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Regulatory authorities established draft guidelines that outline a modular framework demanding qualitative, quantitative, microstructure and product performance equivalence to support generic products. In line with these guidelines, our study aimed to evaluate the relationship between microstructure and performance attributes in both originator and generic semi-solid products applied to the skin. In this context, reference and three generics of ketoprofen gel were selected as models for semi-solid formulations. Microstructure of all products was assessed regarding pH, specific gravity, drying rate, formulation rheology and potential drug polymorphism. Additionally, performance attributes of products were evaluated using <jats:italic>in vitro<\/jats:italic> release testing and <jats:italic>in vitro<\/jats:italic> permeation testing. Polymorphism and drying rate data showed no significant difference in microstructure of ketoprofen gels. All tested products exhibited <jats:italic>pseudo-plastic<\/jats:italic> flow behavior with <jats:italic>thixotropic<\/jats:italic> characteristic. However, differences in pH, specific gravity and viscosity values at low shear stress were observed between reference product and generic products, according to EMA guidance. Although IVRT outcomes did not entirely align with Q3 attributes, IVRT results for reference product <jats:italic>versus<\/jats:italic> Generic Product-I and Generic Product-II met the acceptance limits according to FDA guidance, which differs from EMA's assessment. Furthermore, <jats:italic>in vitro<\/jats:italic> release rate results were consistent with IVPT data. Consequently, it can be concluded that microstructure of semi-solid products applied to the skin may not consistently correlate with performance attributes due to various alternations influenced by manufacturing process parameters and\/or formulation components.<\/jats:p>\n          <jats:p>\n            <jats:bold>Graphical Abstract<\/jats:bold>\n          <\/jats:p>","DOI":"10.1208\/s12249-025-03044-4","type":"journal-article","created":{"date-parts":[[2025,2,4]],"date-time":"2025-02-04T20:47:27Z","timestamp":1738702047000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Evaluation of Physicochemical, Microstructure Parameters (Q3) and Performance Attributes of Commercial Ketoprofen Gels"],"prefix":"10.1208","volume":"26","author":[{"given":"\u015eeyma","family":"\u0130\u015fkin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emine","family":"Kahraman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8199-3010","authenticated-orcid":false,"given":"Sevgi","family":"G\u00fcng\u00f6r","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,2,4]]},"reference":[{"key":"3044_CR1","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1007\/s00403-020-02042-9","volume":"312","author":"MC Kwa","year":"2020","unstructured":"Kwa MC, Tegtmeyer K, Welty LJ, Raney SG, Luke MC, Xu S, Kong B. 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