innovative bulk drying of frozen microspheres by spray ... · pdf filemicrospheres for...

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


Background / History:

Specific past R&D work performed

5

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


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)


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.


Spray Freezing

Generation of frozen bulk product

insulation

temperature

probes

double wall

8

(nozzle)

© MERIDION Technologies GmbH

9

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


10

Spray Freezing

Temperature Profile during Freezing


• 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

11

Spray Freezing

Resulting Product Properties


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

12

Dynamic Freeze Drying

Bulk Freeze drying in a Rotating Drum


13


Rotary Freeze Dryer for Bulk Freeze Drying

Main components:

• vacuum housing with

• rotating drum;

• condensor;

• heat source(s)


charging rotary joint

condensor discharging

cantilevered

drum

14


Drying Profile (without pressure regulation)


15


Product Movement During Drying


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


• 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)

17


Process Characteristics


Innovative Bulk Freeze Drying of Microspheres

Case Study of an

Integrated Manufacturing Line


• 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


• 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


Production size process line

21

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

21


Production size process line

Freezing chamber

22

Freezing Chamber Spray

Section

with

• liquid feed

by peristaltic pump

• 4 frequency nozzles

• droplet counter for IPC

• CiP / SiP feed lines

22


Production size process line:

Rotary freeze dryer

23

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


Production size process line:

Rotary freeze dryer, front section

24

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

24


Scale Down of Technologies

25

• 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:


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)


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

28


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


Acknowledgements


• Matthias Plitzko

• Thomas Gebhard

(Meridion Technologies)

• Serguei Tchessalov

(Pfizer Inc)

contact:

[email protected]

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