March 19, 2013

Manjari Lal, PhDTechnical Officer, Formulation and Stabilization TechnologiesPATH, Seattle, WA

Technologies for the Development of Thermostable Vaccines

New Cells, New Vaccines VII: From Protein to Product

Presentation Outline

• Introduction to PATH.

• Introduction to PATH’s Vaccine Technologies Group.

• Technologies for thermostable vaccines.

03/19/2013Slide 2

About PATH (Program for Appropriate Technology in Health)

Approximately 1,200 employees.

Budget of US$334.5 million.

Use of funds:

03/19/2013Slide 3

Vaccines and immunization

Includes vaccine development and introduction

Emerging and epidemic diseasesReproductive health

Includes drug development (PATH/One World Health)

Health technologies Includes vaccine technologies

Maternal and child health and nutrition

32.7%

26.6%

19.2%

12.0%

9.5%

Vaccine Technologies at PATH

Formulation and stabilization methods

Delivery technologies

Packaging and cold chain technologies

03/19/2013Slide 4

Save for where noted, all photos ©PATH.

©G

eorgia Tech

Team goal:

• To assess, advance, and apply appropriate and affordable formulation technologies to priority vaccines for global health.

Where we fit in the research and development process:

• Translational space, bridging research and product development.

Our work includes:

• Advancement of technologies, including alternatives.

• Cost analysis and manufacturing.

• Access to intellectual properties.

Vaccine Formulation and Stabilization

03/19/2013Slide 5

PATH’s Laboratory and Product Development Shop

Biosafety level 2 laboratory equipped with current analytical and processing equipment.

Product development shop to develop prototype delivery devices.

Spray dryer Differential scanning calorimeter

03/19/2013Slide 6

Blister machine Freeze dryer

Stabilization Technologies and Vaccines Investigated

Technologies Products or disease targets

Stable liquid formulations Hep B, Hib, influenza, rotavirus

Freeze-stable formulations Hep B and DTP-Hep B-Hib

Spray-dried formulations Meningitis, influenza, Hep B, measles, Marburg virus, influenza

Foam-dried (modified lyophilization) formulations

Influenza, measles

Mucosal formulations (thermoresponsive gel and fast-dissolving tablet [FDT])

HIV, inactivated poliovirus, enterotoxigenic E. coli (ETEC), Newcastle disease

Adjuvant formulations Alum, dmLT, oil-in-water emulsion, etc.

03/19/2013Slide 7

PATH has been working on vaccine stabilization for over a decade to support national and global public health.

Desirable Attributes of Vaccines

Low manufacturing cost.

Compact packaging—easy to store and transport.

Fewer parts—easy to prepare before immunization.

Stability and Efficacy

03/19/2013Slide 8

Vaccine Stabilization: Comparison of Drying Processes

“Best” process is empirically determined and varies with product.

Freeze drying:

• Pro: industry standard method to prepare dried, sterile product.

• Pro: commonly used for parenteral products, including vaccines.

• Con: batch process, long run times

Spray drying:

• Pro: continuous process, common in food industry (few pounds to hundreds of pounds per hour), short run times

• Pro: control of particle size—ideal for inhaled/pulmonary delivery

• Con: limited use in parenteral products.

03/19/2013Slide 9

Oral vaccine for infants.

Multiple components—3 bacteria strains + antacid buffer.

• Multiple components.

• High manufacturing cost.

• Large cold chain footprint.

• Multiple preparation steps before immunization.

ACE 527: Live Attenuated Enterotoxigenic E.Coli (ETEC) Bacterial Vaccine

CS1CS2CS3LT-B

CS5CS6LT-B

CFA/ILT-B

ACAM2025 ACAM2027 ACAM2022

03/19/2013Slide 10

Most clinically advanced candidate addressing both CFAs and toxin–projected ETEC coverage of ~80 percent.

ETEC Vaccine—Different Drying Approaches

Traditional freeze drying:

• Vaccine produced in glass vial with a rubber/silicon stopper.

• “Lyo cake” has high surface area to volume ratio.

• Type of stress: Freezing (low temp)

Spray drying:

• Vaccine solution aerosolized.

• Powder produced in bulk.

• Partitioned after production into containers.

• Type of stress : Thermal (high temp)

Fast-dissolving tablets (FDTs):

• Vaccine is freeze dried in a traditional manner in blister packs

• Vaccine FDTs sealed in blister packs

• Formulation designed for physically robust tablet that dissolves quickly.

03/19/2013Slide 11

Spray Drying

Formulations:

• Over three dozen formulations were screened.

– Examples: polymers, sugars, buffers, skim milk

• Influence of cell membrane permeabilizers.

• Included in growth media for better incorporation.

Process adjustments:

• Low inlet temperature

• Atomization pressure

• Spray drying under nitrogen in a closed system.

03/19/2013Slide 12

Lyophilization—Glass Vials

Formulations:

• Screened 20 formulations

• Examples: polymers, sugars, buffers, skim milk

Process adjustments:

• impact of vial size,

• fill volume,

• bacterial concentration, and

• lyophilization cycle.

03/19/2013Slide 13

Lyophilization — Fast Dissolving Tablets

Formulations:

• Over a dozen formulations tested.

• Focus on robust tablet, quick dissolution and stability

Blister packs:

• Various tablet sizes.

• Freezing methods and Sealing process evaluated : impact on process loss and tablet quality.

Administration strategies:

• Optimal antacids, doses.

• Mixing of vaccine and antacid.

0 Seconds

2 Seconds

4 Seconds

03/19/2013Slide 14

Comparison of Process Loss

Glass vial:

• Vial is stoppered in lyophilizer.

• Can store under inert conditions.

Spray dried:

• High process loss.

• Drying under nitrogen reduces loss but still remains high.

FDTs:

• Tablets dry quickly and efficiently.

• Cannot exclude ambient moisture and oxygen.

03/19/2013Slide 15

All Methods: 4°C Stability

4 ° C O n ly

T im e (w e e k s )

Tit

er (

log

cfu

/mL

)

0 2 0 4 0 6 0

0

2

4

6

8

1 0

1 2

1 4

S p ra y D r ie d

L y o p h iliz e d - F D T

L y o p h iliz e d - V ia l

03/19/2013Slide 16

All Methods: 25°C Stability

2 5 ° C O n ly

T im e (w e e k s )

Tit

er (

log

cfu

/mL

)

0 5 1 0 1 5 2 0 2 5

0

2

4

6

8

1 0

1 2

1 4

S p ra y D r ie d

L y o p h iliz e d - F D T

L y o p h iliz e d - V ia l

03/19/2013Slide 17

Formulation Optimization: Improved Thermostability

0.26 0.26

1.49

2.28

0.47

0.04

0.20

0.49

0.0

0.5

1.0

1.5

2.0

2.5

Process Loss Loss: 4 wks.,25 °C

Loss: 2 wks.,37 °C

Loss: 4 wks.,37 °C

Loss

(lo

g cf

u/m

L)

Form. D

VLF

03/19/2013Slide 18

• Optimized formulations (VLF) demonstrates less than 0.1 log loss at the end of 4 weeks at 25°C

• Optimized formulation (VLF) demonstrates less than 0.5 log loss at the end of 4 weeks at 37°C

Manufacturing Cost Comparison Lyophilized FDTs Versus Lyophilized in Glass vial

a Communication with Oregon Freeze Dry. October 2010.b Assumes that overfill requirements are the same for both methods.c Automatic High Speed Blister Packing for PVC/AL (ALP 220A). Price: US$52,610.00; http://www.induction-sealers.com/filler/217-Automatic-High-Speed-Blister-Packing-for-PVC-AL-Pharma-Machinery-Blister-Packaging.asp.d Lloyd J. UNICEF carton dimensions, consolidation of vaccine manufacturers' inner and shipping carton dimensions and weights. 2009.

For FDTs, there is potential for lower manufacturing cost compared to lyophilized vaccine in vials due to an estimated 2-fold decrease in drying time, 7-fold increase in throughput, and decrease in packaging cost.a,b,c

There is a projected decrease in purchasing and delivery costs due to lower packaging volumes that require less cold chain and transport capacity and no need for reconstitution or autodisable syringes.d

$0.00

$5.00

$10.00

$15.00

$20.00

$25.00

$30.00B

ase E

PI

vaccin

es

Base E

PI

+Lyo v

accin

eta

ble

t

Base E

PI

+Lyo v

accin

evia

lTo

tal v

accin

e c

ost

(US

$)

Schedule

Vaccine purchase and delivery costs per fully immunized child

ETEC vx cost

Base EPI schedule costs

03/19/2013Slide 19

Advantages of the FDT Formulation for ETEC Vaccine

Manufacturing:

• Standard technology with low regulatory hurdle.

• Lower manufacturing cost:

– Foil blister is cheaper than glass vial.

– High manufacturing capacity.

Distribution and use:

• Oral administration without reconstitution and with no choking hazard.

• Can be reconstituted (in antacid buffer) in seconds before oral administration.

• Compact packaging for cold chain storage.

03/19/2013Slide 20

FDT Technologies and Products

Technologies:

• Tablet technology is standard for the drug industry.

• Lyophilization technology is standard for the vaccine industry.

• Formulation technology is product specific. Typical stabilizers include sucrose, mannitol, and binders.

Products on the market in FDT formulation:

• More than 20 drugs.

• Allergy vaccines.

• Veterinary vaccines.

03/19/2013Slide 21

FDTs Are a Potential Platform For Other Vaccines

Human vaccines to prevent:

• Cholera

• Shigella

• Salmonella

• Rotavirus

• Poliovirus

• Norovirus

Vaccines against animal diseases:

• Newcastle disease

• Others

03/19/2013Slide 22

Summary

Progress:

• FDTs represent an attractive, efficient, and cost-effective product presentation of the trivalent ETEC vaccine.

• ETEC vaccines can be produced in a tablet format using standard lyophilization approach

• The ETEC FDT is robust and disintegrates within 10 seconds.

• The lead FDT formulation is stable for 1 year at 4°C and for several weeks at room temperature.

Additional work required:

• Process development and scale-up.

• Clinical evaluation.

• Cost of setting up production and manufacturing.

• Analyses of freedom of operation.

03/19/2013Slide 23

Acknowledgements

PATH:

Scott Priddy

Dexiang Chen

Lou Bourgeois

Richard Walker

George Robertson

Oregon Freeze Dry:

Walt Pebley

James Brown

James Desai

TD Vaccines:

Mike Darsley

03/19/2013Slide 24