【摘要】 目的：通过对比《中华人民共和国药典》2020年版（ChP 2020）、2023年美国药典（USP-NF2023）、欧洲药典11.0版（EP 11.0）、日本药典18版（JP 18）中注射剂不溶性微粒检测方法相关内容，分析不同药典对不溶性微粒的监管要求，供业界参考。以治疗性蛋白注射液为代表，结合目前各监管机构对注射液中不溶性微粒的要求，指出现有要求未能对此类生物技术药物中具有免疫原性潜力的小粒径（0.1～10μm）蛋白聚集体微粒进行控制，并从三方面提出建议以加强此类药物的质量控制，更好地保障患者的用药安全。方法：通过对比ChP 2020、USP-NF 2023、EP 11.0、JP 18中注射剂不溶性微粒检测的章节内容，对检测方法、限定标准和系统适用性检测等内容进行分析总结。通过收集归纳中、美、日、欧关于生物技术药物中不溶性微粒的药典要求和相关技术指导原则，明确目前不同机构对于生物技术药物中不溶性微粒的监管要求。结果与结论：（1）对于注射液中不溶性微粒检查方法，不同药典收载的方法均为光阻法和显微计数法，但是对各方法的适用条件的限定不同。此外，USP-NF 2023、EP 11.0和JP 18中提出的检测方法一致，Chp 2020主要在25 mL以下规格的供试品检测方面与其他三部药典有较大差异；在系统适用性检测方面，USP-NF 2023更为全面，Chp 2020在此方面要求较少；在微粒计数和限定标准方面，各药典一致；（2）对于生物技术药物，除Chp 2020外，其他药典均收载了生物技术药物不溶性微粒的检测方法，但是并未对0.1～10μm小粒径微粒进行计数和控制，仍然无法控制小粒径蛋白聚集体可能带来的免疫原性的危害；也未见各机构明确对生物技术药物中有免疫原风险的小粒径不溶性微粒的监管要求和标准。为此笔者分别在方法学研究方面、数据收集方面、研发技术要求方面提出三点建议，以更好地保障患者的用药安全。更多还原

【Abstract】 Objective: To analyze the regulatory requirements for sub-visible particles in different pharmacopoeias for industry reference, by comparing the regulatory requirements of sub-visible particles of the Chinese Pharmacopoeia 2020 edition(ChP 2020), the 2023 US Pharmacopoeia(USP-NF 2023), European Pharmacopoeia 11.0th edition(EP 11.0), Japanese Pharmacopoeia 18th edition(JP 18). Taking therapeutic protein injection as a representative, combined with the current regulatory requirements for sub-visible particles in injections, it is pointed out that the existing requirements fail to control the small-size particles(0.1-10 μm) which with immunogenic potential in such biotech drugs, and suggestions are put forward from three aspects to improve the quality control to better ensure the safety of patients. Methods: By comparing the sections of sub-visible particles testing in injections in ChP 2020, USP-NF 2023, EP 11.0 and JP 18, the contents of the testing methods,limited standards and system suitability tests are analyzed and summarized. By collecting and summarizing the requirements in pharmacopoeias and technical guidelines for sub-visible particles of biotech drugs in China, US, Japan and Europe, the current regulatory requirements for sub-visible particles in biotech drugs are clarified. Results and Conclusion:(1) For the determination of sub-visible particles, two procedures, Light Obscuration Particle Count Test and Microscopic Particle Count Test are specified in all the 4 pharmacopoeias,but the applicable conditions of each method are dif ferent. In addition, for testing methods, the requirements in USP-NF 2023, EP 11.0 and JP 18 are same. The mainly dif ference in ChP 2020 is the test requirements of the samples which are less than 25 mL. For system suitability testing, the requirements in USP-NF 2023 are more comprehensive, while which in ChP 2020 are less. For particle count and limited standards, the requirements are consistent for the 4 pharmacopoeias.(2) Testing methods for sub-visible particles in biotech drugs are included in USP-NF 2023, EP 11.0, JP 18, except ChP 2020. However, in the 3 pharmacopoeias, the particles with 0.1-10 μm size are not required to count and control. The possible immunogenicity hazards which may be caused by these small-size protein aggregates are still not controlled. Since there is no clear technical requirements and standards for these small-size particles, three suggestions are put forward in methodology research, data collection and development technical requirements, so as to better ensure the drug safety of patients.更多还原