Dr Roberto Pisano of Politecnico di Torino Continuous Lyophilisation

3rd International Symposium on Continuous Manufacturing of Pharmaceuticals October 3-4, 2018, London, UK

CONTINUOUS LYOPHILISATION AND ITS RELEVANCE TO THE PRODUCTION OF PHARMACEUTICALS AND BIOPHARMACEUTICALS

Roberto Pisano Department of Applied Science and Technology POLITECNICO di TORINO E-mail: roberto.pisano@polito.it Tel. +39 011 0904679

Batch lyophilization Freeze–drying /Lyophilization is a process where water, or another solvent, is removed from a frozen solution at low temperature and pressure via sublimation A freeze–drying cycle encompasses three steps Freezing Primary drying Secondary drying Almost 50% of biopharmaceuticals listed by FDA and EMA is lyophi-lized, proving that freeze-drying is the preferred way to stabilize large molecules that are not stable in liquid, despite its high energy con-sumptions and long processing time.

R. Pisano Continuous lyophilisation and its relevance to the production of pharmaceuticals and biopharmaceuticals

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Continuous lyophilization Why? Freeze-drying of pharmaceuticals is performed batch-wise vial-to-vial heterogeneity

Long and expensive process 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 of individual vials

Examples of lyophilized samples belonging to the same lot of production R. Pisano Continuous lyophilisation and its relevance to the production of pharmaceuticals and biopharmaceuticals

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continuous manufacturing

Continuous lyophilization Why? Reduce the risk of product contamination

Modular and smaller equipment Eliminate scale-up from R&D to manufacturing Uniformity of the lot of production In-line control of product quality

continuous lyophilization

Process efficiency Manage variability

Uniformity in freezing behavior Uniformity in drying behavior

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Objectives

Continuous lyophilization How? Properties of the lyophilized product (SSA, reconstitution time, etc..) similar to those obtained by batch lyophilization No changes in formulation

Uniformity in heat and mass transfer Operating principle. Realize a continuous flow of vials, which undergoes the same freezing and drying conditions.

Vials are suspended over a track and continuously move through the equipment.

Example of load/lock systems

FILLING

FREEZING & CONDITIONING

DRYING MODULE

BACK/STOPPERING

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Continuous lyophilization Equipment design

Design of the continuous freeze-dryer (throughput: 50k vials/week) R. Pisano Continuous lyophilisation and its relevance to the production of pharmaceuticals and biopharmaceuticals

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Continuous lyophilization Functional prototype & Experimental set-up

experimental validation

experimental apparatus

temperature-controlled shelf

Crystallizable (mannitol) and amorphous (sucrose, trehalose and lactose) formulations Various solid contents (5%, 10% and 25%) Two types of vials (R4 and R10) Lactacte Dehydrogenase (LDH) as model API

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No. of via

80 Batch vs. continuous lyophilization 60 Freezing

40 In a conventional batch freeze-dryer20…

Continuous lyophilization can temperature of nucleation is not0uniform within the batch of vialsprecisely control nucleation time and temperature via VISF.

0 to vial 1 cake morphology changes from vial

2

3

4

Residual moisture , %

Tn = -10 °C

1 00 m

5

6

Tn = -15 °C

1 00 m

SEM micrographs of mannitol 5% as produced by batch freeze-drying R. Pisano Continuous lyophilisation and its relevance to the production of pharmaceuticals and biopharmaceuticals

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Batch vs. continuous lyophilization Freezing Batch Lyophilization

Continuous Lyophilization

▼ nucleation temperature

▲ nucleation temperature

▼ ice crystal size

▲ ice crystal size

▲ temperature gradient

▼ temperature gradient Smaller resistance to vapor flow Reduce drying time Reduce vial-to-vial heterogeneity Reduce intra-vial heterogeneity

SEM micrographs of mannitol 5% as produced by batch and continuous lyo R. Pisano Continuous lyophilisation and its relevance to the production of pharmaceuticals and biopharmaceuticals

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Continuous

Batch

Batch vs. continuous lyophilization Primary Drying

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Batch vs. continuous lyophilization Primary Drying

Batch

@ end of primary drying 5% sucrose

Continuous

@ end of primary drying 5% sucrose

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Batch vs. continuous lyophilization Secondary Drying

Batch

after 4 h of secondary drying 5% sucrose

Continuous

after 4 h of secondary drying 5% sucrose

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Batch

Batch vs. continuous lyophilization Process performances

Continuous

Timeline for the batch and continuous strategy.

Shorter primary drying time (3-5 times) Shorter secondary drying time (up to 10 times)

Smaller equipment size (up to 10-12 times) Uniformity in freezing and drying behavior Uniformity in residual moisture (variations within experimental uncertainty)

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Conclusions Reduce the risk of product contamination No manual handling, increased safety The processing time is shorter

Modular and smaller equipment and facilities More flexible operation Reduced inventory Lower capital costs, less work-in-progress materials

Eliminate scale-up from lab to production units Process flexibility Bulk vs. particle-based material Yield can be adjusted on market request

Improve product quality Uniformity of the lot of production In-line control of product quality R. Pisano Continuous lyophilisation and its relevance to the production of pharmaceuticals and biopharmaceuticals

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Acknowledgements

Politecnico di Torino Department of Applied Science and Technology Luigi C. Capozzi

Massachusetts Institute of Technology Department of Chemical Engineering Prof. Bernhardt Trout

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Continuous Lyophilisation and its relevance to the production of Pharmaceuticals and Biopharmaceuticals

Thanks for ‌ your attention!