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PROCESS SYSTEMS ENGINEERING TOOLS IN THE
PHARMACEUTICAL INDUSTRY
Abstract
The purpose of this paper is to provide a summary of the current state of the application of
process systems engineering tools in the pharmaceutical industry. In this paper, we present the
compiled results of an industrial questionnaire submitted to pharmaceutical industry
professionals. The topics covered in the questionnaire include process analytics, process
monitoring, plant-wide information systems, unit operation modeling, quality control, and
process optimization. A futuristic view of what process systems engineering tools will enable
the pharmaceutical industry will be also be presented. While the industry is regularly using the
traditional Design of Experiments approach to identify key parameters and to define control
spaces, these approaches result in passive control strategies that do not attempt to compensate
for disturbances. Special new approaches are needed for batch processes due to their essential
dependence on time-varying conditions. Lastly, we briefly describe a novel data driven
modeling approach, called Design of Dynamic Experiments that enables the optimization of
batch processes with respect to time-varying conditions through an example of a simulated
chemical reaction process. Many more approaches of this type are needed for the calculation
of the Design and Control Spaces of the process, and the effective design of feedback systems.
Keywords
INTRODUCTION
eight years since "PAT A Framework for
Almost a decade has elapsed since the FDA
innovative Pharmaceutical Manufacturing and
publication "Pharmaceutical cGMPs for the 21st
Quality Assurance" were issued. Much progress
Century: A Risk-Based Approach" and almost
and innovation in pharmaceutical manufacturing
* To whom all correspondence should be addressed (gregory_troup@merck.com). Inquires about the Design of Dynamic Experiments
methodology should be addressed to the second author (christos.georgakis@tufts.edu).
Troup & Georgakis, 2012 CPC
has occurred since the publication of these Table 1. Profile of Participating Companies (from
landmark documents. For example, Wikipedia): Number of employee and revenue data
pharmaceutical companies have readily adopted (US dollars)
in-process measurements systems, such as near Abbreviations: BPh is Biopharmaceutical, Pha is
infrared spectroscopy for concentration, and pharmaceutical, CR is contract research, B is billions, M is
millions. Superscripts: a is data from 2010, b is data from 2009, c
focused beam reflectance measurements for data from Oregon business.com
estimation of particle size distribution. The
application of multivariate process monitoring for Company Category Employees,
real time fault detection and isolation has also Revenue
found it's way into pharmaceutical manufacturing. Alkermes BPh 610, 178Ma
The industry has moved away from quality control Johnson & Johnson Pha 114,00, 61.6Ba
strategies based on uni-variate parameters
Bend Research CR 159, ~30Mb,c
specifications, and towards the multivariate design
space approach. While, tremendous progress has Bristol-Myers Squibb Pha 28,000, 18.8Bb
been achieved in the decade, there is work to be Merck Pha 94,000, 46.0Ba
done to realize the full potential of the process Cephalon BPh 3700, 2.8Ba
systems engineering (PSE) toolbox. Eli Lilly Pha 38,350, 23.1Ba
The purpose of the paper is to describe the Pfizer Pha 110,600, 67.8Ba
current state of the art of the application of PSE Vertex Pha 1,800, 102M b
tools in the pharmaceutical industry. The sub
areas of PSE discussed in this work are process
analytical technology (PAT) measurement The paper is organized as follows, for each of
systems, process monitoring, plant wide the sub areas of PSE covered; we provide a brief
information technology systems, process control, background on how PSE tools are currently used
modeling, and optimization methodologies. This in the pharmaceutical industry. Where possible,
paper focuses on PSE applications primarily literature references have been provided, with a
related to active pharmaceutical ingredient (API), preference towards papers published by
and solid oral dosage manufacturing. Details on pharmaceutical industry professionals. The
the application of PAT measurement systems, and questionnaire results pertaining to each PSE area
process control in biologics are out of scope of this are presented at the end of each section. We then
work, for readers interested in biologics PSE discuss the impact of increased out-sourcing of
applications we are listing a few relevant review product development and manufacturing and the
papers1, 2. prospect of continuous processes on the future
To augment information available in the open utilization of PSE tools. Lastly, we present the
literature, we conducted an industrial application of a novel method for batch process
benchmarking survey on the above-mentioned optimization called dynamic design of
PSE sub areas that contained twenty-one questions experiments. A simulated API synthesis reaction
in totala. The survey was submitted to current process is used to explain the method.
pharmaceutical industry professionals in all areas
of the industry: active pharmaceutical ingredient, THE CURRENT STATE OF PSE TOOLS IN PHARMA
solid oral dosage, and biologics, in both We describe the current state of the utilization
development and manufacturing. The companies PSE tools in the pharmaceutical industry. The sub
that submitted responses to the survey are listed in areas of PSE discussed are measurement systems,
Table 1. multivariate process monitoring, plant wide
information systems, and process control and
optimization methodologies. The results of this
section are a combination of work documented in
the literature by authors in the pharmaceutical
a Blank questionnaires are available upon request from the
industry, and the results of the industrial
benchmarking survey.
authors, see author contact information on the title page.
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Troup & Georgakis, 2012 CPC
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Troup & Georgakis, 2012 CPC
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Troup & Georgakis, 2012 CPC
high frequency measurements are not needed at depending on particle size. Traditional sensors,
this stage. In manufacturing, in-line NIR methods such as temperature, pressure, and spray rate, tell
are used for drying end-point determination31 and the story for spray drying processes, and additional
process optimization32, in this scenario the real instrumentation is often not applied during
time measurement system is valuable. At-line manufacturing operations.
method for drying end-point determination in
Compression
manufacturing are time consuming, because
sampling often requires collapsing the bed during For the tablet compression unit operation, a
at-line analysis to avoid over drying. Similar to state of the art process analytical system would
drying equipment, scale up of fluid bed operations include an at-line tablet method38, 39 for API
is challenging, therefore in-line method concentration measurements. Ideally, this would
development is often deferred until full-scale be coupled with a simultaneous measurement of
operations where the method implementations tablet mass, to provide tablet assay and API
have more impact. content uniformity information. In-line NIR
measurements systems for real time segregation
Hot Melt Extrusion
monitoring in the feed frame of a tablet press are
In hot melt extrusion, the state of the art in also available and in use40. For many
process analytical tools includes the use of in-line pharmaceutical products, compression is the last
spectroscopy such as NIR33, and Raman34 for processing step, only to be followed by release
multi-component compositional monitoring. In testing and packaging.
process development and scale up, the
Film Coating
spectroscopic in-line compositional methods are
used for determination of residence time Film coating is generally considered
distributions, process characterization, and system undesirable from a cost and cycle time
identification35, 36. In a manufacturing setting perspective, and is only used when the product
these tools are used for continuous verification requires it. Film coating is applied to tablets to
that the process is producing material at the target function as a taste-masking agent, to provide
composition, and for real time isolation of off protection from light. Tablets are sprayed with a
specification product due to disturbances from the coating suspension until a desired weight gain has
feeding systems. Commercial extruders come been achieved. The traditional quality metrics of
with melt temperature, die pressure, and torque the process are coating weight uniformity, and
sensors. These measurements combined with tablet elegance. In some cases, the API is in the
spectroscopic systems are amenable to coating of the tablet, and at-line API concentration
multivariate control charting for fault detection36. and uniformity measurements can be made with
Additionally, in-line/on-line visible spectroscopy spectroscopy techniques, such as NIR.
has potential for monitoring of degradation37 and Process Analytical Technology Measurement System
extrudate color, if color matching is important for Questionnaire Results
the product.
The results of our industrial benchmarking
Spray Drying survey indicate that all of the responding
Spray drying is a unit operation where off-line companies actively use the measurement systems
characterization tools are used extensively during described above, with an emphasis on
development to develop process understanding, spectroscopic tools such as NIR, Raman, MidIR,
and then the knowledge is deployed in and particle size measurements with FBRM
manufacturing. Spray dried intermediates are systems. The majority, 75%, of the responding
typically tested for particle morphology, chemical companies indicated that these tools were
and physical stability, and bio performance. These primarily used in research and development and
attributes are difficult to measure, estimate, or not deployed into routine manufacturing
correlate with data from in-line instrumentation. operations, with the remaining 25%, reporting
In-line measurement systems that could determine routine use in manufacturing. Dedicated process
characteristics of the spray zone may be of value. analytical technology groups exist in 75% of the
There is also some potential for in-line/at-line participated companies, with the mean group size
particle size distribution measurement systems, of 86 people, with additional people fractionally
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Troup & Georgakis, 2012 CPC
dedicated to the PAT effort. Figure 1, shows a available. Table 2 presents some examples of
breakdown of how the participating companies are commercially available run time multivariate
applying PAT measurements systems. Process process monitoring technology products. Most of
monitoring is the largest reported use, with 75% of these products listed utilize latent variable
and product release testing and process control are methods (PCA, PLS), and descriptive statistics,
the least reported applications of the tools. but other types of analysis are possible, such as
neural networks, cluster analysis, and tree
methods.
Reported Application of PAT Measurement Systems
Table 2. Example Real Time Multivariate
100%
Process Monitoring and Predictive Analytics
% of Responding Compaines
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Troup & Georgakis, 2012 CPC
that descriptive statistical analysis of plant some cases can developed for the real time
historical data was practiced. Most, 67% of the prediction of product quality attributes. Figure 3,
industrial responders reported using a real time shows a block diagram of the data streams and
multivariate process monitoring technology information flows handled by plant wide
product. A breakdown of the products reported to information systems with real time multivariate
be in use are shown in Figure 2. The same process monitoring and predictive analytics. To
percentage, 67%, indicated that multivariate handle process data streams shown in Figure 3, a
analysis tools (principle components analysis and plant wide information systems must be able to
partial least squares) are used to analyze historical accept a variety of data types (scalar, vector, text,
process and plant data. continuous, discrete), and coming at a variety of
frequencies. The data needs to be formatted for
Reported Use of Run Time Multivariate Process Monitoring Tools
analysis. Before predictive analytics computations
100% can be preformed, the data must be cleaned and
% of Responding Compaines
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Troup & Georgakis, 2012 CPC
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Troup & Georgakis, 2012 CPC
advantages. Additionally, the overwhelming that the models are not fully transferrable between
response was that fundamental models offered sites and scale of unit operations. Model
increased process understanding, were robust, and development takes a lot of effort in sample
allowed extrapolation in many cases. The generation, data aggregation, and analytical
disadvantages of fundamental models reported testing. Data-driven models cannot be
were that the effort and time to develop them is extrapolated beyond their validated limits.
prohibitive, they require modeling expertise, Additionally, data-driven models have to be
model validation is resource extensive, and that coupled with physical observations of the process
model assumptions are often not consistent with and products. Instrument sensitivity and data
full scale process operating conditions. acquisition noise need to be understood to develop
robust models. No mechanistic understanding is
Reported Percentage of Process Unit Operations With Fundamental Models
obtained, and it is difficult to physically or
Percentage of Companies Reporting
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Troup & Georgakis, 2012 CPC
reported applying the modeling approaches shown only the feasible region is defined. Additionally,
in Figure 6 on the individual unit operation level, in the pharmaceutical industry the objective
while 33% reported modeling on the plant functions are usually solely based on product
wide/entire process train level. quality attributes, and not economic
considerations.
Quality Control: From Univariate Specifications to
the Multivariate Design Space Concept An example approach to design/control space
Historically, in the pharmaceutical industry development and definition could include a risk
the approach to process control was defining analysis tool to indentify material and process
univariate raw material attributes ranges and variables that potentially could affect quality for
process equipment parameters ranges. The the specific product, then some initial screening
process was validated by executing three batches. DOEs to verify main effects and interactions of the
They were at one-tenth commercial batch scale, candidate variables. Followed by response surface
with extensive analytical testing at each process DOEs, such as Box-Behnken, and Central
step. If the results of the three batches were within Composite designs for example, conducted on key
the pre defined acceptable ranges, then the process variables and attributes for optimization and
was considered validated. A validated process determination of the design spaces for the
could be run with only end-product release testing. individual unit operations. It is theoretically
If raw material attributes or process changes were possible to extend response surface methodology
introduced, the entire process would often need to to an entire process train. The choice of risk
be re-validated by the same protocol as described management tools and design space definition are
above. Process optimization activities were largely left to drug producers to decide.
completed in development, before process Process Modeling Questionnaire Results
validation. This mode of quality control was the
Of the companies surveyed, 67% reported
norm in the pharmaceutical industry for decades.
using the multivariate design space approach to
While this approach to process control has quality control for all new products. The design
been demonstrated to be both feasible and capable spaces include raw materials and process
of producing/ensuring quality pharmaceutical parameters. These companies report the use of
products, it created an environment where the design space strategies to identify a robust area of
communication of technical process/product operation with respect to all major disturbances to
knowledge between drug producers and the the process. Augmented, with empirical models to
regulatory agencies was reduced. (i.e., if the relate input and process variables to end-product
processes were truly robust, this information was performance, manufacturability and stability.
not conveyed to the regulatory agencies in a Individual parameter specification or control is
systematic and understandable way). This was used to maintain operation in a robust space to
perceived as an obstacle to initiating post-approval ensure end-product quality. The process can only
process changes, and potentiality limiting process operate under known and measured input
improvements. The FDA's PAT/QbD initiatives conditions. One potential shortcoming in most
promoted the use of risk analysis tools and the companies application of the design space
process design/control space approach. The approach is that it results in passive and potentially
Design/Control Space concept is similar to the restrictive quality control policy. Disturbances are
Feasible Region Concept in the classical process not compensated for by manipulated variable
optimization literature. A related but more moves, and the process is operated in a smaller
appropriate concept is that of process operability44- control space then it is capable of operating. The
54
. This concept, initially developed for continuous idea that there is an optimal pairing of process
processes, starts from an estimated range of the parameters to respond to different process inputs is
process disturbances and calculates the desired not leveraged to reduce product variability and to
ranges of the control variables so that a control enable a larger operating space55. Most companies
strategy can ensure that the product qualities are are currently seeking to find one set of process
within the acceptable range. Although, an actual conditions that can ensure product quality over a
optimal run condition is not typically computed,
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Troup & Georgakis, 2012 CPC
pre-defined range of process inputs (process cost, and in most cases lower technology facilities.
operability). This outsourcing trend is both a set back and an
opportunity for PSE tools. In the short term,
When asked about the potential benefits of
products that are developed and manufactured
dynamic control strategies (advanced process
outside of innovator companies will not have PSE
control) that actively seek to control end-product
tools applied to them or even be developed and
quality, by reducing variability, and enabling
manufactured in a true Quality by Design fashion.
larger operating space, responding companies
A future speculation would be that this would
indicated that these approaches would be
eventually be considered unacceptable to
beneficial and consistent with ICH quality
regulatory agencies. It is reasonable to expect that
guidelines. Figure 7 shows a summary of the
eventually CMO will need to invest in PSE tools
reported barriers to advanced process control
to meet customer and regulatory requirements, and
implementations. The overwhelming response is
that competency in their use will be a significant
that engineers and scientists at pharmaceutical
differentiator in the CMO market place.
companies are not familiar with APC techniques,
and the potential benefits are not clear. Lastly, Continuous Processing
50% of the questionnaire respondents reported at
Continuous processing for API manufacturing
lack of predictive models to predict end of batch is not economically feasible for most compounds.
quality attributes from in-process measurements. This is due to the complexity of the chemistries
and the number of synthesis and purification steps
THE FUTURE OF PHARMACEUTICAL
involved in most processes. It is very common to
MANUFACTURING AND PSE TOOLS
have in excess of ten synthesis steps in an API
In this section, we briefly discuss the future manufacturing process. Additionally, the long
trends of contract manufacturing and continuous secondary drying times associated with most
processing in the pharmaceutical industry and their processes are a serious obstacle to fully continuous
impact on the utilization and advancement of PSE API production. The idea of continuous processing
tools. for solid oral dosages is not a novel concept, but
currently is it not widely practiced within the
Summry of reported barriers to APC implementations
pharmaceutical industry. Many individual solid
Percentage of Companies Reporting
100%
oral dosage manufacturing process unit operations
80% are already continuous/semi-continuous, like roller
60% compaction and compression for example. With
40%
the addition of powder feeders and continuous
blending equipment, direct compression and roller
20%
compaction processes could be made fully
0% continuous. Not all products are expected to
Lack of Understanding of Need Demonstration of Lack of models to predict
approach benefits the end quality before the amenable to continuous processing, such as
end of the batch:
products with low drug loads ( ~5wt%), and
products that have extremely poor flowing API.
Figure 7: Summary of reported barriers to advanced
process control implementations.
Additionally, appropriately scaled continuous film
coating equipment is not currently commercially
Contract Manufacturing available, but batch sequencing this unit operation
The services of contract manufacturing with continuous process train seems feasible.
organizations have been utilized by the Adoption of continuous processing for solid oral
pharmaceutical industry for many years. It is dosages would enable the application of traditional
expected that pharmaceutical companies will PSE tools for system identification and process
continue to utilize CMO, and that the fraction of control. This would give the benefits of more
product development and manufacturing work rigorous design space development through
being outsourced will only increase in the coming multivariable system identification techniques.
years. This increase in outsourcing will slow For example, process models could be identified
down the rate of utilization of PSE tools, as using generalized binary noise test protocols that
financial pressures pull manufacturing to lower allow up to ten simultaneous manipulated variable
moves per test condition. The biggest advantage
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Troup & Georgakis, 2012 CPC
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Troup & Georgakis, 2012 CPC
component analysis (PCA) and Partial Least number of interconnected process units, aiming to
Squares or Projection to Latent Structures (PLS) develop a plant-wide DD model. For example, if
have been extensively used. They reduce the the factors are increased to 10, the quadratic RSM
dimensionality of the available data and help model requires 66 (plus 6-10) runs and the cubic
distinguish the informative from the non- RSM 286 (plus 6-10) runs. Consequently, one
informative data segments or variables. They have needs to perform a substantial number of
been used in a variety of situations, as several of experiments in such a limited time window
the references given above demonstrate. Even available for the development of a process to
though they are statistically sound, such tools have manufacture a product that might or might not be
two major limitations. They are linear and they are successful in clinical trials and might or might not
not explicitly dynamic. Contrast this with the be approved by the FDA. To remedy such
nonlinear and dynamic character of the majority of shortcomings, one tries to utilize historical data
pharmaceutical processes that are auto-correlated and experience that, with a much-reduced number
in time. Both batch and continuous pharmaceutical of additional experiments, might provide the
processes can be approximated by linear models if needed coverage of the operating region.
they do not depart substantially from a nominal
Another type of DD nonlinear model that
operating mode. However, recent FDA regulatory
people have explored is that of neural network
guidelines allow the substantial enlargement of the
models. Such models can represent a richer set of
operating window as long we understand the
nonlinearities than the RSM type of models.
consequences on the product quality and we have
However, they require a similar large number of
a reliable approach ensuring that quality attributes
experiments. Despite their substantial promise, no
will remain within their acceptable limits.
systematic statistical analysis tool is available to
Enlargement of the operating window necessitates
assess the accuracy of the developed model in a
the development of nonlinear DD models. This is
similar fashion that the Analysis of Variance does
often achieved by the development of mostly
for RSM modelsb.
quadratic Response Surface Models (RSMs)
related to the methodology of Design of A further restriction of the above-mentioned
Experiments (DoE)56, 57. models is that they do not account explicitly for
the dynamic character of the pharmaceutical
RSM models with higher than quadratic
process unless they are coupled to parameterized
nonlinearities (including cubic, quartic, or higher
dynamic linear models. In the case the process is a
terms) are definitely possible. However, the
batch or semi-batch one, as in happens in the
number of experiments that need to be performed
majority of cases, the dynamic character is a
to estimate the increased number of model
critical one. The same is true when the
constants is often prohibitive. For example, in a
manufacturing process is a continuous one as it
process unit with five input variables (factors in
has started to happen and will happen more
the DoE terminology) that need to be varied, a
frequently in the near future. Without the use of
quadratic RSM model requires a minimum of 21
the most rudimentary data driven (DD) dynamic
experiments for the estimation of all of its
models the systematic design of feedback
parameters while a cubic and a quartic RSM
controllers will be difficult. These feedback
model require 56 and 126 experiments,
controllers are our main mechanism for
respectively. To these experiments one needs to
compensating, using on-line measurements, the
add 3-5 replicated runs for the estimation of the
variability on the input feedstock and the
inherent variability of the process and another 3-5
variability on the operating conditions in order to
runs to assess the lack-of-fit statistic. This last
ensure the desired tight product quality
statistic is often neglected, but it is very useful in
specifications.
providing an assessment whether the estimated
RSM is able to represent the majority of variability
in the data that is not due to inherent experimental
error. The number of experiments increases very b A search in the Web of Science database with Neural
rapidly as the number of input variables or factors networks and Analysis of Variance and Pharmaceutical
increases. This happens when either the process process at the three topics yielded no entry. A search with
unit is more complex or we consider a larger the first and last of the above three topics yielded only 3
publications.
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Troup & Georgakis, 2012 CPC
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Troup & Georgakis, 2012 CPC
However, the true major limitation might be due to dependant function for the decision variable and
the nonlinear character of batch processes and the the performance of the batch is measured at the
lack of modeling approach for the development of end. The data from all the experiments are used to
simple nonlinear dynamic models to be used in the estimate a response surface model from which the
design of these controllers. Here we focus our best time-dependent operation is calculated. The
attention on the task of controlling the end-product detailed explanation of the methodology is given
quality and for this task the Model Predictive elsewhere86. This methodology was been applied
Controller (MPC) would be the most appropriate successfully to a crystallization process87, 88 and a
approach but in conjunction of a simplified pharmaceutical hydrogenation process89. Here we
modeling methodology to lessen the will present the main idea of this methodology
developmental costs. If attention is not focused on through its application to the following simple but
directly controlling the characteristics of the illustrative batch reactor problem.
product, a substitute strategy might be
We will simulate the following reaction
implemented by controlling a surrogate variable,
network, assuming that the reactor temperature
such as temperature, cooling rate, or super-
and volume of the reactor are kept constant.
saturation. This is much easier to affect with
simpler (P, PI or PID) controllers. Their success is Rxn1: A + B C , r1 = k1C AC B
dependent on how close the surrogate variable(s)
is(are) related to the product qualities. with k1 = 2 lt gmol hr 1
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Troup & Georgakis, 2012 CPC
We now define a nominal feeding profile, To satisfy that the w() values are in the (-1, 1)
u0(t), in the same spirit that we defined the interval, we require that:
nominal values of tf and BT. This profile should
1 a0 a1 a2 1 (9)
use the nominal amount of B, 15 gmol, and the
nominal batch time of 1 hr. Then the above Because the experimental region shrinks to zero at
constraining equation is: the end of the batch, we will also impose the
1 following constraint, w(1)=0, which yields:
15 = u0 (t )dt (4)
0 a0 + a1 + a2 = 0 (10)
Besides satisfying the above constraint, we To ensure that the amount of reactant B fed is
have a lot of choices for the selection of u0(t) the desired one, we impose a constraint on the u()
because of its time dependant character. Keeping (or u(t) ) flow rate.
in mind that B is a reactant, we here choose the
simplest meaningful profile; a feeding flow of B tb
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Troup & Georgakis, 2012 CPC
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Troup & Georgakis, 2012 CPC
many aspects to provide for a wide opportunity for Partha Mudipalli, Roger Bakale, Steve Mehrman,
innovative new approaches that have not been Becky Taillon, Trevor Wigle, Dan Dobry, Dafni
considered so far. Bika, Sze Wing Wong, Gert Thurau, Koji Muteki,
and Martin Warman.
ACKNOWLEDGMENTS
The authors would like the thank the following
individuals for providing completed
questionnaires: Hector Guzman, Daniel Patience,
x2 x3
# x1 x0 a0 ys ym
(=a1) (=a2)
1 0.00 0.00 -0.50 1.000 0.50 0.4227 0.4252
2 -1.00 0.50 -0.50 -0.333 0.00 0.1973 0.1961
3 -1.00 0.50 -0.50 -0.333 0.00 0.1973 0.1958
4 1.00 0.50 -0.50 -0.333 0.00 0.3718 0.3670
5 1.00 -0.16 -0.28 0.987 0.44 0.3702 0.3679
6 0.00 0.45 -0.10 -1.000 -0.35 0.3011 0.2995
7 -1.00 0.00 -0.01 0.020 0.01 0.2268 0.2295
8 1.00 0.28 0.04 -0.827 -0.32 0.3386 0.3305
9 0.13 -0.10 0.10 0.067 0.00 0.3804 0.3895
10 -1.00 -0.50 0.17 0.993 0.33 0.2836 0.2790
11 -1.00 -0.50 0.17 0.993 0.33 0.2836 0.2785
12 1.00 -0.50 0.17 0.993 0.33 0.3583 0.3474
13 0.00 -0.50 0.50 0.333 0.00 0.3844 0.3769
14 -1.00 0.00 0.50 -1.000 -0.50 0.1653 0.1726
15 -1.00 0.00 0.50 -1.000 -0.50 0.1653 0.1633
16 1.00 0.00 0.50 -1.000 -0.50 0.3138 0.3199
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Troup & Georgakis, 2012 CPC
Figure 8: The 13 distinct feeding profiles of the co- Figure 10: The feeding profiles of the
reactant B in the DoDE set of experiments. Dashed coreactant B that correspond to Opt-1 and
line: Base Case, Dotted line: Best of 13 cases Opt-2 that maximize CC(tb )or CC(tb )/tb,
respectively.
Figure 9: Concentration profiles for an example feeding profile
corresponding to the first experiment (#1).
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Troup & Georgakis, 2012 CPC
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