Process Analytical Technology for Online Monitoring of Organic Reactions by Mass Spectrometry and UV–Vis Spectroscopy

Continuous manufacturing opens up new operation windows with improved product quality in contrast to documented lot deviations in batch or fed-batch operations. A more sophisticated process control strategy is needed to adjust operation parameters and keep product quality constant during long-term operations. In the present study, the applicability of a combination of spectroscopic methods was evaluated to enable Advanced Process Control (APC) in continuous manufacturing by Process Analytical Technology (PAT). In upstream processing (USP) and aqueous two-phase extraction (ATPE), Raman-, Fourier-transformed infrared (FTIR), fluorescence- and ultraviolet/visible- (UV/Vis) spectroscopy have been successfully applied for titer and purity prediction. Raman spectroscopy was the most versatile and robust method in USP, ATPE, and precipitation and is therefore recommended as primary PAT. In later process stages, the combination of UV/Vis and fluorescence spectroscopy was able to overcome difficulties in titer and purity prediction induced by overlapping side component spectra. Based on the developed spectroscopic predictions, dynamic control of unit operations was demonstrated in sophisticated simulation studies. A PAT development workflow for holistic process development was proposed.

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Development of a General PAT Strategy for Online Monitoring of Complex Mixtures—On the Example of Natural Product Extracts from Bearberry Leaf (Arctostaphylos uva-ursi)

Processes ◽

10.3390/pr9122129 ◽

2021 ◽

Vol 9 (12) ◽

pp. 2129

Author(s):

Christoph Jensch ◽

Larissa Knierim ◽

Martin Tegtmeier ◽

Jochen Strube

Keyword(s):

Online Monitoring ◽

Process Development ◽

Process Analytical Technology ◽

Complex Mixture ◽

Complex Mixtures ◽

Data Set ◽

Methodical Approach ◽

Extraction Processes ◽

First Time ◽

Analytical Technology

For the first time, a universally applicable and methodical approach from characterization to a PAT concept for complex mixtures is conducted—exemplified on natural products extraction processes. Bearberry leaf (Arctostaphylos uva-ursi) extract is chosen as an example of a typical complex mixture of natural plant origin and generalizable in its composition. Within the quality by design (QbD) based process development the development and implementation of a concept for process analytical technology (PAT), a key enabling technology, is the next necessary step in risk and quality-based process development and operation. To obtain and provide an overview of the broad field of PAT, the development process is shown on the example of a complex multi-component plant extract. This study researches the potential of different process analytical technologies for online monitoring of different component groups and classifies their possible applications within the framework of a QbD-based process. Offline and online analytics are established on the basis of two extraction runs. Based on this data set, PLS models are created for the spectral data, and correlations are conducted for univariate data. In a third run, the prediction potential is researched. Conclusively, the results of this study are arranged in the concept of a holistic quality and risk-based process design and operation concept.

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Process Analytical Technology in Bioprocess Development and Manufacturing

Comprehensive Biotechnology ◽

10.1016/b978-0-444-64046-8.00183-x ◽

2011 ◽

pp. 535-544

Author(s):

J.C. Menezes

Keyword(s):

Process Analytical Technology ◽

Bioprocess Development ◽

Analytical Technology

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Synthesis, Biomacromolecular Interactions, Photodynamic NO Releasing and Cellular Imaging of Two [RuCl(qn)(Lbpy)(NO)]X Complexes

Molecules ◽

10.3390/molecules26092545 ◽

2021 ◽

Vol 26 (9) ◽

pp. 2545

Author(s):

Luna Song ◽

Hehe Bai ◽

Chenyang Liu ◽

Wenjun Gong ◽

Ai Wang ◽

...

Keyword(s):

Mass Spectrometry ◽

Confocal Imaging ◽

Epr Spectra ◽

Distorted Octahedral Geometry ◽

Ionization Mass ◽

Time Resolved ◽

Pbr322 Dna ◽

Vis Spectroscopy ◽

No Release ◽

Ft Ir

Two light-activated NO donors [RuCl(qn)(Lbpy)(NO)]X with 8-hydroxyquinoline (qn) and 2,2′-bipyridine derivatives (Lbpy) as co-ligands were synthesized (Lbpy1 = 4,4′-dicarboxyl-2,2′-dipyridine, X = Cl− and Lbpy2 = 4,4′-dimethoxycarbonyl-2,2′-dipyridine, X = NO3−), and characterized using ultraviolet–visible (UV-vis) spectroscopy, Fourier transform infrared (FT-IR) spectroscopy, nuclear magnetic resonance (1H NMR), elemental analysis and electrospray ionization mass spectrometry (ESI-MS) spectra. The [RuCl(qn)(Lbpy2)(NO)]NO3 complex was crystallized and exhibited distorted octahedral geometry, in which the Ru–N(O) bond length was 1.752(6) Å and the Ru–N–O angle was 177.6(6)°. Time-resolved FT-IR and electron paramagnetic resonance (EPR) spectra were used to confirm the photoactivated NO release of the complexes. The binding constant (Kb) of two complexes with human serum albumin (HSA) and DNA were quantitatively evaluated using fluorescence spectroscopy, Ru-Lbpy1 (Kb~106 with HSA and ~104 with DNA) had higher affinity than Ru-Lbpy2. The interactions between the complexes and HSA were investigated using matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF-MS) and EPR spectra. HSA can be used as a carrier to facilitate the release of NO from the complexes upon photoirradiation. The confocal imaging of photo-induced NO release in living cells was successfully observed with a fluorescent NO probe. Moreover, the photocleavage of pBR322 DNA for the complexes and the effect of different Lbpy substituted groups in the complexes on their reactivity were analyzed.

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