Processes2013, 1(3), 330-348; doi:10.3390/pr1030330 - published online 29 November 2013 Show/Hide Abstract
Abstract: The judicious use of buffering capacity is important in the development of future continuous pharmaceutical manufacturing processes. The potential benefits are investigated of using optimal-averaging level control for tanks that have buffering capacity for a section of a continuous pharmaceutical pilot plant involving two crystallizers, a combined filtration and washing stage and a buffer tank. A closed-loop dynamic model is utilized to represent the experimental operation, with the relevant model parameters and initial conditions estimated from experimental data that contained a significant disturbance and a change in setpoint of a concentration control loop. The performance of conventional proportional-integral (PI) level controllers is compared with optimal-averaging level controllers. The aim is to reduce the production of off-spec material in a tubular reactor by minimizing the variations in the outlet flow rate of its upstream buffer tank. The results show a distinct difference in behavior, with the optimal-averaging level controllers strongly outperforming the PI controllers. In general, the results stress the importance of dynamic process modeling for the design of future continuous pharmaceutical processes.
Processes2013, 1(3), 312-329; doi:10.3390/pr1030312 - published online 22 November 2013 Show/Hide Abstract
Abstract: This paper presents a study based on real plant data collected from chiller plants at the University of Texas at Austin. It highlights the advantages of operating the cooling processes based on an optimal strategy. A multi-component model is developed for the entire cooling process network. The model is used to formulate and solve a multi-period optimal chiller loading problem, posed as a mixed-integer nonlinear programming (MINLP) problem. The results showed that an average energy savings of 8.57% could be achieved using optimal chiller loading as compared to the historical energy consumption data from the plant. The scope of the optimization problem was expanded by including a chilled water thermal storage in the cooling system. The effect of optimal thermal energy storage operation on the net electric power consumption by the cooling system was studied. The results include a hypothetical scenario where the campus purchases electricity at wholesale market prices and an optimal hour-by-hour operating strategy is computed to use the thermal energy storage tank.
Processes2013, 1(3), 296-311; doi:10.3390/pr1030296 - published online 11 October 2013 Show/Hide Abstract
Abstract: Chinese hamster ovary (CHO) cells are a source of multi-ton quantities of protein pharmaceuticals. They are, however, immortalized cells, characterized by a high degree of genetic and phenotypic diversity. As is known for any biological system, this diversity is enhanced by selective forces when laboratories (no sharing of gene pools) grow cells under (diverse) conditions that are practical and useful. CHO cells have been used in culture for more than 50 years, and various lines of cells are available and have been used in manufacturing. This article tries to represent, in a cursory way, the history of CHO cells, particularly the origin and subsequent fate of key cell lines. It is proposed that the name CHO represents many different cell types, based on their inherent genetic diversity and their dynamic rate of genetic change. The continuing remodeling of genomic structure in clonal or non-clonal cell populations, particularly due to the non-standardized culture conditions in hundreds of different labs renders CHO cells a typical case for “quasispecies”. This term was coined for families of related (genomic) sequences exposed to high mutation rate environments where a large fraction of offspring is expected to carry one or more mutations. The implications of the quasispecies concept for CHO cells used in protein manufacturing processes are significant. CHO genomics/transcriptomics may provide only limited insights when done on one or two “old” and poorly characterized CHO strains. In contrast, screening of clonal cell lines, derived from a well-defined starting material, possibly within a given academic or industrial environment, may reveal a more narrow diversity of phenotypes with respect to physiological/metabolic activities and, thus, allow more precise and reliable predictions of the potential of a clone for high-yielding manufacturing processes.
Processes2013, 1(3), 279-295; doi:10.3390/pr1030279 - published online 11 October 2013 Show/Hide Abstract
Abstract: This work describes how the design and operation parameters of the Multi-Stage Flash (MSF) desalination process are optimised when the process is subject to variation in seawater temperature, fouling and freshwater demand throughout the day. A simple polynomial based dynamic seawater temperature and variable freshwater demand correlations are developed based on actual data which are incorporated in the MSF mathematical model using gPROMS models builder 3.0.3. In addition, a fouling model based on stage temperature is considered. The fouling and the effect of noncondensable gases are incorporated into the calculation of overall heat transfer co-efficient for condensers. Finally, an optimisation problem is developed where the total daily operating cost of the MSF process is minimised by optimising the design (no of stages) and the operating (seawater rejected flowrate and brine recycle flowrate) parameters.
Processes2013, 1(3), 263-278; doi:10.3390/pr1030263 - published online 30 September 2013 Show/Hide Abstract
Abstract: The nonlinear behavior of metabolic systems can arise from at least two different sources. One comes from the nonlinear kinetics of chemical reactions in metabolism and the other from nonlinearity associated with regulatory processes. Consequently, organisms at a constant growth rate (as experienced in a chemostat) could display multiple metabolic states or display complex oscillatory behavior both with potentially serious implications to process operation. This paper explores the nonlinear behavior of a metabolic model of Escherichia coli growth on mixed substrates with sufficient detail to include regulatory features through the cybernetic postulate that metabolic regulation is the consequence of a dynamic objective function ensuring the organism’s survival. The chief source of nonlinearity arises from the optimal formulation with the metabolic state determined by a convex combination of reactions contributing to the objective function. The model for anaerobic growth of E. coli was previously examined for multiple steady states in a chemostat fed by a mixture of glucose and pyruvate substrates under very specific conditions and experimentally verified. In this article, we explore the foregoing model for nonlinear behavior over the full range of parameters, γ (the fractional concentration of glucose in the feed mixture) and D (the dilution rate). The observed multiplicity is in the cybernetic variables combining elementary modes. The results show steady-state multiplicity up to seven. No Hopf bifurcation was encountered, however. Bifurcation analysis of cybernetic models is complicated by the non-differentiability of the cybernetic variables for enzyme activities. A methodology is adopted here to overcome this problem, which is applicable to more complicated metabolic networks.
Processes2013, 1(3), 238-262; doi:10.3390/pr1030238 - published online 30 September 2013 Show/Hide Abstract
Abstract: Composite membranes with stimuli-responsive properties can be made by coating a thermo-responsive hydrogel onto a micro- or macroporous support. These hydrogels undergo a temperature induced volume-phase transition, which contributes towards the composite membrane’s stimuli-responsive properties. This paper reviews research done on complimentary forms of temperature responsive “thermophilic” hydrogels, those exhibiting positive volume-phase transitions in aqueous solvent. The influences of intermolecular forces on the mechanism of phase-transition are discussed along with case examples of typical thermophilic hydrogels.