Pharmaceutical Sciences and Clinical Supply, Merck & Co., Inc., Rahway, New Jersey 07065, United States.
Belgian Federal Agency for Medicines and Health Products, Galileelaan 5/03, Brussels 1210, Belgium.
Mol Pharm. 2024 Nov 4;21(11):5353-5372. doi: 10.1021/acs.molpharmaceut.4c00758. Epub 2024 Sep 30.
The proceedings from the 30th August 2023 (Day 2) of the workshop "Physiologically Based Biopharmaceutics Models (PBBM) Best Practices for Drug Product Quality: Regulatory and Industry Perspectives" are provided herein. Day 2 covered PBBM case studies from six regulatory authorities which provided considerations for model verification, validation, and application based on the context of use (COU) of the model. PBBM case studies to define critical material attribute (CMA) specification settings, such as active pharmaceutical ingredient (API) particle size distributions (PSDs) were shared. PBBM case studies to define critical quality attributes (CQAs) such as the dissolution specification setting or to define the bioequivalence safe space were also discussed. Examples of PBBM using the credibility assessment framework, COU and model risk assessment, as well as scientific learnings from PBBM case studies are provided. Breakout session discussions highlighted current trends and barriers to application of PBBMs including: (a) PBBM credibility assessment framework and level of validation, (b) use of disposition parameters in PBBM and points to consider when iv data are not available, (c) conducting virtual bioequivalence trials and dealing with variability, (d) model acceptance criteria, and (e) application of PBBMs for establishing safe space and failure edges.
本文提供了 2023 年 8 月 30 日(第 2 天)研讨会“基于生理学的生物药剂学模型(PBBM)药物产品质量最佳实践:监管和行业视角”的会议记录。第 2 天涵盖了来自六个监管机构的 PBBM 案例研究,这些案例研究根据模型的使用情境(COU)提供了模型验证、确认和应用的考虑因素。还分享了用于定义关键物料属性(CMA)规范设置的 PBBM 案例研究,例如活性药物成分(API)粒度分布(PSD)。还讨论了用于定义关键质量属性(CQA)的 PBBM 案例研究,例如溶解规范设置或定义生物等效性安全范围。还提供了使用可信度评估框架、COU 和模型风险评估以及从 PBBM 案例研究中获得的科学经验的 PBBM 示例。分组讨论强调了 PBBM 应用的当前趋势和障碍,包括:(a)PBBM 可信度评估框架和验证水平,(b)在 PBBM 中使用处置参数以及在无法获得静脉内数据时需要考虑的要点,(c)进行虚拟生物等效性试验和处理变异性,(d)模型验收标准,以及(e)应用 PBBM 建立安全范围和失效边缘。