48062
2019
eng
3037
3046
14
411
article
Springer Nature
Heidelberg
1
--
--
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Flexible automation with compact NMR spectroscopy for continuous production of pharmaceuticals
Modular plants using intensified continuous processes represent an appealing concept for the production of pharmaceuticals. It can improve quality, safety, sustainability, and profitability compared to batch processes; besides, it enables plug-and-produce reconfiguration for fast product changes. To facilitate this flexibility by real-time quality control, we developed a solution that can be adapted quickly to new processes and is based on a compact nuclear magnetic resonance (NMR) spectrometer. The NMR sensor is a benchtop device enhanced to the requirements of automated chemical production including robust evaluation of sensor data. Beyond monitoring the product quality, online NMR data was used in a new iterative optimization approach to maximize the plant profit and served as a reliable reference for the calibration of a near-infrared (NIR) spectrometer. The overall approach
was demonstrated on a commercial-scale pilot plant using a metal-organic reaction with pharmaceutical relevance.
Analytical and Bioanalytical Chemistry
10.1007/s00216-019-01752-y
1618-2642
urn:nbn:de:kobv:b43-480623
1618-2650
27.05.2019
https://nbn-resolving.org/urn:nbn:de:kobv:b43-480630
Creative Commons - CC BY - Namensnennung 4.0 International
Simon Kern
Lukas Wander
Klas Meyer
Svetlana Guhl
A. R. Gottu Mukkula
M. Holtkamp
M. Salge
C. Fleischer
N. Weber
S. Engell
Andrea Paul
M. Pereira Remelhe
Michael Maiwald
eng
uncontrolled
NMR Spectroscopy
eng
uncontrolled
NIR Spectroscopy
eng
uncontrolled
Real-time process monitoring
eng
uncontrolled
Real-time quality control
eng
uncontrolled
Continuous processes
eng
uncontrolled
CONSENS
eng
uncontrolled
Data Fusion
Analytische Chemie
1 Analytische Chemie; Referenzmaterialien
1.4 Prozessanalytik
Umwelt
Chemie und Prozesstechnik
Chemische Charakterisierung und Spurenanalytik
Verlagsliteratur
Datei für die Öffentlichkeit verfügbar ("Open Access")
Wissenschaftliche Artikel der BAM
Sensorik
Bundesanstalt für Materialforschung und -prüfung (BAM)
https://opus4.kobv.de/opus4-bam/files/48062/ABC_411_2019_3037-3046_Kern.pdf
48063
2018
eng
researchdata
Zenodo
Geneva
0
--
--
--
Raw data of pilot plant runs for CONSENS project (Case study 1)
In case study one of the CONSENS project, two aromatic substances were coupled by a lithiation reaction, which is a prominent example in pharmaceutical industry. The two aromatic reactants (Aniline and o-FNB) were mixed with Lithium-base (LiHMDS) in a continuous modular plant to produce the desired product (Li-NDPA) and a salt (LiF). The salt precipitates which leads to the formation of particles. The feed streams were subject to variation to drive the plant to its optimum.
The uploaded data comprises the results from four days during continuous plant operation time. Each day is denoted from day 1-4 and represents the dates 2017-09-26, 2017-09-28, 2017-10-10, 2017-10-17.
In the following the contents of the files are explained.
10.5281/zenodo.1438233
Datensatz
https://nbn-resolving.org/urn:nbn:de:kobv:b43-480623
Creative Commons - CC BY - Namensnennung 4.0 International
Simon Kern
Lukas Wander
Klas Meyer
Svetlana Guhl
A. R. Gottu Mukkula
M. Holtkamp
M. Salge
C. Fleischer
N. Weber
S. Engell
Andrea Paul
R. King
Michael Maiwald
eng
uncontrolled
Process Analytical Technology
eng
uncontrolled
Multivariate Data Analysis
eng
uncontrolled
Nuclear Magnetic Resonance
eng
uncontrolled
Near Infrared Spectroscopy
eng
uncontrolled
Continuous Manufacturing
eng
uncontrolled
CONSENS
Analytische Chemie
1 Analytische Chemie; Referenzmaterialien
1.4 Prozessanalytik
Umwelt
Chemie und Prozesstechnik
Chemische Charakterisierung und Spurenanalytik
Datei für die Öffentlichkeit verfügbar ("Open Access")
Graue Literatur
Forschungsdatensätze der BAM
Sensorik
Bundesanstalt für Materialforschung und -prüfung (BAM)
52453
2020
eng
11773
11779
2
53
article
Elsevier
Amsterdam
1
--
--
--
An Application of Modifier Adaptation with Quadratic Approximation on a Pilot Scale Plant in Industrial Environment
The goal of this work is to identify the optimal operating input for a lithiation reaction that is performed in a highly innovative pilot scale continuous flow chemical plant in an industrial environment, taking into account the process and safety constraints. The main challenge is to identify the optimum operation in the absence of information about the reaction mechanism and the reaction kinetics. We employ an iterative real-time optimization scheme called modifier adaptation with quadratic approximation (MAWQA) to identify the plant optimum in the presence of plant-model mismatch and measurement noise. A novel NMR PAT-sensor is used to measure the concentration of the reactants and of the product at the reactor outlet. The experiment results demonstrate the capabilities of the iterative optimization using the MAWQA algorithm in driving a complex real plant to an economically optimal operating point in the presence of plant-model mismatch and of process and measurement uncertainties.
IFAC-PapersOnLine
1522-2640
10.1016/j.ifacol.2020.12.685
urn:nbn:de:kobv:b43-524531
publish
24.06.2021
Creative Commons - CC BY-NC-ND - Namensnennung - Nicht kommerziell - Keine Bearbeitungen 4.0 International
A. R. Gottu Mukkula
Simon Kern
M. Salge
M. Holtkamp
Svetlana Guhl
C. Fleischer
Klas Meyer
M. Remelhe
Michael Maiwald
S. Engell
eng
uncontrolled
Process Analytical Technology
eng
uncontrolled
Online NMR Spectroscopy
eng
uncontrolled
Process Industry
eng
uncontrolled
Iterative real-time optimization
eng
uncontrolled
Modifier adaptation
eng
uncontrolled
Plant-model mismatch
eng
uncontrolled
Reactor control
eng
uncontrolled
CONSENS
Analytische Chemie
1 Analytische Chemie; Referenzmaterialien
1.4 Prozessanalytik
Umwelt
Chemie und Prozesstechnik
Chemische Charakterisierung und Spurenanalytik
Verlagsliteratur
Datei für die Öffentlichkeit verfügbar ("Open Access")
Wissenschaftliche Artikel der BAM
Sensorik
Bundesanstalt für Materialforschung und -prüfung (BAM)
https://opus4.kobv.de/opus4-bam/files/52453/IFAC_53_2020_11773-11779_Gottu-Mukula_Modifier_Adaptation_CONSENS.pdf
47715
2019
eng
poster
0
--
--
--
Flexible Automation with compact NMR instruments
Modular plants using intensified continuous processes represent an appealing concept to produce pharmaceuticals. It can improve quality, safety, sustainability, and profitability compared to batch processes, and it enables plug-and-produce reconfiguration for fast product changes. To facilitate this flexibility by real-time quality control, we developed a solution that can be adapted quickly to new processes and includes a compact Nuclear Magnetic Resonance (NMR) spectrometer for online quality monitoring as well as a new model-based control approach. The NMR sensor is a benchtop device enhanced to the requirements of automated chemical production including ro-bust evaluation of sensor data.
Here, we present alternatives for the quantitative determination of the analytes using modular, physically motivated models. These models can be adapted to new substances solely by the use of their corresponding pure component spectra, which can either be derived from experimental spectra as well as from quantum mechanical models or NMR predictors. Modular means that spec-tral models can simply be exchanged together with alternate reagents and products. Beyond that, we comprehensively calibrated an NIR spectrometer based on online NMR process data for the first time within an industrial plant. The integrated solution was developed for a metal organic reac-tion running on a commercial-scale modular pilot plant and it was tested under industrial conditions.
7th Annual PANIC Conference
Hilton Head Island, South Carolina, USA
03.03.2019
07.03.2019
false
true
Simon Kern
Lukas Wander
Klas Meyer
Svetlana Guhl
A. R. Gottu Mukkula
M. Holtkamp
M. Salge
C. Fleischer
N. Weber
R. King
S. Engell
Andrea Paul
M. Pereira Remelhe
Michael Maiwald
eng
uncontrolled
Online NMR Spectroscopy
Analytische Chemie
1 Analytische Chemie; Referenzmaterialien
1.4 Prozessanalytik
Umwelt
Datei im Netzwerk der BAM verfügbar ("Closed Access")
Präsentation
Sensorik