Besseling Rut, Damen Michiel, Tran Thanh, Nguyen Thanh, van den Dries Kaspar, Oostra Wim, Gerich Ad
Pharmaceutical Sciences and Clinical Supplies, Merck/MSD, PO Box 20, 5340 BH Oss, The Netherlands; Currently at InProcess-LSP, Molenstraat 110, 5342 CC Oss, The Netherlands.
Pharmaceutical Sciences and Clinical Supplies, Merck/MSD, PO Box 20, 5340 BH Oss, The Netherlands; Currently at InProcess-LSP, Molenstraat 110, 5342 CC Oss, The Netherlands.
J Pharm Biomed Anal. 2015 Oct 10;114:471-81. doi: 10.1016/j.jpba.2015.06.019. Epub 2015 Jun 17.
Dry powder mixing is a wide spread Unit Operation in the Pharmaceutical industry. With the advent of in-line Near Infrared (NIR) Spectroscopy and Quality by Design principles, application of Process Analytical Technology to monitor Blend Uniformity (BU) is taking a more prominent role. Yet routine use of NIR for monitoring, let alone control of blending processes is not common in the industry, despite the improved process understanding and (cost) efficiency that it may offer. Method maintenance, robustness and translation to regulatory requirements have been important barriers to implement the method. This paper presents a qualitative NIR-BU method offering a convenient and compliant approach to apply BU control for routine operation and process understanding, without extensive calibration and method maintenance requirements. The method employs a moving F-test to detect the steady state of measured spectral variances and the endpoint of mixing. The fundamentals and performance characteristics of the method are first presented, followed by a description of the link to regulatory BU criteria, the method sensitivity and practical considerations. Applications in upscaling, tech transfer and commercial production are described, along with evaluation of the method performance by comparison with results from quantitative calibration models. A full application, in which end-point detection via the F-test controls the blending process of a low dose product, was successfully filed in Europe and Australia, implemented in commercial production and routinely used for about five years and more than 100 batches.
干粉混合是制药行业中一种广泛应用的单元操作。随着在线近红外（NIR）光谱技术和质量源于设计原则的出现，过程分析技术在监测混合均匀度（BU）方面发挥着越来越重要的作用。然而，尽管近红外技术可能带来更好的过程理解和（成本）效率提升，但在该行业中，将其常规用于监测混合过程，更不用说控制混合过程，却并不常见。方法维护、稳健性以及向法规要求的转化一直是实施该方法的重要障碍。本文提出了一种定性近红外 - 混合均匀度方法，该方法提供了一种便捷且合规 的途径，可用于常规操作和过程理解中的混合均匀度控制，而无需大量校准和方法维护要求。该方法采用移动F检验来检测测量光谱方差的稳态和混合终点。首先介绍了该方法的基本原理和性能特征，随后描述了与法规混合均匀度标准的联系、方法灵敏度和实际考虑因素。还介绍了该方法在放大生产、技术转移和商业生产中的应用，以及通过与定量校准模型的结果进行比较来评估方法性能。一个完整的应用案例，即通过F检验进行终点检测来控制低剂量产品的混合过程，已在欧洲和澳大利亚成功备案，应用于商业生产并常规使用了约五年，涉及100多批次。
