Use of ultrafiltration/diafiltration for the processing of antisense oligonucleotides
Ultrafiltration/diafiltration (UF/DF) has been the hallmark for concentrating and buffer exchange of protein and peptide‐based therapeutics for years. Here we examine the capabilities and limitations of UF/DF membranes to process oligonucleotides using antisense oligonucleotides (ASOs) as a model. U...
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| Veröffentlicht in: | Biotechnology progress 2023-07, Vol.39 (4), p.e3350-n/a |
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| creator | Gronke, Robert S. Ruanjaikaen, Krisada Delavari, Armin Immel‐Brown, Jonas P. Penrod, Joseph C. Lam, Yik Antia, Firoz D. |
| description | Ultrafiltration/diafiltration (UF/DF) has been the hallmark for concentrating and buffer exchange of protein and peptide‐based therapeutics for years. Here we examine the capabilities and limitations of UF/DF membranes to process oligonucleotides using antisense oligonucleotides (ASOs) as a model. Using a 3 kDa UF/DF membrane, oligonucleotides as small as 6 kDa are shown to have low sieving coefficients ( |
| doi_str_mv | 10.1002/btpr.3350 |
| format | Article |
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Here we examine the capabilities and limitations of UF/DF membranes to process oligonucleotides using antisense oligonucleotides (ASOs) as a model. Using a 3 kDa UF/DF membrane, oligonucleotides as small as 6 kDa are shown to have low sieving coefficients (<0.008) and thus can be concentrated to high concentrations (≤200 mg/mL) with high yield (≥95%) and low viscosity (<15 centipoise), provided the oligonucleotide is designed not to undergo self‐hybridization. In general, the oligonucleotide should be at least twice the reported membrane molecular weight cutoff for robust retention. Regarding diafiltration, results show that a small amount of salt is necessary to maintain adequate flux at concentrations exceeding about 40 mg/mL. Removal of salts along with residual solvents and small molecule process‐related impurities can be robust provided they are not positively charged as the interaction with the oligonucleotide can prevent passage through the membrane, even for common divalent cations such as calcium or magnesium. Overall, UF/DF is a valuable tool to utilize in oligonucleotide processing, especially as a final drug substance formulation step that enables a liquid active pharmaceutical ingredient.</description><identifier>ISSN: 8756-7938</identifier><identifier>EISSN: 1520-6033</identifier><identifier>DOI: 10.1002/btpr.3350</identifier><identifier>PMID: 37186510</identifier><language>eng</language><publisher>Hoboken, USA: John Wiley & Sons, Inc</publisher><subject>Antisense oligonucleotides ; Antisense therapy ; Cations ; Divalent cations ; Hybridization ; Impurities ; Magnesium ; membrane polarization ; Membranes ; Molecular weight ; oligonucleotide ; Oligonucleotides ; Robustness ; Ultrafiltration ; ultrafiltration and diafiltration</subject><ispartof>Biotechnology progress, 2023-07, Vol.39 (4), p.e3350-n/a</ispartof><rights>2023 American Institute of Chemical Engineers.</rights><rights>2023 American Institute of Chemical Engineers</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3530-99a00d4fbed4329a5db331e63057e7bc29d4eeb51caf25ddc658c87072efe2a73</citedby><cites>FETCH-LOGICAL-c3530-99a00d4fbed4329a5db331e63057e7bc29d4eeb51caf25ddc658c87072efe2a73</cites><orcidid>0000-0001-6971-4536 ; 0000-0002-0630-7789</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fbtpr.3350$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fbtpr.3350$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37186510$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gronke, Robert S.</creatorcontrib><creatorcontrib>Ruanjaikaen, Krisada</creatorcontrib><creatorcontrib>Delavari, Armin</creatorcontrib><creatorcontrib>Immel‐Brown, Jonas P.</creatorcontrib><creatorcontrib>Penrod, Joseph C.</creatorcontrib><creatorcontrib>Lam, Yik</creatorcontrib><creatorcontrib>Antia, Firoz D.</creatorcontrib><title>Use of ultrafiltration/diafiltration for the processing of antisense oligonucleotides</title><title>Biotechnology progress</title><addtitle>Biotechnol Prog</addtitle><description>Ultrafiltration/diafiltration (UF/DF) has been the hallmark for concentrating and buffer exchange of protein and peptide‐based therapeutics for years. Here we examine the capabilities and limitations of UF/DF membranes to process oligonucleotides using antisense oligonucleotides (ASOs) as a model. Using a 3 kDa UF/DF membrane, oligonucleotides as small as 6 kDa are shown to have low sieving coefficients (<0.008) and thus can be concentrated to high concentrations (≤200 mg/mL) with high yield (≥95%) and low viscosity (<15 centipoise), provided the oligonucleotide is designed not to undergo self‐hybridization. In general, the oligonucleotide should be at least twice the reported membrane molecular weight cutoff for robust retention. Regarding diafiltration, results show that a small amount of salt is necessary to maintain adequate flux at concentrations exceeding about 40 mg/mL. Removal of salts along with residual solvents and small molecule process‐related impurities can be robust provided they are not positively charged as the interaction with the oligonucleotide can prevent passage through the membrane, even for common divalent cations such as calcium or magnesium. Overall, UF/DF is a valuable tool to utilize in oligonucleotide processing, especially as a final drug substance formulation step that enables a liquid active pharmaceutical ingredient.</description><subject>Antisense oligonucleotides</subject><subject>Antisense therapy</subject><subject>Cations</subject><subject>Divalent cations</subject><subject>Hybridization</subject><subject>Impurities</subject><subject>Magnesium</subject><subject>membrane polarization</subject><subject>Membranes</subject><subject>Molecular weight</subject><subject>oligonucleotide</subject><subject>Oligonucleotides</subject><subject>Robustness</subject><subject>Ultrafiltration</subject><subject>ultrafiltration and diafiltration</subject><issn>8756-7938</issn><issn>1520-6033</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><recordid>eNp1kE1LxDAQhoMouq4e_ANS8KKHupNk0zRHXfyCBUXcc0mTqUa6zZq0yP57W1dFBC8zDDzz8PISckThnAKwSdmuwjnnArbIiAoGaQacb5NRLkWWSsXzPbIf4ysA5JCxXbLHJc0zQWFEFouIia-Srm6DrtwwW-ebiXW_rqTyIWlfMFkFbzBG1zwPP7ppXcRmENTu2TedqdG3zmI8IDuVriMefu0xWVxfPc1u0_n9zd3sYp4aLjikSmkAO61KtFPOlBa25JxixkFIlKVhyk4RS0GNrpiw1mQiN7kEybBCpiUfk9ONtw_21mFsi6WLButaN-i7WLCcTgVTIEWPnvxBX30Xmj5dTwkBSkmueupsQ5ngYwxYFavgljqsCwrF0HUxdF0MXffs8ZexK5dof8jvcntgsgHeXY3r_03F5dPD46fyA56oimM</recordid><startdate>202307</startdate><enddate>202307</enddate><creator>Gronke, Robert S.</creator><creator>Ruanjaikaen, Krisada</creator><creator>Delavari, Armin</creator><creator>Immel‐Brown, Jonas P.</creator><creator>Penrod, Joseph C.</creator><creator>Lam, Yik</creator><creator>Antia, Firoz D.</creator><general>John Wiley & Sons, Inc</general><general>Wiley Subscription Services, Inc</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QL</scope><scope>7QO</scope><scope>7T7</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>M7N</scope><scope>P64</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-6971-4536</orcidid><orcidid>https://orcid.org/0000-0002-0630-7789</orcidid></search><sort><creationdate>202307</creationdate><title>Use of ultrafiltration/diafiltration for the processing of antisense oligonucleotides</title><author>Gronke, Robert S. ; 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Removal of salts along with residual solvents and small molecule process‐related impurities can be robust provided they are not positively charged as the interaction with the oligonucleotide can prevent passage through the membrane, even for common divalent cations such as calcium or magnesium. Overall, UF/DF is a valuable tool to utilize in oligonucleotide processing, especially as a final drug substance formulation step that enables a liquid active pharmaceutical ingredient.</abstract><cop>Hoboken, USA</cop><pub>John Wiley & Sons, Inc</pub><pmid>37186510</pmid><doi>10.1002/btpr.3350</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0001-6971-4536</orcidid><orcidid>https://orcid.org/0000-0002-0630-7789</orcidid></addata></record> |
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| source | Wiley Online Library Journals Frontfile Complete |
| subjects | Antisense oligonucleotides Antisense therapy Cations Divalent cations Hybridization Impurities Magnesium membrane polarization Membranes Molecular weight oligonucleotide Oligonucleotides Robustness Ultrafiltration ultrafiltration and diafiltration |
| title | Use of ultrafiltration/diafiltration for the processing of antisense oligonucleotides |
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