{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T22:40:18Z","timestamp":1792190418121,"version":"4.4.0"},"reference-count":64,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,2,3]],"date-time":"2023-02-03T00:00:00Z","timestamp":1675382400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["TRR 156-KS01"],"award-info":[{"award-number":["TRR 156-KS01"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["CRC 1066"],"award-info":[{"award-number":["CRC 1066"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["Project K\u00f6rpereigene Barrieren"],"award-info":[{"award-number":["Project K\u00f6rpereigene Barrieren"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"name":"RMU Initiative","award":["TRR 156-KS01"],"award-info":[{"award-number":["TRR 156-KS01"]}]},{"name":"RMU Initiative","award":["CRC 1066"],"award-info":[{"award-number":["CRC 1066"]}]},{"name":"RMU Initiative","award":["Project K\u00f6rpereigene Barrieren"],"award-info":[{"award-number":["Project K\u00f6rpereigene Barrieren"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>The present article exemplifies the application of the concept of quality by design (QbD) for the systematic development of a nanoparticulate imiquimod (IMQ) emulsion gel formulation as an investigational medicinal product (IMP) for evaluation in an academic phase-I\/II clinical trial for the treatment of actinic keratosis (AK) against the comparator Aldara (EudraCT: 2015-002203-28). The design of the QbD elements of a quality target product profile (QTPP) enables the identification of the critical quality attributes (CQAs) of the drug product as the content of IMQ, the particle-size distribution, the pH, the rheological properties, the permeation rate and the chemical, physical and microbiological stability. Critical material attributes (CMAs) and critical process parameters (CPPs) are identified by using a risk-based approach in an Ishikawa diagram and in a risk-estimation matrix. In this study, the identified CPPs of the wet media ball-milling process\u2019s milling time and milling speed are evaluated in a central composite design of experiments (DoEs) approach, revealing criticality for both factors for the resulting mean particle size, while only the milling time is significantly affecting the polydispersity. To achieve a mean particle size in the range of 300\u2013400 nm with a minimal PdI, the optimal process conditions are found to be 650 rpm for 135 min. Validating the model reveals a good correlation between the predicted and observed values. Adequate control strategies were implemented for intermediate products as in-process controls (IPCs) and quality control (QC) tests of the identified CQAs. The IPC and QC data from 13 \u201cIMI-Gel\u201d batches manufactured in adherence to good manufacturing practice (GMP) reveal consistent quality with minimal batch-to-batch variability.<\/jats:p>","DOI":"10.3390\/pharmaceutics15020514","type":"journal-article","created":{"date-parts":[[2023,2,3]],"date-time":"2023-02-03T05:31:24Z","timestamp":1675402284000},"page":"514","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Quality by Design (QbD) Approach for a Nanoparticulate Imiquimod Formulation as an Investigational Medicinal Product"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7498-1855","authenticated-orcid":false,"given":"Jonas","family":"Pielenhofer","sequence":"first","affiliation":[{"name":"Department for Biopharmaceutics and Pharmaceutical Technology, Johannes Gutenberg University Mainz, 55128 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie Luise","family":"Meiser","sequence":"additional","affiliation":[{"name":"Department for Biopharmaceutics and Pharmaceutical Technology, Johannes Gutenberg University Mainz, 55128 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karsten","family":"Gogoll","sequence":"additional","affiliation":[{"name":"Department for Biopharmaceutics and Pharmaceutical Technology, Johannes Gutenberg University Mainz, 55128 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna-Maria","family":"Ciciliani","sequence":"additional","affiliation":[{"name":"Department for Biopharmaceutics and Pharmaceutical Technology, Johannes Gutenberg University Mainz, 55128 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Denny","sequence":"additional","affiliation":[{"name":"Department for Biopharmaceutics and Pharmaceutical Technology, Johannes Gutenberg University Mainz, 55128 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Klak","sequence":"additional","affiliation":[{"name":"Department for Biopharmaceutics and Pharmaceutical Technology, Johannes Gutenberg University Mainz, 55128 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Berenice M.","family":"Lang","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Staubach","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6863-8719","authenticated-orcid":false,"given":"Stephan","family":"Grabbe","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hansj\u00f6rg","family":"Schild","sequence":"additional","affiliation":[{"name":"Institute for Immunology, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3991-5721","authenticated-orcid":false,"given":"Markus P.","family":"Radsak","sequence":"additional","affiliation":[{"name":"3rd Department Internal Medicine, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilde","family":"Spahn-Langguth","sequence":"additional","affiliation":[{"name":"Department for Biopharmaceutics and Pharmaceutical Technology, Johannes Gutenberg University Mainz, 55128 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Langguth","sequence":"additional","affiliation":[{"name":"Department for Biopharmaceutics and Pharmaceutical Technology, Johannes Gutenberg University Mainz, 55128 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,3]]},"reference":[{"key":"ref_1","unstructured":"(2022, August 01). 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