OPTIMIZE MANUFACTURING OF PHARMACEUTICAL PRODUCTS WITH 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
The global competition in the pharmaceutical industry and the increasing demands by governments and citizens for affordable medicines has focused the industrys attention on manufacturing efciency. In this new era, improvements in process and product development approaches and streamlining of manufacturing operations can have a profound impact on the bottomline. Process simulation and scheduling tools can play an important role in this endeavor. The role of such tools in the development and manufacturing of active pharmaceutical ingredients (APIs) has been reviewed in the past (Petrides et al., 1996, 2002a, b; Petrides and Siletti, 2004; Thomas, 2003; Hwang, 1997; Harrison et al., 2003; Tan et al., 2006). The focus of this article is on the role of such tools in the development and manufacturing of pharmaceutical products. Common forms of pharmaceutical products include tablets, capsules, ointments, creams, solutions in syringes and vials. Their preparation involves mixing of the active ingredient(s) with various excipients that increase the shelf-life of the product and facilitate the delivery of the active ingredient. Manufacturing of inject able products involves lling of syringes or vials under aseptic conditions. During process development, process simulation software is used to perform the following tasks: . represent the entire process on the computer; . perform material and energy balances; . estimate the size of equipment;
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. calculate demand for utilities as a function of time; . estimate the cycle time of the process; . perform cost analysis; . asses the environmental impact, and so on. The availability of a good model on the computer improves the understanding of the entire process by the team members and facilitates communication. What-if and sensitivity analyses are greatly facilitated by such tools. The objective of such studies is to evaluate the impact of critical parameters on various key performance indicators (KPIs), such as production cost, cycle times and plant throughput. If there is uncertainty for certain input parameters, sensitivity analysis can be supplemented with Monte Carlo simulation to quantify the impact of uncertainty. Cost analysis, especially capital cost estimation, facilitates decisions related to in-house manufacturing versus outsourcing. Estimation of the cost-of-goods identies the expensive processing steps and such information is used to guide R&D work in a judicious way. When a process is ready to move from development to manufacturing, process simulation facilitates technology transfer and process tting. A detailed computer model provides a thorough description of a process in a way that can be readily understood and adjusted by the recipients. Process adjustments are commonly required when a new process is moved into an existing facility whose equipment is not ideally sized for the new process. The simulation model is used to adjust batch sizes, gure out cycling of certain steps (for equipment that cannot
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Correspondence to: Dr D. Petrides, Intelligen, Inc., 2326 Morse Avenue, Scotch Plains, New Jersey, USA. E-mail: dpetrides@ intelligen.com

DOI: 10.1205/cherd06240 02638762/07/ $30.00 0.00 Chemical Engineering Research and Design Trans IChemE, Part A, July 2007 # 2007 Institution of Chemical Engineers

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handle a batch in one cycle), estimate recipe cycle times, and so on. Production scheduling tools play an important role in manufacturing (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 oor (Plenert and Kirchmier, 2000). Production schedules generated by ERP (Enterprise Resource Planning) and MRPII (Manufacturing 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 facilities 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 production, low work-in-progress (WIP), and low product inventories cannot be implemented without good production scheduling tools that can accurately estimate capacity.

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COMMERCIALLY AVAILABLE SIMULATION AND SCHEDULING TOOLS

Process simulation programs, also known as process simulators, have been in use in the chemical and petrochemical 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 SimSciEsscor, Inc. (Lake Forest, CA). The above simulators have been designed to model primarily 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 simulators that account for time-dependency and sequencing of events. Batches from Batch Process Technologies, Inc. (West Lafayette, IN) was the rst simulator specic 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 pharmaceutical 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 balances, equipment sizing, and cost analysis tasks are usually

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-specic 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 Applications) that comes with Excel. K-TOPS from Alfa Laval Biokinetics, Inc. (Philadelphia, PA) belongs to this category. In terms of production scheduling, established tools include Optiex 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 nite capacity scheduling tool that focuses on scheduling of batch and semi-continuous chemical and related processes. It is a recipe driven tool with emphasis on generation of feasible solutions that can be readily improved by the user in an interactive manner. Examples that illustrate the benets from the use of simulation and scheduling tools in the production of pharmaceutical products follow.

MODELLING AND ANALYSIS OF A TABLET MANUFACTURING PROCESS

We will use a tablet manufacturing process as a representative example to demonstrate the use of process simulation and scheduling tools in the development and manufacturing of nished pharmaceutical products. To model an integrated process on the computer using SuperPro Designer, the user starts by developing a owsheet that represents the overall process. Figure 1, for instance, displays part of the owsheet of a tablet manufacturing process. The owsheet is developed by putting together the required unit procedures (see next paragraph for explanation), and joining them with material ow streams. Next, the user initializes the owsheet 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 semicontinuous mode. This is in contrast to petrochemical and other industries that handle large throughputs and use continuous 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 Preparation step (P-1 in V-101) includes the following operations (see Figure 2): Sanitize, Charge USP Water, Charge

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Figure 1. The owsheet 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 individual 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 specied. 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 signicance 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 operations within a unit procedure dictate different sizes for a certain 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 overlled during any operation, but it is no larger than necessary (in order to minimize capital

costs). If the equipment size is specied by the user, the simulator checks to make sure that the vessel is not overlled. In addition, the tool checks to ensure that the vessel contents will not fall below a user-specied 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-ofgoods 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 (garbage-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 engineers. 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, experience from similar projects can be exploited to ll-in the information gaps. In all cases, a certain level of model verication is necessary after the model is developed. In its simplest

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Figure 2. The operations associated with the rst unit procedure of Figure 1.

form, a review of the results by an experienced engineer can play the role of verication. Running a sensitivity analysis on key input variables can reveal the parameters with the greatest impact on the models most important outputs. These parameters 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 process simulators can be used to model, visualize, and analyse ne 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 owsheet 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 specic 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

homogenization, the material is transferred into a 2000 L tank (V-103) where 70 kg of an excipient and 50 kg of a avouring 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 (V104) by dissolving 80 kg of the stabilizer into 180 L of USP water. The stabilizer solution is combined with the homogenized 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 (nal 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 completed 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.

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Table 1. Material requirements. Material USP Water Sucrose API-1 Stabilizer Excipient-1 Mannitol Flavoring OpaDry Hot-USP-Water Total kg/batch 1 049 200 400 80 70 400 50 24 47 454 49 727

PAPAVASILEIOU et al. Process Scheduling and Resource Tracking

Figure 3 displays the Equipment Occupancy chart for four consecutive batches (each colour represents a different batch). The recipe scheduling summary dialogue is shown on the top right hand corner. The recipe batch time is approximately 102 h. This is the total time between the start of the rst step of a batch and the end of the last step of that batch. However, since most of the equipment items are utilized for shorter periods within a batch, a new batch is initiated every 30 h, which is known as the recipe cycle 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 operations. The single CIP skid (top line in Figure 3) is the only shared equipment in this process. White space between procedure bars represents idle time. White space within a procedure bar represents waiting time. For instance, the white spaces in the procedure bars of V-103 and V-104 represent waiting for cleaning because of the constraints imposed by the single CIP skid. This type of charts is an invaluable tool for visualizing cycle times and scheduling bottlenecks. Figure 4 displays the Operations Gantt chart which provides more detailed scheduling information. Notice, for instance, the duration of the TRANSFER-OUT-1 operation in P-6 (V-105) that feeds material to the granulator (P-7/GRN-101). The granulator handles a batch in two cycles due to its limited bowl volume. The duration of TRANSFER-OUT-1 in P-6 is from the start of the rst granulation operation in P-7 to the end of the second granulation operation in P-7. In reality there are two shorter transfer-out

The coating solution is prepared ahead of time in a 150 L mixing tank (V-106). Approximately, 10 mg of coating solution is required per tablet. A coating cycle takes around 6 h. Warm air is pumped through the drum of the coater during the coating process to vaporize the water of the coating solution. The coated tablets are stored in drums (not shown in the owsheet) and taken to the packaging area. All the unit procedures up to the granulator (P-7/GRN-101) require a sanitization operation prior to the main processing activities and a CIP (clean in place) operation after the main processing activities. Table 1 provides information on raw material requirements for the entire process. A batch consists of approximately 2.4 million product tablets that have a total mass of around 1224 kg. The API is approximately 33% of the nal tablet mass. Notice the large amount of Hot-USP-Water, which is consumed for equipment cleaning.

Figure 3. Equipment occupancy chart for four consecutive batches. This gure is available in colour online via www.icheme.org/cherd Trans IChemE, Part A, Chemical Engineering Research and Design, 2007, 85(A7): 10861097

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Figure 4. The operations Gantt chart. This gure 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 process 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, granulation, 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 perform 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 displays the demand for puried water (USP water) for eight consecutive batches. This demand includes USP water consumed 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 pharmaceutical processes. It is frequently used by multiple processing steps simultaneously, in activities such as solution preparation and equipment cleaning. If not enough instantaneous (or cumulative) capacity is available, one or more process steps may be delayed, possibly with severe

consequences. During design of new facilities or retrot 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 utilization 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 relevant point in a process. The volume content of vessels is also used in sizing new vessels. For existing vessels, it determines their capacity utilization by all procedures executed in them. This, in turn, identies the equipment-procedure pair that constitutes the size bottleneck and determines the maximum possible batch size that the plant can undertake. Any effort to exploit the economy of scale through larger batches should rst 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), reshufing 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 important for a number of reasons. For a new product, if the company lacks a suitable manufacturing facility with available capacity, it must decide whether to build a new plant or outsource the production. Building a new plant is a major capital

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

expenditure and a lengthy process. To make a decision, management must have information on capital investment required and time to complete the facility. When production is outsourced, a cost-of-goods analysis serves as a basis for negotiation with contract manufacturers. A sufciently detailed computer model can be used as the basis for the discussion and negotiation of the terms. Contract manufacturers usually base their estimates on requirements of equipment utilization and labor per batch, which is information that is provided by a good model. SuperPro performs thorough cost analysis and project economic evaluation calculations. It estimates capital as well as operating cost. The cost of equipment is estimated using built-in cost correlations that are based on data derived from a number of vendors and literature sources. The xed capital investment is estimated based on equipment cost and using various multipliers, some of which are equipment specic (e.g., installation cost) while others are process specic (e.g., cost of piping, buildings, and so on). The approach is described in detail in the literature (Harrison et al., 2003). The rest of this section provides a summary of the cost analysis results for this example process. Table 2 shows the key economic evaluation results for this project. The xed capital investment for a manufacturing facility of this size is around $145 million. The annual operating cost (assuming the facility is dedicated to a single product) is around $87 million, resulting in a unit production cost of

$0.14/tablet. Assuming a product selling price of $0.25/ tablet, the facility generates annual revenues of $160 million and has an attractive return on investment. Table 3 provides a breakdown of the manufacturing cost, including (two left columns) and excluding (two right columns) the cost of API. A purchasing price of $500/kg was assumed for the API, resulting in an annual API cost of $52.2 million. When the cost of API is considered in the cost-of-goods, then, the cost of raw materials becomes the dominant cost (63% of total). If the cost of API is ignored, then, the facility overhead becomes the dominant item of the manufacturing cost (75% of total). In the latter case, the unit production cost drops to $0.05/tablet. That

Table 2. Key economic evaluation results. Capital investment Operating cost Production rate Unit production cost Selling price Total revenues Gross margin Return on investment Payback time IRR (after taxes) NPV (at 7.0% interest) 144 939 000 86 898 000 638 960 000 0.14 0.25 159 740 000 45.60 39.28 2.55 32.58 280 709 000 $ $/year Tablets/year $/tablet $/tablet $/year % % Years % $

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Table 3. Breakdown of the annual manufacturing cost. Including cost of API Cost item Raw Materials Labor Facility-Overhead Laboratory/QC/QA Consumables Utilities Total $/year 54 805 4 653 26 048 1 163 67 162 86 898 000 000 000 000 000 000 000 % 63.07 5.35 29.98 1.34 0.08 0.19 100.00 Excluding cost of API $/year 2 605 4 653 26 048 1 163 67 162 34 698 000 000 000 000 000 000 000 % 7.51 13.41 75.07 3.35 0.19 0.47 100.00

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is representative of the incremental cost of contract manufacturers.

Cycle Time Reduction

In a batch manufacturing facility, the annual throughput is equal to the batch size times the number of batches that can be processed per year. Consequently, increasing the batch size or the number of batches per year increases the annual plant throughput. Process simulation tools enable users to readily experiment with options that have the potential of increasing the batch size and/or reducing the cycle time. The base case process already operates at its maximum batch size

(imposed by the granulator). Consequently, the only option for throughput increase is by reducing the cycle time of the time bottleneck equipment, which is the bin (DB-101) that supplies material to the tablet coater (TB-101). The availability of a second bin of the same size (e.g., DB-101b) that handles alternating batches will eliminate that bottleneck and shorten the recipe cycle time to 27.4 h (the cycle time of the base case is 30 h). The addition of a new bin shifts the time bottleneck to V-105, the tank that feeds the granulator. Addition of a new tank of the same size (e.g., V-105b) 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 feeding tank (V-102b) reduces the cycle time to 26 h. Figure 6 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? A denite answer to the question can be provided by performing a cost-and-benets analysis using the simulator. Additional information on cycle time reduction and debottlenecking approaches and methodologies can be found in the literature (Petrides et al., 2002b).

Uncertainty and Variability Analysis

Process simulation tools typically used for batch process design, debottlenecking, and cost estimation employ

Figure 6. The equipment occupancy chart after the addition of the new equipment. This gure is available in colour online via www.icheme.org/cherd Trans IChemE, Part A, Chemical Engineering Research and Design, 2007, 85(A7): 1086 1097

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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 parameters, however, such an approach does not account for the relative likelihood of the various cases. Monte Carlo simulation 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 dened probability distribution for the uncertain variables 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 condence 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 uncertainty 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 compounds 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 stochastic analysis early on in the design phase increases the models robustness and minimizes the risk of encountering unpleasant surprises later on. For models developed in SuperPro, Monte Carlo simulation can be performed by combining SuperPro with Crystal Ball from Decissioneering, Inc. (Denver, Colorado). Crystal Ball is an Excel add-in application that facilitates Monte Carlo simulation. It enables the user to designate the uncertain input variables, specify their probability distributions and select the output (decision) variables whose values are recorded and analysed during the simulation. For each simulation trial (scenario) Crystal Ball generates random values for the uncertain input variables selected in frequency dictated by their probability distributions using the Monte Carlo method. Crystal Ball also calculates the uncertainty involved in the outputs in terms of their statistical properties, mean, median, mode, variance, standard deviation and frequency distribution. As explained in the previous section, the storage units that supply material to the tablet coater, the granulator, and the nano-mill have the longest cycle times and therefore are the most likely scheduling bottlenecks. Since the process operates with a cycle time of 30 h which is very close to the minimum of 29.6 h, variability in the tablet coating, granulation, 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 of operators, differences in skills of operators that affect setup and operation of equipment, and so on. For illustration purpose, the Weibull distributions of Figure 7(a c) were assumed for the process times of tablet coating, granulation, and nano-milling, respectively. Their base case values are 6 h, 7.6 h and 21.8 h, respectively. Please note that the coater has the longest cycle time among the above three

Figure 7. Assumed probability distributions for the process times of tablet coating (a), granulation (b) and nano-milling (c).

because it handles a batch in four cycles and each cycle lasts 6 h. If this type of analysis is done for an existing facility, historical data should be used to derive the probability distributions. The decision (output) variable considered in this example is the recipe cycle time that determines the throughput of the facility. Figure 8 displays the results of the Monte Carlo simulation. The analysis reveals that the process can operate with a cycle time of less than 30 h with a certainty of 80% (blue area of Figure 8). If campaign production plans are based on the base case cycle time, the above analysis reveals that production can be completed on time with a certainty of only 80%. Such ndings can assist the management of a company in the decision making process. Additional information on Monte Carlo simulation and risk assessment can be found in the literature (Achileos et al., 2006).

PRODUCTION PLANNING AND SCHEDULING

Pharmaceutical manufacturing facilities are typically equipped with multiple production lines that share utilities and labour resources. They may also share auxiliary equipment, such as CIP skids, transfer panels, and delivery lines, and occasionally main equipment. They operate 24/7 or with other shift patterns. Production is typically

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Figure 8. Calculated probability distribution for the cycle time of the entire process. This gure 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 scheduler 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 justications for facility expansions and/or outsourcing of production (if the current facility cannot meet the expected future demand). Results of scheduling tools are communicated to stakeholders 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 corresponds to a tablet manufacturing facility equipped with two production lines (A and B). The two production lines utilize dedicated main equipment but share two cleaningin-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 ve 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 rst (blue colour rectangles) and second (magenta colour rectangles) campaigns of line A represent such a 24-h changeover time. A production schedule is readily updated through the chart. Updates are required when a piece of equipment

goes down or when the completion of a task is delayed. For the latter case, the user simply species the new completion time of the delayed operation and adjusts the schedule to eliminate conicts. The adjustment can be done automatically by the tool or manually by the user by dragging and dropping activities in an interactive manner. In essence the chart becomes an intelligent electronic Lego Board whose activities are linked and conicts are readily identied and eliminated. Lego boards and other mechanisms of manual scheduling are still prevalent in many pharmaceutical manufacturing facilities. Interactive scheduling 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 operators (10 in this case) in that production line. For short periods of time there is a need for a total of eleven operators. Scheduling tools enable manufacturing personnel to readily visualize and resolve such conicts. The resolution of such conicts 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 oating operators for lines A and B, such conicts also can be resolved by utilizing the oating operators during peak demand periods. Constraints imposed by inventories of raw materials, intermediates, and nal products and waste materials are handled in a similar manner. The tool calculates the level of materials and schedules accordingly (to avoid conicts) or simply warns the user of conicts 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

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

Figure 10. Line-A labour demand as a function of time. This gure is available online via www.icheme.org/cherd Trans IChemE, Part A, Chemical Engineering Research and Design, 2007, 85(A7): 10861097

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production schedules that are feasible and easily modiable. The end result is increased productivity, improved customer service, and reduced manufacturing cost.

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REFERENCES
Achilleos, E.C., Calandranis, J.C., and Petrides, D.P., 2006, Quantifying the impact of uncertain parameters in the batch manufacturing of active pharmaceutical ingredients, Pharmaceutical Engineering, 34 40. Harrison, R.G., Todd, P., Rudge, S.R. and Petrides, D.P., 2003, Bioseparations Science and Engineering (Oxford University Press). Hwang, F., 1997, Batch pharmaceutical process design and simulation, Pharmaceutical Engineering, 28 43. Petrides, D.P., Koulouris, A. and Lagonikos, P.T., 2002a, The role of process simulation in pharmaceutical process development and product commercialization, Pharmaceutical Engineering, 22(1): 1. Petrides, D., Koulouris, A. and Siletti, C., 2002b, Throughput analysis and debottlenecking of biomanufacturing facilities, a job for process simulators, BioPharm. Petrides, D.P. and Siletti, C.A., 2004, The role of process simulation and scheduling tools in the development and manufacturing of biopharmaceutical, Proceedings of the 2004 Winter Simulation Conference, Ingalls, R.G., Rossetti, M.D., Smith, J.S. and Peters, B.A. (eds). 2046 2051. Petrides, D.P., Calandranis, J. and Cooney, C.L., 1996. Bioprocess optimization via CAPD and simulation for product commercialization, Genetic Engineering News, 16(16): 24 40. Plenert, G. and Kirchmier, B., 2000, Finite Capacity Scheduling Management, Selection, and Implementation (John Wiley & Sons). Tan, J., Foo, D.C.Y., Kumaresan, S. and Aziz, R.A., 2006, Debottlenecking of a batch pharmaceutical cream production, Pharmaceutical Engineering, 7282. Thomas, C.J., 2003, A design approach to biotech process simulations, BioProcess International, 2 9. The manuscript was received 11 December 2006 and accepted for publication after revision 6 February 2007.

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 technology transfer and process tting. Production scheduling tools play a valuable role in manufacturing. They are used to generate production schedules based on the accurate estimation 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 signicant 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 integration 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 efcient manufacturing leading to more affordable medicines.

Trans IChemE, Part A, Chemical Engineering Research and Design, 2007, 85(A7): 1086 1097