(11f) An Integrated Approach to Modelling, Data, and Control for Pharmaceutical Manufacturing

An integrated Quality-by-Design approach for pharmaceutical manufacturing is described. Continuous manufacturing is an approach that brings process research and development into closer alignment and execution with manufacturing, by significantly reducing the amount of scale up needed to go from laboratory scale to production scale. Dynamic process and plant models are used for integration across different value streams, from a seamless connection from raw materials through drug substance and drug product. The streamlined process development workflow incorporates best practices from the relevant ICH guidelines [1-4], including the selection of control strategies for each critical quality attribute, and the effective use of modular plant-wide simulation. The main concepts are illustrated for small-molecule pharmaceutical pilot plants and bench-scale biologic drug manufacturing platforms. Additional challenges associated with biologic drugs are discussed. Aided with in-line process analytical technology, automated plant-wide control systems are designed and implemented to satisfy specifications on the critical quality attributes. The presentation draws from Quality by Design strategies that were developed and applied in the pharmaceutical industry from before the ICH guidelines were published [e.g., 5-7], up to recent advances [8-22].

References

1. ICH Q8(R2) Pharmaceutical Development, ICH Harmonised Tripartite Guideline, International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2009
2. ICH Q9 Quality Risk Management, ICH Harmonised Tripartite Guideline, International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2005
3. ICH Q10(R2) Pharmaceutical Quality System, ICH Harmonised Tripartite Guideline, International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2009
4. ICH Q11(R2) Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities), ICH Harmonised Tripartite Guideline, International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2012
5. Togkalidou, R. D. Braatz, B. K. Johnson, O. Davidson, and A. Andrews. Experimental design and inferential modeling in pharmaceutical crystallization. AIChE J., 47:160-168, 2001
6. Togkalidou, H.-H. Tung, Y. Sun, A. Andrews, and R. D. Braatz. Solution concentration prediction for pharmaceutical crystallization processes using robust chemometrics and ATR FTIR spectroscopy. Org. Process Res. Dev., 6:317-322, 2002
7. Togkalidou, H.-H. Tung, Y. Sun, A. Andrews, and R. D. Braatz. Parameter estimation and optimization of a loosely-bound aggregating pharmaceutical crystallization using in-situ infrared and laser backscattering measurements. Ind. Eng. Chem. Res., 43:6168- 6181, 2004
8. S. Hong, K. A. Severson, M. Jiang, A. E. Lu, J. C. Love, and R. D. Braatz. Challenges and opportunities of biopharmaceutical manufacturing control. Computers & Chemical Engineering, 110:106-114, 2018
9. Lakerveld, P. L. Heider, K. D. Jensen, R. D. Braatz, K. F. Jensen, A. S. Myerson, and B. L. Trout. End-to-end continuous manufacturing: Integration of unit operations. In Continuous Manufacturing of Pharmaceuticals, edited by P. Kleinebudde, J. Khinnast, and J. Rantanen, Wiley, New York, Chapter 13, pages 447-483, 2017
10. Mo Jiang and Richard D. Braatz. Integrated control of continuous (bio)pharmaceutical manufacturing. Am. Pharm. Rev., 19(6):110-115, 2016
11. Lakerveld, B. Benyahia, P. L. Heider, H. Zhang, A. Wolfe, C. J. Testa, S. Ogden, D. R. Hersey, S. Mascia, J. M. B. Evans, R. D. Braatz, and P. I. Barton. The application of an automated control strategy for an integrated continuous pharmaceutical pilot plant. Organic Process Research & Development, 19(9):1088-1100, 2015
12. Jiang, Y. E. D. Li, H. H. Tung, and R. D. Braatz. Effect of jet velocity on crystal size distribution from antisolvent and cooling crystallizations in a dual impinging jet mixer. Chemical Engineering and Processing: Process Intensification, 97:242-247, 2015
13. Jiang, Y. E. D. Li, H. H. Tung, and R. D. Braatz. Effect of jet velocity on crystal size distribution from antisolvent and cooling crystallizations in a dual impinging jet mixer. Chemical Engineering and Processing: Process Intensification, 97:242-247, 2015
14. Amos E. Lu, Joel A. Paulson, Nicholas J. Mozdzierz, Alan Stockdale, Ashlee N. Ford Versypt, Kerry R. Love, J. Christopher Love, and Richard D. Braatz. Control systems technology in the advanced manufacturing of biologic drugs. Proceedings of the IEEE Conference on Control Applications, Sydney, Australia, 1505-1515, 2015.
15. T. Zhang, R. Lakerveld, P. L. Heider, M. Y. Tao, M. Su, C. J. Testa, A. N. D'Antonio, P. I. Barton, R. D Braatz, B. L. Trout, A. S. Myerson, K. F. Jensen, and J. M. B. Evans. Application of continuous crystallization in an integrated continuous pharmaceutical pilot plant. Crystal Growth & Design, 14(5):2148-2157, 2014
16. Mascia, P. L. Heider, H. Zhang, R. Lakerveld, B. Benyahia, P. I. Barton, R. D. Braatz, C. L. Cooney, J. M. B. Evans, T. F. Jamison, K. F. Jensen, A. S. Myerson, and B. L. Trout. End-to-end continuous manufacturing of pharmaceuticals: Integrated synthesis, purification, and final dosage formation. Angewandte Chemie Int. Ed., 52(47):12359-12363, 2013
17. Lakerveld, B. Benyahia, R. D. Braatz, and P. I. Barton. Model-based design of a plant-wide control strategy for a continuous pharmaceutical plant, AIChE Journal, 59:3671-3685, 2013
18. C. S. Kee, R. B. H. Tan, and R. D. Braatz. Semiautomated identification of the phase diagram for enantiotropic crystallizations using ATR-FTIR spectroscopy and laser backscattering. Ind. Eng. Chem. Res., 50:1488-1495, 2011
19. C. S. Kee, P. D. Arendt, L. M. Goh, R. B. H. Tan, and R. D. Braatz. Nucleation and growth kinetics estimation for L-phenylalanine hydrate and anhydrate crystallization. CrystEngComm, 13:1197-1209, 2011
20. C. S. Kee, P. D. Arendt, R. B. H. Tan, and R. D. Braatz. Selective crystallization of the metastable anhydrate form in the enantiotropic pseudo-dimorph system of L-phenylalanine using concentration feedback control. Crystal Growth & Design, 9:3052-3061, 2009
21. C. S. Kee, R. B. H. Tan, and R. D. Braatz. Selective crystallization of the metastable alpha-form of L-glutamic acid using concentration feedback control. Crystal Growth & Design, 9:3044-3051, 2009
22. X. Zhou, M. Fujiwara, X. Y. Woo, E. Rusli, H.-H. Tung, C. Starbuck, O. Davidson, Z. Ge, and R. D. Braatz. Direct design of pharmaceutical antisolvent crystallization through concentration control. Crystal Growth & Design, 6:892-898, 2006