Objective To determine elemental impurities in Xiao′er Xiaoji Zhike oral liquid packaged with pharmaceutical composite films by inductively coupled plasma-mass spectrometry (ICP-MS) and conduct safety evaluation, to provide data support for the replacement of pharmaceutical packaging materials.

Methods Stability tests were performed for Xiao′er Xiaoji Zhike oral liquid packaged with pharmaceutical composite films. The levels of elemental impurities in the oral liquid at month 0 were compared between the new composite film packaging and the original packaging material. The limit of quantitation of the analytical method was compared with the analytical evaluation threshold (AET), and the determined elemental impurity contents at each test time point were compared with the permitted daily exposure (PDE), to evaluate the applicability of the detection method and potential safety risks of the samples.

Results The limits of quantitation for all elemental impurities determined by this method were lower than the AET, indicating that the method is suitable for the determination of elemental impurities in the product. At month 0, the contents of elemental impurities in the oral liquid were basically consistent between the two types of packaging materials. No significant difference in elemental impurity levels was found between the two groups, and all test results were lower than the corresponding PDE values. Stability test results showed no obvious increasing trend in elemental impurities during the study period, with all values remaining below the corresponding PDE values, indicating that the composite film is suitable for packaging Xiao'er Xiaoji Zhike oral liquid.

Conclusion The pharmaceutical composite film presents good compatibility with the oral liquid and can be used as the packaging material for this product.

1. 原国家食品药品监督管理总局.国家药包材标准 (2015年版)[S/OL]. (2015-08-11) [2026-03-12]. https://www.nmpa.gov.cn/directory/web/nmpa/xxgk/ggtg/ypggtg/ypbzhgg/20150811120001744. html.

2. 李樾, 杨锐, 赵霞, 等. 药用棕色中硼硅玻璃安瓿与吸入用盐酸氨溴索溶液的相容性研究[J]. 中南药学, 2024, 22 (9): 2337-2342.LiY, YangR, ZhaoX, et al. Compatibility study between pharmaceutical brown borosilicate glass ampoules and inhalation ambroxol hydrochloride solution[J]. Central South Pharmacy, 2024, 22(9): 2337-2342. DOI: 10.7539/j.issn.1672-2981.2024.09.013.

3. 李朝圆, 李秀英, 贺一峰, 等. 医药包装用玻璃材料的研究进展[J]. 陶瓷学报, 2023, 44 (6): 1103-1115.LiCY, LiXY, HeYF, et al. Research progress of glass materials for pharmaceutical packaging[J]. Journal of Ceramics, 2023, 44(6): 1103-1115. DOI: 10.13957/j.cnki.tcxb.2023.06.005.

4. 成婕, 蒲小聪, 张罗红, 等. UPLC-MS/MS法筛查口服液体药用复合膜中12种常见抗氧剂[J]. 包装工程, 2024, 45 (11): 226-233.ChengJ, PuXC, ZhangLH, et al. Screening of 12 common antioxidants in oral liquid pharmaceutical composite films by UPLC-MS/MS[J]. Packaging Engineering, 2024, 45(11): 226-233. DOI: DOI:10.19554/j.cnki.1001-3563.2024.11.027.

5. 苏传健, 张黎明. 食品包装印刷油墨存在的安全隐患及控制[J]. 中国印刷物资商情, 2006(10): 54-56. doi：JournalArticle/5aea0e7cc095d713d8a00a3c [SuCJ, ZhangLM. Potential safety hazards and control of printing inks for food packaging [J]. China Print Material Market, 2006(10): 54-56.https://kns.cnki.net/kcms2/article/abstract?v=m07J8nP_wCHz0KDIV18FHcooAkk7Q55eHA1ei28PnuJBnwvoutJwNPX_YIPSOtRsk51p5YUbmHOA6rbOY9WXklNzAPM8OeJIg3qd1slZ0dzc1TAAJohq8JFhQ-AP8emZMvApgNN4cXsJbKUkXujxNa2n20AljD1yvED9J6pGUdhVrwIjwy41dw==&uniplatform=NZKPT&language=CHS. doi：JournalArticle/5aea0e7cc095d713d8a00a3c

6. 洪燕, 游媛, 刘宁, 等. 药用复合膜原料膜及添加物体外细胞毒性研究[J]. 药品评价, 2022, 19 (15): 908-911.HongY, YouY, LiuN, et al. In vitro cytotoxicity study on raw films and additives of pharmaceutical composite films[J]. Drug Evaluation, 2022, 19(15): 908-911. DOI: 10.19939/j.cnki.1672-2809.2022.15.04.

7. 国家药品监督管理局. 关于药包材药用辅料与药品关联审评审批有关事项的公告(2016年第134号)[EB/OL]. (2016-08-10) [2026-03-12]. https://www.cde.org.cn/main/policy/view/a47e8bc 225207265224cf494e0d98aa5.

8. 国家药品监督管理局. 原料药、药用辅料及药包材与药品制剂共同审评审批管理规定[EB/OL]. (2018-11-19) [2026-03-12].http://www.nmpa.gov.cn/xxgk/fgwj/gzwj/gzwjylq/201811/2018 1119_537777.html.

9. 中国药典2015年版. 四部[S]. 2015: 73-79.

10. 国家药品监督管理局药品审评中心. 化学药品注射剂与塑料包装材料相容性研究技术指导原则(试行)[EB/OL]. (2012-09-05) [2026-03-12]. https://www.cde.org.cn/main/news/viewInfo Common/8a4f9f16844fbed617f8e8ed59485c1d.

11. 人用药品注册技术要求国际协调会(ICH). 元素杂质指导原则:Q3D(R2)[R/OL]. (2006-12-30) [2026-03-12]. https://www.cde.org.cn/main/news/viewInfoCommon/d4942097ca4b8868971a5c24bb0b5ae8.

12. 国家药品监督管理局药品审评中心. 《化学药品注射剂包装系统密封性研究技术指南(试行)》和《化学药品注射剂生产所用的塑料组件系统相容性研究技术指南(试行)》的通告(2020年第33号)[EB/OL]. (2010-10-21) [2026-03-12]. https://www.cde.org.cn/main/news/viewInfoCommon/8a4f9f16844fbed617f8e8ed59485c1d.

13. 国家食品药品监督管理局. 中药、天然药物稳定性研究技术指导原则 [R/OL]. (2012-09-05) [2026-03-12]. https://www.cde.org.cn/zdyz/domesticinfopage?zdyzIdCODE=a941d23017df025ec84043d9784e9baf.

14. 蒋煜, 马玉楠, 霍秀敏, 等. 《化学药品注射剂与塑料包装材料相容性研究技术指导原则》解读——提取迁移试验方法设计[J]. 中国新药杂志, 2014, 23(15): 1738-1742.JiangY, MaYN, HuoXM, et al. Interpretation of Guideline for Compatibility Study Between Chemical Injection and Plastic Packaging Materials: design of extraction and migration test [J]. Chinese Journal of New Drugs, 2014, 23(15): 1738-1742. DOI: 10.20251/j.cnki.1003-3734.2014.15.005.

15. 国家药品监督管理局药品审评中心. 已上市化学仿制药(注射剂)一致性评价技术要求(征求意见稿)[EB/OL]. (2017-06-12) [2026-03-12]. https://www.cde.org.cn/main/news/viewInfoCommon/ d9c6f118b773f54e8feba3519bf78a11.

16. 国家卫生健康委员会, 国家市场监督管理总局. 食品安全国家标准食品接触材料及制品用添加剂使用标准: GB 9685-2016 [S]. 2016.

17. 国家药品监督管理局. 医疗器械生物学评价第18部分: 风险管理过程中医疗器械材料的化学表征: GB/T 16886.18-2023[S]. 2023.