An Economic Comparison of Three Cell Culture Techniques - Comparing the economic feasibility of a typical glycosylated protein. - BioPharm International

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An Economic Comparison of Three Cell Culture Techniques
Comparing the economic feasibility of a typical glycosylated protein.


BioPharm International
Volume 24, Issue 2, pp. 54-60

ABSTRACT

Fed-batch and perfusion culture are the two dominant modes of operation for mammalian-cell-culture based processes, especially for the production of glycosylated proteins required in large amounts. This article provides an economic comparison for the production of a typical glycosylated protein using the fed-batch, concentrated fed-batch (CFB), and concentrated perfusion (CP) technologies. The CFB and CP processes are based on the ATF System, a platform technology developed by Refine Technology for biologics production.


(REFINE TECHNOLOGY)
The market for protein-derived products has grown significantly in the past decade and continues to accelerate at a rapid rate. As more recombinant therapeutic proteins enter development and get through the approval phase, more efficient large-scale production of such proteins is necessary to meet the surging demand. Fed-batch and perfusion culture are the two dominant modes of operation for mammalian-cell-culture based processes, especially for the production of glycosylated proteins required in large amounts.1 Challenges in the industry (such as competitive products for the same indication or desired cost reductions) are forcing many to explore new production options.

In fed-batch culture, there is a gradual addition of a fresh volume of selected nutrients during the growth–culture cycle to improve productivity and growth. The culture is subsequently harvested and the product recovered. Fed-batch culture has been an attractive choice for large-scale production due to its operational simplicity and familiarity as a carryover process from fermentation. However, fed-batch mode of operation typically also involves high start-up costs, resulting from the need for larger bioreactor plant capacity.

In perfusion culture, a continuous supply of fresh media is fed into the bioreactor while growth-inhibitory by-products are constantly removed. The increasing interest in the use of perfusion culture can be attributed to the higher product output from a reduced reactor size (hence, simplifying operation, cleaning, and sterilization). The cell densities achieved in perfusion culture (30–100 x 106 cells/mL) are typically higher than for fed-batch modes (5–25 x 106 cells/mL).2 The principal aspect of perfusion operation, which is different from fed-batch, is the added requirement of a cell-retention device. Cell-retention systems add a level of complexity to the process, requiring management, control, and maintenance for successful operation. Perfusion bioreactors can suffer operational difficulties such as malfunction or failure of the cell-separation device, which can lead to shortening of the production run, leading further, to increased operating costs. This has previously limited their attractiveness.

In recent years, a platform technology has been developed for biologics production—the ATF System, introduced by Refine Technology (Pine Brook, NJ). Used in the alternating tangential flow mode, it is a low shear filtration system that inhibits filter-membrane fouling. This external cell-separation system is able to maintain continuous culture for extended periods of time and offers the capability of rapid filter change without compromising the culture run.3 The ATF System allows increased volumetric productivity and reduced bioreactor size.

Concentrated fed-batch and concentrated perfusion are two production techniques based on the ATF System, which simultaneously nourishes the culture and concentrates the product within the bioreactor. These manufacturing methods permit great increases in cell and product concentrations as compared with fed-batch and perfusion. For example, in the concentrated fed-batch production platform, one of Refine Technology's pharmaceutical clients has reported a protein product titer of 17 g/L with an unoptimized Chinese hamster ovary (CHO) cell process.4 Higher titers are expected as process optimization continues. In the concentrated fed-batch operation, ultra-high cell densities of (70–200) x 106 cells/mL have been achieved; similarly, extremely high cell densities in the region of (70–100) x 106 cells/mL have been achieved in systems using the concentrated perfusion mode.


Table 1. Guideline working volume sizes for each ATF system
The system scales on a linear basis from 1 L to greater than 1,000 L and can be used with traditional or disposable bioreactors and with all cell types including anchorage-dependent lines. Table 1 indicates the working volume sizes for each ATF System in the scale-up process. The figures in the table are provided as guidelines. Actual capacity and vessel size depend on process conditions.

This article compares the economic feasibility of a typical glycosylated protein manufactured using three production techniques—fed-batch (FB), concentrated fed-batch (CFB), and concentrated perfusion (CP). The Excel-based process-cost modeling tool, BioSolve from BioPharm Services (Chesham, Buckinghamshire, UK), was used for the economic assessment. The methodology, assumptions, and key results of the cost model are described. The analysis will use the cost of goods (CoG) metric expressed on a per gram basis for comparability.


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