dry Powder Inhalers

Many different designs, but two

basic types
–Factory metered dose
–unit dose or multiple unit
dose
(e.g. Diskhaler®, Diskus®,
Spinhaler®)

–Device metered dose

–reservoir (e.g. Turbuhaler®)
Particle properties critical to inhalation

Adhesion / Cohesion properties

Particle size
Surface roughness
Surface “energetics”
– Amorphous / disorder / surface energy
Electrostatic properties
Particle bridging
– As a result of changes at the surface with time.
Dispersion energy
Particle Size and Surface Area of Powders

Particle size reduction results in an increase in specific surface area of

powders
–Pharmacological Effects:
Dissolution rate
Absorption rate/Bioavailability
Stability (chemical, suspension)
Content Uniformity
Drug Targetting (e.g. respirable drugs)
–Processability:
Powder Flow
Powder Mixing
Bulk Density
Compressibility
DPIs – aerosolisation driven by patients inhalation

Inspiratory Flow & Fine Particle

Deaggregation
Force Pressure Mass

Drug

Lactose
Airflow Generated By
Patient’s Inspiratory Effort

DPI devices vary in their airflow resistance

– High airflow resistance can require significant patient effort
Particle size and agglomerate-strength regions in
which various binding mechanisms predominate

1,000
Adhesive binding;
STRENGTH (kg/cm2)

100 solid bridging

10

0.1 Van der Waals

Forces
0.01
0.1 1 10 100 1,000

PARTICLE DIAMETER (m)

Beddow,1980
Input Material Size Reduction for a Typical DPI

API Lactose
Size Reduction 5-10 times 2-4 times

Target MPS (µm) 1-2 50-100

SSA (m2g-1) 10-20 0.2-0.8

Process Micronisation Milling

Descriptive Term Typical Size Examples

Coarse (or broken) solid 5 – 100mm Coal, aggregates, etc.

Granular solid 0.3 – 5mm Granulated sugar, rice, etc

Particulate solid:
Coarse powder 100 - 300m Table salt
Fine powder 10 - 100 m Icing sugar
Super fine powder 1 - 10 m Face powder
Ultra fine powder <1 m Paint pigments
 Objective of Inhalation formulation

Agglomeration between particles sufficiently large to enable

manufacture without segregation
–DPIs: Particle transport, blending, filling
–MDIs: consistent, stable suspension
Sufficiently small to allow dispersion during inhalation
–Target fine particle mass (lung dose & distribution)
Agglomeration does not increase on storage (or forces <
dispersion energy)
–Stable fine particle mass
DPIs – drug-drug agglomerates or may use excipient
MDIs – solution/dispersion within propellant
Lactose (4-O-(ß-D-galactosido)-D-glucose)

Widely used
–Generally Regarded as Safe (GRS)
–Pleasant taste
–Relatively cheap
–Good powder flow properties
But
–Bovine origin (BSE precautions)
–Reducing sugar so potential to react with drugs containing primary
amine groups (Maillard Reaction)
–Environmental moisture adsorption can be a problem
Different crystalline forms available commercially, e.g.
–α-lactose monohydrate
–anhydrous α-lactose
–anhydrous β-lactose
–amorphous lactose
Stearates

Hydrophobic lubricants used in tabletting:

–Stearic Acid 1-4%
–Ca Stearate 0.25-2%
–Mg Stearate 0.25-2% (most widely used)
Also used as ternary excipients in DPI formulations
–Improve stability profiles
–Hydrophobic nature repels moisture from lactose particles

Mg(C18H35O2)2
Octadecanoic acid, magnesium salt
Key elements/stages of a DPI product.

Respiratory System

PSD of delivered dose

(Fine Particle Fraction)

De-agglomeration during
inhalation

Device filling & assembly

Mixing/blending process

Active Product Ingredient

Excipient/carrier
(API)
API Characterisation and
CQAs
 Drug Product CQA key:

Particle Size 1. PSD of emitted dose

Distribution 2. Emitted dose uniformity
3. Impurities Purity
Surface Area 4. Plume geometry
5. Micro quality
Particle Size
6. Moisture content Distribution
Moisture Content
7. Airflow resistance
Measured on
Raw Materials
iIncoming Impurities
Amorphous
Materiais MIcronization Content

Microbial Content Moisture

Content
Bulk Powder
Properties
Specific
Surface Area

Assembly /Pack Critical Quality

Attributes
Content
Uniformity
Particle Size
Distribution Moisture
Content
Blister Fill Weight
Standard Deviation
Microbial
Mean Strip Fill Blending Contnet
Weight

Strip Fill Weight

Filling Energy
Standard Deviation

Particle Size
Strip Seal Intgrity Distribution

Bulk Blend
Properties

Microbial Content
Lactose Characterisation
and CQAs
 Drug Product CQA key:

Particle Size 1. PSD of emitted dose

Distribution 2. Emitted dose uniformity
3. Impurities Purity
Surface Area 4. Plume geometry
5. Micro quality
Particle Size
6. Moisture content Distribution
Moisture Content
7. Airflow resistance
Measured on
Raw Materials
iIncoming Impurities
Amorphous
Materiais MIcronization Content

Microbial Content Moisture

Content
Bulk Powder
Properties
Specific
Surface Area

Assembly /Pack Critical Quality

Attributes
Content
Uniformity
Particle Size
Distribution Moisture
Content
Blister Fill Weight
Standard Deviation
Microbial
Mean Strip Fill Blending Contnet
Weight

Strip Fill Weight

Filling Energy
Standard Deviation

Particle Size
Strip Seal Intgrity Distribution

Bulk Blend
Properties

Microbial Content
Measurement of Particle size

Typically use laser diffraction

– supplemented with microscopy

Could be liquid dispersed or gas dispersed (dry powder)

– The critical part is the amount of energy imparted to disperse the
particles.
Too much energy and you loose any discrimination. Worst case you
could mill your particles.
Too little and you just measure particle clumps.

Careful particle size method development is one of the key steps in

characterising inhalable particles.
Production Unit Operations
Micronisation
 Drug Product CQA key:

Particle Size 1. PSD of emitted dose

Distribution 2. Emitted dose uniformity
3. Impurities Purity
Surface Area 4. Plume geometry
5. Micro quality
Particle Size
6. Moisture content Distribution
Moisture Content
7. Airflow resistance
Measured on
Raw Materials
iIncoming Impurities
Amorphous
Materiais MIcronization Content

Microbial Content Moisture

Content
Bulk Powder
Properties
Specific
Surface Area

Assembly /Pack Critical Quality

Attributes
Content
Uniformity
Particle Size
Distribution Moisture
Content
Blister Fill Weight
Standard Deviation
Microbial
Mean Strip Fill Blending Contnet
Weight

Strip Fill Weight

Filling Energy
Standard Deviation

Particle Size
Strip Seal Intgrity Distribution

Bulk Blend
Properties

Microbial Content
 Spiral Jet Mill - Principles of Operation

Grinding zone

Material outlet

Inter-particulate collisions cause attrition of input material

Air flow drag forces carry small particles to exit
Centrifugal forces return large particles to the grinding zone
Cyclone cone separates exhaust air/superfines from micronised drug
Optimisation of process is based on fine tuning feed rate plus feed air and grind air
pressures (residence time)
Critical Attributes for micronisation

Particle size
– Too small and the particles pass “untouched” through the mill
Powder Flow
– Needs to be even and consistent
Particle cohesion
– Sticky or electrostatic particles may block on the way in or the way
out.
Mechanical Properties
Soft particles that deform elastically or plastically may not micronise
well.
Change post micronisation

Particles can be damaged or left in a high energy state after high

energy milling,
– e.g. may be left with disordered areas at the surface.
They can change or relax over time following micronisation.
– Amorphous / disordered regions may revert back to crystalline
– Particle size may change
– Surface properties may change
Surface area and roughness
– May be electrostatically charged, which dissipates with time.
Blending
 Drug Product CQA key:

Particle Size 1. PSD of emitted dose

Distribution 2. Emitted dose uniformity
3. Impurities Purity
Surface Area 4. Plume geometry
5. Micro quality
Particle Size
6. Moisture content Distribution
Moisture Content
7. Airflow resistance
Measured on
Raw Materials
iIncoming Impurities
Amorphous
Materiais MIcronization Content

Microbial Content Moisture

Content
Bulk Powder
Properties
Specific
Surface Area

Assembly /Pack Critical Quality

Attributes
Content
Uniformity
Particle Size
Distribution Moisture
Content
Blister Fill Weight
Standard Deviation
Microbial
Mean Strip Fill Blending Contnet
Weight

Strip Fill Weight

Filling Energy
Standard Deviation

Particle Size
Strip Seal Intgrity Distribution

Bulk Blend
Properties

Microbial Content
Blending

DPI’s typically require a high shear blending process to achieve

–Homogenous blend
–Attach API to carrier

– High Shear Mixers

Filling
 Drug Product CQA key:

Particle Size 1. PSD of emitted dose

Distribution 2. Emitted dose uniformity
3. Impurities Purity
Surface Area 4. Plume geometry
5. Micro quality
Particle Size
6. Moisture content Distribution
Moisture Content
7. Airflow resistance
Measured on
Raw Materials
iIncoming Impurities
Amorphous
Materiais MIcronization Content

Microbial Content Moisture

Content
Bulk Powder
Properties
Specific
Surface Area

Assembly /Pack Critical Quality

Attributes
Content
Uniformity
Particle Size
Distribution Moisture
Content
Blister Fill Weight
Standard Deviation
Microbial
Mean Strip Fill Blending Contnet
Weight

Strip Fill Weight

Filling Energy
Standard Deviation

Particle Size
Strip Seal Intgrity Distribution

Bulk Blend
Properties

Microbial Content
Key attributes for filling

Powder flow
– Too poorly flowing and dies will not fill
– Too well flowing and will fall out of the die prematurely.
Mechanical properties
– Need to hold together on compaction, i.e. deform plastically
Adhesion properties
– Must not stick to the punches
– Must not segregate during the process
Filling into blister strips
Product Performance
 Drug Product CQA key:

Particle Size 1. PSD of emitted dose

Distribution 2. Emitted dose uniformity
3. Impurities Purity
Surface Area 4. Plume geometry
5. Micro quality
Particle Size
6. Moisture content Distribution
Moisture Content
7. Airflow resistance
Measured on
Raw Materials
iIncoming Impurities
Amorphous
Materiais MIcronization Content

Microbial Content Moisture

Content
Bulk Powder
Properties
Specific
Surface Area

Assembly /Pack Critical Quality

Attributes
Content
Uniformity
Particle Size
Distribution Moisture
Content
Blister Fill Weight
Standard Deviation
Microbial
Mean Strip Fill Blending Contnet
Weight

Strip Fill Weight

Filling Energy
Standard Deviation

Particle Size
Strip Seal Intgrity Distribution

Bulk Blend
Properties

Microbial Content
 In-Vitro Assessment of Particle size of emitted
dose

Air flow

Jet exit

Pump

Impaction disc
Andersen Cascade Impactor
In-vitro Particle Size and Delivery to the Lung

Sizes for 28l/min flowrate

Andersen Cascade Impactor – size distribution
profiles
CI Profile - Salmeterol (µg/actn) vs CI Stage

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C an 3
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Micrograms of
drug
x
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x x
Stage (or size)
Conclusion
Dry Powder Inhalers are
extremely complex systems
(patient, device & formulation)
A DPI product can be broken
down into key controllable
elements, variables and
attributes (Quality by design).
Control of particle attributes
to achieve a stable formulation
and consistent product
performance remains a major
challenge.
Respiratory System
Lung Target area
Lung deposition
Molecule size
Fine Particle Fraction
Aerodynamic Particle Size
Geometric standard deviation
De-agglomeration during inhalation
Inhalation volume
Inhalation rate
Device specific resistance
Induced Shear forces
Drug excipient cohesive/adhesive forces
Mixing/blending process
Mixer type (high shear/low shear)
Energy input
Environmental conditions
Dose Uniformity
Excipient/carrier Active Product Ingredient (API)
Particle Size Distribution Particle Size Distribution
Particle shape Aerodynamic particle size
Surface area Particle Shape
Surface roughness Surface roughness
Surface charge Surface charge
Moisture content Crystallinity
Bulk Flow properties Bulk flow properties