Continuous manufacturing opens up new operation windows with improved product quality in contrast to documented lot deviations in batch or fed-batch operations. A more sophisticated process control strategy is needed to adjust operation parameters and keep product quality constant during long-term operations. In the present study, the applicability of a combination of spectroscopic methods was evaluated to enable Advanced Process Control (APC) in continuous manufacturing by Process Analytical Technology (PAT). In upstream processing (USP) and aqueous two-phase extraction (ATPE), Raman-, Fourier-transformed infrared (FTIR), fluorescence- and ultraviolet/visible- (UV/Vis) spectroscopy have been successfully applied for titer and purity prediction. Raman spectroscopy was the most versatile and robust method in USP, ATPE, and precipitation and is therefore recommended as primary PAT. In later process stages, the combination of UV/Vis and fluorescence spectroscopy was able to overcome difficulties in titer and purity prediction induced by overlapping side component spectra. Based on the developed spectroscopic predictions, dynamic control of unit operations was demonstrated in sophisticated simulation studies. A PAT development workflow for holistic process development was proposed.

中文翻译：

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通过先进的过程控制实现自主操作—连续生物抗体生产的过程分析技术

连续生产打开了新的操作窗口，与批次或补料分批操作中记录的批次偏差形成对比，从而提高了产品质量。需要更复杂的过程控制策略来调整操作参数并在长期操作期间保持产品质量恒定。在本研究中，对光谱方法组合的适用性进行了评估，以通过过程分析技术（PAT）实现连续生产中的高级过程控制（APC）。在上游处理（USP）和水两相萃取（ATPE）中，拉曼，傅立叶变换红外（FTIR），荧光和紫外/可见-（UV / Vis）光谱已成功应用于滴度和纯度预测。拉曼光谱法是USP，ATPE，和降水，因此推荐作为主要的PAT。在随后的工艺阶段，UV / Vis和荧光光谱的结合能够克服因重叠的侧组分光谱而导致的滴定度和纯度预测方面的困难。基于已开发的光谱预测，在复杂的模拟研究中演示了单元操作的动态控制。提出了用于整体过程开发的PAT开发工作流程。