title: An efficient, maintenance free and approved method for spectroscopic control and monitoring of blend uniformity: The moving F-test.
abstract: 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.
authors.affiliation: 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. Electronic address: r.besseling@inprocess-lsp.com.
authors.forename: Rut
authors.initials: R
authors.lastname: Besseling
authors.affiliation: 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.
authors.forename: Michiel
authors.initials: M
authors.lastname: Damen
authors.affiliation: Center for Mathematical Sciences, Merck/MSD, Oss, The Netherlands.
authors.forename: Thanh
authors.initials: T
authors.lastname: Tran
authors.affiliation: Pharmaceutical Sciences and Clinical Supplies, Merck/MSD, PO Box 20, 5340 BH Oss, The Netherlands; Currently at InnoCore Pharmaceuticals, LJ Zielstraweg 1, 9713 GX Groningen, The Netherlands.
authors.forename: Thanh
authors.initials: T
authors.lastname: Nguyen
authors.affiliation: Pharmaceutical Sciences and Clinical Supplies, Merck/MSD, PO Box 20, 5340 BH Oss, The Netherlands; Currently at Patheon, Posthoornstraat 7, 5048 AS Tilburg, The Netherlands.
authors.forename: Kaspar
authors.initials: K
authors.lastname: van den Dries
authors.affiliation: Pharmaceutical Sciences and Clinical Supplies, Merck/MSD, PO Box 20, 5340 BH Oss, The Netherlands; Currently at Abbott Healthcare Products, C.J. van Houtenlaan 36, 1381CP Weesp, The Netherlands.
authors.forename: Wim
authors.initials: W
authors.lastname: Oostra
authors.affiliation: 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.
authors.forename: Ad
authors.initials: A
authors.lastname: Gerich
mesh_terms: D002138:Calibration; D004339:Drug Compounding / Q000379:methods*; D015195:Drug Design; D005079:Excipients; D004364:Pharmaceutical Preparations / Q000737:chemistry; D011208:Powders; D012016:Reference Values; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013053:Spectrophotometry / Q000379:methods*; D019265:Spectroscopy, Near-Infrared / Q000379:methods*
chemical_list: D005079:Excipients; D004364:Pharmaceutical Preparations; D011208:Powders
keywords: Blend Uniformity; Dry powder mixing; NIR; PAT; Process control; QbD