Abstract
Introduction
The US Food and Drug Administration requires pharmaceutical companies to develop extensive process understanding prior to routine manufacturing of drug products. Through development and validation, drug manufacturers enhance their process understanding and identify an acceptable range of process parameters for each unit operation; this is referred to as the design space. Typically, limited work is done to study the effect of long-term raw material variations on the robustness of the design space. In the present study, the development of a design space for a tablet formulation containing two APIs (acetaminophen, caffeine) through a direct compression process was investigated.
Material and Methods
A design of experiment including different excipient ratios of microcrystalline cellulose and lactose, two croscarmellose sodium levels, four tablet compression forces, and four blend parameters was created using an industrial-size press to define a knowledge space. Quality attributes (disintegration time, dissolution, radial tensile strength, and friability) were measured and a design space derived. In order to test the robustness of the design space, raw material properties, specifically particle size of acetaminophen and ratio of lactose anhydrous to monohydrate, were modified. Also, compression parameters were varied.
Results
Tablets were analyzed for relevant critical quality attributes (CQAs) to investigate how variability in raw materials can change the design space. The modification of the process parameters was used as a means of compensating for raw material variability to produce tablets that met CQA requirements. An adaptive design space approach based on the adaptation of critical process parameters is proposed to facilitate the creation of tablets meeting specifications despite variation in raw material properties.
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References
Yu LX. Pharmaceutical quality by design: product and process development, understanding, and control. Pharm Res. 2008;25:781–90.
Lionberger RA, Lee SL, Lee L, Raw A, Yu LX. Quality by design: concepts for ANDAs. AAPS J. 2008;10:268–76.
International Conference on Harmonization. Pharmaceutical Development Q8R2. Available at http://private.ich.org/LOB/media/MEDIA4986.pdf. Accessed 21 December 2010
MacGregor JF, Bruwer MJ. A framework for the development of design and control spaces. J Pharm Innov. 2008;3:15–22.
Chamarthy SP, Pinal R, Carvajal MT. Elucidating raw material variability—importance of surface properties and functionality in pharmaceutical powders. AAPS PharmSciTech. 2009;10:780–8.
Hlinak AJ, Kuriyan K, Morris KR, Reklaitis GV, Basu PK. Understanding critical material properties for solid dosage form design. J Pharm Innov. 2006;1:12–7.
Shi Z, Cogdill RP, Short SM, Anderson CA. Process characterization of powder blending by near-infrared spectroscopy: blend end-points and beyond. J Pharm Biomed Anal. 2008;47:738–45.
Igne B, Zacour BM, Shi Z, Talwar S, Anderson CA, Drennen JK. Online monitoring of pharmaceutical materials using multiple NIR sensors—Part I: blend homogeneity. J Pharm Innov. 2011;6:47–59.
Zacour BM, Igne B, Drennen JK, Anderson CA. Efficient near infrared spectroscopic calibrations for pharmaceutical blend monitoring. J Pharm Innov. 2011;6:10–23.
Haaland DM, Melgaard DK. New classical least-squares/partial least-squares hybrid algorithm for spectral analyses. Appl Spectrosc. 2001;55:1–8.
United States Pharmacopeia-National Formulary. Acetaminophen and caffeine tablets, Official Monographs. USP24 NF19. United States Pharmacopeia-National Formulary; 1999.
United States Pharmacopeia-National Formulary. <1216> Tablet Friability. USP24 NF19. United States Pharmacopeia-National Formulary; 1999.
Mereton R.C. Disintegrants in tableting. In: Augburger LL, Hoag SW, editors. Pharmaceutical dosage forms: tablets, volume 2: rational design and formulation, 3rd ed. New York: Taylor & Francis; 2008. pp. 240.
Zacour B.M., Drennen J.K., Anderson C.A. Hybrid controls combining first principle calculations with empirical modeling for fully automated fluid bed processing. Journal of Pharmaceutical Innovation; 2012 (in press)
Garcia-Munoz S, Dolph S, Ward II HW. Handling uncertainty in the establishment of a design space for the manufacture of a pharmaceutical product. Comput Chem Engng. 2010;34:1098–107.
Acknowledgments
Authors would like to acknowledge Dr. Michael Moore and Robert W. Bondi, Jr. for their help in operating the tablet press to create the tablets used in this article.
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Igne, B., Shi, Z., Talwar, S. et al. Adaptive Design Space as an Integrated Component of Quality by Design. J Pharm Innov 7, 119–126 (2012). https://doi.org/10.1007/s12247-012-9132-z
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DOI: https://doi.org/10.1007/s12247-012-9132-z