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This article investigates the development of a pilot-scale continuous distillation system for in-line removal of an excess amine reactant (\n                      <jats:italic>i.e.<\/jats:italic>\n                      , tert-butylamine) when incorporated within an advanced manufacturing technology (AMT) for continuous drug substance production.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Initial design parameters were simulated in ASPEN\u2009+\u2009to assess potential process solvents, setpoint parameters, and azeotrope formation. Complementary analytical characterization was performed with high performance liquid chromatography (HPLC) and gas chromatography \u2013 flame ionization detection (GC-FID). Early continuous distillation prototypes and key engineering design decisions are highlighted.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The final engineered system is comprised of a\u2009+\u20093-foot distillation column fitted with an Allihn condenser, a 250\u00a0mL three-necked round bottom flask, and an automated system for reflux ratio (R\n                      <jats:sub>D<\/jats:sub>\n                      ) control. The column is readily integrated within an advanced manufacturing system to continuously remove amine reagent during continuous manufacturing of albuterol sulfate at a 3.0\u00a0mL\/min process basis, corresponding to a theoretical throughput of approximately 1,800 doses per hour based on the demonstrated process flowrate, reaction stoichiometry, and operating conditions.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The application of continuous distillation offers a unique strategy for impurity removal during advanced pharmaceutical manufacturing and can be scaled to meet target throughputs. Here we provide general criteria necessary for successful implementation of similar continuous in-line distillation systems.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s11095-026-04172-7","type":"journal-article","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T14:53:24Z","timestamp":1786028004000},"page":"2301-2317","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Continuous Distillation for Drug Substance Manufacturing"],"prefix":"10.1007","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6611-1676","authenticated-orcid":false,"given":"Kimberly E.","family":"Penzer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel G.","family":"Gregory","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin T.","family":"Turnage","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin D.","family":"Thieken","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha G.","family":"Kohn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0710-7287","authenticated-orcid":false,"given":"James K.","family":"Ferri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,6]]},"reference":[{"key":"4172_CR1","doi-asserted-by":"crossref","unstructured":"Liebmann AJ. 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