Boston, May 17 th, 2016 2016 AAPS National Biotechnology Conference Session: Next-Generation Drying Technologies for Processing of Biotherapeutics (#118) Innovative Bulk Drying of Frozen Microspheres by Spray-Freeze-Drying 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
BioTherapeutics Pharmaceutical Sciences 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 Recent literature on spray-freeze drying 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-freezedrying method and evaluation of survival in simulated gastrointestinal conditions. J Microencapsul 28(6):568 574
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
Background / History: Specific past R&D work performed 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 5
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 (T p : <-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
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
Spray Freezing Generation of frozen bulk product (nozzle) insulation temperature probes double wall 8
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 9
Spray Freezing Temperature Profile during Freezing 10
Spray Freezing Resulting Product Properties 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
Dynamic Freeze Drying Bulk Freeze drying in a Rotating Drum 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 Rotary Freeze Dryer for Bulk Freeze Drying Main components: vacuum housing with rotating drum; condensor; heat source(s) charging rotary joint cantilevered drum discharging condensor 13
Dynamic Freeze Drying Drying Profile (without pressure regulation) 14
Dynamic Freeze Drying Product Movement During Drying 15
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
Dynamic Freeze Drying Process Characteristics 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
Innovative Bulk Freeze Drying of Microspheres Case Study of an Integrated Manufacturing Line Process Line Setup Product Handling / Containment Aspects Innovation Potential 18
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
Process Line Setup Process Line Characteristics 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) 20
Production size process line 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 21
Production size process line Freezing chamber Freezing Chamber Spray Section with liquid feed by peristaltic pump 4 frequency nozzles droplet counter for IPC CiP / SiP feed lines 22 22
Production size process line: Rotary freeze dryer Rotary Freeze Dryer with 23 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 23
Production size process line: Rotary freeze dryer, front section 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 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
Innovation Potential: (1) (process) (2) product related (3) free flowing, dust free lyophilized bulkware 26
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
Innovation Potential Lyophilized Bulkware physical properties are prerequisite for subsequent filling homogeneous,lyophilized bulkware allows for filling on demand (independent 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 29
Acknowledgements Matthias Plitzko Thomas Gebhard (Meridion Technologies) Serguei Tchessalov (Pfizer Inc) contact: bernhard.luy@meridion-technologies.de 30