Process Development & Scale-Up of the AIR Technologyweb.mit.edu/10.490/Barton05/MIT ICE Scale-up...
Transcript of Process Development & Scale-Up of the AIR Technologyweb.mit.edu/10.490/Barton05/MIT ICE Scale-up...
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Process Development & Scale-Up of the AIR® Technology
Lloyd Johnston, Ph.D.Vice President of Process Development & ManufacturingOctober 6, 2005
™
COPYRIGHT © 2002 ALKERMES, INC.
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Pharmaceutical Industryo Delivering needed therapeutics to the marketo Most highly regulated industry in the USo Many products greater than $1 billion per year in sales
- smaller volume higher value than most chemicalso Typical patent lifetime of 20 yearso Average product development cycle of 7 to 12 yearso Manufacturing costs have not been a significant
portion of product costs in the pasto Increasing price pressures will raise importance of
efficient manufacturing in pharmaceuticalso Chemical engineers in best position to make
contributions in this area
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Pharmaceutical Product Developmento Pre-clinical
- discovery, toxicologyo Phase 1 Clinical
- ~ 10 healthy volunteers, tests safety in humanso Phase 2 Clinical
- 100’s of patients, dose ranging studieso Phase 3 Clinical
- 1000’s of patients, efficacy and long term safety
o Chemistry, Manufacturing and Controls (CMC) needs to keep pace at all stages of development
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State-of-the-art drug delivery
Effective delivery of highly engineered particlesvia
Injectable SRInjectable SR•• ProLeaseProLease®®
•• MedisorbMedisorb®®
PulmonaryPulmonary•• AIRAIR®®
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Pulmonary delivery
AIR®
o Local or systemic deliveryo Proteins, peptides, small
molecules o Large porous particleso Simple inhalero Patented and proprietary
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The Lung … an Effective Filter
… contingent upon ρ = 1 g/cc
(true in naturally occurring aerosols)
> 5 µmMucociliary Escalator
< 5 µmPhagocytosis
(Greenspan, B. J., 1995)
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Why the Difficulty?
Particles Stick Together
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What’s Available?
Standard Inhalation Devices
X low dose
X low efficiency
X flow rate dependent
√ simple device
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What Can Be Done?
Design complex,high energy
devices to disperse small particles
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Engineer the Inhalation Device
Avoid Breath-Actuation
X low-moderate dose
√ high efficiency
√ flow rate independent
X complex device• more mass, more power
• more power, more complexity
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Is There Another Way?
Produce Large, Porous ParticlesX
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Decoupled Geometric and Aerodynamic Size
Standard Aerosols AIRTM Technology
da = dg ρ1/2
ρ = 1 g/cc
dg = 3 µm
da = 3 µm
ρ = 0.03 g/cc
dg = 14 µm
da = 2.4 µm
Ease of dispersibility
Targeted Lung Delivery
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0
1
2
3
4
5
0 1 2 3 4Disperser Shear Rate (Bar)
Geo
met
ric S
ize
of E
mitt
ed A
eros
ol(N
orm
aliz
ed)
3 µm (micronized)12 µm (AIR protein)10 µm (AIR small molecule)
Dispersibility - Experiment
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The AIR™ Solution
Large, Porous Particles
√ low-high dose
√ high efficiency
√ flow rate independent
√ simple device
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√ high efficiencyFor high efficiency
demanding powders
(systemic protein delivery)
> 70 % of nominal dose delivered to the
lungs
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AIR Technology
High Tech Particles, not High Tech Inhaler
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AIR Product Development Cycle
Spray DryingOptimization Scale-up I Scale-up II
Tox I
Phase I
Tox II
Phase II/III
Commercialization
PRODUCT
FormulationDevelopment
Goals:1. Yield2. Production rate3. Maintain product
characteristics
Goals:1. Large Porous Particles2. Drug product stability3. In vivo PK/PD Profile
Goals:1. Geometric size2. Aerodynamic size3. Aerosol performance4. Drug product stability5. In vivo characteristics
Goals:1. Increase
equipment size2. Yield3. Production rate4. Maintain product
characteristics
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Process Scale-upo Scale-up - a working definition
- “Make a lot more of the same stuff - with a robust, reproducible, reliable process”
o Determine manufacturing targets- Too much capacity can be as big a problem as too
little capacityo Determine unit operations
- Same as research?- Ideal to have engineering/manufacturing involved in
research phase- Use “tried and true” unit operations if possible, even
if you use them in a new way- Need mechanically robust processes
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Process Scale-up
o Build flexibility into processing solutions to accommodate uncertainty- Low to high market forecast can vary by 5 to 10 fold
o Determine long term manufacturing strategy- Large production train vs. staging multiple trains
o Test scale-up relationships and design ideas at smaller scales
o Use any available similar “scaled-up” test equipment- suppliers, contract sites, etc.
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General Scale-Up Challengeso When different attributes of the same system
scale differently- e.g. Heat Transfer in a cylindrical vessel
- Total heat to transfer ∝ volume (D2L)- Heat transfer area ∝ sidewall area (DL)- If diameter is increased, imbalance between area
for heat transfer and total heat to add or remove
D
L
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Scale-up Challengeso Safety - increased volumes of hazardous substanceso Cost considerations
- capital for new facilities- cost of increased need for drug substance for experiments
o Time pressure for completing scale-up and manufacturing facilities- do not want to spend money for scale-up work and new
facilities until new product is demonstrated in clinic- once proved in clinic want scaled-up, online manufacturing
facilities yesterdayo Pharmaceutical industry regulations limit process
degrees of freedom once in pivotal clinical trials
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AIR™ Manufacturing Unit Operations
Formulation SprayDrying
CapsuleFilling
BlisterPackaging
InhalerProduction Consumer
Packaging
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Open System Spray Drying ProcessSuitable for small scale production
Heater
FeedTank
Pump
Spray Dryer
Product
Drying gas
Liquid Feed
Gas/PowderMixture
Powder
NitrogenSupply
Gas
PowderCollection
HEPAFilter
SolventRecovery
Exhaust
RecoveredSolvents
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Closed System Spray Drying Process
Heater
FeedTank
Spray Dryer
Product
Drying gas
Liquid Feed
Gas/PowderMixture
Powder
Make-up NitrogenSupply
Gas
Pump
PowderCollection
HEPAFilter
SolventRecovery
Needed for large scale production
RecycleNitrogen
PoliceFilter Blower
PurgeNitrogen
RecoveredSolvents
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Spray Drying Scale-up Modeling
o AIR process scale-up desired result was a particle size, density, morphology and chemical purity- no appropriate models for detailed simulation- built conceptual models to drive development
o In spray drying scale-up the mixing dynamics of atomized feed and drying gas is crucial- spray drying supplier uses sophisticated computer
models (computational fluid dynamics) to ensure consistency from small to large scale
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Spray Dryer Scale-Upo Increase batch size
- Increase process timeo Increase production rate and batch size
- Concentrate solutions- Increase flow rates- Increase yield- Parallel spray dryers- Increase spray dryer size
Focus on maximizing scale in existing small scale equipment
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AIR Commercial Manufacturing Facilityo Alkermes needed a full scale production facilityo 90,000 square foot site in Chelsea, MAo Complete re-development of existing structureo $40 million dollar projecto 18 months from start of construction to operation
- design/build approach to shorten timelineo Additional 6 months for validationo Peak workforce of 150 contractors
- Safety record 16 times better than national average
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Small Scale Spray Drying
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COPYRIGHT © 2002 ALKERMES, INC. COPYRIGHT © 2004 ALKERMES, INC.
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Construction Methods to Keep on Schedule
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Construction Methods to Keep on Schedule
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Commercial Scale Spray Dryer
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Powder Production Scale-up
o Approximately 30 minutes of production eacho Scale-up of powder production by > 100,000 times
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Spray Dryer Scale-up Challenges
o Increase process time- drug stability in process and in collection vessel
o Concentrate solutions- solubility issues- particle formation and morphology
o Increase feed rate- Atomization of liquid feed
- keep drop size constant with increased feed rate- rotary atomization - issues with max achievable rotation- two-fluid atomization
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Spray Dryer Scale-up Challengeso Yield
- powder collection technology- minimize adherence of powder to surfaces- increased from ~20% to > 90%
o Increase equipment size- atomization- powder collection- equipment cleaning- solution preparation and handling- feed transfer - dead volumes
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Overcoming Batch Scale-up Challenges
o Use steady state unit operations when possibleo Alternate method of heat transfer to a batch tank
o Can cause other issues
vs.
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Summaryo Scale-up of a process can be very challengingo Batch processes have the additional complexity of timeo Use steady state processing tools when possible to
reduce complexity of batch process scale-upo Run a continuous process for longer times to scale-up a
batch processo Pharmaceutical industry has many interesting process
challenges that chemical engineers are best suited to handle
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™
www.alkermes.com
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