Hudson Valley LyoMac Webinar -May 30, 2018 Continuous Lyophilization of Pharmaceutical Products in Unit Doses Roberto Pisano Department of Applied Science and Technology P OLITECNICO di T ORINO e-mail: roberto.pisano@polito.it Bernhardt Trout Department of Chemical Engineering M ASSACHUSETTS I NSTITUTE OF T ECHNOLOGY e-mail: trout@mit.edu
Background & Problem statement Blue-sky thinking Continuous ous Manufa factu cturin ring QbD & PAT Traditional Batch Seamlessly integrated & full Manufacturing characterized process Understanding role and impact of individual steps Disconnected process steps Near future Past Present >2020 2
Batch freeze-drying Almost 50% of biopharmaceuticals listed by FDA and EMA is lyophilized, proving that freeze-drying is the preferred way to stabilize large molecules that are not stable in liquid, despite its high energy consumptions and long processing time. Freeze-drying of pharmaceuticals is performed batch-wise Long and expensive process heterogeneity vial-to-vial Heat and mass transfer is not uniform within the batch of vials Heterogeneity in freezing behavior Heterogeneity in drying behavior Poor control of product quality Examples of lyophilized samples belonging to 3 the same lot of production
Drawbacks of batch freeze-drying Heterogeneity in freezing behavior … temperature of nucleation is not uniform within the batch of vials, but is stochastically distributed, Distribution of the nucleation temperature as observed in a batch freeze-drying cycle 4
Drawbacks of batch freeze-drying Heterogeneity in freezing behavior … temperature of nucleation is not uniform within the batch of vials, but is stochastically distributed ice structure and, hence, cake morphology changes from vial to vial T n = -10 ° C T n = -15 ° C 1 00 m 1 00 m SEM micrographs of mannitol 5% as produced by batch freeze-drying 5
Drawbacks of batch freeze-drying Heterogeneity in freezing behavior … temperature of nucleation is not uniform within the batch of vials, but is stochastically distributed ice structure and, hence, cake morphology changes from vial to vial both primary and secondary drying behavior change from vial to vial vial-to-vial variations in polymorphs composition large distributions in residual moisture and potentially in API activity/stability Continuous freeze-drying might be beneficial to … achieve a narrow distribution in nucleation temperature make the frozen product morphology more uniform make drying behavior more uniform among the vials of the batch reduce vial-to-vial heterogeneity 6
Drawbacks of batch freeze-drying Heterogeneity in heat transfer … 25 1 20 2 K v , W m -2 K -1 15 3 4 10 5 5 6 7 6 7 12 345 0 K J I H G F E D C B A Spatial and statistical distribution of the heat transfer coefficient, between shelf and container, within a batch of vials. Data refer to primary drying, 10 Pa as chamber pressure 7
Drawbacks of batch freeze-drying Heterogeneity in heat transfer … Evolution of pressure ratio as observed in Statistical distribution of the residual a batch freeze-dryer moisture within the lyophilized samples (sucrose 5%) at the end of primary drying 8
Drawbacks of batch freeze-drying Variations in product morphology due to freezing Variations in the residual moisture at the end of primary drying Variations in the residual moisture at the end of secondary drying Statistical distribution of residual moisture within the lyophilized samples (sucrose 5%) as observed at the end of secondary drying The extent of heterogeneity in freezing and drying behavior is equipment-specific. A cycle developed in a laboratory freeze-dryer cannot be transferred without modifications to the production unit → scale up 9
A new concept for the continuous freeze- drying of unit doses O BJECTIVE : development of a continuous freeze-dryer that produces a final product having similar properties and structures to those obtained by a conventional batch unit. VACUUM PRIMARY SECONDAR CONDITIO BACK/STO FILLING CHAMBE DRYING Y DRYING N-ING PPERING R MODULE MODULE 10
A new concept for the continuous freeze- drying of unit doses O BJECTIVE : development of a continuous freeze-dryer that produces a final product having similar properties and structures to that obtained by a conventional batch unit. VACUUM PRIMARY SECONDAR CONDITIO BACK/STO FILLING CHAMBE DRYING Y DRYING N-ING PPERING R MODULE MODULE 11
A new concept for the continuous freeze- drying of unit doses Filling and Loading Moving of vials Conditioning module Nucleation module Freezing module Primary drying module Secondary drying module The continuous flow of vials is achieved by suspending the vials over a track → uniformity in heat transfer 12
A new concept for the continuous freeze- drying of unit doses Filling and Loading Conditioning module Nucleation module Freezing module Primary drying module Secondary drying module 13
A new concept for the continuous freeze- drying of unit doses Example of nucleation Filling and Loading chambers Conditioning module Nucleation module Freezing module Primary drying module Secondary drying module 14
A new concept for the continuous freeze- drying of unit doses Filling and Loading The nucleated solution is Conditioning module further cooled by forced Nucleation module convection until the its Freezing module complete solidification. Primary drying module Secondary drying module The external surface of the vessel is equally Cold air INLET “WARM”air OUTLET (from the flushed by the cryogenic (to the cooling system) cooling gas. system) Different freezing protocols can be performed modulating temperature and velocity of cryogenic gas. 15
A new concept for the continuous freeze- drying of unit doses In the primary drying module … Filling and Loading Conditioning module Nucleation module Vials are exposed to low Freezing module temperature and pressure Primary drying module Heat is transferred by Secondary drying module radiation from temperature- controlled surfaces Vacuum system (condenser + vacuum pump) Cooling/heating system Sluice-gate/load-lock 16
A new concept for the continuous freeze- drying of unit doses Filling and Loading Conditioning module In the secondary drying module Nucleation module … Freezing module Primary drying Vials are exposed to high Secondary drying module temperature and low pressure so as to promote desorption of bounded water Vacuum system (condenser + vacuum pump) Cooling/heating system Sluice-gate/load-lock Stoppering/sealing 17
A new concept for the continuous freeze- drying of unit doses Flexibility & Modularity The various modules can be combined to make the system more flexible and treating products from different upstream feeds. 18
Experimental results Product morphology More precise control of freezing conditions Larger pores and hence smaller resistance to mass transfer during primary drying Batch Continuous SEM images of lyophilized mannitol samples produced on constant drying conditions. Images refer to the same enlargement 19
Experimental results Product morphology More precise control of freezing conditions Larger pores and hence smaller resistance to mass transfer during primary drying Intra-vial heterogeneity is less evident Batch top Continuous center bottom SEM images of lyophilized mannitol samples 20
Experimental results Primary drying & heat transfer 21
Experimental results Primary drying Freeze-drying of sucrose (5% w/w) in R10 vials, fill volume is 2 mL Process Controlled Drying Onset-offset Max product temp., ° C freezing time, h time, h Batch No 18 2.9 -33 Continuous No 8 0.9 -33 Continuous Yes 5 0.5 -34 A similar result was experimentally observed for other formulations containing mannitol, lactose, phosphate buffer and a higher solid content. 22
Experimental results Process performances Larger pores and hence shorter primary drying Breaks of a typical batch production can be 20% to 50% of the total cycle time The overall cycle time is up to 5 times shorter Defrost/CIP/ Secondary Soak time Unloading SIP/H2O2 Leak test Freezing Loading Primary Closing drying drying ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ Batch 5 h 2-3 h 6 h LONG 6 h 1 h 6 h 6 h SHORT ✓ ✓ ✓ Continuous < 1 h SHORTER SHORTER 23
Experimental results Process performances Process performances Larger pores and hence shorter primary drying Breaks of a typical batch production can be 20% to 50% of the total cycle time The overall cycle time is up to 5 times shorter Distribution of the residual moisture at the end of drying is more uniform Batch Continuous Distribution of the final residual moisture for sucrose 5% at the end of primary drying 24
Experimental results Process performances Process performances Larger pores and hence shorter primary drying Breaks of a typical batch production can be 20% to 50% of the total cycle time The overall cycle time is up to 5 times shorter Distribution of the residual moisture at the end of drying is more uniform Batch Continuous Distribution of the final residual moisture for sucrose 5% at the end of secondary drying 25
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