Process Analytical Technology for Precipitation Process Integration into Biologics Manufacturing towards Autonomous Operation—mAb Case Study

Abstract

The integration of real time release testing into an advanced process control (APC) concept in combination with digital twins accelerates the process towards autonomous operation. In order to implement this, on the one hand, measurement technology is required that is capable of measuring relevant process data online, and on the other hand, a suitable model must be available to calculate new process parameters from this data, which are then used for process control. Therefore, the feasibility of online measurement techniques including Raman-spectroscopy, attenuated total reflection Fourier transformed infrared spectroscopy (ATR-FTIR), diode array detector (DAD) and fluorescence is demonstrated within the framework of the process analytical technology (PAT) initiative. The best result is achieved by Raman, which reliably detected mAb concentration (R2 of 0.93) and purity (R2 of 0.85) in real time, followed by DAD. Furthermore, the combination of DAD and Raman has been investigated, which provides a promising extension due to the orthogonal measurement methods and higher process robustness. The combination led to a prediction for concentration with a R2 of 0.90 ± 3.9% and for purity of 0.72 ± 4.9%. These data are used to run simulation studies to show the feasibility of process control with a suitable digital twin within the APC concept.

Process analytical technology as key‐enabler for digital twins in continuous biomanufacturing

“…The following section summarizes a series of studies, which address and highlight the challenges of operational costs and process development for the continuous bioprocessing of a monoclonal antibody by alternative unit operations and the development of a digital twin thereof. [46][47][48][49][50] Upstream processing A macroscopic kinetic model based on Monod kinetics for mammalian cell cultivation suitable for digital twin purposes was developed by Kornecki et al and verified according to a general valid model validation workflow. 51 The macroscopic model was verified and validated on the basis of four decision criteria (plausibility, sensitivity, accuracy and precision as well as equality) and subjected to a case study, comprising a Chinese hamster ovary fed-batch cultivation for the production of a monoclonal antibody.…”

“…Lohmann et al investigated the feasibility of online measurement techniques of mAb and side components by Raman spectroscopy, attenuated total reflection-Fourier-transform infrared spectroscopy (ATR-FTIR), diode array detection (DAD) and fluorescence for precipitation. 48 The digital twin is fed with the input data of the ATPE and the online measured spectral data. The model enables control of key process parameters to ensure compliance of the critical quality attributes.…”

“…Simplified illustration of proposed advanced process control (APC) for the precipitation unit. Precipitation tanks are merged into one tank and the subunits are filter modules 48 …”

“…In terms of automation, digital twins in continuous biomanufacturing rely on online process data that update the information fed into the process models in real time 2,47‐49,67 . Besides simple process parameters like pressure, conductivity, pH and temperature, concentration of the target component and main impurities is necessary to ensure that the information gathered from the digital twin is reliable.…”

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

“…Digital twins in mRNA manufacturing rely on online process data that updates the information fed into the process models in real-time [81][82][83][84][85]. Besides simple process parameters like pressure, conductivity, pH, temperature, etc., concentration of the target component and main impurities are necessary to ensure that the information gathered from the digital twin are reliable.…”