Novartis Pharma AG, Continuous Manufacturing (CM) Unit, CH-4002 Basel, Switzerland; Institute of Pharmaceutics and Biopharmaceutics, Heinrich Heine University, Universitaetsstr. 1, 40225 Dusseldorf, Germany.
Novartis Pharma AG, Continuous Manufacturing (CM) Unit, CH-4002 Basel, Switzerland.
J Pharm Biomed Anal. 2019 Jan 5;162:101-111. doi: 10.1016/j.jpba.2018.09.016. Epub 2018 Sep 13.
The use of Near Infrared Spectroscopy (NIRS) as a fast and non-destructive technique was employed for the control and monitoring of the tableting step during a continuous manufacturing process. Two NIRS methods were optimized in order to in-line control the blend uniformity in the tablet feed frame and the API concentration of freshly pressed tablets prior the ejection. The novelty of this work first lies in the acquisition speed of NIR spectra reaching up to 70,000 tablets/h. Partial Least Square (PLS) regression was used as chemometric tool for the computation that resulted in excellent predictive calibration results. A coefficient of correlation (r) value of 0.99 was obtained for both probes. The root mean square error of calibration (RMSEC) and the root mean square error of prediction (RMSEP) were respectively 1.8% and 1.8% for active content in the tablet feeder and 2.2% and 2.3% for the tablet content. In addition, calibration performance and robustness of the methods were evaluated. Moreover several qualitative methods were proposed to monitor the tableting process in different stages of development (single wavelength, Principal Component Analysis, and Independent Component Analysis). In early phase development, the requirement/quality of the input material is not established yet; hence the use of a qualitative approach allows to confirm the suitability of the PAT methodology for in-process material monitoring & control. Later, the qualitative approach constitutes the foundation for the quantitative approach when input materials are fixed and larger production size occurs. The proposed strategy is a performant PAT tool for continuous manufacturing and a step forward to real time release.
近红外光谱（NIRS）作为一种快速且无损的技术，被用于控制和监测连续制造过程中的压片步骤。为了在线控制压片料斗中的混合均匀度和刚压出的片剂中的 API 浓度，对两种 NIRS 方法进行了优化。这项工作的新颖之处首先在于 NIR 光谱的采集速度高达 70,000 片/小时。偏最小二乘法（PLS）回归被用作计算的化学计量工具，得到了出色的预测校准结果。两个探头的相关系数（r）值均为 0.99。对于压片料斗中的活性成分，校准的均方根误差（RMSEC）和预测的均方根误差（RMSEP）分别为 1.8%和 1.8%，对于片剂中的含量分别为 2.2%和 2.3%。此外，还评估了方法的校准性能和稳健性。此外，还提出了几种定性方法来监测不同开发阶段的压片过程（单波长、主成分分析和独立成分分析）。在早期开发阶段，尚未确定输入材料的要求/质量；因此，定性方法的使用可以确认 PAT 方法在过程中材料监测和控制方面的适用性。后来，当输入材料固定且生产规模较大时，定性方法为定量方法奠定了基础。所提出的策略是连续制造的高性能 PAT 工具，是实时放行的一个进步。
