目的 基于中药质量标志物（quality marker，Q-Marker）理论，在既往确证人参皂苷Rb₁、Rg₁、Rf、Rh₁、Rc、Rb₂、Ro、Rg₃、Re、Rd和麦冬皂苷C、麦冬苷元-3-O-α-L-吡喃鼠李糖基-(1→2)-β-D-吡喃葡萄糖苷、偏诺皂苷元-3-O-α-L-吡喃鼠李糖基-(1→2)-β-D-吡喃木糖基-(1→4)-β-D-吡喃葡萄糖苷、果糖以及五味子醇甲15个Q-Marker的基础上，识别并确证注射用益气复脉（冻干）（Yiqi Fumai Lyophilized Injection，YQFM）中与安全性相关的过程控制Q-Marker——5-羟甲基糠醛（5-hydroxymethylfurfural，5-HMF），并建立其全过程控制策略，丰富与完善该产品的Q-Marker体系，保障产品质量与用药安全。方法 通过分析5-HMF的生成机制及其在产品制造过程中的传递规律，结合药理毒理试验证据，研究确证其安全性相关过程控制Q-Marker属性；基于近红外光谱（near-infrared spectroscopy，NIRS）结合多变量统计过程控制（multivariate statistical process control，MSPC）技术，建立生产过程5-HMF等关键质量属性的动态监测与控制体系；按照“药材-提取物-制剂”3级质控架构，采用HPLC法对各级单元中5-HMF含量进行测定，开展产品制造过程质量评价。结果 明确了5-HMF主要来源于麦冬和五味子药材在受热加工过程中的降解转化，确证其为YQFM安全性相关的过程控制Q-Marker；建立的NIRS-MSPC体系实现了关键质量目标在复杂生产状态中的可视化监测，确保了工艺过程的批间稳定性；3级质控体系下，20批YQFM产品中5-HMF含量为21～29 μg/支，处于安全可控水平。结论 将5-HMF定义并确证为YQFM安全性相关的过程控制Q-Marker，构建了“识别-确证-监测-控制”的完整研究体系，实现了产品质量由终端检验向过程控制的转变，可为加快Q-Marker理论及其研究成果在中药制药行业的转化应用提供参考。

Objective Based on the quality marker (Q-Marker) theory of traditional Chinese medicine (TCM), and building on the previous identification of 15 Q-Markers of Yiqi Fumai Lyophilized Injection [YQFM, 注射用益气复脉（冻干）]—including the ginsenosides Rb₁, Rg₁, Rf, Rh₁, Rc, Rb₂, Ro, Rg₃, Re, Rd, and ophiopogonin C, ophiopogenin-3-O-α-L-rhamnopyranosyl-(1→2)-β-D-glucopyranoside, pennogenin-3-O-α-L-rhamnopyranosyl-(1→2)-β-D-xylopyranosyl-(1→4)-β-D-glucopyranoside, fructose, and schisandrin—this study aimed to identify and confirm 5-hydroxymethylfurfural (5-HMF) as a safety-related process control Q-Marker of YQFM, to establish a whole-process control strategy for this compound, and thereby to enrich and refine the Q-Marker system of YQFM for assuring product quality and medication safety. Methods 5-HMF was confirmed as a safety-related process control Q-Marker by analyzing its formation mechanism and transfer behavior during the manufacturing process, in combination with pharmacological and toxicological evidence. A dynamic monitoring and control system for 5-HMF and other critical quality attributes (CQAs) was established based on near-infrared spectroscopy (NIRS) combined with multivariate statistical process control (MSPC). Furthermore, quality evaluation of the manufacturing process was performed using HPLC determination of 5-HMF content at each stage under a three-tier quality control framework of “crude materials-extracts-final product”. Results 5-HMF was found to originate mainly from the thermal degradation and conversion of Maidong (Ophiopogonis Radix) and Wuweizi (Schisandrae Chinensis Fructus) during processing, and was confirmed as a safety-related process control Q-Marker of YQFM. The established NIRS-MSPC system enabled visual monitoring of critical quality targets under complex manufacturing conditions and ensured inter-batch stability of the process. Under the three-tier quality control system, the 5-HMF content in 20 batches of YQFM ranged from 21 to 29 μg per vial, a level considered safe and well controlled. Conclusion This study defined and confirmed 5-HMF as a safety-related process control Q-Marker of YQFM, established an integrated research framework of “identification-confirmation-monitoring-control”, and shifted quality assurance from end-product testing toward process control, providing a reference for accelerating the translation of the Q-Marker theory and its research outcomes into the TCM pharmaceutical industry.

R283.6

中华人民共和国工业和信息化部消费品工业司课题“中药注射剂安全风险管控体系”（2440STCZB2616）