Production Of Biologically Active Substances By Serumfree Cultures

Animal cell technology has allowed the production of a great diversity of biological substances including monoclonal antibodies, vaccines, hormones, and other regulatory molecules. The development of serum-free media has improved these processes by conferring many advantages as discussed previously.

The vaccine industry has seen the emergence of new processes for production utilizing serum-free culture systems. In many cases the traditional method of production has led to many problems including adverse allergic reactions (e.g., from chick eggs used to propagate the virus) to the transfer of biological contaminants from animal components used in the process. Furthermore, many of the more traditional processes were inefficient and time-consuming. The use of animal cells for the production of vaccines alleviated some of these problems by allowing large-scale production with minimal supervision and monitoring. However, the use of serum in the culture medium was still required, which posed the threat of transferring contaminants to the end product. The recent advancements in serum-free formulations have reduced the dependence on serum in industrial-scale processes. This has allowed the minimization of potential contamination by adventitious agents.

It has been demonstrated that serum-free cultures can have comparable productivity to their serum-supplemented counterparts and have been widely accepted in industry. Some examples of vaccines produced today under serum-free conditions are rabies, polio, and influenza (122-126). Other important viruses, such as HIV, adenovirus, and reovirus (to name a few) have also been produced under serum-free conditions (127-129).

Serum-free culture systems have also been used for the production of other biologically active substances. Cytokines, which include the lymphokines and interferons, are of particular interest to industry due to their involvement in the immune and inflammatory responses within the body. IL-2, for example, has been produced from BHK cells under serum-free conditions employing both stirred tank reactors and a hollow fiber system (130). The yields of the system ranged from 0.75 mg/L in the stirred tank system to 0.23 mg/L in the hollow fiber module, where the cell densities reached 3.0 x 107 cells/mL and 6.0 x 107 cells/mL, respectively. Another group discovered that IL-2 production between serum-containing and serum-free cultures resulted in identical titers (131).

The production of interferon has been achieved in a wide variety of cell lines under serum-free conditions. Gamma-interferon, for example, normally obtained from T- or B-lymphocytes, has been produced using CHO cells (132). In this case certain components of the serum-free medium were important for interferon production and affected the productivity of the culture system. They included BSA, sodium pyruvate, glutamate, methionine, proline, histidine, hydroxyproline, tyrosine, and phenylalanine. Similarly, the production of beta-interferon in Namalwa cells under serum-free conditions has been studied (133).

Other biologicals, such as tissue plasminogen activators (tPA), blood clotting factors, hormones, and polypeptide growth factors have been produced in vitro in serum-free cultures. Some examples of these processes include the production of tPA. In this serum-free system, cultures of fibroblasts on Cytodex-3 microcarriers gave yields comparable to that of 5% fetal bovine serum-containing media (134). Also, a serum-free culture of CHO cells in the production of recombinant human growth hormone allowed the elimination of a final purification step (135). The elimination of serum has allowed continuous nutrient optimization to improve the productivity (136).

The importance and wide-spread use of monoclonal antibodies in the pharmaceutical industry has led to the development of better serum-free formulations for large-scale production. They are becoming a standard for industry due to the high reproducibility of growth conditions, the ability to optimize nutrient requirements, and the reduction of possible contaminants. Furthermore, hybridoma cells grow well in suspension culture and are relatively easy to adapt to serum-free formulations compared to anchorage-dependent cell lines, which tend to be more fastidious. For these reasons they are commonly adapted to serum-free media for large-scale production systems.

In most cases the conversion to serum-free media has led to improvements for the biopharmaceutical industry, including increased productivity, efficiency, and cost-effectiveness.

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  • ines marcelo
    What are the biological active substances that are used in the production of vaccine?
    2 years ago
  • jill
    What are the biological active substances that are used in the production of vaccines?
    2 years ago

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