目的:建立和验证氦质谱检测法测试定量压力气雾剂(pressurized metered dose inhalers,pMDIs)容器密封系统(container closure system,CCS)的密封完整性。方法:确定pMDIs的CCS在全生命周期内最大可允许泄漏限度(maximum allowable leakage limit,MALL)。设计并制作专属化的测试腔体以及充氦装置,分别在充氦压力为高压状态(绝对压力672 kPa)和常压状态(绝对压力100 kPa)的条件下,对阴性及阳性对照样品进行检测。根据方法学验证的要求,完成了检测限、系统适用性、精密度、专属性和检测范围等指标的验证,并实现了稳定性考察期间加速3、6个月,长期3、12、24个月等各点的样品密封完整性检测。结果:在2种充氦压力条件下,方法学验证指标均符合可接受标准,稳定性样品检测结果均小于检测限。该方法能够100%检出pMDIs产品CCS等效孔径为0.095 μm及以上的漏孔。结论:采用氦质谱检测方法能够快速定量考察pMDIs产品的泄漏率并证明CCS的密封完整性,具有较高的灵敏度,满足行业内对pMDIs产品质量控制的要求。
Objective: To establish and verify the helium mass spectrometry detection method to test the sealing integrity of the container closure system (CCS) of pressurized metered dose aerosols (pMDIs). Methods: Determined the maximum allowable leakage limit (MALL) of pMDIs of CCS in the whole life cycle. The special test chambers and helium filling devices were designed and manufactured, and helium filling devices to test the negative and positive control samples under high pressure (absolute pressure 672 kPa) and normal pressure (absolute pressure 100 kPa) respectively. According to the requirements of methodology validation, the validation of detection limit, system suitability, precision, specificity and detection range indicators were completed.The accelerated sample sealing integrity testing for 3, 6 months and 3, 12, 24 months in the long-term stability inspection period was achieved. Results: Under both helium-filled pressure conditions, the methodological validation indicators were in line with the acceptable standards, and the results of the stability samples were less than the detection limits. This method can detect 100% that the equivalent pore diameter of pMDIs product CCS was 0.095 μm and above. Conclusion: The helium mass spectrometry detection method can quickly and quantitatively investigate the leakage rate of pMDIs products, prove the seal integrity of CCS with high sensitivity, and meet the industry's requirements for pMDIs product quality control.
[1] MYRDAL PB, SHETH P, STEIN SW, et al. Advances in metered dose inhaler technology: formulation development[J]. AAPS PharmSciTech, 2014, 15(2):434
[2] STEIN SW, SHETH P, HODSON PD, et al. Advances in metered dose inhaler technology: hardware development[J]. AAPS PharmSciTech, 2014, 15(2):326
[3] ZULEGER B, WERNER U, KORT A, et al. Container/closure integrity testing and the identification of a suitable vial/stopper combination for low-temperature storage at -80 ℃[J]. PDA J Pharm Sci Technol, 2012, 66(5):453
[4] 翁琳琳, 唐黎明, 陈桂良, 等. 吸入给药制剂的质量控制及其安全性研究进展[J]. 药物分析杂志, 2013, 33(5):724
WENG LL, TANG LM, CHEN GL, et al. The progress of the research on quality control and safety evaluation of inhalation preparations[J]. Chin J Pharm Anal, 2013, 33(5):724
[5] 中华人民共和国药典 2015 年版. 四部[S]. 2015: 70
ChP 2015. Vol Ⅳ [S]. 2015: 70
[6] USP 40 [S]. 2017:354
[7] 国家药品监督管理局药品审评中心. 化学药品注射剂仿制药质量和疗效一致性评价技术要求[EB/OL]. 2020 [2022-02-09]. https://www.cde.org.cn/main/news/viewInfoCommon/d9c6f118b773f54e8feba3519bf78a11
Center for Drug Evaluationm, NMPA. Technical Requirements for Quality and Efficacy Consistency Evaluation of Generic Drugs for Chemical Injections[EB/OL]. 2020 [2022-02-09]. https://www.cde.org.cn/main/news/viewInfoCommon/d9c6f118b773f54e8feba3519bf78a11
[8] 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) [EB/OL]. 2020 [2022-02-09]. https://www.cde.org.cn/main/news/viewInfoCommon/8a4f9f16844fbed617f8e8ed59485c1d
Center for Drug Evaluation,NMPA. Guideline to container-closure integrity test for chemical injections (Trial) [EB/OL]. 2020 [2022-02-09]. https://www.cde.org.cn/main/news/viewInfoComm-on/8a4f9f16844fbed617f8e8ed59485c1d
[9] 马骏威, 郭涤亮, 刘涓, 等. 胶塞/玻璃瓶容器密封完整性研究的探讨[J]. 中国新药杂志, 2021, 30(5):5
MA JW, GUO DL, LIU J, et al. Discussion on the container closure integrity of rubber stopper/glass container[J]. Chin J New Drugs, 2021, 30(5):5
[10] Sterile Product Packaging-Integrity Evaluation[S]. 2020:40
[11] 封二飞. 无菌药品包装完整性研究[J]. 中国医药工业杂志, 2019, 50(11):1352
FENG EF. Research of sterile products packaging integrity[J]. Chin J Pharm, 2019, 50(11): 1352
[12] PELÁEZ SS, MAHLER HC, HERDLITSCHKA C, et al. Comparing physical container closure integrity test methods and artificial leak methodologies[J]. PDA J Pharm Sci Technol, 2019, 73(3):220
[13] BROWN H, MAHLER HC, MELLMAN J, et al. Container closure integrity testing—practical aspects and approaches in the pharmaceutical industry[J]. PDA J Pharm Sci Technol, 2017, 71(2):147
[14] USP. General Chapter 1207.2. Package Integrity Leak Test Technologies [S]. 2016
[15] 陆维怡, 姚雪凌, 孙甜甜. 氦质谱(真空模式)考察管制玻璃注射剂瓶包装密封完整性[J]. 药物分析杂志, 2022, 42(4):704
LU WY, YAO XL, SUN TT. Helium mass spectrometry (vacuum mode) used to investigate the container closure integrity of the vials system for injection[J]. Chin J Pharm Anal, 2022, 42(4):704
[16] ASTM F 2391-05(2016). Measuring Package and Seal Integrity Using Helium as the Tracer Gas[S]. 2016
[17] 肖祥正. 泄漏检测方法与应用[M]. 北京: 机械工业出版社, 2010: 5
XIAO XZ. Leak Detection Method and Application[M]. Beijing: China Machine Press, 2010:5
[18] GLAXO WELLCOME SA. 葛兰素史克公司原研硫酸沙丁胺醇说明书[Z]. 2022:2
GLAXO WELLCOME SA. Instructions Forsalbutamol Sulfate Originally Developed by Glaxo Smith Kline[Z]. 2022:2
[19] CHEN SC. Container closure integrity testing of primary containers for parenteral products[J]. Chall Prot Prod Dev, 2018, 68(5):253
[20] 张景辰, 邵奇, 胡玥, 等. 基于风险的定量吸入气雾剂包装容器系统相关研究要点[J]. 中国医药工业杂志, 2019, 50(7):722
ZHANG JC, SHAO Q, HU Y, et al. Risk based key points of research on packaging container system of metered dose inhaler[J]. Chin J Pharm, 2019, 50(7):722
