Continuous manufacturing (CM) is an emerging technology in the pharmaceutical manufacturing sector, and the understanding of the impact on product quality is currently evolving. As the final purification and isolation step, crystallization has a significant impact on the final physicochemical properties of drug substance and is considered a critical process step in achieving the continuous manufacturing of drug substances. Although many publications previously focused on various innovative techniques to continuously make crystals with desired properties, engineering difficulties such as system design, automation, and integration with process analytical technology (PAT) tools have not been thoroughly discussed. Here, we focus on how to develop a continuous crystallization system, from the perspective of process engineering, and the related risk considerations on product quality. Specifically, we designed and built an automated two-stage mixed suspension mixed product removal (MSMPR) crystallization platform for a model compound (carbamazepine, CBZ) that exhibits multiple polymorphs. The crystallization process includes the integration of PAT tools (online Raman microscopy and focused beam reflectance microscopy, FBRM) for real-time monitoring. A series of case studies were done to evaluate the performance of the continuous system and PAT tools. Specifically, the drawing schemes, slurry transport, and variations on process variables are considered as the three key risk areas for continuous crystallization process development. Our proof-of-concept continuous crystallization system uses feedback/feedforward controls to achieve constant levels in crystallizers, a centralized automation program coded in LabVIEW, and PAT monitoring for polymorphs and particle size distribution (Raman and FBRM). To the best of our knowledge, this is also the first study on continuous crystallization of carbamazepine for form III and its polymorphic transition (between form II and form III).
Crystallization has a significant
impact on the properties of the
active pharmaceutical ingredient (API) since it is the final step
in the manufacturing of the drug substance and determines particle
size distribution, purity, shape, and polymorphs. Many publications
have focused on the implementation of Process Analytical Technology
(PAT) tools for monitoring batch and continuous operation; however,
a comprehensive method development and validation of Raman spectroscopy
to monitor continuous crystallization has not been presented. This
work demonstrates the development and validation of a method to monitor
the solute concentration of Carbamazepine and quantifies the limit
of detection for a metastable polymorphic form. The experiments were
based on the cooling crystallization of Carbamazepine to produce the
most stable form. The method was validated following the principles
described in USP general chapter ⟨1225⟩ validation procedures
for analytical methods. The results demonstrate the model can predict
the solute concentration with a root-mean-square-error of prediction
of 2.46 mg/mL. The repeatability and intermediate precision were evaluated,
and the relative standard deviation is below 5%. The limit of detection
for the metastable form was determined by monitoring the ratio of
characteristic peaks when increasing the percentage of the metastable
form in the total amount of crystals in the solution. A significant
change in the peak ratio is observed when 22.9% of the crystals are
of the metastable form. In addition, this PAT method was used to monitor
a continuous run for 10 residence times, in which the system reached
a controlled state of operation after six residence times.
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