Active pharmaceutical ingredient (API) production involving continuous processes - A process system engineering (PSE)-assisted design framework
Department of Chemical and Biochemical Engineering, Technical University of Denmark (DTU), Building 229, DK-2800 Kgs. Lyngby, Denmark.European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V (Impact Factor: 3.38). 07/2012; 82(2):437-56. DOI: 10.1016/j.ejpb.2012.07.001
A systematic framework is proposed for the design of continuous pharmaceutical manufacturing processes. Specifically, the design framework focuses on organic chemistry based, active pharmaceutical ingredient (API) synthetic processes, but could potentially be extended to biocatalytic and fermentation-based products. The method exploits the synergic combination of continuous flow technologies (e.g., microfluidic techniques) and process systems engineering (PSE) methods and tools for faster process design and increased process understanding throughout the whole drug product and process development cycle. The design framework structures the many different and challenging design problems (e.g., solvent selection, reactor design, and design of separation and purification operations), driving the user from the initial drug discovery steps - where process knowledge is very limited - toward the detailed design and analysis. Examples from the literature of PSE methods and tools applied to pharmaceutical process design and novel pharmaceutical production technologies are provided along the text, assisting in the accumulation and interpretation of process knowledge. Different criteria are suggested for the selection of batch and continuous processes so that the whole design results in low capital and operational costs as well as low environmental footprint. The design framework has been applied to the retrofit of an existing batch-wise process used by H. Lundbeck A/S to produce an API: zuclopenthixol. Some of its batch operations were successfully converted into continuous mode, obtaining higher yields that allowed a significant simplification of the whole process. The material and environmental footprint of the process - evaluated through the process mass intensity index, that is, kg of material used per kg of product - was reduced to half of its initial value, with potential for further reduction. The case-study includes reaction steps typically used by the pharmaceutical industry featuring different characteristic reaction times, as well as L-L separation and distillation-based solvent exchange steps, and thus constitutes a good example of how the design framework can be useful to efficiently design novel or already existing API manufacturing processes taking advantage of continuous processes.
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ABSTRACT: The current trend in the pharmaceutical industry to move from batch-wise to continuous production processes strengthens the need for monitoring and controlling the process in-line. The ConsiGma™ continuous tableting line collects data of the different subunits in real-time, but these are not really used. In this paper the data of the six-segmented fluidized bed dryer in the line are used for the development and evaluation of a mass and energy balance. The objectives are multiple: (1) prediction of the moisture content of the granules leaving the dryer solely based on the currently logged data and (2) prediction of the gas outlet temperature to check the mass balances. Once a validated system is established the gas temperature in different horizontal sections of the drying unit can be predicted. Calculations are also used to identify errors in the system and to propose alternative sensor locations. A calibration is performed in order to predict the evaporation rate. The balances were able to predict both the moisture content of the granules at the end of the drying process and the gas outlet temperature quite accurately. Combining the gathered information with the height of the bed in the fluidized bed can be used to predict the gas temperature in different horizontal sections of the dryer. An extra sensor measuring the gas temperature and the humidity at the wet transfer line would increase the accuracy of the calculations. An extra gas velocity sensor at the outlet would be useful to incorporate an extra supervision of the calculations.
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ABSTRACT: This work presents a mathematical approach to make the most efficient use of historical data from development experiments (or commercial manufacture) to select the ingredients for the composition of a new product or to select the materials from inventory for the manufacture of a new lot of finished product The method relies in the construction of a latent variable regression model that will serve to predict the result of combining certain materials. This predictive model is then embedded into an optimization framework to find the best combination among the pool of available materials according to a well-defined objective and subject to the predefined constraints. The framework is illustrated with two successful applications: the selection of the formulation and process for the design of a new solid oral drug product with high drug concentration and a continuous improvement project in Commercial manufacture seeking to select the optimal set of lots of raw materials from the inventory to be mixed together in the manufacture a new lot for a controlled release product, given certain targets of dissolution levels and subject to material availability.
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ABSTRACT: The manufacturing of pharmaceutical dosage forms, which has traditionally been a batch-wise process, is now also transformed into a series of continuous operations. Some operations such as tabletting and milling are already performed in continuous mode, while the adaptation towards a complete continuous production line is still hampered by complex steps such as granulation and drying which are considered to be too inflexible to handle potential product change-overs. Granulation is necessary in order to achieve good flowability properties and better control of drug content uniformity. This paper reviews modelling and supporting measurement tools for the high shear wet granulation (HSWG) process, which is an important granulation technique due to the inherent benefits and the suitability of this unit operation for the desired switch to continuous mode. For gaining improved insight of the complete system, particle-level mechanisms are required to be better understood, and linked with an appropriate meso- or macro-scale model. A brief review has been provided to understand the mechanisms of the granulation process at micro or particle-level such as those involving wetting and nucleation, aggregation, breakage and consolidation. Further, population balance modelling (PBM) and the discrete element method (DEM), which are the current state-of-the-art methods for granulation modelling at micro- to meso-scale, are discussed. The DEM approach has a major role to play in future research as it bridges the gap between micro- and meso-scales. Furthermore, interesting developments in the measurement technologies are discussed with a focus towards inline measurements of the granulation process to obtain experimental data which are required for developing good models. Based on the current state of the developments, the review focuses on the twin screw granulator as a device for continuous HSWG and attempts to critically evaluate the current process. As a result, a set of open research questions are identified. These questions need to be answered in the future in order to fill the knowledge gap that currently exists both at micro- and macro-scale, and which is currently limiting the further development of the process to its full potential in pharmaceutical applications.
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