仿制药质量拉曼光谱快速评价系统研究

目的 探索建立通过仿制药一致性评价品种上市后药品质量一致性快速评判方法,用于市场仿制药质量快速评价。方法 基于拉曼光谱法,根据质量控制需求,分别采用一致性评价参比制剂、申报批、同批次制剂作为参比标准,以相似度值、置信区间、不确定度作为评判指标。检验流程分为建库和快检 2 部分,建库：参比制剂和申报批的拉曼光谱作为标准谱图存于云端数据库,或取市售仿制药某批样品自身某片药品建库;快检：采集 10 片药物制剂样品拉曼光谱分别上传,与拉曼光谱库“四同”（同生产企业、同品种、同规格、同批号）样品标准谱图比对,在标准拉曼光谱库中未能获取标准谱图时,进行市售批自身片与片之间比对。基于中国拉曼光谱云计算中心“药品追溯”模块,优化升级成“仿制药评价”模块,与仿制药评价专用手持式拉曼光谱仪联合,形成“仿制药质量拉曼光谱快速评价系统（CEVAR 系统）”。该项目在2020 年度山东省药品质量风险监测项目中进行了应用,共征集到省内 18 家企业、45 个品种（73 个品规）、225 批次的市售批样品;征集到 3 家企业、3 个品种、5 个批次的参比制剂;3 家企业、4 个品种、12 个批次的申报批样品。取瑞舒伐他汀钙片参比试剂和市售批用拉曼光谱成像系统进行验证。结果 将相似度 99% 作为通用判定阈值;征集到的绝大多数品种的自身相似度都大于 99%,但是有 5 个品种样品虽然平均相似度值大于 99%,但是每批次有 3～5 片与标准比对相似度小于 99%;充分证实CEVAR 系统检测的准确性。瑞舒伐他汀钙片拉曼光谱成像系统的验证结果与 CEVAR 系统结果一致。结论 通过大批量样品测试数据,相似度 99% 可以作为质量优劣判定的阈值,CEVAR 系统适合于对药物制剂工艺质量的普遍筛查。

Study on rapid evaluation system of generic drug quality by Raman spectroscopy

Objective To establish a rapid evaluation method of drug that passed the consistency evaluation of generic drugs, which can be used to quickly evaluate the quality of the generic drugs in the market. Method Based on Raman spectroscopy, according to the quality control needs, the reference preparations, the submitted batch, and the batches of the same batch of the drug were used as reference standards respectively, and the similarity index, the confidence interval, and the uncertainty were used as evaluation indicators. The inspection process is divided into two parts: building a database and fast inspection. The building of the database: The Raman spectra of the reference preparations and the submitted batch are stored as standard spectra in the cloud database or built by taking a certain batch of a commercial imitation drug. The fast inspection: The Raman spectra of 10 drug preparations are collected and uploaded separately, and compared with the standard Raman spectra of the "four same" (same manufacturer, same variety, same specifications, and same batch number) samples in the Raman spectral database. When the standard Raman spectra of the database cannot be obtained, the comparison is made between the same batch of the commercial imitation drug and the same batch of the drug. Based on the China Raman Spectrum Cloud Computing Center''s "Drug Traceability" module, the "Imitation Drug Evaluation" module is optimized and upgraded, combined with the imitation drug evaluation dedicated handheld Raman spectrometer, forming the "Imitation Drug Quality Raman Spectrum Rapid Evaluation System (CEVAR system)". This project was applied in the 2020 annual drug quality risk monitoring project in Shandong Province, a total of 18 enterprises from the province, 45 varieties (73 specifications), and 225 batches of commercial batch samples were collected; 3 enterprises, 3 varieties, and 5 batches of reference preparations were collected. Three enterprises, four varieties, and twelve batches of application batch samples were collected. The reference reagent and the in-market batch-use Raman spectrometry imaging system were used for validation. Result A general threshold of similarity of 99% was used as the criterion; the majority of the varieties collected had a self-similarity of greater than 99%, but five varieties had an average similarity value greater than 99%, but 3-5 pieces per batch had a similarity value with the standard less than 99%. This strongly confirms the accuracy of the CEVAR system. The validation results of the Raman spectrometry imaging system for Rosuvastatin calcium tablets were consistent with those of the CEVAR system. Conclusion According to data of mass sample testing, the similarity of 99% can be used as the threshold value for the determination of quality, and this method is suitable for the general screening of process quality of pharmaceutical preparations