TY  - JOUR
U1  - Zeitschriftenartikel, wissenschaftlich - begutachtet (reviewed)
A1  - Hengelbrock, Alina
A1  - Helgers, Heribert
A1  - Schmidt, Axel
A1  - Vetter, Florian Lukas
A1  - Juckers, Alex
A1  - Rosengarten, Jamila Franca
A1  - Stitz, Jörn
A1  - Strube, Jochen
ED  - Sun, Tao
T1  - Digital Twin for HIV-Gag VLP Production in HEK293 Cells
JF  - Processes
N2  - The development and adoption of digital twins (DT) for Quality-by-Design (QbD)-based processes with flexible operating points within a proven acceptable range (PAR) and automation through Advanced Process Control (APC) with Process Analytical Technology (PAT) instead of conventional process execution based on offline analytics and inflexible process set points is one of the great challenges in modern biotechnology. Virus-like particles (VLPs) are part of a line of innovative drug substances (DS). VLPs, especially those based on human immunodeficiency virus (HIV), HIV-1 Gag VLPs, have very high potential as a versatile vaccination platform, allowing for pseudotyping with heterologous envelope proteins, e.g., the S protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As enveloped VLPs, optimal process control with minimal hold times is essential. This study demonstrates, for the first time, the use of a digital twin for the overall production process of HIV-1 Gag VLPs from cultivation, clarification, and purification to lyophilization. The accuracy of the digital twins is in the range of 0.8 to 1.4% in depth filtration (DF) and 4.6 to 5.2% in ultrafiltration/diafiltration (UFDF). The uncertainty due to variability in the model parameter determination is less than 4.5% (DF) and less than 3.8% (UFDF). In the DF, a prediction of the final filter capacity was demonstrated from as low as 5.8% (9mbar) of the final transmembrane pressure (TMP). The scale-up based on DT in chromatography shows optimization potential in productivity up to a factor of 2. The schedule based on DT and PAT for APC has been compared to conventional process control, and hold-time and process duration reductions by a factor of 2 have been achieved. This work lays the foundation for the short-term validation of the DT and PAT for APC in an automated S7 process environment and the conversion from batch to continuous production.
KW  - Digitaler Zwilling
KW  - Digital Twin (DT)
KW  - Advanced Process Control (APC)
KW  - Quality-by-Design (QbD)
KW  - Process Analytical Technology (PAT)
KW  - Real-Time-Release Testing (RTRT)
KW  - Human Embryonic Kidney 293 (HEK293)
KW  - Human Immunodeficiency Virus (HIV)
KW  - Virus-like Particles (VLPs)
KW  - HIV
KW  - Virus-like Particles
Y1  - 2022
UN  - https://nbn-resolving.org/urn:nbn:de:hbz:832-epub4-19824
SN  - 2227-9717
SS  - 2227-9717
U6  - https://doi.org/10.3390/pr10050866
DO  - https://doi.org/10.3390/pr10050866
VL  - 10
IS  - 5
SP  - 23
S1  - 23
PB  - MDPI
ER  -