(328f) Integrated Quality By Design for Continuous Pharmaceutical Manufacturing: Accounting for Dynamics and Feedback

Design spaces are sets of critical process parameters (CPPs) that guarantee that critical quality attributes (CQAs) of a manufacturing process are within specifications [Q8-Q10]. The design spaces can be constructed through extensive experimentation, mathematical models, or a combination of the two. For individual continuous pharmaceutical processes, design spaces are typically determined by assuming steady-state operation. The full design space from drug substance through drug product can be calculated using a plantwide approach or a unit-by-unit approach. Common inner approximations of the design space (e.g., hyper-rectangles) can result in significant conservatism, especially when a unit-by-unit approach is employed. Approximation of the design space by polytopes [e.g., Q11, page 25], however, is an effective means for the construction of design spaces for end-to-end continuous manufacturing facilities by combining the design spaces for individual unit operations [LF]. This approach means that the design spaces for individual processes constructed by individual research and development teams can be integrated to construct the design space for the entire continuous manufacturing facility at scale. In particular, design spaces across different value streams and between R&D and manufacturing can be integrated together in a “plug-and-play” manner in the same way as dynamic models [AM, MH, RL] without introducing any additional constraints on the process operations.

The effects of feedback control should be considered during the construction of design spaces. Due to the presence of lower level feedback control systems, design spaces for closed-loop processes can often be calculated using low-order Taylor series approximations, which results in simple expressions for the full design space (e.g., polytopes). Feedback control loops also tend to enlarge design spaces, sometimes by more than an order of magnitude. Unfortunately, disturbances, noise, and uncertainties will prevent real manufacturing processes from ever reaching "steady state". Therefore, design spaces calculated at steady state should not be used to guarantee quality specifications. This presentation will describe how to take feedback control and dynamics into account during the assurance of critical quality attributes for drug substance, intermediates, and drug product. The approach is to explicitly incorporate information on the dynamics and control systems directly into the analysis of the full integrated manufacturing facility. The approach is demonstrated for both a model predictive control and a classical plant-wide control strategy.

Although the focus of the presentation is on continuous manufacturing processes, most of the observations and approaches are also applicable to batch processing, and dynamics and feedback are as relevant to batch processing as there are to continuous manufacturing.

References

[AM] A. T. Myerson, M. Krumme, M. Nasr, H. Thomas, and R. D. Braatz. Control systems engineering in continuous pharmaceutical processing. Journal of Pharmaceutical Sciences, 104(3):832-839, 2015.

[LF] Lucas Charles Foguth, “Integration of Quality-by-Design into Control Systems Design for Continuous Pharmaceutical Manufacturing.” Ph.D. thesis, Massachusetts Institute of Technology, Cambridge, 2016.

[MH] Moo Sun Hong, Kristen A. Severson, Mo Jiang, Amos E. Lu, J. Christopher Love, and Richard D. Braatz. Challenges and opportunities in biopharmaceutical manufacturing control. Computers & Chemical Engineering, 110:106-114, 2018,

[Q8] Q8 (R2) Pharmaceutical Development. U.S. Department of Health and Human Services, Food and Drug Administration, Silver Spring, Maryland, November 2009.

[Q9] Q9 Quality Risk Management. U.S. Department of Health and Human Services, Food and Drug Administration, Silver Spring, Maryland, June 2006.

[Q10] Q10 Pharmaceutical Quality System. U.S. Department of Health and Human Services, Food and Drug Administration, Silver Spring, Maryland, April 2009.

[Q11] Q11 Development and Manufacture of Drug Substances. U.S. Department of Health and Human Services, Food and Drug Administration, Silver Spring, Maryland, November 2012.

[RL] R. 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.