This manuscript discusses the role of process systems engineering (PSE) in ensuring quality manufacturing of Mesenchymal Stem Cells (MSCs) through seeding, cultivation, and stabilization. A comparison of the MSC production to small molecule and therapeutic protein production processes illustrated the leap in complexity in ensuring quality manufacturing of MSCs. As a result, applying standard Quality by Design (QbD) concepts to ensure MSC quality is challenging. The identity, potency, and purity of MSCs, which are irreversible biological quality parameters, were identified as critical quality aspects that must be maintained to ensure MSC quality. Drawing inspiration from process control and monitoring concepts, a path forward is proposed to ensure quality MSC production at scale. The proposed method combines process operations and passive statistical process control concepts of QbD with targeted “real-time” control actions. The role of process models, monitoring, and process analytical technology (PAT) in ensuring MSC product quality is also discussed.