A PAT-based qualification of pharmaceutical excipients produced by batch or continuous processing

• Qualification of entire processes based on CQAs of the final product (excipient).
• Use of analytical methods (Raman, X-ray- and laser diffraction) with MVA.
• The value of such combined strategy is to produce a better diagnostics of quality.
• Evidence-driven diagnostics of which process delivers a more consistent end-product.
• Strategy for a risk-based supplier qualification using an analytical data matrix.

Pharmaceutical excipients have an influence on the main requirements for medicinal products (viz., quality, safety and efficacy) but also on their manufacturability. During product lifecycle it may become necessary to introduce minor changes (e.g., to continuously improve it) or major changes in the validated process (e.g., moving it to a new production site, replacing process version or even disruptively changing processing type). Those changes can influence the critical to quality attributes of the product. Therefore, it is important to enhance process understanding to avoid the risk of any significant quality changes. Process analytical technology can support better decision making and risk-management as required in quality by design – viz., by many pharmaceutical regulatory authorities.This study compares the quality of the pharmaceutical excipient sodium carbonate (anhydrous) produced either in a batch or a continuous process. For continuous processing two different production lines were available that differed on the dryer and crystallizer types used. Therefore their influence on critical to quality attributes of sodium carbonate was investigated for each of the three processing alternatives. The overall goal was to identify which of the continuous processes ensures a similar product quality to batch processing. Namely, changes on chemical and physical attributes of the product were investigated with Raman spectroscopy, laser diffraction and X-ray powder diffraction. Principal component analysis, a very common multivariate analysis technique, was applied to extract relevant information from small differences at multiple spectral regions from samples from each process type and from each analytical technique used. Changing processing from batch to continuous improved consistency of certain attributes (e.g., particle size distribution) but affected others. However, the increased process/product knowledge gained can lead to an enhanced control strategy and ensure a similar product quality is obtained from distinct process versions.

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