Accelerating Biologics Manufacturing by Modeling or: Is Approval under the QbD and PAT Approaches Demanded by Authorities Acceptable without a Digital-Twin?

Abstract

Innovative biologics, including cell therapeutics, virus-like particles, exosomes,recombinant proteins, and peptides, seem likely to substitute monoclonal antibodies as the maintherapeutic entities in manufacturing over the next decades. This molecular variety causes agrowing need for a general change of methods as well as mindset in the process development stage,as there are no platform processes available such as those for monoclonal antibodies. Moreover,market competitiveness demands hyper-intensified processes, including accelerated decisionstoward batch or continuous operation of dedicated modular plant concepts. This indicates gaps inprocess comprehension, when operation windows need to be run at the edges of optimization. Inthis editorial, the authors review and assess potential methods and begin discussing possiblesolutions throughout the workflow, from process development through piloting to manufacturingoperation from their point of view and experience. Especially, the state-of-the-art for modeling inred biotechnology is assessed, clarifying differences and applications of statistical, rigorousphysical-chemical based models as well as cost modeling. “Digital-twins” are described and effortsvs. benefits for new applications exemplified, including the regulation-demanded QbD (quality bydesign) and PAT (process analytical technology) approaches towards digitalization or industry 4.0based on advanced process control strategies. Finally, an analysis of the obstacles and possiblesolutions for any successful and efficient industrialization of innovative methods from processdevelopment, through piloting to manufacturing, results in some recommendations. A centralquestion therefore requires attention: Considering that QbD and PAT have been required byauthorities since 2004, can any biologic manufacturing process be approved by the regulatoryagencies without being modeled by a “digital-twin” as part of the filing documentation?

Model-Based Design and Process Optimization of Continuous Single Pass Tangential Flow Filtration Focusing on Continuous Bioprocessing

“…Developments of process variables like concentration, flux, or pressure, based on modelling are investigated and by using a model for process optimization, the experimental effort can be drastically reduced, which is especially relevant for multiparameter dependent unit operations. With a systematic approach, modelling can substitute experiments and accelerate the process design [29,44,45]. For this study an experimentally validated physico-chemical model [1] is enhanced and transferred.…”

Accelerating Biomanufacturing by Modeling of Continuous Bioprocessing—Piloting Case Study of Monoclonal Antibody Manufacturing

“…Further emphasis to simplify operation, improve process robustness and reduce handling efforts is; therefore, focused on PAT techniques and process control strategies by advanced process control approaches. This is a logical consequence and straight forward, as those process models are existing and have been experimentally validated [46][47][48]58].…”

Accelerating Biologics Manufacturing by Modeling: Process Integration of Precipitation in mAb Downstream Processing

“…Additionally, a mechanistic model approach for the precipitation curve was presented by Großhans et al [43]. Previous work has already presented a general model development and validation concept, which can be used to construct physico-chemical models of unit operations [66][67][68][69][70][71][72]. The described process is broken down into the individual building blocks and described with physical principles and laws.…”