CMC DP & Ana Development, Novo Nordisk A/S, Måløv, Denmark.
Product Supply, Novo Nordisk A/S, Bagsværd, Denmark.
Pharm Res. 2024 Oct;41(10):1991-2014. doi: 10.1007/s11095-024-03771-6. Epub 2024 Oct 8.
The prevalence of follow-on and compounded products of glucagon-like peptide-1 analogs is increasing. We assessed glucagon-like peptide-1 analogs semaglutide and liraglutide for purity, potential immunogenicity, and expected stability, by comparing a representative selection of commercially available follow-on drug substances (DSs) and drug products (DPs) with their corresponding originators.
Tests included several chromatography methods coupled with ultraviolet and mass spectrometry detectors, inductively coupled plasma optical emission spectroscopy, inductively coupled plasma mass spectrometry, nuclear magnetic resonance, dissolution analyses, in silico peptide/major histocompatibility complex II-binding prediction, and fibrillation assays.
Overall, 16 injectable semaglutide, 8 oral semaglutide, and 2 injectable liraglutide follow-on products were analyzed alongside originator products. Compared with originator, follow-on injectable semaglutide DSs and DPs had new impurities and impurity patterns, including high molecular weight proteins, trace metals, anions, counterions, and residual solvents. Analyses showed that several commercialized follow-on oral semaglutide DPs had a markedly lower quantity of semaglutide than the label claim, while dissolution tests indicated different semaglutide and sodium N-(8-[2-hydroxybenzoyl] amino)caprylate (SNAC) release profiles, which may reduce bioavailability. Neoepitopes were identified in DS and DP semaglutide follow-ons, indicating potential immunogenicity. Fibrillation assays showed increased fibrillation tendency and reduced physical stability in liraglutide follow-on DP samples compared with originator.
This study highlights that differences in the manufacturing processes of follow-on semaglutide and liraglutide (vs those used for originators) can result in several changes to the DSs and DPs. The impact of these changes on efficacy and safety outcomes remains unknown and should be investigated by clinical studies.
胰高血糖素样肽-1 类似物的后续产品和复方产品的流行率正在上升。我们通过比较代表性的商业化后续药物物质（DS）和药物产品（DP）与相应的原创药物，评估了胰高血糖素样肽-1 类似物司美格鲁肽和利拉鲁肽的纯度、潜在的免疫原性和预期的稳定性。
测试包括几种与紫外和质谱检测器、电感耦合等离子体发射光谱、电感耦合等离子体质谱、核磁共振、溶解分析、肽/主要组织相容性复合体 II 结合的计算机预测、以及纤颤测定相结合的色谱方法。
总体而言，分析了 16 种可注射司美格鲁肽、8 种口服司美格鲁肽和 2 种可注射利拉鲁肽的后续产品以及原创产品。与原创药物相比，后续可注射司美格鲁肽 DS 和 DP 具有新的杂质和杂质模式，包括高分子量蛋白质、痕量金属、阴离子、反离子和残留溶剂。分析表明，一些商业化的后续口服司美格鲁肽 DP 的实际含量明显低于标签声称，而溶解试验表明不同的司美格鲁肽和钠 N-（8-[2-羟基苯甲酰]氨基）己酸酯（SNAC）释放曲线，这可能会降低生物利用度。在 DS 和 DP 司美格鲁肽后续产品中鉴定出了新表位，表明潜在的免疫原性。纤颤试验表明，与原创药物相比，利拉鲁肽后续 DP 样品的纤颤倾向增加，物理稳定性降低。
本研究表明，后续司美格鲁肽和利拉鲁肽（与原创药物相比）的制造工艺的差异可能导致 DS 和 DP 发生多种变化。这些变化对疗效和安全性结果的影响尚不清楚，应通过临床研究进行调查。
