Digital Twin for Lyophilization by Process Modeling in Manufacturing of Biologics

Abstract

Lyophilization stabilizes formulated biologics for storage, transport and application to patients. In process design and operation it is the link between downstream processing and with final formulation to fill and finish. Recent activities in Quality by Design (QbD) have resulted in approaches by regulatory authorities and the need to include Process Analytical Technology (PAT) tools. An approach is outlined to validate a predictive physical-chemical (rigorous) lyophilization process model to act quantitatively as a digital twin in order to allow accelerated process design by modeling and to further-on develop autonomous process optimization and control towards real time release testing. Antibody manufacturing is chosen as a typical example for actual biologics needs. Literature is reviewed and the presented procedure is exemplified to quantitatively and consistently validate the physical-chemical process model with aid of an experimental statistical DOE (design of experiments) in pilot scale.

Digital Twin of mRNA-Based SARS-COVID-19 Vaccine Manufacturing towards Autonomous Operation for Improvements in Speed, Scale, Robustness, Flexibility and Real-Time Release Testing

“…The processes reported in literature and the process framework depicted in this work are both summarized in Figure 4. For this total pDNA to mRNA process, a digital twin is proposed based on literature data, pre-existing knowledge and experimental experience as well as existing basically validated process models [41][42][43][44][45][46][47].…”

“…A one-dimensional sorption sublimation model introduced by Klepzig et al models the lyophilization [47]. The publication shows the exact derivation of the proposed model.…”

“…For the simulation of the Lyophilization process, two model parameters are necessary: the vial heat transfer and the hydraulic flow resistance. These parameters are adopted from literature [47]. For this study, similar heat transfer coefficients are assumed for the pilot and manufacturing scale.…”

Advanced Process Analytical Technology in Combination with Process Modeling for Endpoint and Model Parameter Determination in Lyophilization Process Design and Optimization

“…Validated pyhsico-chemical process models deepen process knowledge because they describe the separated physical effects by a coupled mass and energy balance. For Lyophilization, a broad range of models has been developed [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34]. In combination, PAT and modeling can result in advanced autonomous process control, and real-time release testing can be the final benefit.…”

Towards Autonomous Operation by Advanced Process Control—Process Analytical Technology for Continuous Biologics Antibody Manufacturing

“…In addition to appropriate PAT, digital twins for the whole process are a central key-technology for achieving RTRT. It has been proven that, for all unit operations, such distinct validated process models are available as digital twins [1,5,8,26,27,[29][30][31][32].…”