Impact of Manufacturing Process and Compounding on Properties and Quality of Follow-On GLP-1 Polypeptide Drugs.

IF 3.5 3区医学 Q2 CHEMISTRY, MULTIDISCIPLINARY Pharmaceutical Research Pub Date : 2024-10-01 Epub Date: 2024-10-08 DOI:10.1007/s11095-024-03771-6

Morten Hach, Dorthe Kot Engelund, Simon Mysling, Jesper Emil Mogensen, Ole Schelde, Kim F Haselmann, Kasper Lamberth, Thomas Kvistgaard Vilhelmsen, Joan Malmstrøm, Kim Bonde Højlys-Larsen, Tina Secher Rasmussen, Jonas Borch-Jensen, Rasmus Worm Mortensen, Thomas Marker Thams Jensen, Julie Regitze Kesting, Andrei-Mircea Catarig, Désirée J Asgreen, Leif Christensen, Arne Staby

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Abstract

Purpose: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

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生产工艺和复配对后续 GLP-1 多肽药物特性和质量的影响

目的：胰高血糖素样肽-1 类似物的后续产品和复方产品越来越多。我们通过比较具有代表性的市售后续药物物质 (DS) 和药物产品 (DP) 与相应的原研药，评估了胰高血糖素样肽-1 类似物 semaglutide 和 liraglutide 的纯度、潜在免疫原性和预期稳定性：测试包括几种与紫外线和质谱检测器相结合的色谱法、电感耦合等离子体光发射光谱法、电感耦合等离子体质谱法、核磁共振法、溶解分析法、肽/主要组织相容性复合体 II 结合预测法和纤维化测定法：共分析了16种注射用塞马鲁肽、8种口服塞马鲁肽和2种注射用利拉鲁肽后续产品以及原研产品。与原研产品相比，后续注射用塞马鲁肽DS和DP具有新的杂质和杂质模式，包括高分子量蛋白质、微量金属、阴离子、反离子和残留溶剂。分析表明，几种商业化的后续口服塞马鲁肽DP的塞马鲁肽含量明显低于标签声称的含量，而溶出试验表明塞马鲁肽和N-(8-[2-羟基苯甲酰基]氨基)辛酸钠(SNAC)的释放曲线不同，这可能会降低生物利用度。在 DS 和 DP semaglutide 后继药物中发现了新表位，表明可能存在免疫原性。与原研药相比，纤溶试验显示利拉鲁肽后续DP样品的纤溶趋势增加，物理稳定性降低：本研究强调，后续用塞马鲁肽和利拉鲁肽生产工艺的不同（与原研药生产工艺的不同）会导致DSs和DPs发生一些变化。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。

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来源期刊

Pharmaceutical Research 医学-化学综合

CiteScore

6.60

自引率

5.40%

发文量

276

审稿时长

3.4 months

期刊介绍： Pharmaceutical Research, an official journal of the American Association of Pharmaceutical Scientists, is committed to publishing novel research that is mechanism-based, hypothesis-driven and addresses significant issues in drug discovery, development and regulation. Current areas of interest include, but are not limited to: -(pre)formulation engineering and processing- computational biopharmaceutics- drug delivery and targeting- molecular biopharmaceutics and drug disposition (including cellular and molecular pharmacology)- pharmacokinetics, pharmacodynamics and pharmacogenetics. Research may involve nonclinical and clinical studies, and utilize both in vitro and in vivo approaches. Studies on small drug molecules, pharmaceutical solid materials (including biomaterials, polymers and nanoparticles) biotechnology products (including genes, peptides, proteins and vaccines), and genetically engineered cells are welcome.