Process Analytical Technology:  An Investment in Process Knowledge

Abstract

Process analytical technology (PAT) is fast becoming an integral part of many active pharmaceutical ingredient (API) production facilities. The incorporation of early PAT devices, such as pH probes for example, was shown to increase process efficiency and safety by acting on data in real time and by eliminating sampling. PAT applications, such as online redox, NIR, and sophisticated particle size analysis, increase (in real time) detailed knowledge of processes, thus affording increased robustness and greater straight-through processing (right-first-time) opportunities. Modern developments in analytical technologies provide chemical and analytical insights for all types of chemical reactions and process monitoring such as drying, distillations, crystallizations, hydrogenations, and others. This article will discuss two applications; each is very different from the other. The first application, redox monitoring, is a traditional PAT application used to monitor differences in the oxidation state of two reaction constituents. Our discussion will describe an oxidation/reduction (redox) application used to monitor the reduction of excess bromine with sodium bisulfite using an online probe. The second application is crystallization and granulation monitoring using a Lasentec Focused Beam Reflectance Measurement (FBRM) instrument for the optimization of a crystallization and granulation process in manufacturing (reference information is publicly available on this equipment; visit the Mettler-Toledo website at: http:// www.lasentec.com/method_of_measurement.html).

Particle Size Analysis of Simulant Sludge Slurries and Tank 40 Radioactive Sludge Slurry

“…The results obtained upon sieving the NIST 1984 SRM agree with literature data that the coefficient of variance (precision) may be 5-10% when different sets of sieves with large aperture widths are used and greater than 10% when different sieves with small aperture widths are used. 9 Precision was excellent considering the particle morphology. For most of the sieves tested, except the 12-14 µm sieve, the accuracy (as compared to Microtrac volume data) was approximately ±30% of the accepted value.…”

“…The coefficient of variance (precision) can be 10% or larger for sieves with small aperture widths which has been documented. 9 The goal here was to obtain ≤10% difference for sieves larger than 20 microns and ≤20% difference for sieves under 20 µm. The difference being the weave of the wire mesh for sieves having aperture widths less than 20 µm (see Figure 2.1).…”

“…Sonication has been shown to be most effective at reducing agglomerations during the first minute of use but if the sample is sonicated more than three minutes it can start to dissolve due to thermal heating caused by the sonication. 9 No additives were added to any of the experiments to prevent reagglomeration of the particles after sonication. The PSD came out to be very different when this simulant slurry was analyzed on the Microtrac X-100 'hot' instrument.…”

Monitoring Granulation Rate Processes Using Three PAT Tools in a Pilot-Scale Fluidized Bed

“…Each measurement was done in triplicate. The laser diffraction technique was needed because the particle chord length data from FBRM were not directly transferable to PSD (14). The sample moisture content was analyzed using loss on drying (LOD) method.…”

“…As particles pass by the window surface, the focused beam will intersect the edge of a particle. The backscatter of the laser beam by the particle is collected by the FBRM optics and converted to size measurement (chord length) of the particle (14). However, there are currently few reports on using this technique to monitor the granulation process.…”