8 Pharmaceutical Technology
®
Innovations in mRNA eBook April 2024 PharmTech.com
А
Л
Е
К
С
А
Н
Д
Р
Б
Е
С
П
А
Л
Ы
Й
-
STOCK.ADOBE.COM
Cynthia A. Challener, PhD,
is a contributing editor to
Pharmaceutical Technology®.
Increasing mRNA
Product Stability
with Lyophilization
Developing freeze-drying processes requires patience and deep product and process understanding.
M
essenger RNA (mRNA) molecules are in-
herently unstable and readily degrade
when exposed to ubiquitous enzymes such
as RNase and undergo pH-dependent hy-
drolysis of phosphorus-oxygen bonds when exposed
to water. That instability creates challenges for
manufacturing, formulation, storage, and transport
of mRNA-based vaccines and therapeutics. While
encapsulation of mRNA drug substances in lipid
nanoparticles (LNPs) enhances their stability (and
facilitates their delivery into cells), mRNA-LNP prod-
ucts still typically require low-temperature storage
and present distribution challenges in areas where
cold-chain management is limited.
One solution for overcoming mRNA instability is
lyophilization, or freeze-drying, which is used in the
manufacture of many biologic and small-molecule
drugs that exhibit instability in aqueous solutions.
Lyophilization involves the removal of frozen water
(ice crystals) via sublimation under vacuum at low
temperature to ideally produce a solid cake that typ-
ically can be stored at room temperature for extended
periods. The challenge with mRNA-LNP products is
to find the right lyophilization conditions that do not
harm the product particles (change their size and
polydispersity, among other attributes) and produce
a solid with desirable properties.
While there was insufficient time during develop-
ment of the mRNA-LNP COVID-19 vaccines to identify
an effective lyophilization process, several compa-
nies have since then developed effective lyophiliza-
tion solutions. Pfizer/BioNTech and Moderna are two
