Systematic Evaluation of Single-Use Systems Using Process Simulation Tools - Simulation tools can reveal whether disposables will be economical even after scale-up. - BioPharm International


Systematic Evaluation of Single-Use Systems Using Process Simulation Tools
Simulation tools can reveal whether disposables will be economical even after scale-up.

BioPharm International Supplements

Commercially Available Simulation Tools

Computer-aided process design and simulation tools have been used in the chemical and petrochemical industries since the early 1960s. Simulators for these industries have been designed to model continuous processes and their transient behavior for process-control purposes. Most biopharmaceutical products, however, are manufactured in batch and semi-continuous mode. Such processes are best modeled with batch-process simulators that account for time dependency and sequencing of events. In the mid 1990s, Aspen Technology (Cambridge, MA) introduced Batch Plus, a recipe-driven simulator that targeted batch pharmaceutical processes. Around the same time, Intelligen, Inc. (Scotch Plains, NJ) introduced SuperPro Designer. The initial focus of SuperPro Designer was on bioprocessing. Over the years, its scope has been extended to include modeling of small-molecule active pharmaceutical ingredient (API) and secondary pharmaceutical manufacturing processes.

Discrete-event simulators have also found applications in the pharmaceutical industry, especially in the modeling of secondary pharmaceutical manufacturing processes. Established tools of this type include ProModel from ProModel Corporation (Orem, UT), Arena and Witness from Rockwell Automation, Inc. (Milwaukee, WI), and Extend from Imagine That, Inc. (San Jose, CA). The focus of models developed with such tools is usually on the minute-by-minute time-dependency of events and on animations 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 customizable and third-party companies occasionally use them as platforms to create industry-specific modules. For instance, BioPharm Services, Ltd. (Bucks, UK), has created an Extend-based module with emphasis on biopharmaceutical processes.

Microsoft Excel 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 Excel applications that capture the time-dependency of batch processes. This is typically done by writing extensive code (in the form of macros and subroutines) in visual basic for applications (VBA) that comes with Excel. The K-TOPS tool from Biokinetics, Inc. (Philadelphia, PA), belongs to this category.

Building a model in a batch-process simulator

Figure 1
The article uses SuperPro Designer to illustrate the modeling and evaluation of MAb manufacturing process alternatives. The first step is to create a flow diagram of the overall process (Figure 1). The various equipment-shaped icons, called unit procedures, represent the processing steps required for making a batch of a certain product. The lines that connect the unit procedures represent material transfers. Batch process simulators usually come with a library of unit procedures. A unit procedure represents a set of activities or operations that are carried out in a piece of equipment during a processing step. A unit procedure may include any number of operations. The fermentation procedure (P-11) of Figure 1 includes the following operations: SIP-1, SET UP, TRANSFER-IN-1, TRANSFER-IN-2, FERMENT-1, TRANSFER-OUT-1, and CIP-1. The combination of unit procedures and operations enables the user to represent and model the various activities of batch-processing steps in detail.

For every operation of a unit procedure, the simulator includes a mathematical model that performs material and energy balancing, and equipment-sizing calculations. If multiple operations within a unit procedure dictate different sizes for the equipment, the program reconciles the different demands and selects an equipment size that is appropriate for all operations. If the equipment size is specified by the user, the simulator 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 terms of cost analysis, simulation tools facilitate the process of estimating capital as well as operating costs. Some tools are equipped with built-in functions and databases for estimating equipment cost as a function of size, material of construction, operating pressure, and other parameters.8,9 The tools also may include databases for materials (pure components and mixtures), utilities, consumables, and other resources. The size and unit cost of single-use systems is stored in the consumables database. The user associates consumables with a processing step and the tool calculates the number of units and the cost.

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