OPTIMIZE MANUFACTURING OF
PHARMACEUTICAL PRODUCTS WITH


Correspondence to:
Dr D. Petrides, Intelligen,
Inc., 2326 Morse Avenue,
Scotch Plains, New Jersey,
USA.
E-mail: dpetrides@
intelligen.com
DOI: 10.1205/cherd06240
0263–8762/07/
$30.00 þ 0.00
Chemical Engineering
Research and Design
Trans IChemE,
Part A, July 2007
# 2007 Institution
of Chemical Engineers
PROCESS SIMULATION AND PRODUCTION
SCHEDULING TOOLS
V. Papavasileiou, A. Koulouris, C. Siletti and D. Petrides

Abstract: This article describes how batch process simulators and scheduling tools can be used
to facilitate and expedite development and commercialization of pharmaceutical products.
Keywords: pharmaceutical manufacturing; process simulation; computer-aided process modelling;
production scheduling; cost analysis; cycle time reduction; risk assessment; Monte Carlo simulation;
lean manufacturing.
INTRODUCTION . calculate demand for utilities as a function
of time;
The global competition in the pharmaceutical . estimate the cycle time of the process;
industry and the increasing demands by gov- . perform cost analysis;
ernments and citizens for affordable medicines . asses the environmental impact, and so on.
has focused the industry’s attention on manu-
The availability of a good model on the
facturing efficiency. In this new era, improve-
computer improves the understanding of the
ments in process and product development
entire process by the team members and
approaches and streamlining of manufacturing
facilitates communication. What-if and sensi-
operations can have a profound impact on the
tivity analyses are greatly facilitated by such
bottomline. Process simulation and scheduling
tools. The objective of such studies is to
tools can play an important role in this endea-
evaluate the impact of critical parameters on
vor. The role of such tools in the development
various key performance indicators (KPIs),
and manufacturing of active pharmaceutical
such as production cost, cycle times and
ingredients (APIs) has been reviewed in the
plant throughput. If there is uncertainty for cer-
past (Petrides et al., 1996, 2002a, b; Petrides
tain input parameters, sensitivity analysis can
and Siletti, 2004; Thomas, 2003; Hwang,
be supplemented with Monte Carlo simulation
1997; Harrison et al., 2003; Tan et al., 2006).
to quantify the impact of uncertainty. Cost
The focus of this article is on the role of such
analysis, especially capital cost estimation,
tools in the development and manufacturing
facilitates decisions related to in-house manu-
of pharmaceutical products.
facturing versus outsourcing. Estimation of
Common forms of pharmaceutical products
the cost-of-goods identifies the expensive
include tablets, capsules, ointments, creams,
processing steps and such information is
solutions in syringes and vials. Their prep-
used to guide R&D work in a judicious way.
aration involves mixing of the active ingredi-
When a process is ready to move from
ent(s) with various excipients that increase
development to manufacturing, process
the shelf-life of the product and facilitate the
simulation facilitates technology transfer and
delivery of the active ingredient. Manufactur-
process fitting. A detailed computer model
ing of inject able products involves filling of
provides a thorough description of a process
syringes or vials under aseptic conditions.
in a way that can be readily understood and
During process development, process
adjusted by the recipients. Process adjust-
simulation software is used to perform the
ments are commonly required when a new
following tasks:
process is moved into an existing facility
. represent the entire process on the whose equipment is not ideally sized for the
computer; new process. The simulation model is used
. perform material and energy balances; to adjust batch sizes, figure out cycling of
. estimate the size of equipment; certain steps (for equipment that cannot
1086 Vol 85 (A7) 1086–1097
 OPTIMIZE MANUFACTURING OF PHARMACEUTICAL PRODUCTS
handle a batch in one cycle), estimate recipe cycle times, and
so on.
Production scheduling tools play an important role in man-
ufacturing (large scale as well as clinical). They are used to
generate production schedules on an on-going basis in a
way that does not violate constraints related to the limited
availability of equipment, labor resources, utilities, inventories
of materials, and so on. Production scheduling tools close the
gap between ERP/MRP II tools and the plant floor (Plenert
and Kirchmier, 2000). Production schedules generated by
ERP (Enterprise Resource Planning) and MRPII (Manufac-
turing Resource Planning) tools are typically based on
coarse process representations and approximate plant
capacities and, as a result, solutions generated by these
tools may not be feasible, especially for multi-product facili-
ties that operate at high capacity utilization. That often
leads to late orders that require expediting and/or to large
inventories in order to maintain customer responsiveness.
‘Lean manufacturing’ principles, such as just-in-time pro-
duction, low work-in-progress (WIP), and low product inven-
tories cannot be implemented without good production
scheduling tools that can accurately estimate capacity.
COMMERCIALLY AVAILABLE SIMULATION AND
SCHEDULING TOOLS
Process simulation programs, also known as process
simulators, have been in use in the chemical and petrochem-
ical industries since the early 1960s. Established simulators
for those industries include: Aspen Plus and HYSYS from
Aspen Technology, Inc. (Cambridge, MA), ChemCAD from
Chemstations, Inc. (Houston, TX), and PRO/II from SimSci-
Esscor, Inc. (Lake Forest, CA).
The above simulators have been designed to model pri-
marily continuous processes and their transient behaviour
for process control purposes. Most pharmaceutical products,
however, are produced in batch and semi-continuous mode.
Such processes are best modeled with batch process simu-
lators that account for time-dependency and sequencing of
events. Batches from Batch Process Technologies, Inc.
(West Lafayette, IN) was the first simulator specific to batch
processes. It was commercialized in the mid-1980s. All of
its operation models are dynamic and simulation always
involves integration of differential equations over a period of
time. In the mid-1990s, Aspen Technology introduced Batch
Plus, a recipe-driven simulator that targeted batch pharma-
ceutical processes. At around the same time, Intelligen, Inc.
(Scotch Plains, NJ) introduced SuperPro Designer. The initial
focus of SuperPro was on production of APIs (synthetic and
biosynthetic) and specialty chemicals. Over the years its
scope has been extended to include modeling of processes
for the production of pharmaceutical and consumer products.
Discrete-event simulators have also found applications in
the pharmaceutical industries, especially in modeling and
debottlenecking of packaging operations. Established tools
of this type include ProModel from ProModel Corporation
(Orem, UT), Arena and Witness from Rockwell Automation,
Inc. (Milwaukee, WI), Extend from Imagine That, Inc. (San
Jose, CA), and FlexSim from FlexSim Software Products,
Inc. (Orem, UT). The focus of models developed with such
tools is usually on the minute-by-minute time-dependency
of events and the animation of the process. Material bal-
ances, equipment sizing, and cost analysis tasks are usually
Trans IChemE, Part A, Chemical Engineering Research and Design, 2007, 85(A7): 1086– 1097
1087
out of the scope of such models. Some of these tools are
quite customizable and third party companies occasionally
use them as platforms to create industry-specific modules.
For instance, BioPharm Services, Ltd. (Bucks, UK) have
created a module with emphasis on biopharmaceutical
processes that runs on top of Extend.
MS Excel from Microsoft is another common platform for
creating models for pharmaceutical processes that focus on
material balances, equipment sizing, and cost analysis.
Some companies have even developed models in Excel
that capture the time-dependency of batch processes. This
is typically done by writing extensive code (in the form of
macros and subroutines) in VBA (Visual Basic for Appli-
cations) that comes with Excel. K-TOPS from Alfa Laval Bio-
kinetics, Inc. (Philadelphia, PA) belongs to this category.
In terms of production scheduling, established tools include
Optiflex from i2 Technologies, Inc. (Irving, TX), SAP APO
from SAP AG (Walldorf, Germany), ILOG Plant PowerOps
from ILOG SA (Gentilly, France), Aspen SCM (formerly
Aspen MIMI) from Aspen Technology, Inc. (Cambridge,
MA), and so on. Their success in the pharmaceutical industry,
however, has been rather limited so far. Their primary focus
on discrete manufacturing (as opposed to batch chemical
manufacturing) and their approach to scheduling from a
mathematical optimization viewpoint are some of the reasons
of the limited market penetration.
SchedulePro from Intelligen, Inc. (Scotch Plains, NJ) is a
new finite capacity scheduling tool that focuses on schedul-
ing of batch and semi-continuous chemical and related
processes. It is a recipe driven tool with emphasis on gener-
ation of feasible solutions that can be readily improved by the
user in an interactive manner.
Examples that illustrate the benefits from the use of simu-
lation and scheduling tools in the production of pharma-
ceutical products follow.
MODELLING AND ANALYSIS OF A TABLET
MANUFACTURING PROCESS
We will use a tablet manufacturing process as a repre-
sentative example to demonstrate the use of process simu-
lation and scheduling tools in the development and
manufacturing of finished pharmaceutical products. To
model an integrated process on the computer using Super-
Pro Designer, the user starts by developing a flowsheet that
represents the overall process. Figure 1, for instance, dis-
plays part of the flowsheet of a tablet manufacturing pro-
cess. The flowsheet is developed by putting together the
required unit procedures (see next paragraph for expla-
nation), and joining them with material flow streams. Next,
the user initializes the flowsheet by registering the various
materials that are used in the process and specifying
operating conditions and performance parameters for the
various operations.
Most pharmaceutical processes operate in batch or semi-
continuous mode. This is in contrast to petrochemical and
other industries that handle large throughputs and use con-
tinuous processes. In continuous operations, a piece of
equipment performs the same action all the time. In batch
processing, on the other hand, a piece of equipment goes
through a cycle of operations. For instance, a Slurry Prep-
aration step (P-1 in V-101) includes the following operations
(see Figure 2): Sanitize, Charge USP Water, Charge
1088 PAPAVASILEIOU et al.
Figure 1. The flowsheet for the pharmaceutical tablet manufacturing process.
Sucrose, Charge API, Agitate, Transfer to Mill Recirculation
vessel, and Flush (clean equipment). In SuperPro, the set
of operations that comprise a processing step is called a
‘unit procedure’ (as opposed to a unit operation). The individ-
ual tasks contained in a procedure (e.g., Charge, Heat,
Agitate, and so on) are called operations. A unit procedure
is represented on the screen with a single equipment-looking
icon. In essence, a unit procedure is the recipe that describes
the sequence of actions required to complete a single
processing step. Figure 2 displays the dialogue through
which the recipe of a vessel unit procedure is specified. On
the left-hand side of that dialogue, the program displays the
operations that are available in a vessel procedure; on the
right-hand side, it displays the registered operations. The sig-
nificance of the unit procedure is that it enables the user to
describe and model the various activities of batch processing
steps in detail.
For every operation within a unit procedure the simulator
includes a mathematical model that performs material and
energy balance calculations. Based on the material balances,
it performs equipment-sizing calculations. If multiple oper-
ations within a unit procedure dictate different sizes for a cer-
tain piece of equipment, the software reconciles the different
demands and selects an equipment size that is appropriate
for all operations. The equipment is sized so that it is large
enough that it will not be overfilled during any operation, but
it is no larger than necessary (in order to minimize capital
Trans IChemE, Part A, Chemical Engineering Research and Design, 2007, 85(A7): 1086–1097
costs). If the equipment size is specified by the user, the simu-
lator checks to make sure that the vessel is not overfilled. In
addition, the tool checks to ensure that the vessel contents
will not fall below a user-specified minimum volume (e.g., a
minimum stir volume) for applicable operations.
In addition to material balances, equipment sizing, and cycle
time analysis, the simulator can be used to carry out cost-of-
goods analysis and project economic evaluation. The sections
that follow provide illustrative examples of the above.
Having developed a good model using a process simulator,
the user may begin experimenting on the computer with
alternative process setups and operating conditions. This
has the potential of reducing the costly and time-consuming
laboratory and pilot plant effort. Of course, the GIGO (gar-
bage-in, garbage-out) principle applies to all computer
models. If critical assumptions and input data are incorrect,
so will be the outcome of the simulation.
When modelling an existing plant, input data required by
the model can be extracted from the data recorded by the
actual process. A communication channel must therefore
be established between the modeller and the plant engin-
eers. The application of some data mining technique is
usually required to transform the process data to the form
required by the model. When designing a new plant, experi-
ence from similar projects can be exploited to fill-in the infor-
mation gaps. In all cases, a certain level of model verification
is necessary after the model is developed. In its simplest
 OPTIMIZE MANUFACTURING OF PHARMACEUTICAL PRODUCTS
Figure 2. The operations associated with the first unit procedure of Figure 1.
form, a review of the results by an experienced engineer can
play the role of verification. Running a sensitivity analysis on
key input variables can reveal the parameters with the great-
est impact on the model’s most important outputs. These par-
ameters would then constitute the focal points in the data
acquisition effort in an attempt to estimate their values and
uncertainty limits with the best possible accuracy.
Process Description
The objective of this example is to illustrate how batch pro-
cess simulators can be used to model, visualize, and analyse
fine pharmaceutical processes. It focuses on a process for
manufacturing pharmaceutical tablets in an existing facility
whose equipment sizes are known. Such tools, however,
also can be used to size equipment during the design of
new facilities.
The entire flowsheet of the process is shown in Figure 1. A
batch begins by charging 705 L of USP-Water into a 1500 L
mixing tank (V-101), then adding 200 kg of sucrose and
400 kg of API. The suspension is agitated thoroughly for
8 h. Then the suspension is transferred into another 1500 L
tank (V-102) that feeds the nano-mill (NM-101). The role of
the nano-mill is to homogenize the suspension thoroughly
and reduce the API particles to nanometer scale. This step
is required because this specific API is insoluble in water.
The suspension is pumped through the nano-mill twice
during a period of 22 h. After the completion of the
Trans IChemE, Part A, Chemical Engineering Research and Design, 2007, 85(A7): 1086– 1097
1089
homogenization, the material is transferred into a 2000 L
tank (V-103) where 70 kg of an excipient and 50 kg of a fla-
vouring agent are added along with 100 L of USP water.
The material is agitated thoroughly for 5 h. Then, the material
is transferred into another 2000 L tank (V-105) that feeds the
granulator. A stabilizer solution is prepared in a 500 L tank (V-
104) by dissolving 80 kg of the stabilizer into 180 L of USP
water. The stabilizer solution is combined with the homogen-
ized solution in V-105.
In preparation for the granulation/drying step, mannitol is
added into the bowl of the granulator (GRN-101). Then the
suspension is sprayed into the chamber of the granulator
at a rate of 120 kg h21. Almost all of the water is removed
(final water content 0.005% w/w). The granulated/dried
material is removed from the granulator and stored into
multiple 50 L mobile containers (MC-101). The granulator
handles a batch of homogenized material in two cycles
because of its limited bowl volume that can hold up to
around 1350 L (or 600 kg) of bulk solids.
The mobile tanks are moved into the tablet press room.
The tablet press (TBP-101) makes 0.5 g tablets at a rate of
250 000 tablets per hour. The processing of a batch is com-
pleted in approximately 9.6 h. The tablets are collected in a
storage bin (DB-101).
Then, a tablet coater (TB-101) is used to coat the tablets
with a material that gives them a sweet taste and a blue
colour. A batch is processed in four cycles because the
coater can handle up to around 300 kg of tablets per batch.
1090 PAPAVASILEIOU et al.

Table 1. Material requirements. Process Scheduling and Resource Tracking

Material kg/batch Figure 3 displays the Equipment Occupancy chart for four
USP Water 1 049 consecutive batches (each colour represents a different
Sucrose 200 batch). The recipe scheduling summary dialogue is shown
API-1 400 on the top right hand corner. The recipe batch time is approxi-
Stabilizer 80 mately 102 h. This is the total time between the start of the
Excipient-1 70
Mannitol 400
first step of a batch and the end of the last step of that
Flavoring 50 batch. However, since most of the equipment items are
OpaDry 24 utilized for shorter periods within a batch, a new batch is
Hot-USP-Water 47 454 initiated every 30 h, which is known as the recipe cycle
Total 49 727 time. The minimum possible recipe cycle time is 29.6 h.
Multiple bars of the same colour on the same line represent
reuse (sharing) of equipment by multiple procedures or oper-
The coating solution is prepared ahead of time in a 150 L ations. The single CIP skid (top line in Figure 3) is the only
mixing tank (V-106). Approximately, 10 mg of coating solution shared equipment in this process. White space between pro-
is required per tablet. A coating cycle takes around 6 h. Warm cedure bars represents idle time. White space within a pro-
air is pumped through the drum of the coater during the coat- cedure bar represents waiting time. For instance, the white
ing process to vaporize the water of the coating solution. The spaces in the procedure bars of V-103 and V-104 represent
coated tablets are stored in drums (not shown in the flow- waiting for cleaning because of the constraints imposed by
sheet) and taken to the packaging area. the single CIP skid. This type of charts is an invaluable tool
All the unit procedures up to the granulator (P-7/GRN-101) for visualizing cycle times and scheduling bottlenecks.
require a sanitization operation prior to the main processing Figure 4 displays the Operations Gantt chart which
activities and a CIP (clean in place) operation after the provides more detailed scheduling information. Notice,
main processing activities. for instance, the duration of the TRANSFER-OUT-1 operation
Table 1 provides information on raw material requirements in P-6 (V-105) that feeds material to the granulator
for the entire process. A batch consists of approximately 2.4 (P-7/GRN-101). The granulator handles a batch in two
million product tablets that have a total mass of around cycles due to its limited bowl volume. The duration of
1224 kg. The API is approximately 33% of the final tablet TRANSFER-OUT-1 in P-6 is from the start of the first granu-
mass. Notice the large amount of Hot-USP-Water, which is lation operation in P-7 to the end of the second granulation
consumed for equipment cleaning. operation in P-7. In reality there are two shorter transfer-out

Figure 3. Equipment occupancy chart for four consecutive batches. This figure is available in colour online via www.icheme.org/cherd

Trans IChemE, Part A, Chemical Engineering Research and Design, 2007, 85(A7): 1086–1097
 OPTIMIZE MANUFACTURING OF PHARMACEUTICAL PRODUCTS
Figure 4. The operations Gantt chart. This figure is available in colour online via www.icheme.org/cherd
operations (synchronized to the two granulation operations in
P-7) but for simplicity SuperPro represents that with a single
transfer-out operation that has the correct total duration.
Process scheduling in the context of a simulator is fully pro-
cess driven and the impact of changes can be analysed in a
matter of seconds. For instance, the impact of an increase in
batch size (that affects the duration of charge, milling, granu-
lation, and other scale-dependent operations) on the recipe
cycle time and the number of batches can be evaluated
instantly. Due to the many interacting factors involved with
even a relatively simple process, simulation tools that allow
users to describe their processes in detail, and to quickly per-
form what-if analyses, can be extremely useful.
Another characteristic of batch processing is the variable
demand for resources (e.g., labour, utilities and raw
materials) as a function of time. For instance, Figure 5 dis-
plays the demand for purified water (USP water) for eight
consecutive batches. This demand includes USP water con-
sumed for the CIP operations as well as USP water utilized
for preparing the product mixture. The red lines represent
the instantaneous demand whereas the green line represents
the cumulative demand and corresponds to the y-axis on the
right-hand side. The blue line corresponds to daily demand
(the averaging period can be adjusted by the user). High
purity water is a common potential bottleneck in pharma-
ceutical processes. It is frequently used by multiple proces-
sing steps simultaneously, in activities such as solution
preparation and equipment cleaning. If not enough instan-
taneous (or cumulative) capacity is available, one or more
process steps may be delayed, possibly with severe
Trans IChemE, Part A, Chemical Engineering Research and Design, 2007, 85(A7): 1086– 1097
1091
consequences. During design of new facilities or retrofit of
existing ones, the information provided by such charts is
used for sizing utility systems.
In addition to instantaneous demand of resources, the
simulator provides the means to track the volumetric utiliz-
ation of all vessels throughout the batch cycle. This allows
the user to track maximum working volumes over time, and
ensure that the minimum stir volume is always met at any rel-
evant point in a process. The volume content of vessels is
also used in sizing new vessels. For existing vessels, it deter-
mines their capacity utilization by all procedures executed in
them. This, in turn, identifies the equipment-procedure pair
that constitutes the size bottleneck and determines the maxi-
mum possible batch size that the plant can undertake. Any
effort to exploit the economy of scale through larger batches
should first concentrate in removing the size bottleneck.
Increasing the number of cycles for the offending procedure
(i.e., split the batch in equal portions and process them
separately through the bottleneck equipment), reshuffling
equipment between similar-type procedures based on their
capacity needs or introducing bigger equipment are some
of the ways by which a size bottleneck can be removed.
Cost Analysis
Cost analysis and project economic evaluation are import-
ant for a number of reasons. For a new product, if the com-
pany lacks a suitable manufacturing facility with available
capacity, it must decide whether to build a new plant or out-
source the production. Building a new plant is a major capital
1092 PAPAVASILEIOU et al.

Figure 5. USP-Water demand in eight consecutive batches. This figure is available in colour online via www.icheme.org/cherd

expenditure and a lengthy process. To make a decision, man- $0.14/tablet. Assuming a product selling price of $0.25/
agement must have information on capital investment tablet, the facility generates annual revenues of $160 million
required and time to complete the facility. When production and has an attractive return on investment.
is outsourced, a cost-of-goods analysis serves as a basis Table 3 provides a breakdown of the manufacturing cost,
for negotiation with contract manufacturers. A sufficiently including (two left columns) and excluding (two right col-
detailed computer model can be used as the basis for the dis- umns) the cost of API. A purchasing price of $500/kg
cussion and negotiation of the terms. Contract manufacturers was assumed for the API, resulting in an annual API cost
usually base their estimates on requirements of equipment of $52.2 million. When the cost of API is considered in
utilization and labor per batch, which is information that is the cost-of-goods, then, the cost of raw materials becomes
provided by a good model. SuperPro performs thorough the dominant cost (63% of total). If the cost of API is
cost analysis and project economic evaluation calculations. ignored, then, the facility overhead becomes the dominant
It estimates capital as well as operating cost. The cost of item of the manufacturing cost (75% of total). In the latter
equipment is estimated using built-in cost correlations that case, the unit production cost drops to $0.05/tablet. That
are based on data derived from a number of vendors and lit-
erature sources. The fixed capital investment is estimated
based on equipment cost and using various multipliers,
some of which are equipment specific (e.g., installation Table 2. Key economic evaluation results.
cost) while others are process specific (e.g., cost of piping, Capital investment 144 939 000 $
buildings, and so on). The approach is described in detail Operating cost 86 898 000 $/year
in the literature (Harrison et al., 2003). The rest of this section Production rate 638 960 000 Tablets/year
provides a summary of the cost analysis results for this Unit production cost 0.14 $/tablet
example process. Selling price 0.25 $/tablet
Total revenues 159 740 000 $/year
Table 2 shows the key economic evaluation results for this Gross margin 45.60 %
project. The fixed capital investment for a manufacturing facil- Return on investment 39.28 %
ity of this size is around $145 million. The annual operating Payback time 2.55 Years
cost (assuming the facility is dedicated to a single product) IRR (after taxes) 32.58 %
NPV (at 7.0% interest) 280 709 000 $
is around $87 million, resulting in a unit production cost of

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 OPTIMIZE MANUFACTURING OF PHARMACEUTICAL PRODUCTS 1093

Table 3. Breakdown of the annual manufacturing cost. (imposed by the granulator). Consequently, the only option
Including cost of API Excluding cost of API for throughput increase is by reducing the cycle time of the
time bottleneck equipment, which is the bin (DB-101) that
Cost item $/year % $/year % supplies material to the tablet coater (TB-101). The avail-
ability of a second bin of the same size (e.g., DB-101b) that
Raw Materials 54 805 000 63.07 2 605 000 7.51 handles alternating batches will eliminate that bottleneck
Labor 4 653 000 5.35 4 653 000 13.41
Facility-Overhead 26 048 000 29.98 26 048 000 75.07 and shorten the recipe cycle time to 27.4 h (the cycle time
Laboratory/QC/QA 1 163 000 1.34 1 163 000 3.35 of the base case is 30 h). The addition of a new bin shifts
Consumables 67 000 0.08 67 000 0.19 the time bottleneck to V-105, the tank that feeds the granula-
Utilities 162 000 0.19 162 000 0.47 tor. Addition of a new tank of the same size (e.g., V-105b)
Total 86 898 000 100.00 34 698 000 100.00
eliminates that bottleneck, reduces the recipe cycle time to
26.5 h, and shifts the bottleneck to V-102 (the tank that
feeds the nano-mill). Finally, addition of a new nano-mill feed-
is representative of the incremental cost of contract ing tank (V-102b) reduces the cycle time to 26 h. Figure 6
manufacturers. shows the equipment occupancy chart after the addition of
the new equipment (DB-101b, V-105b, and V-102b). The
new cycle time is 13.3% shorter than the original. Is it worth
installing two new blending tanks and a bin for a 13.3%
Cycle Time Reduction cycle time reduction? A definite answer to the question can
In a batch manufacturing facility, the annual throughput is be provided by performing a cost-and-benefits analysis
equal to the batch size times the number of batches that using the simulator. Additional information on cycle time
can be processed per year. Consequently, increasing the reduction and debottlenecking approaches and method-
batch size or the number of batches per year increases the ologies can be found in the literature (Petrides et al., 2002b).
annual plant throughput.
Process simulation tools enable users to readily exper-
Uncertainty and Variability Analysis
iment with options that have the potential of increasing the
batch size and/or reducing the cycle time. The base case Process simulation tools typically used for batch process
process already operates at its maximum batch size design, debottlenecking, and cost estimation employ

Figure 6. The equipment occupancy chart after the addition of the new equipment. This figure is available in colour online via www.icheme.org/cherd

Trans IChemE, Part A, Chemical Engineering Research and Design, 2007, 85(A7): 1086– 1097
1094 PAPAVASILEIOU et al.

deterministic models. They model the ‘average’ or ‘expected’

situation commonly referred to as the base case or most likely
scenario. Modeling many cases can help determine the
range of performance with respect to key process par-
ameters, however, such an approach does not account for
the relative likelihood of the various cases. Monte Carlo simu-
lation is a practical means of quantifying the risk associated
with uncertainty in process parameters. In a Monte Carlo
simulation, uncertain input variables are represented with
probability distributions. A simulation calculates numerous
scenarios of a model by repeatedly picking values from a
user defined probability distribution for the uncertain vari-
ables and using those values for the model to calculate and
analyse the outputs in a statistical way in order to quantify
risk. The outcome of this analysis is the estimation of the
confidence by which desired values of key performance
indicators can be achieved. Inversely, the analysis can help
identify the input parameters with the greatest effect on the
bottomline and the input value ranges that minimize output
uncertainty.
In batch, and especially pharmaceutical, processing uncer-
tainty can emerge in operation or market-related parameters.
Process times, equipment sizes, material purchasing and
product selling prices are common uncertain variables. The
pressure in the pharmaceutical industry to make new com-
pounds available to patients as soon as possible means
that process design has to be performed in early phases
where, however, the uncertainty is greater. Performing a sto-
chastic analysis early on in the design phase increases the
model’s robustness and minimizes the risk of encountering
unpleasant surprises later on.
For models developed in SuperPro, Monte Carlo simu-
lation can be performed by combining SuperPro with Crystal
Figure 7. Assumed probability distributions for the process times of
Ball from Decissioneering, Inc. (Denver, Colorado). Crystal tablet coating (a), granulation (b) and nano-milling (c).
Ball is an Excel add-in application that facilitates Monte
Carlo simulation. It enables the user to designate the uncer-
tain input variables, specify their probability distributions and
because it handles a batch in four cycles and each cycle
select the output (decision) variables whose values are
lasts 6 h. If this type of analysis is done for an existing facility,
recorded and analysed during the simulation. For each simu-
historical data should be used to derive the probability
lation trial (scenario) Crystal Ball generates random values
distributions.
for the uncertain input variables selected in frequency dic-
The decision (output) variable considered in this example
tated by their probability distributions using the Monte Carlo
is the recipe cycle time that determines the throughput of
method. Crystal Ball also calculates the uncertainty involved
the facility. Figure 8 displays the results of the Monte Carlo
in the outputs in terms of their statistical properties, mean,
simulation. The analysis reveals that the process can operate
median, mode, variance, standard deviation and frequency
with a cycle time of less than 30 h with a certainty of 80%
distribution.
(blue area of Figure 8). If campaign production plans are
As explained in the previous section, the storage units that
based on the base case cycle time, the above analysis
supply material to the tablet coater, the granulator, and the
reveals that production can be completed on time with a cer-
nano-mill have the longest cycle times and therefore are
tainty of only 80%. Such findings can assist the management
the most likely scheduling bottlenecks. Since the process
of a company in the decision making process. Additional
operates with a cycle time of 30 h which is very close to
information on Monte Carlo simulation and risk assessment
the minimum of 29.6 h, variability in the tablet coating, gran-
can be found in the literature (Achileos et al., 2006).
ulation, and nano-milling operations that determine the
cycle times of their feeding units may have an impact on
the recipe cycle time. Likely sources of variability include
random power outages and equipment failures, availability
PRODUCTION PLANNING AND SCHEDULING
of operators, differences in skills of operators that affect
setup and operation of equipment, and so on. For illustration Pharmaceutical manufacturing facilities are typically
purpose, the Weibull distributions of Figure 7(a –c) were equipped with multiple production lines that share utilities
assumed for the process times of tablet coating, granulation, and labour resources. They may also share auxiliary
and nano-milling, respectively. Their base case values are equipment, such as CIP skids, transfer panels, and delivery
6 h, 7.6 h and 21.8 h, respectively. Please note that the lines, and occasionally main equipment. They operate
coater has the longest cycle time among the above three 24/7 or with other shift patterns. Production is typically

Trans IChemE, Part A, Chemical Engineering Research and Design, 2007, 85(A7): 1086–1097
 OPTIMIZE MANUFACTURING OF PHARMACEUTICAL PRODUCTS
Figure 8. Calculated probability distribution for the cycle time of the entire process. This figure is available in colour online via www.icheme.org/
cherd
campaigned. Considerable changeover time is often required
between campaigns of different products.
Scheduling tools employed in the pharmaceutical industry
must be able to quickly generate feasible solutions that
respect all the major constraints. Such tools must be
equipped with intuitive interfaces that enable the scheduler
to visualize and easily modify the schedule. For instance, if
a machine goes down or an operation is delayed, the schedu-
ler must be able to quickly update the state of the system and
generate a new feasible schedule.
Being able to perform ‘what-if’ studies for capacity analysis
exercises is another desirable feature. This is typically done
by evaluating hypothetical production scenarios over a
period of months to years. Such analyses can provide justifi-
cations for facility expansions and/or outsourcing of pro-
duction (if the current facility cannot meet the expected
future demand).
Results of scheduling tools are communicated to stake-
holders through various charts and reports that provide
information on tasks that must be executed during a certain
time period. Figure 9 displays a production schedule in the
form of a Gantt chart generated by SchedulePro. It corre-
sponds to a tablet manufacturing facility equipped with
two production lines (A and B). The two production lines
utilize dedicated main equipment but share two cleaning-
in-place (CIP) skids represented by the top two lines of
the chart. The CIP skids can be used to clean equipment
in either of the two lines. Line A includes a tablet coater,
but not line B. Line A operates seven days a week whereas
line B operates five days a week. The grey columns in line
B represent 48-h weekend breaks. A 24-h changeover time
is assumed between campaigns of different products to
account for equipment adjustments and facility sanitization.
For instance, the white rectangles between the first
(blue colour rectangles) and second (magenta colour rec-
tangles) campaigns of line A represent such a 24-h change-
over time.
A production schedule is readily updated through the
chart. Updates are required when a piece of equipment
Trans IChemE, Part A, Chemical Engineering Research and Design, 2007, 85(A7): 1086– 1097
1095
goes down or when the completion of a task is delayed.
For the latter case, the user simply specifies the new com-
pletion time of the delayed operation and adjusts the sche-
dule to eliminate conflicts. The adjustment can be done
automatically by the tool or manually by the user by drag-
ging and dropping activities in an interactive manner. In
essence the chart becomes an intelligent electronic ‘Lego
Board’ whose activities are linked and conflicts are readily
identified and eliminated. Lego boards and other mechan-
isms of manual scheduling are still prevalent in many
pharmaceutical manufacturing facilities. Interactive sche-
duling tools that resemble the look of Lego boards are
usually adopted without much resistance by manufacturing
personnel.
A production schedule is often constrained not by its main
equipment, but instead by the availability of labor and other
resources. For instance, Figure 10 displays the labour
demand for line A of the schedule of Figure 9. The blue
lines represent the total instantaneous demand for labour.
The red line represents the maximum number of oper-
ators (10 in this case) in that production line. For short
periods of time there is a need for a total of eleven oper-
ators. Scheduling tools enable manufacturing personnel to
readily visualize and resolve such conflicts. The resolution
of such conflicts is accomplished either by the scheduling
algorithm or the user. It typically involves the delay of
some operations that contribute to the peaks. If the facility
employs few floating operators for lines A and B, such con-
flicts also can be resolved by utilizing the floating operators
during peak demand periods.
Constraints imposed by inventories of raw materials, inter-
mediates, and final products and waste materials are handled
in a similar manner. The tool calculates the level of materials
and schedules accordingly (to avoid conflicts) or simply
warns the user of conflicts due to inventories and lets him/
her take corrective action.
In summary, scheduling tools enable manufacturing
personnel to maintain a dynamic model of the entire
facility that evolves with time and facilitates generation of
1096 PAPAVASILEIOU et al.

Figure 9. Production schedule in Gantt chart format. This figure is available online via www.icheme.org/cherd

Figure 10. Line-A labour demand as a function of time. This figure is available online via www.icheme.org/cherd

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 OPTIMIZE MANUFACTURING OF PHARMACEUTICAL PRODUCTS
production schedules that are feasible and easily
modifiable. The end result is increased productivity,
improved customer service, and reduced manufacturing
cost.
SUMMARY
Process simulation and production scheduling tools
can play an important role throughout the life-cycle of
product development and commercialization. In process
development, process simulation tools are becoming
increasingly useful as a means to analyse, communicate
and document process changes. During the transition
from development to manufacturing, they facilitate technol-
ogy transfer and process fitting. Production scheduling tools
play a valuable role in manufacturing. They are used to
generate production schedules based on the accurate esti-
mation of plant capacity, thus minimizing late orders and
reducing inventories. Such tools also facilitate capacity
analysis and debottlenecking tasks.
The pharmaceutical industry has only recently begun
making significant use of process simulation and scheduling
tools. Increasingly, universities are incorporating the use of
such tools in their curricula. In the future, we can expect to
see increased use of these technologies and tighter inte-
gration with other enabling IT technologies, such as supply
chain tools, manufacturing execution systems (MES), batch
process control systems, process analytics tools (PAT), and
so on. The result will be more robust processes and efficient
manufacturing leading to more affordable medicines.
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1097
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