Development of freeze-drying cycle via design space approach: a case study on vaccines

Abstract

Freeze-drying is a dehydration process that provides improved stability of vaccine formulations for shipment and storage. During the primary drying steps of the process, product temperature has to be maintained below a critical value to avoid visual defects of the product, leading to an increase of the sublimation time and thus of the operational costs. In this work, we used the design space approach together with experimental analysis for the development of the primary drying step of a vaccine model formulation. First, the formulation was characterized by determining the glass transition and the collapse temperatures. Successively, the dynamic design space of primary drying was calculated via mathematical modelling, and a proven acceptable range (PAR) was defined around the selected operating values. Finally, the cycle and the PAR were validated by performing a freeze-drying cycle at pilot scale and by evaluating the values of the product critical quality attributes (e.g. moisture content, visual aspect, reconstitution time).

Keywords:

• freeze-drying
• lyophilization
• vaccines
• drying
• sucrose
• glass transition
• mechanistic modeling
• mathematical modeling
• quality by design

Acknowledgments

The authors thank Stephanie Passot, Fernanda Fonseca and Ioan Cristian Trelea (UMR GMPA, INRA/AgroParisTech) for their contribution in the development of the mathematical model, the team of Drying and Related Modeling Technologies (Drug Product, TRD Belgium, GSK) for the support in performing the experimental tests and Pascal Cadot, Yves Mayeresse and Alice Loper (GSK Vaccines) for reviewing the manuscript.

Author contributions

Bernadette Scutellà and Erwan Bourlès, were involved in the conception and design of the study. Bernadette Scutellà acquired the data, analyzed and interpreted the experimental results. Both authors were involved in drafting the manuscript or revising it critically for important intellectual content. Both authors had full access to the data and approved the manuscript before it was submitted by the corresponding author.

Disclosure statement

Erwan Bourlès and Bernadette Scutellà are employees of the GSK group of companies.

Additional information

Funding

This work was sponsored by GlaxoSmithKline Biologicals SA.