Independent Pharmaceutical Consultant, Syosset, New York, USA.
AAPS PharmSciTech. 2019 Sep 16;20(8):313. doi: 10.1208/s12249-019-1515-8.
An integrated approach based on QbD and PAT provides a systematic and innovative framework for product development, manufacturing, and quality risk management. In this context, the significance of the outcome of design of experiments (DOEs) to the selection of the product design, robust commercial manufacturing process, design space, and overall control strategy remains vital for the success of a drug product throughout its life cycle. This paper aims at discussing selected recent DOE case studies conducted during QbD-based and integrated QbD/PAT-based development of solid oral formulations and process improvement studies. The main focus of this paper is to highlight the rationales and importance of design selection during development and applications of mathematical models and statistical tools in analyzing DOE and PAT data for developing a design space, control strategy, and improved process monitoring. A total of 25 case studies (includes 9 PAT application studies) have been discussed in this paper which cover 11 manufacturing processes commonly utilized for solid dosage forms. Two case studies relevant to selection of packaging design for solid dosage forms are also briefly discussed to complete the scope. Overall, for a successful modern QbD approach, it is highly important that DOEs are conducted and analyzed in a logical sequence which involves designs that are phase-appropriate and quality-driven and facilitate both statistical and chemometric thinking at each development stage. This approach can result into higher regulatory flexibility along with lower economic burden during life cycle of a product, irrespective of regulatory path used (NDA or ANDA).
基于质量源于设计（QbD）和过程分析技术（PAT）的综合方法为产品开发、制造和质量风险管理提供了一个系统和创新的框架。在这种情况下，实验设计（DoE）的结果对于产品设计、稳健的商业化制造工艺、设计空间和整体控制策略的选择仍然至关重要，这对于药物产品在整个生命周期内的成功至关重要。本文旨在讨论在基于 QbD 和基于综合 QbD/PAT 的固体口服制剂开发和工艺改进研究中进行的一些选定的最新 DoE 案例研究。本文的主要重点是强调在开发过程中和应用数学模型和统计工具分析 DoE 和 PAT 数据时进行设计选择的合理性和重要性，以开发设计空间、控制策略和改进的工艺监测。本文共讨论了 25 个案例研究（包括 9 个 PAT 应用研究），涵盖了用于固体剂型的 11 个常见制造工艺。还简要讨论了两个与固体剂型包装设计选择相关的案例研究，以完成讨论范围。总的来说，对于成功的现代 QbD 方法，非常重要的是，DoE 是按照逻辑顺序进行的，并且涉及到与阶段相关且以质量为导向的设计，这有助于在每个开发阶段都进行统计和化学计量学思考。无论使用何种监管途径（NDA 或 ANDA），这种方法都可以在产品生命周期中提供更高的监管灵活性和更低的经济负担。
