Optimizing Industrial Solid-Phase Peptide Synthesis: Integration of Raman Spectroscopy as Process Analytical Technology

IF 3.1 3区 化学 Q2 CHEMISTRY, APPLIED
Michael A. Stager*, Carlos Peroza, Julien Villaumie, Christopher Bilham, Cameron Desmond, Marcus Harris, Ramya Sambasivan, Gary Rowe, Lin Chen and Charles Tucker, 
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引用次数: 0

Abstract

Peptide therapeutics have exploded in popularity in recent years, motivating the need for advanced manufacturing methods which can be applied across the solid-phase peptide synthesis (SPPS) process. The Food and Drug Administration’s Process Analytical Technology (PAT) initiative offers a platform to implement advanced methods to improve the efficiency and understanding of pharmaceutical manufacturing processes and shows great promise in application toward industrial SPPS. In this work, Raman spectroscopy was used as the main PAT tool to implement methods for on-line and real-time monitoring of the entire SPPS process, from Fmoc removal, to coupling, and through the extensive solvent-washing steps. Raman spectroscopy is a rapid, specific, and nondestructive technique that can provide rich real-time information for SPPS processes and can be used to improve efficiency in solvent use and save process time. Specifically, this work reports on the development of PAT methods for monitoring of amino acid coupling during the coupling stage and residual piperidine concentration during the post-deprotection washing stage of SPPS, to help reduce solvent use and better understand the coupling reaction and its time frame. We show a significant reduction in solvent use is possible by employing Raman spectroscopy along with a partial least squares model to predict the piperidine concentration in real time during continuous wash. In addition, Raman spectroscopy offers a greater understanding of coupling reaction kinetics during SPPS, which could lead to significant improvements in total SPPS process time.

Abstract Image

优化工业固相肽合成:拉曼光谱作为过程分析技术的集成
肽治疗在近年来的流行爆炸,激发了先进的制造方法,可以应用于整个固相肽合成(SPPS)过程的需要。美国食品和药物管理局的过程分析技术(PAT)计划提供了一个平台来实施先进的方法,以提高效率和对制药生产过程的理解,并在工业SPPS的应用中显示出巨大的前景。在这项工作中,拉曼光谱被用作主要的PAT工具来实现在线和实时监测整个SPPS过程的方法,从去除Fmoc到耦合,以及通过广泛的溶剂洗涤步骤。拉曼光谱是一种快速、特异和非破坏性的技术,可以为SPPS工艺提供丰富的实时信息,并可用于提高溶剂的使用效率和节省工艺时间。具体来说,本工作报告了PAT方法的发展,用于监测偶联阶段的氨基酸偶联和SPPS脱保护后洗涤阶段的残余哌啶浓度,以帮助减少溶剂的使用,更好地了解偶联反应及其时间框架。我们表明,通过使用拉曼光谱和偏最小二乘模型来预测连续洗涤期间实时的哌啶浓度,可以显著减少溶剂的使用。此外,拉曼光谱可以更好地了解SPPS过程中的耦合反应动力学,这可能会显著缩短SPPS过程的总时间。
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来源期刊
CiteScore
6.90
自引率
14.70%
发文量
251
审稿时长
2 months
期刊介绍: The journal Organic Process Research & Development serves as a communication tool between industrial chemists and chemists working in universities and research institutes. As such, it reports original work from the broad field of industrial process chemistry but also presents academic results that are relevant, or potentially relevant, to industrial applications. Process chemistry is the science that enables the safe, environmentally benign and ultimately economical manufacturing of organic compounds that are required in larger amounts to help address the needs of society. Consequently, the Journal encompasses every aspect of organic chemistry, including all aspects of catalysis, synthetic methodology development and synthetic strategy exploration, but also includes aspects from analytical and solid-state chemistry and chemical engineering, such as work-up tools,process safety, or flow-chemistry. The goal of development and optimization of chemical reactions and processes is their transfer to a larger scale; original work describing such studies and the actual implementation on scale is highly relevant to the journal. However, studies on new developments from either industry, research institutes or academia that have not yet been demonstrated on scale, but where an industrial utility can be expected and where the study has addressed important prerequisites for a scale-up and has given confidence into the reliability and practicality of the chemistry, also serve the mission of OPR&D as a communication tool between the different contributors to the field.
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