Pharmaceutical Manufacturing (PM) is undergoing an era of rapid change. The rising costs of drug discovery has forced pharmaceutical companies to rethink their business model. This has given impetus for manufacturing innovations in PM to reduce the cost of producing new drugs. Process Intensification (PI) is a cost-reduction strategy for PM which reduces the number of unit operations in the manufacturing workflow. Traditionally, PM first involved purifying the drug by crystallization from the upstream reaction mixture. This was followed by milling and granulation to increase the bioavailability and manufacturing of the Drug Product (DP). Spherical Agglomeration (SA) is a novel PI strategy which combines the three unit operations, thus decreasing capital and operating costs. Following US Food and Drug Administration’s (FDA) Quality by Design (QbD) initiative, my research involves process design of SA by gaining a thorough scientific understanding of the mechanistic processes behind in-situ agglomeration within the crystallizer. Possible agglomeration mechanisms are compared, and Information Theory is then used to discriminate amongst the different first-principle mechanistic models. The FDA is also encouraging pharmaceutical companies to shift from the traditional Quality by Testing (QbT) to a Quality by Control (QbC) framework. Due to the presence of uncertainties, the QbT framework led to substantial batch failures, which were then discarded. The cost of manufacturing of such discarded batches were passed onto the patients, who ended up paying a higher premium on the marketed drugs. In this work, the model parametric uncertainties were quantified and a surrogate-model (Polynomial Chaos) based Model Predictive Controller (MPC) was then developed to steer the process to the desired end-of-batch state, even in the presence of uncertainties. The developed framework for Pharmaceutical PI will substantially reduce the manufacturing costs by (i) reducing the capital and operating costs (ii) causing less batch failure due to the presence of in-process controls (iii) faster process development for new drugs in the pipelinedue to better process understanding.

Process intensification for pharmaceutical manufacturing: How to make drugs cheaper?

2019 Fall National Meeting

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