On-line monitoring of blend uniformity in continuous drug product manufacturing process—The impact of powder flow rate and the choice of spectrometer: Dispersive vs. FT

Raw Material Variability and Its Impact on the Online Adaptive Control of Cohesive Powder Blend Homogeneity Using NIR Spectroscopy

“…In order to effectively monitor the CQA and system dynamic changes of the mixing process, the pharmaceutical industry is encouraged to adopt new process analysis methods under the American Food and Drug Administration (FDA) guidance on process analytical technology (PAT) [6]. Many techniques such as near infrared (NIR) spectroscopy [7][8][9][10], Raman spectroscopy (RS) [3,11] and chemical imaging (CI) [12,13] have been reported on determination of BU. Compared with the stratified sampling and offline analysis mode, these online methods enable high frequency sampling, multi-point detection, real time and non-invasive process control, as well as increased production efficiency and reduced operation costs.…”

Continuous Heterogeneous Crystallization on Excipient Surfaces

“…The downstream process of the drug product manufacturing starts from the crystallization step of the API (drug substance upstream) and often includes many intermediate steps of milling, mixing (with required excipients) and blending, granulation, drying, sieving, and tablet pressing − (Figure a). Many risks, challenges, technical hurdles, and considerations are associated with each of the aforementioned steps. − The precise final dosage, content uniformity, composition, mechanical properties, and critical quality attribute of every single tablet, which are highly regulated, ,− highly depend on the performance of the involved stages, for instance, component segregation, which can be caused by differences in particle size, density, or shape, and segregation in blending, hoppers, transfer lines, or feeders, and results in heterogeneity in tablet compositions. − Significant academic research and industrial development have been invested to overcome drug product line challenges and enable consistent manufacturing of high-quality tablets. − These challenges, and subsequent effects, are more problematic in the continuous manufacturing arena, , where the continuous flow of material, continuous workload of the drug product line, residence time distribution, and validation of “batches” of the final product enter into the design of already complicated processes. ,,,, …”

“…18−22 These challenges, and subsequent effects, are more problematic in the continuous manufacturing arena, 23,24 where the continuous flow of material, continuous workload of the drug product line, residence time distribution, and validation of "batches" of the final product enter into the design of already complicated processes. 17,20,21,23,24 Recent endeavors in shifting from the traditional batch pharmaceutical processes to the modern and emerging…”

Macro-Raman spectroscopy for bulk composition and homogeneity analysis of multi-component pharmaceutical powders

“…Assessment of the homogeneity of powder mixtures has been a challenge in the pharmaceutical industry [38]. Various off-line, on-line, and in-line techniques of evaluating blend uniformity have been reported in the literature [39].…”

“…Li found that a larger beam size during NIR spectroscopy measurements led to much lower relative standard deviations of measured compositions [61]. The impact of mass flow rate during sampling of flowing powders on homogeneity evaluation using NIR spectroscopy have also been discussed, which can also be interpreted as the effect of sample volumes [38,62].…”