(4fl) Optimal Design and Control of Advanced Biomanufacturing Systems

Biopharmaceuticals are products derived from biological organisms for treating or preventing diseases. The global sales of biopharmaceuticals are continually increased, as the pipeline of biologic drug candidates continues to grow as more diseases are understood at the molecular and cellular levels. This growth in the pipeline requires more efficient ways to move biologics from the development of each drug to its production, namely, systematic methods for the rapid design of manufacturing processes to produce high-quality biologic products.

Some recent trends in biopharmaceutical manufacturing are providing opportunities for process systems engineering to make major advances: (1) process analytical technology (PAT) is providing on-line measurements of critical quality attributes (CQAs) for constructing first-principles and data-based models of each unit operation and enable advanced control, (2) a transition from batch to continuous operation requires process control to handle the propagation of impurities and other disturbances caused by tight integration of unit operations, and (3) the invention of new designs for downstream processes is creating new processes to control.

During my Ph.D. research at Massachusetts Institute of Technology (MIT), I derived mathematical models and optimal control methods for multiple bioreactor configurations including fed-batch stirred-tank bioreactors and perfusion microbioreactors. I also designed and implemented laboratory systems for protein crystallization and continuous viral inactivation, which are optimally designed and controlled based on mathematical models that I developed. In addition, I am combining my experimentally validated individual unit operations into a plant-wide dynamic model to map the raw materials and operations to the product quality attributes and other variables of interest anywhere in the system.

In my own independent research program, I will build on my experience to address key biomanufacturing needs of today, with an initial focus on viral vaccines and gene therapy. Viral vaccine is the dominant class of vaccine because it activates all phases of the immune system and provides the most durable immunity, and is used for measles, mumps, flu, rubella, varicella (chickenpox), smallpox, polio, rotavirus, and yellow fever [1]. The limitations of current viral vaccine manufacturing are that the egg-based technology is not quickly scalable to address the vaccine needs of pandemics, the suspension bioreactor technologies have had low productivity, and the adherent bioreactor technologies have had poor scalability. Preliminary results suggest that order-of-magnitude improvements can be made to both bioreactor technologies to produce highly flexible and low-cost manufacturing.

Gene therapy is the introduction of nucleic acids into a patient’s cells, which then locally manufactures the proteins to treat the disease. Gene therapy treatment has become highly successful with numerous treatments in clinical trials, but the current manufacturing technology has high failure rates and very high process development and manufacturing costs, which contributes to the high cost of current treatments between $373K to $2.1M per person [2,3]. Gene therapy manufacturing has many commonalities with viral vaccine manufacturing, which suggests that the right combination of novel PAT, unit operation designs, and advanced control strategies could increase process reliability and reduce manufacturing costs by at least an order of magnitude.

[1] List of Vaccines Used in United States, Centers for Disease Control and Prevention, Atlanta, Georgia, April 13, 2018. https://www.cdc.gov/vaccines/vpd/vaccines-list.html

[2] Emily Mullin, Tracking the Cost of Gene Therapy, MIT Technology Review, October 24, 2017. https://www.technologyreview.com/2017/10/24/148183/tracking-the-cost-of-gene-therapy/

[3] John Miller and Caroline Humer, Novartis $2 Million Gene Therapy for Rare Disorder is World's Most Expensive Drug, Reuters, May 24, 2019. https://www.reuters.com/article/us-novartis-genetherapy/novartis-2-million-gene-therapy-for-rare-disorder-is-worlds-most-expensive-drug-idUSKCN1SU1ZP

Publications:

https://scholar.google.com/citations?user=616cjRQAAAAJ&hl=en&oi=ao

Teaching Interests:

During my Ph.D. research at Massachusetts Institute of Technology (MIT), I have served as a teaching assistant (TA) for the graduate-level course on Systems Engineering (10.551). This course is required for all Masters students and is taken by most Ph.D. students in the department, and introduces students to Process Systems Engineering and its application in Chemical Engineering Practice. The topics include systems analysis, process simulation software (Aspen Plus), experimental design, applied optimization, and data analytics. My recitation displayed thorough knowledge of subject material, helped students learn, and stimulated their interest (overall rating from subject evaluation: 6.2/7.0; highest among instructors).

My interest in improving teaching skills also led me to take the Grad Teaching Development Tracks from Teaching and Learning Lab (TLL). The tracks included the Lesson Planning Track, which focused on preparing an effective lesson plan for a class session or recitation, developing skills for classroom presentation and effective classroom activities, and giving formative feedback to students; the Subject Design Track, which focused on the fundamentals of designing college-level courses including how to define learning outcomes, select appropriate assessments, create an inclusive classroom, and write a syllabus; the Microteaching Track; and the Inclusive Teaching Track, which focused on creating inclusive and welcoming classrooms.

Incorporating my past teaching experience and teaching skills from the Grad Teaching Development Tracks, I would like to teach undergraduate and graduate students on both the fundamentals and how to apply those fundamentals to solve authentic engineering problems. I am interested in teaching a wide range of upper-level core engineering courses including Process Design and Control, Reaction Engineering, Transport Processes, and Engineering Mathematics. In addition, I am passionate about developing or improving elective courses in the fields of Process Systems Engineering and Advanced Biomanufacturing.