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Quality by Design (QbD) Approach for a Nanoparticulate Imiquimod Formulation as an Investigational Medicinal Product

ORCID
0000-0002-7498-1855
Affiliation
Department for Biopharmaceutics and Pharmaceutical Technology, Johannes Gutenberg University Mainz, 55128 Mainz, Germany
Pielenhofer, Jonas;
Affiliation
Department for Biopharmaceutics and Pharmaceutical Technology, Johannes Gutenberg University Mainz, 55128 Mainz, Germany
Meiser, Sophie Luise;
Affiliation
Department for Biopharmaceutics and Pharmaceutical Technology, Johannes Gutenberg University Mainz, 55128 Mainz, Germany
Gogoll, Karsten;
Affiliation
Department for Biopharmaceutics and Pharmaceutical Technology, Johannes Gutenberg University Mainz, 55128 Mainz, Germany
Ciciliani, Anna-Maria;
Affiliation
Department for Biopharmaceutics and Pharmaceutical Technology, Johannes Gutenberg University Mainz, 55128 Mainz, Germany
Denny, Mark;
Affiliation
Department for Biopharmaceutics and Pharmaceutical Technology, Johannes Gutenberg University Mainz, 55128 Mainz, Germany
Klak, Michael;
Affiliation
Department of Dermatology, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany
Lang, Berenice M.;
Affiliation
Department of Dermatology, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany
Staubach, Petra;
ORCID
0000-0002-6863-8719
Affiliation
Department of Dermatology, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany
Grabbe, Stephan;
Affiliation
Institute for Immunology, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany
Schild, Hansjörg;
ORCID
0000-0002-3991-5721
Affiliation
3rd Department Internal Medicine, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany
Radsak, Markus P.;
Affiliation
Department for Biopharmaceutics and Pharmaceutical Technology, Johannes Gutenberg University Mainz, 55128 Mainz, Germany
Spahn-Langguth, Hilde;
Affiliation
Department for Biopharmaceutics and Pharmaceutical Technology, Johannes Gutenberg University Mainz, 55128 Mainz, Germany
Langguth, Peter

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’s 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 300–400 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 “IMI-Gel” batches manufactured in adherence to good manufacturing practice (GMP) reveal consistent quality with minimal batch-to-batch variability.

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