Optimization of a Coupling Process for Insulin Degludec According to a Quality by Design (QbD) Paradigm
- 73 Downloads
This case study described a successful application of the quality by design (QbD) principles to a coupling process development of insulin degludec. Failure mode effects analysis (FMEA) risk analysis was first used to recognize critical process parameters (CPPs). Five CPPs, including coupling temperature (Temp), pH of desB30 solution (pH), reaction time (Time), desB30 concentration (Conc), and molar equivalent of ester per mole of desB30 insulin (MolE), were then investigated using a fractional factorial design. The curvature effect was found significant, indicating the requirement of second-order models. Afterwards, a central composite design was built with an augmented star and center points study. Regression models were developed for the CPPs to predict the purity and yield of predegludec using above experimental data. The R2 and adjusted R2 were higher than 96 and 93% for the two models respectively. The Q2 values were more than 80% indicating a good predictive ability of models. MolE was found to be the most significant factor affecting both yield and purity of predegludec. Temp, pH, and Conc were also significant for predegludec purity, while Time appeared to remarkably influence the yield model. The multi-dimensional design space and normal operating region (NOR) with a robust setpoint were determined using a probability-based Monte-Carlo simulation method. The verified experimental results showed that the design space was reliable and effective. This study enriches the understanding of acetylation process and is instructional to other complicated operations in biopharmaceutical engineering.
KEY WORDSquality by design design of experiment insulin degludec acylation Monte-Carlo simulation
- 1.US Food and DrugAdministration. Pharmaceutical CGMPs for the 21st century—arisk-based approach: final report. 2004. http://www.fda.gov/downloads/Drugs/DevelopmentApproval Process/Manufacturing/QuestionsandAnswersonCurrentGoodManufacturingPracticescGMPforDrugs/UCM176374.pdf. Accessed 12 Dec 2012.
- 2.ICH Q8 (R2). Pharmaceutical development. 2009. http://www.ich.org/products/guidelines/quality /article/quality-guidelines.html. Accessed 12 Dec 2012.
- 3.ICH Q9. Quality risk management. 2005. http://www.ich.org/products/guidelines/quality/ article/quality-guidelines.html. Accessed 12 Dec 2012.
- 4.ICH Q10. Pharmaceutical quality system. 2008. http://www.ich.org/products/guidelines/ quality/article/quality-guidelines.html. Accessed 12 Dec 2012.
- 5.Eon-duval A, Valax P, Solacroup T, Broly H, Gleixner R, Strat CL, et al. Application of the quality by design approach to the drug substance manufacturing process of an Fc fusion protein: towards a global multi-step design space. J Pharm Sci. 2012;101(10):3604–18. https://doi.org/10.1002/jps.23273.CrossRefPubMedGoogle Scholar
- 9.Zidan AS, Sammour OA, Hammad MA, Megrab NA, Habib MJ, Khan MA. Quality by design: understanding the formulation variables of a cyclosporine A self-nanoemulsified drug delivery systems by Box-Behnken design and desirability function. Int J Pharm. 2007;332(1–2):55–63. https://doi.org/10.1016/j.ijpharm.2006.09.060.CrossRefPubMedGoogle Scholar
- 12.Chen XC, Zhou L, Gupta S, Civoli F. Implementation of design of experiments (DOE) in the development and validation of a cell-based bioassay for the detection of anti-drug neutralizing antibodies in human serum. J Immunol Methods. 2012;376(1–2):32–45. https://doi.org/10.1016/j.jim.2011.11.004.CrossRefPubMedGoogle Scholar
- 13.Nagashima H, Watari A, Shinoda Y, Okamoto H, Takuma S. Application of a quality by design approach to the cell culture process of monoclonal antibody production, resulting in the establishment of a design space. J Pharm Sci. 2013;102(12):4274–83. https://doi.org/10.1002/jps.23744.CrossRefPubMedGoogle Scholar
- 14.Rouiller Y, Solacroup T, Deparis V, Barbafieri M, Gleixner R, Broly H, et al. Application of quality by design to the characterization of the cell culture process of an Fc-fusion protein. Eur J Pharm Biopharm. 2012;81(2):426–37. https://doi.org/10.1016/j.ejpb.2012.02.018.CrossRefPubMedGoogle Scholar
- 17.Jiang C, Flansburg L, Ghose S, Jorjorian P, Shukla AA. Defining process design space for a hydrophobic interaction chromatography (HIC) purification step: application of quality by design (QbD) principles. Biotechnol Bioeng. 2010;107(6):985–97. https://doi.org/10.1002/bit.22894.CrossRefPubMedGoogle Scholar
- 22.Zain H, Ahmad M, Gardner QA, Akhtar M. Hierarchy of N-acylation sites in human insulin studied by RP-HPLC and mass spectrometry. J Chem Soc Pak. 2015;37(6):1249–55.Google Scholar
- 23.Vesper JL. Risk assessment and risk management in the pharmaceutical industry. PDA/DHI: Arlington; 2006.Google Scholar
- 25.Baker JC, Chen VJ, Hanquier JM, Kriauciunas A, Moser BA, Shuman RT. Selective acylation of epsilon-amino groups. US Patents 5646242; 8 July 1997.Google Scholar