Manufacturing classification system in the real world: factors influencing manufacturing process choices for filed commercial oral solid dosage formulations, case studies from industry and considerations for continuous processing

Following the first Manufacturing Classification System (MCS) paper, the team conducted surveys to establish which active pharmaceutical ingredient (API) properties were important when selecting or modifying materials to enable an efficient and robust pharmaceutical manufacturing process. The most commonly identified factors were (1) API particle size: small particle sizes are known to increase risk of processing issues; (2) Drug loading in the formulation: high drug loadings allow less opportunity to mitigate poor API properties through the use of excipients. The next step was to establish linkages with process decisions by identifying publicly-available proxies for these important parameters: dose (in place of drug loading) and BCS class (in place of particle size). Poorly-soluble API were seen as more likely to have controlled (smaller) particle size than more highly soluble API. Analysis of 435 regulatory filings revealed that higher doses and more poorly-soluble API was associated with more complex processing routes. Replacing the proxy factors with the original parameters should give the opportunity to demonstrate stronger trends. This assumption was tested by accessing a dataset relating to commercial tablet products. This showed that, for dry processes, a larger particle size was associated with higher achievable drug loading as determined by percolation threshold.

继首篇《制造分类系统（Manufacturing Classification System, MCS）》论文发表后，研究团队开展了调研工作，以明确在选择或改造物料以实现高效且稳健的制药生产工艺时，哪些原料药（active pharmaceutical ingredient, API）属性至关重要。最常被识别出的关键因素包括：(1) API粒径：已知较小的粒径会提升工艺问题的发生风险；(2) 制剂处方中的药物载药量：高载药量会限制通过辅料改善API不良属性的操作空间。后续研究通过为上述关键参数确定公开可用的替代指标，以建立与工艺决策的关联：以剂量替代药物载药量，以生物药剂学分类系统（Biopharmaceutics Classification System, BCS）分类替代粒径。相较于高溶解性API，低溶解性API更倾向于被调控为较小的粒径。对435份监管申报文件的分析显示，更高的剂量与更低溶解性的API往往对应更复杂的工艺路线。将替代指标替换为原始参数，有望展现出更显著的相关性趋势。研究人员通过获取与商用片剂产品相关的数据集，对该假设进行了验证。结果表明，对于干法工艺而言，更大的粒径对应更高的可实现药物载药量，该结论由渗滤阈值（percolation threshold）所确定。