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Case Study 1:Pharmaceutical Development of EXUBERA®
IPAC-RS ConferenceNovember 2006
Nancy Harper, PhDResearch Fellow,
Parenteral Development Center of EmphasisPfizer Global R&D
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EXUBERA®
• Insulin human (rDNA origin) Inhalation Powder
• Re-usable Exubera® Inhaler
•1 mg, 3 mg unit dose blisters
• Indications: Type 1 and Type 2 Diabetes Mellitus
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EXUBERA®
Clear chamber: designed to hold aerosolized insulin before inhalation
Base: device provides energy required for dispersion of EXUBERA powder via air pump mechanism in the device base (no batteries required)
Insulin release unit: disperses powder from blister into chamber
- -Blisters: available in 1 mg (green) and 3 mg (blue) doses
Closed
Extended
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Pharmaceutical Challenges in EXUBERA® Development
… relative to conventional inhalation products
… specific to insulin
Uniqueness presented challenges as well as opportunities!
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Challenges Relative to Conventional Inhalation Products
• Systemic Delivery
• Importance of Particle Size
• Standard PK/PD studies are possible– BE, Variability, Dose Response, IV / IVc, Interaction Studies, Special
Populations, Other Biopharm
• Defining the Relevant Performance Attributes
• Labeling / Label Claim– Contained Dose vs Emitted Dose vs Respirable Dose
1.02.033.05.10.40.531.01.7
Fine Particle Dose (mg insulin)
Emitted Dose (mg insulin)
Nominal Dose (mg insulin)
Fill Mass (mg powder)
Source: EXUBERA® US Package Insert
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Challenges Specific to Insulin
• A new, non-invasive route of insulin administration
• Insulin dosing based on mg (not units)– Robust Education and Customer Care programs
• Performance benchmark against SC injection– Defining the unit doses
– Performance comparisons in vivo and in vitro
• Biologic
• Stability– Opportunity for improvements over current insulin products
– Refrigeration not required !
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Insulin Stabilization Challenge
IPAC-RS ConferenceNovember 2006
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Insulin Formulation
• Dry powder
• High drug load: 60% insulin in a buffered sugar-based matrix.
• Stabilization approach: Maintain insulin in glassy state– Excipients selected to provide a glass transition temperature well
above pharmaceutically relevant storage temperatures.
– Exhibits a single Tg (indicative of a single amorphous phase).
– The high Tg is maintained over the shelf life of the product and across a range of moisture content.
• Moisture content and its affect on glass transition temperature (Tg) was a critical parameter impacting chemical stability.
• Moisture Control challenges throughout the manufacturing process and for packaging design
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Glass Transition Temperature
• Tg decreases with increasing water content• Spray dried powder water content is ~2 % (w/w),
consistent with a Tg ≈ 80°C.
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Physical Form Stability
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2 θ
Arb
itrar
y in
tens
ity, C
PS
ABC
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2 θ
Arb
itrar
y in
tens
ity, C
PS
ABC
• No evidence of crystallization in insulin powder for inhalation upon moisture or thermal challenge
XRPD patterns after up to 88% RH for (A) 22.5, (B) 26, and (C) 28 hours
XRPD patterns before (A) and after (B) exposure to 150°C for 15 minutes
0100200300400500600700800900
1000
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2 theta
Arb
itrar
y in
tens
ity, C
PS
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A
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ManufacturingChallenges
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Spray Drying
Solution
Atomization
Drying
Powder Collection
Spray Drying enables production of homogenous particles of controlled size with:– Low moisture– High drug purity– Small particle size (<5 µm)– Non-critical excipient physical form
Food 50 to 100µm
Micro-encapsulation
30 to 40µm
Typical Pharm
10 to 20µm
Exubera®
<5 µm
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Maintenance of Insulin Molecular Structure
• The spray-drying process does not affect the secondary structure of insulin, assuring pharmacological activity
• Techniques included Circular Dichroism, FTIR
• Quaternary/Oligomeric Structure: Insulin Monomer (HP-SEC, SDS-PAGE, DLS)
CD spectra for insulin in the formulation matrix before (blue), and after (green) spray drying, compared with ingoing insulin API (red).
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Spray Drying
5 µm
Traditional
Particle Morphology (SEM)
• Uniform, rugose morphology• No effect on particle morphology before (left) and after (right)
exposure to high humidity (75% RH, 25°C for 36 hours)
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Process Scale-Up / Optimization
• DOE on process parameters to map knowledge space
• Design space / control space based on aerosol performance
• Each contour line represents a constant predicted value for FPD
0.600
0.650
0.700
0.750
0.800
0.8500.9000.950 1.000
1.050
1.150
1.100
Inle
t Tem
pera
ture
Atomizer Airflow
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Powder Filling
• Beyond capability of existing technology
• Design Challenges– Low density powders– Micro fill weights
(1.7 mg and 5.1 mg)– High speed
(>1500 fills/min)– Accuracy
(~2% RSD)– Consistency
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75%
80%
85%
90%
95%
100%
105%
110%
115%
0 25 50 75 100 125 150 175 200 225 250
Sample Number
Fill
Mas
s (
Perc
ent o
f Tar
get W
eigh
t)
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RSD
(%)
Individual SamplesMean LimitsMean of IndividualsIndividual LimitsRSD
Fill Weight Control
Sample Number
Fill
Mas
s (%
of t
arge
t wei
ght)
RSD
(%)
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Packaging Design
• Compact Package
– Patient handling
– Device interface
• Foil Forming, Filling, Sealing
– Blister cavity design
– Tooling and manufacturing scale up
– Operation in ultra-low humidity environment
• Drug Product Protection
– High moisture barrier
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Byron PR. J Pharm Sci. 1986;75:433-438.
Particle size: The optimal window for deposition
Alveolar regionAirwaysMouth and throat
1.0
0
0.5
0 5 10 15
Particle size (µm)1
Frac
tiona
l dep
ositi
on
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Powder / Aerosol Particle Size Distribution
§ High dispersibility
§ Aerosol particle size broadly in line with spray dried powder.
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0.1 1 10 100Particle size (microns)
Cum
ulat
ive
perc
ent l
ess
than
Spray Dried Powder
Aerosolized Powder
• MMAD ~ 3 µm
• High FPF
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Inhaler ChallengesIPAC-RS Conference
November 2006
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• Reproducible powder extraction, deagglomeration and dispersion.
• Patient generated compressed air provides energy source
• Capable of aerosolizing relatively cohesive powders
• Suitable for delivering small powder masses (1-10 mg)
• Separate breathing maneuver from aerosol generation
• Chamber allows for patient feedback and dose delivery
• Designed for long-term repeated use
Chamber
Insulin Release Unit
Blister
Pump Handle
Mouthpiece
Actuation Button
Inhaler Design
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Blister
Chamber
Release Unit
Base
pressurizedair inlet
centerhole
sidehole
entrained air fromchamber
to chamber
pressurizedair inlet
centerhole
sidehole
entrained air fromchamber
to chamber
Inhaler Design
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Device Challenges
• Balancing drug product requirements against device requirements
– Heavy reliance on risk based approach in Pharm Dev
• Device world embraces continuous improvement– Educating device design and manufacturing on type/timing
of acceptable changes based on development stage, given regulated as drug product
– Use of comparability protocol for known changes– Building in flexibility as appropriate into submission
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Drug + Inhaler System Challenges
• Elaborate performance characterization programs– Risk based approach: comprehensive FMEA’s
– Inhaler Design Verification Testing
– Testing to failure
– Clinical experience
– Use-Life simulations
– FDA Draft MDI/DPI Guidance (…and beyond)
• Output contributed to:– Comprehensive product understanding
– Assessment of impact on safety/efficacy
– Instructions in labeling/medication guide; Customer Care
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Performance Characterization
• Robust performance (aerosol dose delivery and mechanical integrity) demonstrated over a range of patient usage scenarios
• Environmental (temperature, humidity, altitude)
• Usage reproducibility– Independence from inhalation flow rate (10-60 lpm) and
volume (400-1400 ml)
– No priming effect
– Independence of usage angle
– Rugged performance with long term use
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Inhaler Flow Rate: Little Impact on Aerosol Performance
0.0
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1.0
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0 10 20 30 40 50 60Flow Rate (L/min)
EM (m
g po
wde
r) o
r FP
D (m
g in
sulin
)
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1.0
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MM
AD
(μm
)
Emitted Powder MassFine Particle Dose <4.7 μmFine Particle Dose <3.3 μmMMAD
error bars = 1 SD
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Section IVB Recommendation Studies Conducted/Relevant Data Determination of Appropriate Storage Condition
Stability Studies DVT studies
Stability of Primary (Unprotected) Package Stability Studies Effect of Varying Flow Rates Square W ave flow rate study
Pediatric inhalation profile study Effect of Storage on Particle Size Distribution
Stability Studies
Dose Build-Up and Flow Resistance Use-life studies Cleaning frequency Mass Distribution
Effect of Orientation Dosing orientation Drop and vibration testing
In-Vitro Dose Proportionality Biopharm aceutics studies Effect of Patient Use Planned Returns
Product Investigation Process Effect of M oisture Excursion studies
Use life studies Photostability Stability study Profiling of Doses Near Device Exhaustion Fill Weight
Not applicable since this product is not a DPI reservoir product
Prim ing Priming Device Ruggedness Planned Returns
Design Verification Testing Accelerated Patient Use Sim ulation Product Investigation Process
Cleaning Instructions Cleaning Frequency Cleaning Effectiveness Cleaning Detergents Microbial Inoculation Study
Characterization Studies(FDA MDI / DPI Draft Guidance)
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Drug + Inhaler System Challenges
• Extended-use inhaler: high bar for durability
– Unique patient-use simulations
– Extensive patient-use evaluation
• Findings from clinical experience enabled:
– Early input for robustness improvements
– Optimization and “validation” in vitro tests
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Inhaler Robustness to Long-Term Use
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Days in Use
Mea
n Em
itted
Mas
s
Clinical Retrievals (427 Inhalers)
Accelerated Patient Use Simulation (13 inhalers)
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Additional CMC Challenges
• Release Approach– Blisters; Inhalers
– What are the reference standards?
– (FDA helped to define)
• Controls and Acceptance Criteria– Deep Product and Process understanding was critical
– QbD, Design Space concepts (many variables, interactions)
– Clinical experience
– Test methods
– (FDA helped to define)
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EXUBERA® (insulin human [rDNA origin]) Inhalation Powder
• Insulin naturally absorbed by the lungs without enhancers
• Dry powder insulin stable at room temperature
• Ideal particle size for systemic absorption via the lung
• Packaging system protects formulation from moisture
• Robust delivery device enables dosing as reliable as injections
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Acknowledgements
PfizerBob BergesonRick Conley Don GuzekBrian Lewis Joann ParkerJackie SchumacherSonja Sekulic Greg SluggettFrank Urbanski
NektarDavid BennettScot Cheu Steven GrayJohn Howard Richard Malcolmson Phil RobertsSangita SeshadriCynthia StevensonSteve White**Current affiliation Epic Therapeutics, Inc
IPAC-RS ConferenceNovember 2006
… and many, many more