Department of Chemical and Biochemical Engineering, Rutgers - The State University of New Jersey, Piscataway, NJ 08854, USA.
Department of Chemical and Biomolecular Engineering, University of Delaware, Newark, DE 19716, USA.
Int J Pharm. 2021 Dec 15;610:121248. doi: 10.1016/j.ijpharm.2021.121248. Epub 2021 Nov 5.
While continuous manufacturing (CM) of pharmaceutical solid-based drug products has been shown to be advantageous for improving the product quality and process efficiency in alignment with FDA's support of the quality-by-design paradigm (Lee, 2015; Ierapetritou et al., 2016; Plumb, 2005; Schaber, 2011), it is critical to enable full utilization of CM technology for robust production and commercialization (Schaber, 2011; Byrn, 2015). To do so, an important prerequisite is to obtain a detailed understanding of overall process characteristics to develop cost-effective and accurate predictive models for unit operations and process flowsheets. These models are utilized to predict product quality and maintain desired manufacturing efficiency (Ierapetritou et al., 2016). Residence time distribution (RTD) has been a widely used tool to characterize the extent of mixing in pharmaceutical unit operations (Vanhoorne, 2020; Rogers and Ierapetritou, 2015; Teżyk et al., 2015) and manufacturing lines and develop computationally cheap predictive models. These models developed using RTD have been demonstrated to be crucial for various flowsheet applications (Kruisz, 2017; Martinetz, 2018; Tian, 2021). Though extensively used in the literature (Gao et al., 2012), the implementation, execution, evaluation, and assessment of RTD studies has not been standardized by regulatory agencies and can thus lead to ambiguity regarding their accurate implementation. To address this issue and subsequently prevent unforeseen errors in RTD implementation, the presented article aims to aid in developing standardized guidelines through a detailed review and critical discussion of RTD studies in the pharmaceutical manufacturing literature. The review article is divided into two main sections - 1) determination of RTD including different steps for RTD evaluation including experimental approach, data acquisition and pre-treatment, RTD modeling, and RTD metrics and, 2) applications of RTD for solid dose manufacturing. Critical considerations, pertaining to the limitations of RTDs for solid dose manufacturing, are also examined along with a perspective discussion of future avenues of improvement.
虽然连续制造（CM）制药固体制剂已被证明有利于提高产品质量和工艺效率，符合 FDA 对质量源于设计理念的支持（Lee，2015；Ierapetritou 等人，2016；Plumb，2005；Schaber，2011），但为了实现稳健生产和商业化，充分利用 CM 技术至关重要（Schaber，2011；Byrn，2015）。为此，一个重要的前提是获得对整体工艺特性的详细了解，以便为单元操作和工艺流程图开发具有成本效益和准确的预测模型。这些模型用于预测产品质量并保持所需的制造效率（Ierapetritou 等人，2016）。停留时间分布（RTD）已被广泛用于描述制药单元操作的混合程度（Vanhoorne，2020；Rogers 和 Ierapetritou，2015；Teżyk 等人，2015）和制造线，并开发计算成本低廉的预测模型。已经证明，使用 RTD 开发的这些模型对于各种流程图应用至关重要（Kruisz，2017；Martinetz，2018；Tian，2021）。尽管在文献中广泛使用（Gao 等人，2012），但 RTD 研究的实施、执行、评估和评估尚未得到监管机构的标准化，因此可能导致对其准确实施的模糊性。为了解决这个问题，并随后防止 RTD 实施中的意外错误，本文旨在通过对制药制造文献中的 RTD 研究进行详细审查和批判性讨论，帮助制定标准化指南。综述文章分为两个主要部分-1）RTD 的确定，包括 RTD 评估的不同步骤，包括实验方法、数据采集和预处理、RTD 建模和 RTD 指标，以及 2）RTD 在固体制剂制造中的应用。还检查了与 RTD 用于固体制剂制造的局限性有关的关键注意事项，并对未来改进的途径进行了前瞻性讨论。
