Fuente: PubMed "honey" Zhongguo Zhong Yao Za Zhi. 2025 Nov;50(21):5987-5998. doi: 10.19540/j.cnki.cjcmm.20250430.301.ABSTRACTLarge traditional Chinese medicine(TCM) honeyed pills are widely recognized for their stable therapeutic efficacy and convenient administration, occupying a prominent position among classical TCM dosage forms. However, the honey-refining process not only directly affects the efficacy and stability of these formulations but also serves as the primary source of 5-hydroxymethylfurfural(5-HMF), a potentially toxic compound. In light of its toxicological risks and the residue limits specified in the Pharmacopoeia of the People's Republic of China(2020 edition), achieving real-time and precise control of 5-HMF content has emerged as a key challenge in TCM manufacturing measurement. This review, based on research in TCM manufacturing measurement, outlined the toxicological controversies, quality control challenges, formation mechanisms, and influencing factors associated with 5-HMF during the production of large honeyed pills, with the aim of advancing the standardization and intelligent manufacturing of large honeyed pills. First, it examined the toxicological debates and safety thresholds of 5-HMF, identifying several issues during the manufacturing, including unclear residue limits for large honeyed pills, excessive reliance on empirical control during processing, significant risks from cumulative 5-HMF, and insufficient real-time measurement capabilities. Then, it clarified the dominant roles of the Maillard and caramelization reactions in 5-HMF formation and explored how honey composition, refining parameters, and equipment types influence its generation. Subsequently, recent advances in chromatographic, spectroscopic, electrochemical, and biosensor-based detection methods were reviewed, and their applicability to real-time measurement and intelligent control in manufacturing was evaluated. Finally, an intelligent manufacturing system based on a "point-line-plane" quality control framework was proposed for 5-HMF formed during the honey-refining process, emphasizing a future shift toward digitalization, intelligence, and continuous production to comprehensively enhance the safety, standardization, and global competitiveness of large honeyed pill manufacturing.PMID:41508170 | DOI:10.19540/j.cnki.cjcmm.20250430.301