Application of process analytical technology-based feedback control strategies to improve purity and size distribution in biopharmaceutical crystallization

Purity is a critical quality attribute for both pharmaceutical and biopharmaceutical products. The presence of impurities (solvents, salts, or byproducts of the synthetic path) in drugs can cause a reduction of their effectiveness or can even be toxic for the patients. Biopharmaceuticals are produced by biological processes which are difficult to control. Therefore, the amount of impurities that has to be removed can be significantly higher than in the case of synthetic pharmaceuticals. The aim of this work is to exploit process analytical technology tools and different feedback control strategies (T-control, direct nucleation control, and supersaturation control) for the crystallization of a biopharmaceutical product. UV/vis spectroscopy and focused beam reflectance measurement combined with a Crystallization Process Informatics System (CryPRINS) were used to improve the crystal size distribution and purity of crystallized vitamin B12. The different feedback control strategies were compared to classical crystallization techniques in terms of purity of the final crystal and quality of the crystal size distribution, and it is shown that using suitable crystallization feedback control strategies, the purity and quality of crystals can be improved.