02114nas a2200133 4500008004100000245008800041210006900129260002800198520157300226100002001799700002001819700002201839856011901861 2019 eng d00aPopulation balance-enabled model for batch and continuous crystallization processes0 aPopulation balanceenabled model for batch and continuous crystal bJohn Wiley & Sons, Inc.3 a

Crystallization is a critical unit operation in manufacturing of various active pharmaceutical ingredients and drugs. Irrespective of the large-scale use of crystallization in pharmaceutical manufacturing industry, crystallization is still considered as an art. Recently, quality by design (QbD) is gaining industry acceptance as an approach toward development and commercialization of the pharmaceutical drug molecules. In QbD, the unit operations and the process are designed and controlled to deliver specified quality attributes consistently. The proposed chapter is motivated by the necessity of the prediction of crystallization events like onset of the crystallization, nucleation, and growth during crystallization of active pharmaceutical ingredients. The chapter demonstrates the integrated use of population balance modeling framework for developing a fundamental understanding of the kinetic aspects of crystallization and correlating the developed understanding for scale-up and design for the crystallization processes. Efforts are made to discuss the impact of various critical process parameters like metastable zone width, scale effects, and residence time on crystal size during batch and continuous modes with the help of couple of case studies. The presented model and approach will be useful for implementing QbD for crystallizers.

1 aPandit, Ajinkya1 aBhambure, Rahul1 aRanade, Vivek, V. uhttps://library.ncl.res.in/content/population-balance-enabled-model-batch-and-continuous-crystallization-processes02312nas a2200217 4500008004100000022001400041245011500055210006900170260000800239490000700247520154500254653002501799653001901824653001401843653001401857100002901871700001901900700002001919700002701939856012801966 2023 eng d a1860-676800aPost-refolding stability considerations for optimization of in-vitro refolding: L-asparaginase as a case study0 aPostrefolding stability considerations for optimization of invit cAPR0 v183 a

BackgroundL-Asparaginase is an essential enzyme for the food and biopharmaceutical industry. The stability, however, of L-asparaginase is widely known to be an issue. Commercial manufacturing of any biopharmaceutical involves hold-ups during processing, and can result in product loss if stability is an issue, as is the case with L-asparaginase. This interplay of product intermediate stability and process design is the focus of this investigation. Methods and ResultsIn this study, we propose a strategy to simultaneously increase the refolding yield and stability of refolded L-asparaginase so as to improve overall process yield. Using one variable at a time (OVAT) experiments, urea (6 M), solubilized inclusion bodies (15 mg/ml), refolding method (step dilution), and pH (8.6) were identified as significant process parameters. A design of experiment (DOE)-based optimization was then performed for the refolding step. The net outcome was more than a three-fold increase in enzyme recovery (i.e., 4.90 IU/ml) compared to unoptimized conditions (i.e., 1.26 IU/ml). Further, the L-asparaginase process intermediate was found to be stable for more than a week at room temperature and 2-8 degrees C, while the unoptimized sample was stable at 2-8 degrees C but did not show any activity at room temperature after 72 h. ConclusionsThe current study elucidates how process intermediate stability needs to be given due consideration during process optimization, particularly for products such as L-asparaginase which are labile.

10adesign of experiment10aL-asparaginase10arefolding10astability1 aMihooliya, Kanti, Nandan1 aNitika, Nitika1 aBhambure, Rahul1 aRathore, Anurag, S. S. uhttps://library.ncl.res.in/content/post-refolding-stability-considerations-optimization-vitro-refolding-l-asparaginase-case