Small Molecule Pharmaceutical Sciences, Genentech Inc, 1 DNA Way, South San Francisco, California, 94080, USA.
AAPS J. 2023 Sep 15;25(5):90. doi: 10.1208/s12248-023-00854-x.
Process analytical technology (PAT) in late-stage drug product development is typically used for real-time process monitoring, in-process control, and real-time release testing. In early research and development (R&D), PAT usage is limited as the manufacturing scale is relatively small with frequent changes and only a few batches are produced on an annual basis. However, process understanding is critical at early R&D in order to identify process and formulation boundaries, so PAT applications could be particularly useful in early-stage R&D. For oral solid dosage form, conventional HPLC-based content uniformity (CU) methods with sampling of 3 tablets per stratified sampling location in early R&D are typically not sufficient to identify these manufacturing process boundaries and temporal profile. Here, we report a screening CU method based on a multivariate model using transmission Raman spectroscopy (TRS) data on a phase-appropriate calibration set of only 16 tablets. This initial model was used for multiple pre-GMP development batches to provide critical information about blend uniformity and content uniformity (CU). In this work, the precision of the TRS method was evaluated; multiple spectral preprocessing approaches were compared regarding their effects on measurement precision as well as their ability to mitigate the photo bleaching effects during precision experiments. Overall, the TRS-based CU method was much faster than a traditional HPLC-based method allowing a much larger number of tablets to be screened. This larger number of analyzed tablets enabled the processes boundaries and temporal changes in CU to be identified while providing proper statistical assurance on product quality.
在药物产品开发的后期阶段，过程分析技术 (PAT) 通常用于实时过程监测、过程控制和实时放行测试。在早期的研究和开发 (R&D) 中，由于制造规模相对较小，变化频繁，每年仅生产几批，因此 PAT 的使用受到限制。然而，在早期 R&D 中，工艺理解至关重要，以便确定工艺和配方的边界，因此 PAT 的应用在早期 R&D 中可能特别有用。对于口服固体制剂，在早期 R&D 中，通常采用传统的基于 HPLC 的含量均匀度 (CU) 方法，对每个分层采样位置的 3 片进行采样，不足以识别这些制造工艺边界和时间分布。在这里，我们报告了一种基于多元模型的筛选 CU 方法，该方法使用适用于相适当校准集的透射拉曼光谱 (TRS) 数据，校准集中仅包含 16 片。该初始模型用于多个预 GMP 开发批次，以提供有关混合均匀度和含量均匀度 (CU) 的关键信息。在这项工作中，评估了 TRS 方法的精密度；比较了多种光谱预处理方法，以了解它们对测量精密度的影响，以及它们在精密度实验中减轻光漂白效应的能力。总体而言，基于 TRS 的 CU 方法比传统的基于 HPLC 的方法快得多，允许筛选更多数量的片剂。对更多数量的分析片剂进行分析，使我们能够识别 CU 的工艺边界和时间变化，并为产品质量提供适当的统计保证。
