Active pharmaceutical ingredients (APIs) are traditionally produced through time- and cost-intensive large-scale batch manufacturing.
1 The limitations of this approach have been revealed by the Food and Drug Administration (FDA) to be root causes for drug shortages, a major problem in today’s pharmaceutical manufacturing.
2 A potential solution to overcome this threat are small-scale, end-to-end continuous manufacturing platforms that integrate synthesis, purification, and formulation within the same uninterrupted microfluidic reactor network.
3,4 This approach possesses a unique high demand on process analytical technology (PAT), for instance, to monitor and determine the strength of aqueous formulations (solution and suspension)
in situand in real-time as a critical quality attribute (CQA) prior to the release from the platforms, which are not comparable to lab-scale or industrial-scale needs.
5 The aim of this study is to demonstrate the application of a novel composite sensor array (UV-vis, NIR, Turbidity, Temperature) as a versatile, reliable, cost-effective, and small-scale PAT to measure accurately the concentration of aqueous pharmaceutical formulations (solution/suspension). Four APIs, warfarin sodium and lidocaine hydrochloride, formulated as solutions and acetaminophen and azithromycin formulated as suspensions were measured in their commercial aqueous forms using the composite sensor array. The results were compared with chemometrics data obtained from a state-of-the-art
in situRaman probe to provide a reference for the assessment of real-time monitoring. In addition, the concentrations of all formulations were analyzed by partial least squares (PLS) regression, validated and correlated with offline UV-vis spectrophotometer. Results show PLS regressions of R
2 = 0.9958 with a Bias = 0.061, which correlated well with offline measurements. The composite sensor array demonstrates potential as an
in situreal-time PAT for concentration monitoring (solution and suspensions) in one single compact PAT device, as it is preferred in pharmaceutical manufacturing platforms to maintain small footprints.
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(1) Lee, S. L.; O’Connor, T. F.; Yang, X.; Cruz, C. N.; Chatterjee, S.; Madurawe, R. D.; Moore, C. M. V.; Yu, L. X.; Woodcock, J. Modernizing Pharmaceutical Manufacturing: From Batch to Continuous Production. J. Pharm. Innov.2015, 10(3), 191–199.
(2) FDA. Strategic Plan for Preventing and Mitigating Drug Shortages http://www.fda.gov/downloads/Drugs/DrugSafety/DrugShortages/UCM372566.pdf (accessed Oct 28, 2015).
(3) Adamo, A.; Beingessner, R. L.; Behnam, M.; Chen, J.; Jamison, T. F.; Jensen, K. F.; Monbaliu, J.-C. M.; Myerson, A. S.; Revalor, E. M.; Snead, D. R.; Stelzer, T.; Weeranoppanant, N.; Wong, S. Y.; Zhang, P. On-Demand Continuous-Flow Production of Pharmaceuticals in a Compact, Reconfigurable System. Science (80-. ).2016, 352(6281), 61–67.
(4) Zhang, P.; Weeranoppanant, N.; Thomas, D. A.; Tahara, K.; Stelzer, T.; Russell, M. G.; O’Mahony, M.; Myerson, A. S.; Lin, H.; Kelly, L. P.; Jensen, K. F.; Jamison, T. F.; Dai, C.; Cui, Y.; Briggs, N.; Beingessner, R. L.; Adamo, A. Advanced Continuous Flow Platform for Onâ€Demand Pharmaceutical Manufacturing. Chem. - A Eur. J.2018, 24(11), 2776 –2784.
(5) Stelzer, T.; Wong, S. Y.; Chen, J.; Myerson, A. S. Evaluation of PAT Methods for Potential Application in Small-Scale, Multi-Purpose Pharmaceutical Manufacturing Platforms. Org. Process Res. Dev.2016, 20(8), 1431–1438.
