{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T10:59:19Z","timestamp":1791197959841,"version":"4.1.0"},"reference-count":9,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,6,21]],"date-time":"2026-06-21T00:00:00Z","timestamp":1782000000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,6,21]],"date-time":"2026-06-21T00:00:00Z","timestamp":1782000000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["aiche.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Biotechnology Progress"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Traditional off\u2010line analysis methods to quantify residual metabolite concentrations in a drug substance fermentation process consume valuable time, require costly resources, and demand potentially hazardous manual operations when working with pathogenic biological organisms. This case study focuses on the successful method development and validation of Raman spectroscopy as an in\u2010line process analytical technology (PAT) to replace the existing off\u2010line assay for real\u2010time glucose quantification. The value and feasibility of Raman spectroscopy as an\n                    <jats:italic>in situ<\/jats:italic>\n                    PAT method are recognized and demonstrated as an enabling technology suited to mitigate challenges fundamental to lab\u2010scale process development and commercial manufacturing. Herein, application of chemometric techniques and multivariate analysis of Raman spectral data is described to develop a partial least squares model capable of predicting real\u2010time and accurate glucose concentrations with a root mean square error of prediction of 1.2\u2009g\/L. Through this work, the predictive Raman PAT glucose quantification method was validated to make process decisions in a commercially licensed Pneumococcal vaccine drug substance manufacturing facility for the first time at our company. The method was integral to the process control strategy and applied to accurately and robustly indicate the glucose concentration target \u00b1\u20092\u2009g\/L for triggering subsequent process operations. Several advantages were realized through this work including advanced process control, reduced operating costs, and improved safety posture.\n                  <\/jats:p>","DOI":"10.1002\/btpr.88532","type":"journal-article","created":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T03:15:21Z","timestamp":1782098121000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["In\u2010line Raman spectroscopy real\u2010time glucose prediction method for commercial pneumococcal vaccine drug substance fermentation manufacturing process control"],"prefix":"10.1002","volume":"42","author":[{"given":"Griffin P.","family":"Thomas","sequence":"first","affiliation":[{"name":"Vaccines and Advanced Biotechnologies Process Research and Development MRL, Merck &amp; Co., Inc.  Rahway New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian C.","family":"Marks","sequence":"additional","affiliation":[{"name":"Analytical Enabling Capabilities MRL, Merck &amp; Co., Inc.  Rahway New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara B.","family":"Alvarado\u2010Hernandez","sequence":"additional","affiliation":[{"name":"Analytical Enabling Capabilities MRL, Merck &amp; Co., Inc.  Rahway New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3638-9601","authenticated-orcid":false,"given":"Matthew","family":"Woodling","sequence":"additional","affiliation":[{"name":"Vaccines and Advanced Biotechnologies Process Research and Development MRL, Merck &amp; Co., Inc.  Rahway New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"O'Connor","sequence":"additional","affiliation":[{"name":"Vaccine Drug Substance Commercialization, MMD Merck &amp; Co., Inc.  Rahway New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Ortiz","sequence":"additional","affiliation":[{"name":"Vaccine Drug Substance Commercialization, MMD Merck &amp; Co., Inc.  Rahway New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Higgins","sequence":"additional","affiliation":[{"name":"Analytical Enabling Capabilities MRL, Merck &amp; Co., Inc.  Rahway New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jon","family":"Shanter","sequence":"additional","affiliation":[{"name":"Vaccines and Advanced Biotechnologies Process Research and Development MRL, Merck &amp; Co., Inc.  Rahway New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,21]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.24493"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/1475\u20102859\u20105\u201019"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.3389\/fbioe.2020.00436"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1128\/microbiolspec.gpp3\u20100019\u20102018"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00216\u2010016\u20109824\u20101"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/btpr.1615"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.23023"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2018.07.021"},{"key":"e_1_2_10_10_1","unstructured":"ThomasG.Created in BioRender.2026https:\/\/BioRender.com\/mqyrhle"}],"container-title":["Biotechnology Progress"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/aiche.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/btpr.88532","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/aiche.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/btpr.88532","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/aiche.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/btpr.88532","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T10:00:43Z","timestamp":1791194443000},"score":1,"resource":{"primary":{"URL":"https:\/\/aiche.onlinelibrary.wiley.com\/doi\/10.1002\/btpr.88532"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,21]]},"references-count":9,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,9]]}},"alternative-id":["10.1002\/btpr.88532"],"URL":"https:\/\/doi.org\/10.1002\/btpr.88532","archive":["Portico"],"relation":{},"ISSN":["8756-7938","1520-6033"],"issn-type":[{"value":"8756-7938","type":"print"},{"value":"1520-6033","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,21]]},"assertion":[{"value":"2025-10-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-02","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-21","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e88532"}}