Moving from batch to continuous manufacturing (CM) requires implementation of process analytical technology (PAT), as it is crucial to monitor and control these processes. CM of semi-solids has been demonstrated but implementation of a broader range of PAT tools with in- or on-line process interfacing at the end of the CM line has not been demonstrated. The goal of this work was to continuously manufacture creams and to investigate whether in- and on-line measurement of viscosity, changes in the concentration of active pharmaceutical ingredient (API), and pH could be used to support optimization of a model cream product. Additionally, the torque of the mixers was assessed for determination of the physical properties of the cream. Two Raman probes with different probe optics were compared for characterization of the API concentration. The API concentration, amount of neutralizer, and mixing speed of the CM line were systematically varied. Both the PhAT probe with a larger sampling volume and immersion Raman probe with a smaller sampling volume could detect the step changes in the API concentration. The torque from the mixer was compared with the viscosity measurements, but the torque signal could not be correlated with the viscosity due to the dynamic nature of the polymer conformation and the time-dependency of this property. Adjustment of pH of the cream could be monitored with the current installation. The investigated PAT tools could be implemented into a continuous line and, further, be used to support the optimization of a model cream composition and related process parameters.

中文翻译：

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用工艺分析技术监控聚合物稳定乳液的连续生产。

从批量生产到连续制造（CM）的过程需要实施过程分析技术（PAT），因为监视和控制这些过程至关重要。已经展示了半固体的CM，但尚未演示在CM生产线末端使用在线或在线过程接口实现更广泛的PAT工具的方法。这项工作的目的是连续生产面霜，并研究粘度的在线和在线测量，活性药物成分（API）浓度的变化以及pH值是否可用于支持模型面霜产品的优化。另外，评估混合器的扭矩以确定乳霜的物理性质。比较了具有不同探针光学器件的两种拉曼探针，以表征API浓度。系统地改变了API浓度，中和剂的量和CM线的混合速度。具有较大采样量的PhAT探针和具有较小采样量的浸入拉曼探针都可以检测API浓度的阶跃变化。将来自混合器的扭矩与粘度测量值进行了比较，但是由于聚合物构象的动态性质和该性质的时间依赖性，扭矩信号无法与粘度相关。可以通过当前安装来监视乳霜的pH值调整。可以将研究的PAT工具实施为一条连续生产线，并进一步用于支持模型霜成分和相关工艺参数的优化。具有较大采样量的PhAT探针和具有较小采样量的浸入式拉曼探针都可以检测API浓度的阶跃变化。将来自混合器的扭矩与粘度测量值进行了比较，但是由于聚合物构象的动态性质和该性质的时间依赖性，扭矩信号无法与粘度相关。可以通过当前安装来监视乳霜的pH值调整。可以将研究的PAT工具实施为一条连续生产线，并进一步用于支持模型霜成分和相关工艺参数的优化。具有较大采样量的PhAT探针和具有较小采样量的浸入拉曼探针都可以检测API浓度的阶跃变化。将来自混合器的扭矩与粘度测量值进行了比较，但是由于聚合物构象的动态性质和该性质的时间依赖性，扭矩信号无法与粘度相关。可以通过当前安装监控乳霜的pH值调整。可以将研究的PAT工具实施为一条连续生产线，并进一步用于支持模型霜成分和相关工艺参数的优化。将来自混合器的扭矩与粘度测量值进行了比较，但是由于聚合物构象的动态性质和该性质的时间依赖性，扭矩信号无法与粘度相关。可以通过当前安装来监视乳霜的pH值调整。可以将研究的PAT工具实施为一条连续生产线，并进一步用于支持模型霜成分和相关工艺参数的优化。将来自混合器的扭矩与粘度测量值进行了比较，但是由于聚合物构象的动态性质和该性质的时间依赖性，扭矩信号无法与粘度相关。可以通过当前安装来监视乳霜的pH值调整。可以将研究的PAT工具实施为一条连续生产线，并进一步用于支持模型霜成分和相关工艺参数的优化。