The Storage and In-Use Stability of mRNA Vaccines and Therapeutics: Not A Cold Case

Erik Oude Blenke; Eivor Örnskov; Christian Schöneich; Gunilla A Nilsson; David B Volkin; Enrico Mastrobattista; Örn Almarsson; Daan J A Crommelin

doi:10.1016/j.xphs.2022.11.001

The Storage and In-Use Stability of mRNA Vaccines and Therapeutics: Not A Cold Case

Erik Oude Blenke
, Eivor Örnskov
, Christian Schöneich
, Gunilla A Nilsson
, David B Volkin
, Enrico Mastrobattista
, Örn Almarsson
, Daan J A Crommelin

Research output: Contribution to journal › Review article › peer-review

Abstract

The remarkable impact of mRNA vaccines on mitigating disease and improving public health has been amply demonstrated during the COVID-19 pandemic. Many new mRNA-based vaccine and therapeutic candidates are in development, yet the current reality of their stability limitations requires their frozen storage. Numerous challenges remain to improve formulated mRNA stability and enable refrigerator storage, and this review provides an update on developments to tackle this multi-faceted stability challenge. We describe the chemistry underlying mRNA degradation during storage and highlight how lipid nanoparticle (LNP) formulations are a double-edged sword: while LNPs protect mRNA against enzymatic degradation, interactions with and between LNP excipients introduce additional risks for mRNA degradation. We also discuss strategies to improve mRNA stability both as a drug substance (DS) and a drug product (DP) including the (1) design of the mRNA molecule (nucleotide selection, primary and secondary structures), (2) physical state of the mRNA-LNP complexes, (3) formulation composition and purity of the components, and (4) DS and DP manufacturing processes. Finally, we summarize analytical control strategies to monitor and assure the stability of mRNA-based candidates, and advocate for an integrated analytical and formulation development approach to further improve their storage, transport, and in-use stability profiles.

Original language	English
Pages (from-to)	386-403
Number of pages	18
Journal	Journal of Pharmaceutical Sciences
Volume	112
Issue number	2
Early online date	16 Nov 2022
DOIs	https://doi.org/10.1016/j.xphs.2022.11.001
Publication status	Published - Feb 2023

Bibliographical note

Publisher Copyright:
© 2022 The Authors

Funding

DBV acknowledges support of the Bill & Melinda Gates Foundation [INV-038051]. Under the grant conditions of the Foundation, a Creative Commons Attribution 4.0 Generic License has already been assigned to the Author Accepted Manuscript version that might arise from this submission.

Funders	Funder number
Bill and Melinda Gates Foundation	INV-038051

Keywords

Degradation mechanisms
Formulation
Impurities
Ionizable lipid
LNP
Lipid nanoparticles
Physical and chemical analysis
Shelf life
Stability
Vaccine
mRNA structure

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.xphs.2022.11.001Licence: CC BY

1-s2.0-S0022354922005147-mainFinal published version, 1.25 MBLicence: CC BY

Cite this

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abstract = "The remarkable impact of mRNA vaccines on mitigating disease and improving public health has been amply demonstrated during the COVID-19 pandemic. Many new mRNA-based vaccine and therapeutic candidates are in development, yet the current reality of their stability limitations requires their frozen storage. Numerous challenges remain to improve formulated mRNA stability and enable refrigerator storage, and this review provides an update on developments to tackle this multi-faceted stability challenge. We describe the chemistry underlying mRNA degradation during storage and highlight how lipid nanoparticle (LNP) formulations are a double-edged sword: while LNPs protect mRNA against enzymatic degradation, interactions with and between LNP excipients introduce additional risks for mRNA degradation. We also discuss strategies to improve mRNA stability both as a drug substance (DS) and a drug product (DP) including the (1) design of the mRNA molecule (nucleotide selection, primary and secondary structures), (2) physical state of the mRNA-LNP complexes, (3) formulation composition and purity of the components, and (4) DS and DP manufacturing processes. Finally, we summarize analytical control strategies to monitor and assure the stability of mRNA-based candidates, and advocate for an integrated analytical and formulation development approach to further improve their storage, transport, and in-use stability profiles.",

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doi = "10.1016/j.xphs.2022.11.001",

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T2 - Not A Cold Case

AU - Oude Blenke, Erik

AU - Örnskov, Eivor

AU - Schöneich, Christian

AU - Nilsson, Gunilla A

AU - Volkin, David B

AU - Mastrobattista, Enrico

AU - Almarsson, Örn

AU - Crommelin, Daan J A

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AB - The remarkable impact of mRNA vaccines on mitigating disease and improving public health has been amply demonstrated during the COVID-19 pandemic. Many new mRNA-based vaccine and therapeutic candidates are in development, yet the current reality of their stability limitations requires their frozen storage. Numerous challenges remain to improve formulated mRNA stability and enable refrigerator storage, and this review provides an update on developments to tackle this multi-faceted stability challenge. We describe the chemistry underlying mRNA degradation during storage and highlight how lipid nanoparticle (LNP) formulations are a double-edged sword: while LNPs protect mRNA against enzymatic degradation, interactions with and between LNP excipients introduce additional risks for mRNA degradation. We also discuss strategies to improve mRNA stability both as a drug substance (DS) and a drug product (DP) including the (1) design of the mRNA molecule (nucleotide selection, primary and secondary structures), (2) physical state of the mRNA-LNP complexes, (3) formulation composition and purity of the components, and (4) DS and DP manufacturing processes. Finally, we summarize analytical control strategies to monitor and assure the stability of mRNA-based candidates, and advocate for an integrated analytical and formulation development approach to further improve their storage, transport, and in-use stability profiles.

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KW - Impurities

KW - Ionizable lipid

KW - LNP

KW - Lipid nanoparticles

KW - Physical and chemical analysis

KW - Shelf life

KW - Stability

KW - Vaccine

KW - mRNA structure

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The Storage and In-Use Stability of mRNA Vaccines and Therapeutics: Not A Cold Case

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

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