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. 2020 Aug;30(4):189-197.
doi: 10.1089/nat.2020.0846. Epub 2020 May 6.

Technical Considerations for Use of Oligonucleotide Solution API

Jale Muslehiddinoglu  1 , Robert Simler  2 , Malcolm L Hill  3 , Claudia Mueller  4 , John H A Amery  5 , Leigh Dixon  6 , Anna Watson  6 , Kirsten Storch  4 , Cinzia Gazziola  4 , Frank Gielen  7 , Stefan Andreas Lange  8 , Jeremy D Prail  9 , Doug P Nesta  10
Affiliations

Technical Considerations for Use of Oligonucleotide Solution API

Jale Muslehiddinoglu et al. Nucleic Acid Ther. 2020 Aug.

Abstract

The most common approach for the manufacture of oligonucleotides includes isolation of the active pharmaceutical ingredient (API) via lyophilization to provide a solid product, which is then dissolved to provide an aqueous formulation. It is well known from the development and manufacture of large molecules ("biologics") that API production does not always require isolation of solid API before drug product formulation, and this article provides technical considerations for the analogous use of oligonucleotide API in solution. The primary factor considered is solution stability, and additional factors such as viscosity, concentration, end-to-end manufacturing, microbiological control, packaging, and storage are also discussed. The technical considerations discussed in this article will aid the careful evaluation of the relative advantages and disadvantages of solution versus powder API for a given oligonucleotide drug substance.

Keywords: lyophilization; oligonucleotides; solution API.

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Conflict of interest statement

J.M. and F.G. are employed by Janssen; R.S. is employed by Amgen; M.L.H. retired from GlaxoSmithKline; J.H.A.A. is employed by Pfizer; C.M., C.G., and K.S. are employed by F. Hoffmann-La Roche Ltd.; A.W. and L.D. are employed by AstraZeneca; S.A.L. is employed by Sanofi; and J.D.P and D.P.N. are employed by GlaxoSmithKline. No competing financial interests exist.

Figures

FIG. 1.
FIG. 1.
The typical unit operations for the manufacture of oligonucleotide API. API, active pharmaceutical ingredient.
FIG. 2.
FIG. 2.
Schematic of drug product process for powder API and solution API.
See this image and copyright information in PMC

References

    1. Tivesten A, Aktar N, Stolee J, Fillon Y, Orr R, Hill ML, Van den Bergh L, Huybrechts T, Muslehiddinoglu J, et al. (2018). European Pharma Oligonucleotide Consortium a move to consolidate oligonucleotide knowledge and share experience within the community. Ther Innov Regul Sci 52:687–688 - PubMed
    1. Khvorova A and Watts JK (2017). The chemical evolution of oligonucleotide therapies in clinical utility. Nat Biotechnology 35:238–248 - PMC - PubMed
    1. Lundin KE, Gisberg O and Smith CI (2015). Oligonucleotide therapies: the past and present. Hum Gene Ther 26:475–485 - PMC - PubMed
    1. PharmaCircle February 2019
    1. Elzahar NM, Magdy N, El-Kosasy MA and Bartlett MG (2018). Degradation product characterization of therapeutic oligonucleotides using liquid chromatography mass spectrometry. Anal Bioanal Chem 14:3375–3384 - PubMed

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