What is process analytical technology (PAT) and why is it so important?
PAT is an extremely powerful and useful tool for analyzing, optimizing and controlling chemical processes. Chemical, food and pharmaceutical industries could especially benefit from this technique.
In earlier days, chemical processes were primarily monitored by physical techniques, such as temperature, pH, pressure etc.. A final off-line laboratory quality control check of the product was performed after the chemical reaction was finished to ensure chemical composition. This final quality control reveals no information of the process itself. It merely tells us if the produced batch is inside specifications or not (yield, purity etc). This can result in batch-to-batch variability and little understanding as the cause of this irregularity. To guarantee uniform quality at the end of each batch, the process needs to be monitored, understood and guided. The cost reductions associated with preventing manufacturing errors (i.e., waste batches) increase the efficiency of a process, and subsequently reduce the environmental impact while also improving the safety of productions, thus benefiting manufacturing overall. More about this can be read in the vision of the European Union “Manufuture for 2020” and the PAT/Quality by Design initiative founded by the FDA in 2004, were the PAT first came to the attention of industry.[1]
How can a process be understood?
Physical parameters are not sufficient to describe the actual chemical changes that occur during a manufacturing process. Therefore, it is also necessary to monitor changes in speciation and obtain chemical information. There are many different methods for the PAT already available on the market. Examples include, online titrators, gas chromatographs, mass spectrometers as well as numerous optical spectroscopic methods (UV/VIS, NIR, MIR, Raman).[2]
Chromatographic methods typically require long run measurements, causing a large time delay between sampling at the process and measuring of the result values. Optical spectroscopic methods are very fast, but are strongly affected by the matrix of the sample, require significant calibration beforehand and may miss important structural information (e.g., isomers). Gas bubbles, turbidity and particles in the sample are also problematic. However, online NMR is devoid of these issues and could deliver speciation reaction data without problems.[3]
It seems that PAT is waiting for a method such as 1H NMR spectroscopy: it is independent on the sample matrix, needs no calibration and is able to deliver data quickly and frequently.
Why has NMR not been implemented as process analytical technology yet?
In general, process analytical instruments need to be robust, compact and easy to handle because they are installed in harsh production environments. When we look at traditional high-field NMR spectroscopy, it is obvious that these big and highly sensitive instruments are not robust enough to be placed in such hazardous environments. The high procurement costs, the necessity of cryogens to generate the superconducting magnet, including the related maintenance, and the need of an expert user for the high complex instrument makes traditional high-field NMR instruments not suitable for PAT.
Thanks to the progress of permanent magnets, Nanalysis has developed a magnet architecture which is able to create an instrument with a strong magnetic field with 1.4 T (60 MHz proton resonance frequency), with an incredibly small enclosure: roughly the size of a shoe box and weighing only 25 kg. This so called cylindrical Halbach magnet is operated at or above room temperature - affectively rendering it cryogen- AND maintenance-free. Furthermore, the symmetric bore of the cylindrical Halbach of the instrument makes it easy to implement a flow cell. Consequently, this small size, robustness and the easy usage of the instrument make it perfectly suitable for incorporation into the process environment.
If we look into the history of PAT, gas chromatography and mass spectrometry are techniques that took a very long time to translate from being only a lab tool to being a fully functioning process instrument. However, today these methods are standard and readily available in PAT. As for NMR, the new development of benchtop NMR spectrometers opens the possibility to use it as process analytical tool.[3]
Steps towards a process-NMR-system:
Standard questions about if a method is suitable for PAT are the following:
- How can I get a sample? – Is extensive sample preparation necessary? – Is the sample matrix dependent? - Which type of measurement (continuous flow, stop-flow…)? – Is the data processing and interpretation simple? – Do I need to manually process and interpret the data? How is the accuracy and reproducibility?[1]
Compact NMR spectrometers such as the NMReady can easily be converted to an online detector, for example by using the NMReady-flow . This sampling can work with proteo-solvent reactions or neat solutions and is non-invasive. NMR Spectroscopy is independent on the matrix, because signal areas in the NMR spectra are linear to the sample concentration, which makes it an absolute technique.[5] NMR measurements are also very accurate and reproducible. The NMReady’s file output of the spectral data also makes data processing very simple. The output data file, JCAMP-DX, can be opened and processed with any third-party NMR software (e.g., ACD/Labs, Delta, MNova, TopSpin), or even in more complicated systems like MATLAB, Labview and so on.
At the moment, Nanalysis is working in close cooperation with BASF in Ludwigshafen to implement the NMReady platform into a process environment. The project ‘development of a process-NMR-system’ started in 2015 and has already made big steps in development. The conceptual setup of the process-NMR-system can be seen in Figure 1.