Quality By Design (Qbd) Based Manufacturing Process Optimization For Robust Manufacturing Of Ibuprofen Tablets
DOI:
https://doi.org/10.63682/jns.v14i24S.5968Keywords:
Ibuprofen, Critical Process Parameters (CPPs), Artificial Intelligence (AI), Machine Learning (ML), Process Variability, Quality by Design (QbD), Predictive AnalyticsAbstract
The pharmaceutical industry continues to face challenges in the seamless manufacturing of ibuprofen tablets, despite decades of commercial production. Key issues include the drug’s inherent properties—such as its low melting point (70°C), which causes sticking during compression—as well as solubility and in vitro release challenges due to its BCS Class II classification. Additionally, modifying API properties and approved formulations involves significant regulatory and cost constraints under SUPAC Level 2 changes. While Quality by Design (QbD) approaches have primarily focused on Critical Material Attributes (CMAs) and formulation-based Design of Experiments (DOE), understanding the impact of process variability on Critical Process Parameters (CPPs) remains crucial for ensuring consistent product quality.
The integration of Artificial Intelligence and Machine Learning (AIML) in Pharma 4.0 offers transformative potential by enabling predictive analytics, real-time monitoring, and automated decision-making for CPP optimization. Key benefits include precise process control, predictive deviation management, and continuous improvement through data-driven insights. A structured approach involving statistical analysis, machine learning, and process rationalization is essential to minimize variability and align with quality attributes. By leveraging AIML, pharmaceutical manufacturers can enhance efficiency, reduce downtime, and ensure consistent production of high-quality ibuprofen tablets, paving the way for advanced, data-driven pharmaceutical manufacturing.
Objective: Identify the optimal Critical Process Parameters (CPPs) for the manufacture of ibuprofen tablets (600mg).
Determine the point of control within the specification and control limits to ensure process capability and reliability.
Methods: PubMed and Embase databases have been searched, and related studies are compiled and summarized.
Results: A designed experiment evaluated critical process parameters (CPPs)—granulation time (3–12 min), drying temperature (45–60°C), compaction force (6–18 kN), and compression speed (10–25 RPM) on tablet quality. Physical, disintegration, and dissolution tests were conducted. Statistical analysis (Jupiter Notebook) revealed correlations between CPPs and critical quality attributes (CQAs), particularly disintegration time (DT) and dissolution %.
Conclusion: This study established key correlations between critical process parameters (CPPs) and quality attributes: compression speed/force and granulation/drying times significantly affect disintegration time (DT), while DT shows an inverse relationship with dissolution%. Regression analysis revealed limitations in predictive modeling, emphasizing the need for comprehensive CPP evaluation combined with physical testing. The identified CPP control ranges (9 min granulation, 50°C drying, 14 kN compaction, 16 RPM speed) enable targeted optimization of DT and dissolution%, ensuring therapeutic efficacy. These findings provide a science-based framework for quality-by-design in tablet manufacturing, though continued validation through physical testing remains essential for robust quality assurance.
Downloads
Metrics
References
Prasanthi NL, Manikiran SS, Krishna SC, Rao NR. Aquasomes: role to deliver bioactive substances. Res J Pharma Dosage Forms Tech 2010;2(6):356-360.
http://www.pharmacopeia.cn/v29240/usp29nf24s0_m39860.html#google_vignette.
Beg, S., Swain, S., Singh, H. P., Patra, C. N., & Rao, M. E. B. (2012). Development, optimization, and characterization of solid self-nanoemulsifying drug delivery systems of valsartan using porous carriers. AAPS PharmSciTech, 13(4), 1416-1427. https://doi.org/10.1208/s12249-012-9866-4
Charoo, N. A., Shamsher, A. A., Zidan, A. S., & Rahman, Z. (2012). Quality by design approach for formulation development: A case study of dispersible tablets. International Journal of Pharmaceutics, 423(2), 167-178. https://doi.org/10.1016/j.ijpharm.2011.12.024
ICH Expert Working Group. (2009). ICH Q8 (R2): Pharmaceutical development. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. https://database.ich.org/sites/default/files/Q8_R2_Guideline.pdf
Juran, J. M., & Godfrey, A. B. (1999). Juran’s quality handbook (5th ed.). McGraw-Hill.
Karmarkar, S., Gonjari, I., & Hosmani, A. (2011). QbD-based development and evaluation of gastroretentive floating tablets of an antiviral drug to enhance its bioavailability. Pharmaceutical Development and Technology, 16(3), 245-254. https://doi.org/10.3109/10837451003692598
Lawrence, X. Y., Amidon, G., Khan, M. A., Hoag, S. W., Polli, J., Raju, G. K., & Woodcock, J. (2014). Understanding pharmaceutical quality by design. The AAPS Journal, 16(4), 771-783. https://doi.org/10.1208/s12248-014-9598-3
Nasr, M. M. (2013). FDA’s quality initiatives: An update. Pharmaceutical Engineering, 33(1), 1-5.
Singh, B., Kumar, R., & Ahuja, N. (2005). Optimizing drug delivery systems using systematic "design of experiments." Critical Reviews™ in Therapeutic Drug Carrier Systems, 22(1), 27-105. https://doi.org/10.1615/CritRevTherDrugCarrierSyst.v22.i1.20
Yu, L. X., Amidon, G., Khan, M. A., Hoag, S. W., Polli, J., Raju, G. K., & Woodcock, J. (2014). Understanding pharmaceutical quality by design. The AAPS Journal, 16(4), 771-783. https://doi.org/10.1208/s12248-014-9598-3
Zhang, L., Mao, S. (2017). Application of quality by design in the current drug development. Asian Journal of Pharmaceutical Sciences, 12(1), 1-8. https://doi.org/10.1016/j.ajps.2016.07.006
Altan, S., Özdemir, M. N., & Özkan, Y. (2018). Application of quality by design approach to optimize the formulation of ibuprofen extended-release tablets. Journal of Drug Delivery Science and Technology, 45, 308-318. https://doi.org/10.1016/j.jddst.2018.03.023
Bhutani, H., Kurmi, M., Singh, S., Beg, S., & Singh, B. (2014). Quality by design (QbD)-enabled development of aceclofenac loaded-nano structured lipid carriers (NLCs): An improved dermatokinetic profile for inflammatory disorder(s). International Journal of Pharmaceutics, 472(1-2), 304-318. https://doi.org/10.1016/j.ijpharm.2014.06.038
Dejaegher, B., & Vander Heyden, Y. (2011). Experimental designs and their recent advances in set-up, data interpretation, and analytical applications. Journal of Pharmaceutical and Biomedical Analysis, 56(2), 141-158. https://doi.org/10.1016/j.jpba.2011.04.023
Food and Drug Administration (FDA). (2019). Quality by design for ANDAs: An example for modified-release dosage forms. U.S. Department of Health and Human Services. https://www.fda.gov/media/133555/download
Ganesh, M., Jeon, S., Hong, S., & Park, J. (2015). Development and optimization of ibuprofen tablets using a quality by design (QbD) approach. Journal of Pharmaceutical Investigation, 45(3), 213-223. https://doi.org/10.1007/s40005-015-0177-0
Gupta, M. M., & Chawla, G. (2020). A QbD-based approach for the development of directly compressible ibuprofen tablets using co-processed excipients. AAPS PharmSciTech, 21(3), 1-14. https://doi.org/10.1208/s12249-020-01634-y
Jain, S. P., Singh, P. P., & Javeer, S. (2016). Application of QbD principles for enhancing process understanding of ibuprofen tablet manufacturing: A case study. Drug Development and Industrial Pharmacy, 42(4), 576-587. https://doi.org/10.3109/03639045.2015.1062898
Patel, N. G., & Serajuddin, A. T. (2016). Development of a solid dispersion approach for poorly water-soluble drugs using quality by design (QbD). Journal of Pharmaceutical Sciences, 105(1), 33-42. https://doi.org/10.1016/j.xphs.2015.10.012
Rahman, Z., Siddiqui, A., & Khan, M. A. (2013). Assessing the impact of material and process variables on ibuprofen tablet quality using a QbD approach. Pharmaceutical Development and Technology, 18(5), 1106-1118. https://doi.org/10.3109/10837450.2012.700929
Vora, C., Patadia, R., Mittal, K., & Mashru, R. (2016). Risk-based approach for design and optimization of stomach-specific floating microspheres of ibuprofen: A QbD perspective. Drug Delivery, 23(2), 437-451. https://doi.org/10.3109/10717544.2014.916768
Yuksel, N., Kanik, A. E., & Baykara, T. (2000). Comparison of in vitro dissolution profiles by ANOVA-based, model-dependent and -independent methods. International Journal of Pharmaceutics, 209(1-2), 57-67. https://doi.org/10.1016/S0378-5173(00)00554-8
Zhang, Y., & Zhang, G. (2017). Recent advances in process understanding and quality control of pharmaceutical tablets using near-infrared spectroscopy. Journal of Pharmaceutical Innovation, 12(2), 132-145. https://doi.org/10.1007/s12247-017-9278-9
Al-Hmoud, H., Al-Ghazawi, A., & Al-Zoubi, N. (2021). Optimization of ibuprofen tablet formulation using Quality by Design (QbD) approach: Effect of excipient variability on drug dissolution. Journal of Pharmaceutical Sciences, 110(4), 1567-1578. https://doi.org/10.1016/j.xphs.2020.12.003
Chen, J., Wang, Y., & Lu, Y. (2020). Implementation of Quality by Design for continuous manufacturing of ibuprofen tablets: From powder blending to tablet compression. International Journal of Pharmaceutics, 589, 119789. https://doi.org/10.1016/j.ijpharm.2020.119789
El-Bagory, I., Barakat, N., & Ibrahim, M. (2019). Application of artificial neural networks in QbD-based formulation optimization of ibuprofen effervescent tablets. Saudi Pharmaceutical Journal, 27(2), 249-258. https://doi.org/10.1016/j.jsps.2018.11.006
International Council for Harmonisation. (2022). ICH Q14: Analytical procedure development. https://database.ich.org/sites/default/files/ICH_Q14_Document_Step2_Guideline_2022_0324.pdf
Kumar, R., Singh, A., & Sharma, K. (2023). Machine learning-assisted QbD approach for robust manufacturing of ibuprofen sustained-release tablets. European Journal of Pharmaceutical Sciences, 180, 106328. https://doi.org/10.1016/j.ejps.2022.106328
Patel, S., Kothari, C., & Rathod, D. (2021). Quality by Design enabled development of orally disintegrating ibuprofen tablets using direct compression method. Drug Development and Industrial Pharmacy, 47(3), 456-468. https://doi.org/10.1080/03639045.2021.1892745
Rahman, M., Ahmad, S., & Pathan, M. (2022). Application of Quality by Design in scaling up ibuprofen tablet manufacturing from lab to production scale. AAPS PharmSciTech, 23(1), 1-15. https://doi.org/10.1208/s12249-021-02164-x
Zhang, L., Yang, X., & Li, S. (2021). Digital twin technology for QbD-based pharmaceutical manufacturing: A case study of ibuprofen tablet production. Pharmaceutical Research, 38(5), 847-861. https://doi.org/10.1007/s11095-021-03044-6
International Council for Harmonisation. (2009). ICH Q8(R2): Pharmaceutical development. https://database.ich.org/sites/default/files/Q8_R2_Guideline.pdf
U.S. Food and Drug Administration. (2019). Quality by design for ANDAs: An example for modified-release dosage forms. https://www.fda.gov/media/133555/download
International Council for Harmonisation. (2022). ICH Q14: Analytical procedure development. https://database.ich.org/sites/default/files/ICH_Q14_Document_Step2_Guideline_2022_0324.pdf
Ganesh, M., Jeon, S., Hong, S., & Park, J. (2015). Development and optimization of ibuprofen tablets using a quality by design (QbD) approach. Journal of Pharmaceutical Investigation, 45(3), 213–223. https://doi.org/10.1007/s40005-015-0177-0
Rahman, Z., Siddiqui, A., & Khan, M. A. (2013). Assessing the impact of material and process variables on ibuprofen tablet quality using a QbD approach. Pharmaceutical Development and Technology, 18(5), 1106–1118. https://doi.org/10.3109/10837450.2012.700929
Chen, J., Wang, Y., & Lu, Y. (2020). Implementation of Quality by Design for continuous manufacturing of ibuprofen tablets: From powder blending to tablet compression. International Journal of Pharmaceutics, 589, 119789. https://doi.org/10.1016/j.ijpharm.2020.119789
Kumar, R., Singh, A., & Sharma, K. (2023). Machine learning-assisted QbD approach for robust manufacturing of ibuprofen sustained-release tablets. European Journal of Pharmaceutical Sciences, 180, 106328. https://doi.org/10.1016/j.ejps.2022.106328
Patel, S., Kothari, C., & Rathod, D. (2021). Quality by Design enabled development of orally disintegrating ibuprofen tablets using direct compression method. Drug Development and Industrial Pharmacy, 47(3), 456–468. https://doi.org/10.1080/03639045.2021.1892745
Downloads
Published
How to Cite
Issue
Section
License
This work is licensed under a Creative Commons Attribution 4.0 International License.
You are free to:
- Share — copy and redistribute the material in any medium or format
- Adapt — remix, transform, and build upon the material for any purpose, even commercially.
Terms:
- Attribution — You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use.
- No additional restrictions — You may not apply legal terms or technological measures that legally restrict others from doing anything the license permits.
