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Session:
Next-Generation Drying Technologies for
Processing of Biotherapeutics (#118)
Innovative Bulk Drying of Frozen
Microspheres by Spray-Freeze-Drying
Boston, May 17th, 2016
2016 AAPS National Biotechnology Conference
Bernhard LUY
MERIDION Technologies, Germany
Topics
• Background of the Development
• Presentation of two Core Technologies
– Spray Freezing
– Dynamic Bulk Freeze Drying
• Case Study of an Industrial Project for a
pharmaceutical product
• Potential Impact of Technology on
– process
– product innovation
– production logistics
2 © MERIDION Technologies GmbH
BioTherapeutics Pharmaceutical Sciences BioTherapeutics Pharmaceutical Sciences
• Werly, E.P., Baumann, E.K., 1964. Production of submicronized powder by
spray freezing.Arch. Environ. Health 9, 567–571.
• S.Wanning , R.Süverkrüp, A.Lamprecht. Pharmaceutical spray freeze drying,
Intern. J. of Phramaceutics, 488 (2015) 136–153
• Carpenter JF, Pham BV, Randolph T, Seid R, Truong-Le V. 2003. Spray freeze
dry of compositions for pulmonary administration. WO2003087339.
• Leuenberger H, Plitzko M, Puchkov M. 2006. Spray freeze drying in a fluidized
bed at normal and low pressure. Drying Technol 24(6):711–719.
• Cheow WS, Ng ML, Kho K, Hadinoto K. 2011. Spray-freeze-drying production of
thermally sensitive polymeric nanoparticle aggregates for inhaled drug
delivery: Effect of freeze-drying adjuvants. Int J Pharm 404(1–2):289–300.
• Gao Y, Zhu CL, Zhang XX, Gan L, Gan Y. 2011. Lipid-polymer composite
microspheres for colon-specific drug delivery prepared using an ultrasonic
spray freeze-drying technique. J Microencapsul 28(6):549–556.
• Dolly P, Anishaparvin A, Joseph GS, Anandharamakrishnan C. 2011.
Microencapsulation of Lactobacillus plantarum (mtcc 5422) by spray-freeze-
drying method and evaluation of survival in simulated gastrointestinal
conditions. J Microencapsul 28(6):568–574
Recent literature on spray-freeze drying
Slide with kind permission from S. Tchessalov,
“New life of spray freeze-drying- application to
dehydration of protein solutions”
PepTalk Conference 2016, San Diego CA
Background
Typical Limitations of conventional FD
• static drying (under vacuum) offers
only limited heat & mass transfer
• heat transfer has to occur across
frozen product
• vapor flow limitations, e.g.
– diffusion barrier thickness
• product inhomogeneities may occur (e.g. caking, density variations)
• product handling properties (e.g. flowability, dust)
• primary packaging requirements
• production logistics 4
4 © MERIDION Technologies GmbH
Background / History:
Specific past R&D work performed
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Research Project at Basel School of Pharmacy
(Prof. Hans Leuenberger): Atmospheric Spray Freeze Drying in Fluidized Bed Operations
• started in the mid ‘80s (in coop. with Glatt GmbH)
• 3 research projects realized until the mid ‘90s
5 © MERIDION Technologies GmbH
Background / History:
Specific past R&D work performed
Atmospheric Spray Freeze Drying in Fluidized Bed
Result of Research Work: • 3 step process required (spray freezing (air temp. < -60°C);
primary drying (Tp: <-10°C), secondary drying at amb. temp.)
• very low water uptake of cold air requires long drying times
and / or excessive air flow; →
• „filter drying“ required due to freezing requirements
(air velocity)
Conclusion:
• ‚Single pot processing‘ not feasible, but
• need to separate into two process steps of
• particle formation and
• dynamic bulk freeze drying
• to achieve product movement by air fluidization:
possible, but inefficient (design constraints)
6 © MERIDION Technologies GmbH
Two new Process Steps :
Spray Freezing & Dynamic Bulk FD
A: Spray Freezing:
Frozen microspheres are generated as bulk by
dispersing the substrate liquid using frequency
nozzles into single droplets, which by gravity pass
through a cooling zone, congealing to frozen
spheres (ambient pressure).
B: Dynamic Bulk Freeze Drying:
free flowing frozen bulkware is lyophilized in a
rotational vacuum freeze dryer under constant
gentle mixing.
Sublimation energy is transferred by radiation and
temperature controlled surfaces.
7 © MERIDION Technologies GmbH
Spray Freezing
Generation of frozen bulk product
insulation
temperature
probes
double wall
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(nozzle)
© MERIDION Technologies GmbH
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Spray Freezing: Droplet Generation
Controlled laminar jet break up
• droplet generation by frequency
(but low shear/pressure stress)
• droplet size: 250 µm ….. 1000 µm
• in-process – control (# of droplets)
• throughput : 1 – 1,8 l/h / nozzle
(droplet size vs throughput)
• formulation requirements
© MERIDION Technologies GmbH
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Spray Freezing
Temperature Profile during Freezing
© MERIDION Technologies GmbH
• frozen pellets in the
required particle size (no milling or sieving required)
• homogeneous (e.g. in size,
composition, nucleation)
• dust free
• good flowability
• small particles
with large surface
– large surface area for mass and heat transfer
– short diffusion length for water vapour
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Spray Freezing
Resulting Product Properties
© MERIDION Technologies GmbH
Product is in constant movement
• the entire surface is available for heat and
mass transfer
• intrinsically, the process provides for
product homogeneity and constant
homogeneous process conditions for the
entire batch
• allows direct measurement of product
(environment) temperature
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Dynamic Freeze Drying
Bulk Freeze drying in a Rotating Drum
© MERIDION Technologies GmbH
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Dynamic Freeze Drying
Rotary Freeze Dryer for Bulk Freeze Drying
Main components:
• vacuum housing with
• rotating drum;
• condensor;
• heat source(s)
© MERIDION Technologies GmbH
charging rotary joint
condensor discharging
cantilevered
drum
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Dynamic Freeze Drying
Drying Profile (without pressure regulation)
© MERIDION Technologies GmbH
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Dynamic Freeze Drying
Product Movement During Drying
© MERIDION Technologies GmbH
Product properties (freeze dried 20%sucrose solution)
• good flowability
• residual moisture < 1%
• bulk density: 0.18 g/cm³
• dust free
• yield 95.6 %
• narrow particle size distribution
16 © MERIDION Technologies GmbH
• increased heat & mass transfer (30 – 50% drying time reduction)
• homogenous drying conditions due to constant, gentle mixing of product (no edge effects as compared to conventional shelf freeze drying)
• direct measurement of process relevant parameters
• visual inspection of product flow behavior (stickiness if exceeding glass transition temperature)
• contained charging and discharging possible
• formulation requirements (size of particles vs vapour flow; binding agent)
• in process-adjustments of sublimation rate (to prevent vapor-based entrapment of pellets)
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Dynamic Freeze Drying
Process Characteristics
© MERIDION Technologies GmbH
Innovative Bulk Freeze Drying of Microspheres
Case Study of an
Integrated Manufacturing Line
18 © MERIDION Technologies GmbH
• Process Line Setup
• Product Handling /
Containment Aspects
• Innovation Potential
Process Line Setup
Transfer Liquid Vessel : Nozzle
Spray congealing chamber
Transfer to dryer, incl. vacuum flap
Rotary freeze dryer w. closed charging
& closed discharging
Transfer tube
Discharge vessel &
filling of IBCs
19 © MERIDION Technologies GmbH
• integration of two main process
steps:
particle generation & dynamic
freeze drying incl. transfer
• product flow by gravity & internal
drum discharging; no need for
loading/unloading in sterile area
• process line with total containment
(incl. WiP/CiP & SiP)
• no open handling of
product: room classification
(cost impact, e.g. on analytics)
Process Line Setup
Process Line Characteristics
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Production size process line
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freezing chamber with
spray section
and
cooling area
transfer section to
dryer
rotary freeze dryer with
double wall drum
and IR heating radiators
discharge section to
intermediate hopper
for discharge
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© MERIDION Technologies GmbH
Production size process line
Freezing chamber
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Freezing Chamber Spray
Section
with
• liquid feed
by peristaltic pump
• 4 frequency nozzles
• droplet counter for IPC
• CiP / SiP feed lines
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© MERIDION Technologies GmbH
Production size process line:
Rotary freeze dryer
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Rotary Freeze Dryer with
• double wall
vacuum housing
• cantilevered double
wall drum
with mixing baffles &
discharge scoops
• CiP/ SiP feed lines
• designed for 100 l (liquid)
range: 10l …. 150 l
scale up considerations
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Production size process line:
Rotary freeze dryer, front section
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Front Lid of Rotary
Freeze Dryer with
• charge tube from
transfer section for
gravity drum loading
• IR radiator, fully glass
covered & temp.
controlled
• discharge funnel for
contained discharge
by reverse roatation
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Scale Down of Technologies
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• technologies available in Lab Size
• min. load ca. 150 / 200 ml, up to ca. 1 l (liquid)
• for feasibility testing © MERIDION Technologies GmbH
(1) (process)
(2) product related
(3) free flowing, dust free
lyophilized bulkware
Innovation Potential:
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Innovation Potential
Product
• high homogeneity (e.g. nucleation uniformity)
• physical properties allow
for accurate filling
• reduction of reconstitution time due to large surface
• filling of different products
(compounding)
• Solid Dos. Form technologies
applicable (e.g. coating, ODT formulations)
• suited for Containment applications (dust free appearance)
27 © MERIDION Technologies GmbH
Innovation Potential
Lyophilized Bulkware
• physical properties are prere-
quisite for subsequent filling
• homogeneous,lyophilized bulk-
ware allows for
• filling on demand (indepen-
dent of liquid prep. process)
• dosing flexibility
• no need for primary packaging
to be suited for the lyophilization
process (e.g. vial to vial variability)
• allows for reduced time to market
or DS cold chain requirement
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© MERIDION Technologies GmbH
Conclusion
Dynamic freeze drying resulting in free flowing,
dust free bulkware allows for
• product innovation
• process innovation
process specific aspects
• manufacturing logistics innovation:
fill
– when …….
– how much..
– of what …..
– into what ...
you want
29 © MERIDION Technologies GmbH
Acknowledgements
30 © MERIDION Technologies GmbH
• Matthias Plitzko
• Thomas Gebhard
(Meridion Technologies)
• Serguei Tchessalov
(Pfizer Inc)
contact: