Chromicent GmbH, Johann-Hittorf-Str. 8, 12489 Berlin, Germany; Freie Universität Berlin, Königin-Luise-Str. 2+4, 14195 Berlin, Germany.
Chromicent GmbH, Johann-Hittorf-Str. 8, 12489 Berlin, Germany; Freie Universität Berlin, Königin-Luise-Str. 2+4, 14195 Berlin, Germany.
J Pharm Biomed Anal. 2021 Apr 15;197:113960. doi: 10.1016/j.jpba.2021.113960. Epub 2021 Feb 9.
Since the detection of nitrosamines (NA) in valsartan pharmaceuticals, over two years have passed. At present, the occurrence of NAs can be limited to a few drug substances and drug products, but it is already becoming apparent that the issue appears to be much bigger than initially thought. The impact on the global pharmaceutical market has been tremendous and the problem can be attributed mainly to uncritically adopted approval changes and the lack of suitable, modern analytical methods to detect those impurities in time. We hereby demonstrate how lifecycle management (LCM) can be used to develop and improve suitable and universal analytical methods within short time. The resulting SFC-MS/MS method is intended for a universal nitrosamine investigation in drug substances and drug products. Successful NA analysis was demonstrated for seven sartans, metformin, pioglitazone and ranitidine. Additionally, combination drug products, containing also amlodipine, hydrochlorothiazide, vildagliptin and sitagliptin, were analyzed successfully. The method achieved separation of 16 NAs in 4 min with a total run time of 11.5 min, utilizing a Supel Carbon porous graphitic carbon (PGC) column. Carbon dioxide together with 0.1% TFA in methanol as modifier were used as eluents and 0.35% formic acid in methanol as make-up solvent for mass spectrometric NA detection. By implementing LCM in this case study, development time was reduced and knowledge was implemented fast. At the same time, a high adaptability of this "vital" method was achieved, which makes it possible to implement the constantly changing regulatory requirements within the shortest possible time. Supplemental development data, according to the ICH guidelines Q8, Q12 and the proposed Q14 are disclosed, demonstrating the scientific Quality-by-Design (QbD) development approach, the "fitness for use" and the robustness of the analytical procedure. This method contributes to the still ongoing risk assessment process of the pharmaceutical industry and the regulatory agencies, in order to understand root causes of NA formation, maintain the drug supply and prevent drug shortage.
自缬沙坦药品中检出亚硝胺（NA）以来，已经过去了两年多。目前，NA 的出现可以局限于少数药物物质和药物产品，但显然问题比最初想象的要大得多。这对全球制药市场的影响是巨大的，问题主要归因于不加批判地采用批准变更和缺乏合适的、现代的分析方法来及时检测这些杂质。我们在此展示如何在短时间内使用生命周期管理（LCM）开发和改进合适的通用分析方法。由此产生的 SFC-MS/MS 方法旨在对药物物质和药物产品中的通用亚硝胺进行调查。成功地对七种沙坦类、二甲双胍、吡格列酮和雷尼替丁进行了 NA 分析。此外，还成功分析了含有氨氯地平、氢氯噻嗪、维格列汀和西他列汀的复方药物产品。该方法在 4 分钟内实现了 16 种 NA 的分离，总运行时间为 11.5 分钟，使用 Supel 碳多孔石墨化碳（PGC）柱。二氧化碳与甲醇中的 0.1%TFA 作为改性剂，甲醇中的 0.35%甲酸作为质谱 NA 检测的补加溶剂。通过在本案例研究中实施 LCM，开发时间得以缩短，知识得以快速实施。同时，实现了这种“关键”方法的高适应性，使其能够在最短的时间内实施不断变化的监管要求。根据 ICH 指南 Q8、Q12 和拟议的 Q14 披露了补充开发数据，证明了分析程序的科学质量源于设计（QbD）开发方法、“适用性”和稳健性。该方法有助于制药行业和监管机构正在进行的风险评估过程，以了解 NA 形成的根本原因，维持药物供应并防止药物短缺。
