EVALUATION METHODOLOGY
The commercial process-cost modeling software, BioSolve, is used to assess the process economics of the FB, CFB, and CP production
techniques. The CoG is a useful metric to quantify the operating costs of a manufacturing option. BioSolve is an Excel-based
tool that determines the CoG by accounting for the indirect (fixed) overheads of the facility and the direct (variable) operating
costs of the process. The fixed-cost element consists of capital charges, taxes, and insurance, and direct costs include consumables,
materials, labor, and waste management. Such an approach to estimate the CoG has been used to evaluate the process economics
of disposable membrane chromatography for use in biomanufacturing.4,5
Figure 1. Framework of BioSolve
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Figure 1 illustrates the basic BioSolve framework, which comprises the user interface, process definition, productivity and
cost calculations, and model outputs. The interface allows a rapid assessment of the impact of predefined key input parameters
(e.g., process scale, product titer, disposable options) on the model outputs. The core of the cost model consists of the
process definition, which includes the mass balances, equipment sizing, operating parameters, and resource allocation. The
calculated items include plant productivity, labor requirements, consumable and materials usage, and equipment list. The costs
of these components are maintained in a cost database, which is built with data consisting of benchmarking information from
several biomanufacturing operations. The key outputs generated by the cost model are facility throughput, bill of materials,
CoG, and capital investment.
CASE STUDY BACKGROUND
Figure 2. Process sequence (a) fed-batch (FB), (b) concentrated fed-batch (CFB), and (c) concentrated perfusion (CP) for the
production of a glycosylated protein
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The model compares the manufacture of a glycosylated protein in three different production techniques—FB, CFB, and CP. Figure
2 depicts the process sequences for these production methods. The seed train for the FB process is longer because this option
requires more steps to scale-up to the production cell culture bioreactor. The FB upstream process information was derived
from commercially relevant operations commonly practiced in the industry. The upstream information for the CFB and CP processes
was provided by Refine Technology, based on data supplied by its clients. In the FB and CFB processes, the removal of cells
is achieved by centrifugation and depth filtration. Such recovery-unit operations are not required in the CP process because
the cells are retained in the ATF System. The three processes were assumed to have the same purification sequence. This downstream
sequence was selected according to commercial relevance and sourced from details that are available in the public domain.
Table 2 summarizes the key operating parameters used in the base case study.
Table 2. Summary of the key base-case process parameters
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For the FB process, all the seed steps included in the model are assumed to be batch fermentations. In the production cell
culture step, two additional feeds are added to the bioreactor three days and six days after inoculation. The final growth
phase takes about 13 days.
The CFB and CP seed sequence is performed using a 200 mL bag carried out in batch fermentation mode, followed by a 20 L bioreactor
also run in the CFB mode.
In the FB and CFB processes, the recovery procedure is centrifugation followed by depth filtration. An ultrafiltration/diafiltration
(UF/DF) step is used to concentrate the product stream before the Protein A unit operation. A virus inactivation step occurs.
The product stream is subsequently loaded onto an ion exchange (IEX) bind and elute column and passed through an IEX flow-through
column. A viral filtration step takes place before the UF/DF step. A final sterile filtration step is used to purify the product.
This purification sequence is based on typical unit operations for the production of a glycosylated protein, using typical
solutions and timings. The overall yield for the downstream sequence is 50% and 69% for the FB/CFB and CP processes, respectively.
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