Considerations for the Terminal Sterilization of Oligonucleotide Drug Products
Open accessAbstract
A primary function of the parenteral drug product manufacturing process is to ensure sterility of the final product. The two most common methods for sterilizing parenteral drug products are terminal sterilization (TS), whereby the drug product is sterilized in the final container following filling and finish, and membrane sterilization, whereby the product stream is sterilized by membrane filtration and filled into presterilized containers in an aseptic processing environment. Although TS provides greater sterility assurance than membrane sterilization and aseptic processing, not all drug products are amenable to TS processes, which typically involve heat treatment or exposure to ionizing radiation. Oligonucleotides represent an emerging class of therapeutics with great potential for treating a broad range of indications, including previously undruggable targets. Owing to their size, structural complexity, and relative lack of governing regulations, several challenges in drug development are unique to oligonucleotides. This exceptionality justifies a focused assessment of traditional chemistry, manufacturing, and control strategies before their adoption. In this article, we review the current state of sterile oligonucleotide drug product processing, highlight the key aspects to consider when assessing options for product sterilization, and provide recommendations to aid in the successful evaluation and development of TS processes. We also explore current regulatory expectations and provide our interpretation as it pertains to oligonucleotide drug products.
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Stringent isolation and purification processes are necessary for the clinical application of bioactive nucleic acids to ensure high purity, sterility, and product consistency.
“The clinical application of bioactive nucleic acids necessitates stringent isolation and purification processes to ensure high purity, sterility, and product consistency [20,159].”
From Comparison of Polynucleotide and Polydeoxyribonucleotide in Dermatology: Molecular Mechanisms and Clinical Perspectives (2025) · cites this paper as [159]
The Introduction’s “Sterile drug product manufacturing” section describes chromatographic purification of oligonucleotides and a separate membrane-filtration and aseptic-filling process to ensure sterility. The “Acceptable impurity levels following TS” section discusses impurity control and consistently meeting quality standards. The source supports those manufacturing goals for oligonucleotide drugs, but does not establish that stringent isolation and purification processes themselves ensure sterility across bioactive nucleic acids generally. (LLM, conf=0.82)
Experimental — accuracy not yet measuredThe chemical method for isolating PDRN from salmon is cost-effective and technically accessible.
“While the chemical method is cost-effective and technically accessible”
From Comparison of Polynucleotide and Polydeoxyribonucleotide in Dermatology: Molecular Mechanisms and Clinical Perspectives (2025) · cites this paper as [159]
The Introduction and Problem Statement discuss oligonucleotide formulations and terminal sterilization, not isolation of PDRN from salmon. Searches for PDRN, salmon extraction, and the chemical method found no passage addressing its cost or technical accessibility. The available passages provide no basis to verify the claim. (LLM, conf=0.76)
Experimental — accuracy not yet measuredThe chemical method for isolating PDRN involves multiple steps including thawing, cell lysis, sterilization, molecular weight reduction, precipitation, and granulation.
“it involves multiple steps including thawing, cell lysis, sterilization, molecular weight reduction, precipitation, and granulation”
From Comparison of Polynucleotide and Polydeoxyribonucleotide in Dermatology: Molecular Mechanisms and Clinical Perspectives (2025) · cites this paper as [159]
The Introduction’s “Sterile drug product manufacturing” section describes oligonucleotide formulation, membrane filtration, and aseptic filling, not chemical isolation of PDRN. Searches for PDRN, thawing, cell lysis, molecular-weight reduction, precipitation, and granulation found no passage describing the claimed sequence of steps. (LLM, conf=0.76)
Experimental — accuracy not yet measuredTwo primary extraction methods, chemical and non-organic, are used for isolating PDRN from salmon sources.
“Two primary extraction methods, namely chemical and non-organic approaches, are used for isolating PDRN from salmon sources.”
From Comparison of Polynucleotide and Polydeoxyribonucleotide in Dermatology: Molecular Mechanisms and Clinical Perspectives (2025) · cites this paper as [159]
The Extractables and leachables section discusses chemicals extracted from drug-product packaging, not isolation of PDRN from salmon. Searches for PDRN, salmon, and chemical versus non-organic extraction found no passage addressing the claimed methods; the paper’s Preamble identifies its subject as terminal sterilization of oligonucleotide drug products. Page numbers were not available in our copy. (LLM, conf=0.76)
Experimental — accuracy not yet measuredThe chemical method for isolating PDRN often yields a broad molecular weight distribution.
“often yields a broad molecular weight distribution [159,160,161]”
From Comparison of Polynucleotide and Polydeoxyribonucleotide in Dermatology: Molecular Mechanisms and Clinical Perspectives (2025) · cites this paper as [159]
The Introduction discusses oligonucleotide therapeutics, and the degradation overview discusses breakdown products during sterilization; neither addresses chemical isolation of PDRN. Searches for PDRN, chemical extraction, and molecular-weight distribution found no passage supporting the claimed outcome. (LLM, conf=0.75)
Experimental — accuracy not yet measured
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Cited by
Sorted by citations
Kim, S. T. (2025) · Pharmaceutics · doi:10.3390/pharmaceutics17081024 · Cited by 18 · see citing works
- Authors
- Decollibus, D. P., Searcy, J., Tivesten, A., Akhtar, N., Lindenberg, C., Abarrou, N., Pradhan, S., Fiandaca, M., Franklin, J., Govindan, G., Liu, H.-Y., Royle, D., Soo, P. L., & Storch, K.
- Affiliations
- Amgen (United States) (US)
- Ionis Pharmaceuticals (United States) (US)
- AstraZeneca (Sweden) (SE)
- AstraZeneca (United Kingdom) (GB)
- Novartis (Switzerland) (CH)
- GlaxoSmithKline (United States) (US)
- Biogen (United States) (US)
- Pfizer (United States) (US)
- Pharma Technical Development, Roche Diagnostics GmbH, Mannheim, Germany.
- Corresponding author
- Searcy, Justin
- Venue
- Nucleic Acid Therapeutics
- Publisher
- SAGE Publications
- Published
- 2023-06-01
- Volume
- 33
- Issue
- 3
- Pages
- 159-177
- ISSN
- 2159-3337 (ISSN-L)
- 2159-3345
- PMC
- PMC10277985
- OpenAlex
- W4320719369
- Cited by
- 17
- References
- 24
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 5 · 2023: 1
- FWCI
- 2.20
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Nucleic Acid Therapeutics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- The Novartis Repository (Novartis) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Microbial Inactivation Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Chemistry › Analytical Chemistry › Analytical Methods in Pharmaceuticals
- Keywords
- terminal sterilization, oligonucleotide therapeutics, parenteral products, sterility assurance, membrane sterilization, aseptic processing, heat treatment (food and biological processing), ionizing radiation, chemistry, manufacturing and controls, regulatory expectations
- MeSH terms
- Pharmaceutical Preparations, Oligonucleotides, Sterilization
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