Pfizer R&D UK Limited, Sandwich CT13 9NJ, UK.
Merck KGaA, Frankfurter Str. 250, Darmstadt 64293, Germany.
J Pharm Sci. 2023 Jun;112(6):1615-1624. doi: 10.1016/j.xphs.2022.04.016. Epub 2022 Apr 29.
N-Nitrosamine risk assessment and control have become an integral part of pharmaceutical drug product development and quality evaluation. Initial reports of nitrosamine contamination were linked with the drug substance and its manufacturing process. Subsequently, the drug product and aspects of the formulation process have shown to be relevant. Regarding specific formulation contributions to nitrosamine content in a product, one risk lies in possible interactions between nitrosating agents, derived from nitrite in excipients, and vulnerable amines, either present as moieties of the active molecule or as impurities / degradants. However, the limited validated information on nitrite levels in excipients available until now, has been an obstacle for scientists to assess the risk of nitrosamine formation in pharmaceutical products. This has driven the creation of a database to store and share such validated information. The database, maintained by Lhasa Limited, constitutes a central platform to hold the data donated by the pharmaceutical company members on the nitrite concentrations in common excipients measured with validated analytical procedures. The goal of this data sharing initiative is to provide a common framework to contextualize and estimate the risk posed by presence of nitrites to contribute to the formation of nitrosamines in drug products. The major findings from the database analyses are: (1) average nitrite content and batch to batch variance differ among excipients, (2) for solid dosage forms, the nitrite contribution is dominated by the highest formula % excipients, e.g., the fillers (diluents), which are typically used in larger proportion, and are characterized by low nitrite levels and low variability, leading to an average value of 1 µg/g nitrite in a typical formulation, (3) substantial differences in average nitrite content in batches from different excipient vendors potentially reflecting differences in source materials or processing methods for excipient manufacturing. That final point suggests that future selection of raw materials or processing by excipient manufacturers may help reduce nitrite levels in finished drug product formulations, and thus the overall risk of nitrosamine formation in cases where the product contains vulnerable amines.
亚硝胺风险评估和控制已成为药物产品开发和质量评估不可或缺的一部分。最初的亚硝胺污染报告与药物物质及其制造工艺有关。随后，药物产品及其制剂过程的各个方面都显示出相关性。关于制剂对产品中亚硝胺含量的具体贡献，一个风险在于来自赋形剂中亚硝酸盐的亚硝化剂与易受攻击的胺之间可能发生相互作用，这些胺要么是活性分子的部分，要么是杂质/降解物。然而，直到现在，关于赋形剂中亚硝酸盐水平的有限验证信息一直是科学家评估药物产品中亚硝胺形成风险的障碍。这促使创建了一个数据库来存储和共享此类经过验证的信息。该数据库由 Lhasa Limited 维护，是一个中央平台，用于保存制药公司成员捐赠的关于用经过验证的分析程序测量的常见赋形剂中亚硝酸盐浓度的数据。该数据共享计划的目标是提供一个共同的框架，以了解和估计赋形剂中亚硝酸盐存在对药物产品中亚硝胺形成的风险。数据库分析的主要发现包括：（1）赋形剂中的亚硝酸盐含量和批间差异不同，（2）对于固体制剂，亚硝酸盐的贡献主要由最高配方%赋形剂决定，例如填充剂（稀释剂），它们通常以较大的比例使用，并且具有低亚硝酸盐水平和低变异性，导致典型配方中亚硝酸盐的平均含量为 1μg/g，（3）不同赋形剂供应商批次的亚硝酸盐平均含量存在很大差异，这可能反映了赋形剂制造中原材料或加工方法的差异。最后一点表明，未来赋形剂制造商对原材料的选择或加工可能有助于降低成品药物制剂中亚硝酸盐的水平，从而降低产品中存在易受攻击的胺的情况下亚硝胺形成的总体风险。
