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38 October 2019 Tablets & Capsules References 1. L. X. Yu, "Pharmaceutical quality by design: prod- uct and process development, understanding, and con- trol," Pharmaceutical Research, 2008, Vol. 25, No. 4, pages 781-791. 2. J. F. Gamble, et al., "Investigation into the degree of variability in the solid-state properties of common phar- maceutical excipients—anhydrous lactose," AAPS Pharm- SciTech, 2010, Vol. 11, No. 4, pages 1,552-1,557. 3. J. Kushner, "Utilizing quantitative certificate of analysis data to assess the amount of excipient lot-to-lot variability sampled during drug product development," Pharmaceutical Development and Technology, 2013, Vol. 18, No. 2, pages 333-342. 4. R. V. Haware, "Comparative evaluation of the powder and compression properties of various grades and brands of microcrystalline cellulose by multivariate methods," Pharmaceutical Development and Technology, 2010, Vol. 15, No. 4, pages 394-404. 5. C. Moreton, "Functionality and performance of excipients in a quality-by-design world Part 2: Excipient variability, QbD and robust formulations," American Phar- maceutical Review, 2009, Vol. 12, No. 2. 6. S. D. Novak, "The influence of HPMC viscosity as FRC parameter on the release of low soluble drug from hydrophilic matrix tablets," Pharmaceutical Development and Technology, 2013, Vol. 18, No. 2, pages 343-347. 7. E. Doelker, et al., "Degrees of crystallinity and polymerization of modified cellulose powders for direct tableting," Powder Technology, 1987, Vol. 52, No. 3, pages 207-213. 8. G. E. Amidon, et al., "The effect of moisture on the mechanical and powder flow properties of microcrystal- line cellulose," Pharmaceutical Research, 1995, Vol. 12, No. 6, pages 923-929. influence the functionality-related characteristics or criti- cal material attributes of the final formulation. You could do this by testing all possible variables, but the design of experiments (DoE) for this would become unfathomable. Understanding which contributing variables pose the highest risk and which pose no risk can help to focus a DoE on the most important parameters. Excipients have been shown to introduce variability into a formulation, but this variability differs between excipients and even between suppliers of similar excipients. To make a good risk assessment, you must understand the variability of each individual excipient grade, and MVA is the prefera- ble method for arriving at this understanding. This study used MVA to evaluate more than 300 pro- duction batches of SuperTab 30GR granulated lactose monohydrate produced during the period from January 2011 to December 2017. Batches selected from the edges of the MVA plot—those having the maximum variation during the selected time frame—did not demonstrate any visible effect on the critical quality attributes of resulting lactose placebo tablets. Due to the large number of degrees of freedom asso- ciated with a typical solid dosage form, the consistency of the ingredients alone may not be predictive of the finished product quality. However, pharmaceutical com- panies can evaluate the variability of high-consistency excipients as part of the control strategy, rather than DoE, to identify where there is a low probability of impact. Using well-controlled excipients designed for purpose can reduce life-cycle risk in pharmaceutical development and production. Excipients with low varia- tion in physical/chemical size, density, and specific sur- face area, as in this study, may be classified as low risk, and companies may then use this classification to signifi- cantly reduce their DoE strategy when using such prod- ucts in pharmaceutical development. T&C Figure 5 Properties of placebo tablets made from six batches near extremes of MVA plot a. Tablet tensile strength 1 2 3 4 5 6 7 8 Tensile strength (megapascals) Batch 3.0 2.5 2.0 1.5 1.0 0.5 0.0 b. Tablet disintegration time 1 2 3 4 5 6 7 8 Batch Disintegration time (seconds) 100 90 80 70 60 50 40 30 20 10 0