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34 October 2019 Tablets & Capsules Umetrics Simca-P 16 software was used to generate a PCA model (or score plot) and a loading plot for the quantitative data. A Sympatec Helos dry powder laser diffraction analyzer was used to analyze the particle size distribution. Each sample was tested five times using an R5 lens. The materials' bulk and tapped density were determined in triplicate using an Engelsmann instrument according to USP <616>, and its specific surface area (SSA) was determined using the multipoint SSA method. Differential scanning calorimetry (DSC) was per- formed using a Mettler Toledo DSC 1 instrument. The researchers accurately weighed 5 to 10 milligrams of material into a 40-microliter standard aluminum pan and then crimped on a pierced aluminum lid. Analysis was con- ducted from 20° to 250°C at 10°C per minute in triplicate. Thermogravimetric analysis (TGA) was performed using a Mettler Toledo instrument. The researchers accurately weighed 5 to 10 milligrams of material into a 40-microliter standard aluminum open pan. Analysis was conducted from 20° to 250°C at 10°C per minute in duplicate. The lactose excipient was mixed with 2 percent w/w superdisintegrant (Primojel, DFE Pharma) for 8 minutes and with 0.5 percent w/w magnesium stearate (Sigma Aldrich) a further 2 minutes using a Turbula mixer at 90 rpm. Placebo tablets were compressed at 10 kilonewtons using RoTab tableting equipment with a gravimetric feed and 9-millimeter flat beveled tooling. The target tablet weight was 250 milligrams (±0.5 milligrams). After 24 hours, 20 tablets were tested for hardness (F), diameter (d), and thickness (t) using a Sotax HT100 tablet hard- ness tester. Tablet tensile strength (TTS) was calculated using the following equation [13]: TTS = 2F/πdt Tablet disintegration was tested in an Erweka DT dis- solution tester. Disintegration times for six tablets were purity) on a drug product is evident, studies are increas- ingly showing the importance of considering the variation in functional excipients used in formulations as well [2-6]. Commonly, excipient variation has been studied on a batch-to-batch and vendor-to-vendor basis [2-5]. The impact of batch-to-batch excipient variation depends on the application [7, 8]. The degree of batch-to-batch vari- ation has been shown to differ by excipient vendor [2] and/or type—such as lactose [3], microcrystalline cellu- lose [9], and HPMC [6]. Few researchers have evaluated the use of large data sets to assess the impact of excipient variation on drug product performance. Kushner [3], showed that a greater understanding of excipient variation can reduce the num- ber of experimental studies required during drug product development. Better understanding of excipient variabil- ity is also key to improving the consistency and quality of manufacturing processes in line with the FDA's Qual- ity by Design (QbD) initiative. QbD has driven the use of multivariate analysis (MVA), particularly principal component analysis (PCA) and partial least squares (PLS) regression [10, 11]. Multi- variate analysis is a set of statistical techniques that allows the simultaneous analysis of many variables. The tech- nique is ideally suited to studying relationships within large, complex data sets. PCA is ideally suited for investi- gating batch-to-batch excipient (and/or API) variation, as it can be used to investigate patterns or clusters in com- plex data sets. Using PCA on large excipient data sets allows researchers to identify the major sources of varia- tion as well as noise variables that have no effect. Lactose and microcrystalline cellulose are the most commonly used pharmaceutical excipients for manu- facturing solid oral dosage forms. Lactose is a soluble binder/diluent that produces robust tablets with good disintegration properties [2]. Lactose is widely available and can be obtained in four solid forms (granulated, anhydrous, spray-dried, or milled and sieved) as well as in many grades (or types). Lactose is considered a safe, cost-effective, functional excipient that is tasteless (or slightly sweet), water soluble, and stable, with a low hygroscopicity and good compatibility with APIs and other excipients [12]. This article describes a study conducted to evaluate the multivariate quality of granulated lactose mono- hydrate and show the effect of the variation on func- tional-related properties as tested by a pharmaceutical lactose manufacturer. Materials and methods The study evaluated more than 30 0 production batches of the granulated lactose monohydrate func- tional excipient SuperTab 30GR (Figure 1). The material was produced by DFE Pharma at the company's site in Nörten-Hardenberg, Germany, over the period from Jan- uary 2011 to December 2017. The researchers used cer- tificate of analysis (CoA) data as well as bulk and tapped density data to perform the MVA. Figure 1 Scanning electron micrograph of granulated lactose monohydrate (SuperTab 30GR)