化学药品中亚硝胺杂质风险评估与控制体系的构建及应用

Establishment of a risk assessment and control system for nitrosamine impurities in chemical drugs and its application

摘要

目的: 构建化学药品中亚硝胺杂质风险评估与控制体系,并用于盐酸普萘洛尔片中亚硝胺杂质的研究。方法: 检索各国药品监管机构、PubMed、Elsevier和Wiley网站,对亚硝胺杂质产生机制、毒性评估和控制措施进行分析总结,对药品中亚硝胺杂质风险评估与控制的指导原则进行梳理。结果: 从亚硝胺杂质风险评估要素、杂质限度的确定、确认性检测以及过程控制要素4个方面构建了亚硝胺杂质风险评估与控制体系,并应用于盐酸普萘洛尔片中亚硝胺杂质的评估,采用鱼骨分析法从盐酸普萘洛尔片的原料、辅料、工艺过程和贮存等方面分析亚硝胺杂质风险因素,对抽检样品及其原料进行测定,结合原辅料相容性、影响因素和加速稳定性试验初步探究影响亚硝胺杂质产生的因素并提出控制措施。结论: 构建的化学药品中亚硝胺杂质风险评估与控制体系有助于药品中亚硝胺杂质控制策略的制定,也为监管部门及制药企业实施亚硝胺杂质风险精准控制提供技术参考。

Abstract

Objective: To establish a risk assessment and control system for nitrosamine impurities in chemical drugs and apply it to the study of nitrosamine impurities in propranolol hydrochloride tablets. Methods: Information was retrieved from various national drug regulatory agencies, PubMed, Elsevier and Wiley websites, and the formation mechanisms, toxicity assessment, and control measures of nitrosamine impurities were analyzed and summarized. Guidelines for risk assessment and control of nitrosamine impurities in pharmaceuticals were systematically reviewed. Results: A risk assessment and control system for nitrosamine impurities was constructed, covering four key aspects: risk assessment elements, determination of impurity limits, confirmatory testing, and process control factors. This system was applied to evaluate nitrosamine impurities in propranolol hydrochloride tablets. Using fishbone diagram analysis, risk factors for nitrosamine impurities were identified from aspects such as active ingredients, excipients, manufacturing processes, and storage conditions of the tablets. Samples from market surveillance and their raw materials were tested. Factors influencing the formation of nitrosamine impurities were preliminarily investigated through excipient compatibility studies, stress testing, and accelerated stability testing, and corresponding control measures were proposed. Conclusion: The established risk assessment and control system for nitrosamine impurities in pharmaceuticals will aid in the development of strategies for managing these impurities. It also provides technical references for regulatory authorities and pharmaceutical companies to implement precise control of nitrosamine-related risks.

关键词

化学药品 / 亚硝胺杂质 / 风险评估与控制体系 / 盐酸普萘洛尔片

Key words

chemical drug / nitrosamine impurities / risk assessment and control system / propranolol hydrochloride tablets

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基金资助

2024年国家药品抽检计划资助项目(国药监药管〔2024〕1号)