Processes 2018, 6,82
Research and Development (R&D) performances of 12 major biopharmaceutical companies. The rate
of return declined from 10.1% in 2010 to 3.7% in 2016 [5]. The response of the industry has been mainly
strategic [6]. The industry has tried to increase the value of the drug pipeline through mergers and
acquisitions and the identification of priority customers and emerging markets. It also has pursued
a reduction in the cost of launching new assets by developing explicit therapy area focus, balancing
in-house and outsourced activities, defining specific missions for the enterprise, utilization of new
technologies and advanced analytics in R&D, and data exploitation.
Fulfilling strategic plans depends on the execution of tactical decisions [7]. For example, strategic
R&D management involves project selection, budgeting, and commercialization, while tactical R&D
addresses the scheduling and resource management necessary for the accomplishment of the project.
Integrated decision-making as a means for efficient use of data and knowledge has been highlighted
in the “National Strategic Plan for Advanced Manufacturing” published by the Executive Office
of the President in 2012. Enterprise-wide decision-making demands the integration of operational
activities of planning, scheduling, and control [8]. Control of unit operations needs mechanistic models.
These models capture complex reactions and transport phenomena and may demand many CPU
hours due to heterogeneity and dynamics of certain systems. Maintaining computational feasibility
has been approached by substituting the original detailed model with a reduced model. Reduced
models have been developed either by reduction of the order of the model based on evaluation of
the significance of its components or development of surrogate models using data obtained through
careful experimental design.
1.2. Bioreactor
The goal in the operation of a bioreactor is to enhance the growth, viability, and productivity of
organisms by adjusting their environment. Figure 1 presents a cause and effect diagram of bioreactor
operation. The main operational parameters are impeller rotation speed, gas sparging flow rate, pH,
and temperature. Inefficient mixing creates spatial gradients in mechanical shear, volume fraction of gas
phase, dissolved oxygen (DO), carbon dioxide and metabolites concentrations, pH, and temperature.
As organisms move inside the reactor they experience fluctuations in environmental conditions that
affect metabolism, yield, and quality of product [9]. Due to low solubility in water, high densities of
organisms quickly consume all the oxygen in a saturated culture and produce enough carbon dioxide
to have inhibitory effects. Therefore, the addition and removal of gases are inevitable parts of fermenter
operation. Bioreactor systems can operate under different modes: batch, fed-batch, continuous, and
perfusion [10]. Considerations regarding the set-up, operation, and control of bioreactors can be found
in the literature [11–15].
The environment refers to the physical and chemical stimuli acting on organisms. Physical
stimuli of bubble size distribution and dissipation rate of energy directly affect the viability of cells.
Hydrodynamic forces acting on an organism can be quantified using shear stress and energy dissipation
rate. Some of the effects of mechanical stress are lysis, change in distribution and number of surface
receptors, alteration in production of specific proteins, rate of DNA synthesis, rate of certain metabolic
processes, and induction of apoptosis [16]. Chemical stimuli include concentrations of metabolites (e.g.,
glucose, glutamine, lactate, and ammonia), dissolved oxygen concentration, and pH. Concentrations
of other supplements that have functions such as species transport enhancement, growth stimulation,
shear protection, and surface charge modification can also be considered. The dynamics of organisms
and environment interaction should be modeled based on an understanding of the response times
of biological and physical mechanisms. Prokop compared the characteristic times of physical and
biological mechanisms [17]. Characteristic time is a measure of the time needed by the mechanism to
smooth out a change to a certain extent. It was observed that physical mechanisms of mixing, oxygen
transfer to the liquid phase, and diffusion are faster compared to the biological mechanisms of oxygen
and substrate consumption.
115
Research and Development (R&D) performances of 12 major biopharmaceutical companies. The rate
of return declined from 10.1% in 2010 to 3.7% in 2016 [5]. The response of the industry has been mainly
strategic [6]. The industry has tried to increase the value of the drug pipeline through mergers and
acquisitions and the identification of priority customers and emerging markets. It also has pursued
a reduction in the cost of launching new assets by developing explicit therapy area focus, balancing
in-house and outsourced activities, defining specific missions for the enterprise, utilization of new
technologies and advanced analytics in R&D, and data exploitation.
Fulfilling strategic plans depends on the execution of tactical decisions [7]. For example, strategic
R&D management involves project selection, budgeting, and commercialization, while tactical R&D
addresses the scheduling and resource management necessary for the accomplishment of the project.
Integrated decision-making as a means for efficient use of data and knowledge has been highlighted
in the “National Strategic Plan for Advanced Manufacturing” published by the Executive Office
of the President in 2012. Enterprise-wide decision-making demands the integration of operational
activities of planning, scheduling, and control [8]. Control of unit operations needs mechanistic models.
These models capture complex reactions and transport phenomena and may demand many CPU
hours due to heterogeneity and dynamics of certain systems. Maintaining computational feasibility
has been approached by substituting the original detailed model with a reduced model. Reduced
models have been developed either by reduction of the order of the model based on evaluation of
the significance of its components or development of surrogate models using data obtained through
careful experimental design.
1.2. Bioreactor
The goal in the operation of a bioreactor is to enhance the growth, viability, and productivity of
organisms by adjusting their environment. Figure 1 presents a cause and effect diagram of bioreactor
operation. The main operational parameters are impeller rotation speed, gas sparging flow rate, pH,
and temperature. Inefficient mixing creates spatial gradients in mechanical shear, volume fraction of gas
phase, dissolved oxygen (DO), carbon dioxide and metabolites concentrations, pH, and temperature.
As organisms move inside the reactor they experience fluctuations in environmental conditions that
affect metabolism, yield, and quality of product [9]. Due to low solubility in water, high densities of
organisms quickly consume all the oxygen in a saturated culture and produce enough carbon dioxide
to have inhibitory effects. Therefore, the addition and removal of gases are inevitable parts of fermenter
operation. Bioreactor systems can operate under different modes: batch, fed-batch, continuous, and
perfusion [10]. Considerations regarding the set-up, operation, and control of bioreactors can be found
in the literature [11–15].
The environment refers to the physical and chemical stimuli acting on organisms. Physical
stimuli of bubble size distribution and dissipation rate of energy directly affect the viability of cells.
Hydrodynamic forces acting on an organism can be quantified using shear stress and energy dissipation
rate. Some of the effects of mechanical stress are lysis, change in distribution and number of surface
receptors, alteration in production of specific proteins, rate of DNA synthesis, rate of certain metabolic
processes, and induction of apoptosis [16]. Chemical stimuli include concentrations of metabolites (e.g.,
glucose, glutamine, lactate, and ammonia), dissolved oxygen concentration, and pH. Concentrations
of other supplements that have functions such as species transport enhancement, growth stimulation,
shear protection, and surface charge modification can also be considered. The dynamics of organisms
and environment interaction should be modeled based on an understanding of the response times
of biological and physical mechanisms. Prokop compared the characteristic times of physical and
biological mechanisms [17]. Characteristic time is a measure of the time needed by the mechanism to
smooth out a change to a certain extent. It was observed that physical mechanisms of mixing, oxygen
transfer to the liquid phase, and diffusion are faster compared to the biological mechanisms of oxygen
and substrate consumption.
115