{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T11:00:05Z","timestamp":1770894005006,"version":"3.50.1"},"reference-count":113,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2023,10,28]],"date-time":"2023-10-28T00:00:00Z","timestamp":1698451200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>The pharmaceutical industry has entered an era of transformation with the emergence of Pharma 4.0, which leverages cutting-edge technologies in manufacturing processes. These hold tremendous potential for enhancing the overall efficiency, safety, and quality of non-biological complex drugs (NBCDs), a category of pharmaceutical products that pose unique challenges due to their intricate composition and complex manufacturing requirements. This review attempts to provide insight into the application of select Pharma 4.0 technologies, namely machine learning, in silico modeling, and 3D printing, in the manufacturing process of NBCDs. Specifically, it reviews the impact of these tools on NBCDs such as liposomes, polymeric micelles, glatiramer acetate, iron carbohydrate complexes, and nanocrystals. It also addresses regulatory challenges associated with the implementation of these technologies and presents potential future perspectives, highlighting the incorporation of digital twins in this field of research as it seems to be a very promising approach, namely for the optimization of NBCDs manufacturing processes.<\/jats:p>","DOI":"10.3390\/pharmaceutics15112545","type":"journal-article","created":{"date-parts":[[2023,10,30]],"date-time":"2023-10-30T09:27:28Z","timestamp":1698658048000},"page":"2545","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Exploiting Pharma 4.0 Technologies in the Non-Biological Complex Drugs Manufacturing: Innovations and Implications"],"prefix":"10.3390","volume":"15","author":[{"given":"Vera","family":"Malheiro","sequence":"first","affiliation":[{"name":"Drug Development and Technology Laboratory, Faculty of Pharmacy, University of Coimbra, P\u00f3lo das Ci\u00eancias da Sa\u00fade, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal"}]},{"given":"Joana","family":"Duarte","sequence":"additional","affiliation":[{"name":"Drug Development and Technology Laboratory, Faculty of Pharmacy, University of Coimbra, P\u00f3lo das Ci\u00eancias da Sa\u00fade, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal"}]},{"given":"Francisco","family":"Veiga","sequence":"additional","affiliation":[{"name":"Drug Development and Technology Laboratory, Faculty of Pharmacy, University of Coimbra, P\u00f3lo das Ci\u00eancias da Sa\u00fade, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal"},{"name":"LAQV, REQUIMTE, Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, P\u00f3lo das Ci\u00eancias da Sa\u00fade, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0786-6280","authenticated-orcid":false,"given":"Filipa","family":"Mascarenhas-Melo","sequence":"additional","affiliation":[{"name":"Drug Development and Technology Laboratory, Faculty of Pharmacy, University of Coimbra, P\u00f3lo das Ci\u00eancias da Sa\u00fade, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal"},{"name":"LAQV, REQUIMTE, Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, P\u00f3lo das Ci\u00eancias da Sa\u00fade, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal"},{"name":"Higher School of Health, Polytechnic Institute of Guarda, Rua da Cadeia, 6300-307 Guarda, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.drudis.2021.09.002","article-title":"Towards Pharma 4.0 in clinical trials: A future-orientated perspective","volume":"27","author":"Hariry","year":"2022","journal-title":"Drug Discov. 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