{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T05:03:11Z","timestamp":1789534991207,"version":"build-2803163510"},"reference-count":25,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012541","name":"Herculesstichting","doi-asserted-by":"publisher","award":["AKUL\/13\/21"],"award-info":[{"award-number":["AKUL\/13\/21"]}],"id":[{"id":"10.13039\/501100012541","id-type":"DOI","asserted-by":"publisher"}]},{"award":["AKUL\/13\/21"],"award-info":[{"award-number":["AKUL\/13\/21"]}],"id":[{"id":"https:\/\/ror.org\/04at1ex44","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002913","name":"Flemish Government","doi-asserted-by":"publisher","award":["AH.2016.134, via the hermes fund"],"award-info":[{"award-number":["AH.2016.134, via the hermes fund"]}],"id":[{"id":"10.13039\/501100002913","id-type":"DOI","asserted-by":"publisher"}]},{"award":["AH.2016.134, via the hermes fund"],"award-info":[{"award-number":["AH.2016.134, via the hermes fund"]}],"id":[{"id":"https:\/\/ror.org\/04qxsrb28","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003130","name":"Research Foundation - Flanders","doi-asserted-by":"publisher","award":["I001321N: Nuclear Magnetic Resonance Spectroscopy Platform for Molecular Water Research"],"award-info":[{"award-number":["I001321N: Nuclear Magnetic Resonance Spectroscopy Platform for Molecular Water Research"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"award":["I001321N: Nuclear Magnetic Resonance Spectroscopy Platform for Molecular Water Research"],"award-info":[{"award-number":["I001321N: Nuclear Magnetic Resonance Spectroscopy Platform for Molecular Water Research"]}],"id":[{"id":"https:\/\/ror.org\/03qtxy027","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: Oral solid dosage (OSD) forms are historically categorized as low-risk vectors for leachables under the assumption that solid-state matrices impose severe kinetic barriers against migrant migration and reactivity. This study investigates an unexpected unknown impurity, detected as part of a routine ICH Q3B testing program to control drug product impurities in a blister-packed tablet. Since the impurity exceeded the ICH Q3B identification threshold applicable for this drug product (1.0% w\/w relative to API or 5 \u00b5g total daily intake (TDI), whichever is lower), a forensic investigation into the origins and identity of the impurity was performed. Methods: Placebo and packaging line studies were performed to isolate the origin of the impurity. Systematic structure elucidation was carried out using high-resolution mass spectrometry (HRMS), isotopic fine structure analysis, and de novo chemical synthesis. To enable definitive characterization, preparative HPLC was utilized to isolate the compound for high-field 2D-NMR spectroscopy (801 MHz). Results: The impurity was proven to be independent of active pharmaceutical ingredient degradation, forming only when tablet excipients were stored in sealed PVC blister packaging. Co-incubation of the PVC heat stabilizer derivative dimethyltin bis(2-ethylhexyl mercaptoacetate) (DMTE) with pyrrolidin-2-one (a povidone excipient degradation product) generated an identical chromatographic and MS\/MS spectral profile. NMR spectroscopy unambiguously identified the structure as 2-ethylhexyl 2-((5-oxopyrrolidin-2-yl)thio)acetate. Conclusions: This study provides the first direct evidence of an organotin-catalyzed solid-state reaction between a packaging leachable and a tablet excipient under 25 \u00b0C\/60% RH storage conditions. While this implies that the impurity should not be evaluated under the ICH Q3B guidelines, the findings directly challenge the assumed \u201clow-risk\u201d status of OSD packaging regarding leachables and highlight the necessity for interaction-focused, chemistry-based risk assessments, as outlined in emerging ICH Q3E guidelines.<\/jats:p>","DOI":"10.3390\/pharmaceutics18091153","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T15:19:04Z","timestamp":1789399144000},"page":"1153","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Leachable-Derived Impurities in Oral Solid Dosage Forms Generated by Solid-State Packaging\u2013Excipient Interactions: A Case Study of a Polyvinyl Chloride Heat Stabilizer Reacting with Povidone"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2681-6246","authenticated-orcid":false,"given":"Ewoud","family":"Vaneeckhaute","sequence":"first","affiliation":[{"name":"NMRCoRe, NMR\/X-Ray Platform for Convergence Research, KU Leuven, Celestijnenlaan 200F-Box 2461, B-3001 Leuven, Belgium"},{"name":"Center for Surface Chemistry and Catalysis\u2014Characterisation and Application Team, KU Leuven, Celestijnenlaan 200F-Box 2461, B-3001 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Van Hooste","sequence":"additional","affiliation":[{"name":"Nelson Labs, Romeinsestraat 12, B-3001 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8796-8265","authenticated-orcid":false,"given":"Pasquinel","family":"Weckx","sequence":"additional","affiliation":[{"name":"NMRCoRe, NMR\/X-Ray Platform for Convergence Research, KU Leuven, Celestijnenlaan 200F-Box 2461, B-3001 Leuven, Belgium"},{"name":"Center for Surface Chemistry and Catalysis\u2014Characterisation and Application Team, KU Leuven, Celestijnenlaan 200F-Box 2461, B-3001 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Teasdale","sequence":"additional","affiliation":[{"name":"Nelson Labs, Romeinsestraat 12, B-3001 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruud","family":"Cuyvers","sequence":"additional","affiliation":[{"name":"Nelson Labs, Romeinsestraat 12, B-3001 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Hammond","sequence":"additional","affiliation":[{"name":"Norgine Pharmaceutical Ltd., ARC Uxbridge, Building 01, Sanderson Road, Uxbridge UB8 1DH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Wood","sequence":"additional","affiliation":[{"name":"Norgine Pharmaceutical Ltd., ARC Uxbridge, Building 01, Sanderson Road, Uxbridge UB8 1DH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5667-6989","authenticated-orcid":false,"given":"Ward","family":"D\u2019Autry","sequence":"additional","affiliation":[{"name":"Nelson Labs, Romeinsestraat 12, B-3001 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4859-437X","authenticated-orcid":false,"given":"Laura","family":"Martin","sequence":"additional","affiliation":[{"name":"Norgine Pharmaceutical Ltd., ARC Uxbridge, Building 01, Sanderson Road, Uxbridge UB8 1DH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3499-0455","authenticated-orcid":false,"given":"Eric","family":"Breynaert","sequence":"additional","affiliation":[{"name":"NMRCoRe, NMR\/X-Ray Platform for Convergence Research, KU Leuven, Celestijnenlaan 200F-Box 2461, B-3001 Leuven, Belgium"},{"name":"Center for Surface Chemistry and Catalysis\u2014Characterisation and Application Team, KU Leuven, Celestijnenlaan 200F-Box 2461, B-3001 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1208\/pt030206","article-title":"Pharmaceutical Impurities\u2014A Mini-Review","volume":"3","author":"Roy","year":"2002","journal-title":"AAPS PharmSciTech"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.addr.2006.10.005","article-title":"Strategies for the Investigation and Control of Process-Related Impurities in Drug Substances","volume":"59","author":"Argentine","year":"2007","journal-title":"Adv. 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