Case Study 1: Pharmaceutical Development of EXUBERA...Case Study 1: Pharmaceutical Development of EXUBERA® IPAC-RS Conference November 2006 Nancy Harper, PhD Research Fellow, Parenteral

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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

2IPAC-RS Conference November 2006

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


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


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



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.


Physical Form Stability

0

200

400

600

800

1000

1200

1400

1600

0 5 10 15 20 25 30 35 40 45

2 θ

Arb

itrar

y in

tens

ity, C

PS

ABC

0

200

400

600

800

1000

1200

1400

1600

0 5 10 15 20 25 30 35 40 45

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

0 10 20 30 40 50

2 theta

Arb

itrar

y in

tens

ity, C

PS

B

A

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ManufacturingChallenges



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).


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


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)

0

2

4

6

8

10

12

RSD

(%)

Individual SamplesMean LimitsMean of IndividualsIndividual LimitsRSD

Fill Weight Control

Sample Number

Fill

Mas

s (%

of t

arge

t wei

ght)

RSD

(%)


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


Powder / Aerosol Particle Size Distribution

§ High dispersibility

§ Aerosol particle size broadly in line with spray dried powder.

0

10

20

30

40

50

60

70

80

90

100

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


• 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


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


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

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

0 10 20 30 40 50 60Flow Rate (L/min)

EM (m

g po

wde

r) o

r FP

D (m

g in

sulin

)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

MM

AD

(μm

)

Emitted Powder MassFine Particle Dose <4.7 μmFine Particle Dose <3.3 μmMMAD

error bars = 1 SD


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


Inhaler Robustness to Long-Term Use

0

1

2

3

4

5

0 100 200 300 400 500 600 700 800 900 1000

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)


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


… and many, many more

Documents

Case Study 1: Pharmaceutical Development of EXUBERA...Case Study 1: Pharmaceutical Development of EXUBERA® IPAC-RS Conference November 2006 Nancy Harper, PhD Research Fellow, Parenteral