Pielenhofer Jonas, Meiser Sophie Luise, Gogoll Karsten, Ciciliani Anna-Maria, Denny Mark, Klak Michael, Lang Berenice M, Staubach Petra, Grabbe Stephan, Schild Hansjörg, Radsak Markus P, Spahn-Langguth Hilde, Langguth Peter
Department for Biopharmaceutics and Pharmaceutical Technology, Johannes Gutenberg University Mainz, 55128 Mainz, Germany.
Department of Dermatology, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany.
Pharmaceutics. 2023 Feb 3;15(2):514. doi: 10.3390/pharmaceutics15020514.
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.
本文举例说明了质量源于设计（QbD）理念在纳米微粒咪喹莫特（IMQ）乳胶凝胶制剂系统研发中的应用。该制剂作为一种研究用药品（IMP），用于在一项学术性I/II期临床试验中评估其治疗光化性角化病（AK）的效果，对照药物为Aldara（欧盟临床试验数据库编号：2015-002203-28）。质量目标产品概况（QTPP）的QbD要素设计能够确定药品的关键质量属性（CQA），包括IMQ含量、粒度分布、pH值、流变学性质、渗透速率以及化学、物理和微生物稳定性。通过在石川图和风险评估矩阵中采用基于风险的方法，确定关键物料属性（CMA）和关键工艺参数（CPP）。在本研究中，采用中心复合设计实验（DoE）方法评估湿介质球磨工艺中确定的CPP（研磨时间和研磨速度），结果表明这两个因素对最终平均粒径均至关重要，而只有研磨时间对多分散性有显著影响。为了在最小化多分散指数（PdI）的情况下实现300 - 400 nm范围内的平均粒径，发现最佳工艺条件为135分钟650转/分钟。对模型进行验证发现预测值与观测值之间具有良好的相关性。针对中间产品实施了适当的控制策略，作为已识别CQA的过程控制（IPC）和质量控制（QC）测试。来自按照良好生产规范（GMP）生产的13批“IMI - Gel”产品的IPC和QC数据显示，产品质量一致，批次间差异最小。
