Balancing Media Development with Patient Safety - - BioPharm International


Balancing Media Development with Patient Safety

BioPharm International Supplements

Serum and the Impact on Patients

Media development and the need for chemically defined and non-animal–derived materials has become very significant in today's industry to eliminate potential risks to patients.

Animal-derived components have hit the headlines on several occasions. The 1970s brought cases of mycoplasma contamination, endotoxin concerns were raised in the 1980s, and bovine spongiform encephalitis (BSE) and the resulting transmissible spongiform encephalopathy (TSE) fears dominated the 1990s. The biopharmaceutical industry has since tightened controls over the sourcing and final composition of raw materials. In February 2002, the US Food and Drug Administration strengthened its regulations for BSE protection systems for the pharmaceutical sector to reduce theoretical risks associated with it.

Animal cell culture was first established for the production of viral vaccines in the 1950s, using monkey kidney cells to produce the polio vaccine. Successful growth of this adherent cell line depended on the addition of serum to the growth media.

Bovine serum contains numerous beneficial components, including macromolecular proteins, low-molecular weight nutrients, anti-oxidants, and carrier proteins for water-insoluble components such as hormones, lipids, amino acids, and globulins. In addition, serum contains a high level of albumin and transferrin. The former is believed to protect cells from shear forces and stress factors generated under bioreactor conditions, such as fluctuations in pH or nutrient concentrations, and the latter is an iron-carrying glycoprotein needed by CHO and NS0 cell lines for optimal growth.

Despite the positive properties of bovine serum, this undefined raw material can contain adventitious agents and detrimental by-products such as bacterial endotoxins or immunogenic contaminants. More commonly, it can contain viral contaminants, which often do not produce cytopathic effects or morphological changes in cell cultures, and once present, viral contaminants are almost impossible to remove. Other potential contaminants include fungi, prions, and bacteria/mycoplasma, thus raising concerns about patient safety.

It was not until the middle of the 1960s that a serum-free medium was first used for mammalian cell culture.8 To achieve the same growth-promoting effects as experienced with serum, it was necessary to replace the role of serum with other animal-derived components such as albumin, insulin, and transferrin, which for many years were obtained from animal-derived sources.

The adaptation of mammalian cells to serum-free conditions greatly increases the safety of the subsequent bioproduct and there are regulations to avoid animal-origin components for fermentation. Research into serum replacement gained momentum in the 1970s, when studies replaced the complex serum component with an equally complex animal-derived protein hydrolysate, thus still presenting a contamination risk to the bioproduct. This work was subsequently followed by their replacement with non-animal–derived protein hydrolysates, such as vegetable peptones. These are being used extensively in the industry to replace serum and now chemically defined serum replacements are widely available.

Unfortunately for a few cell lines, chemically defined media do not adequately meet the specific nutrient requirements, so media screening has become exhaustive and supplementation may still be necessary in many instances. Fortunately in these cases, many of the necessary supplements, including insulin, transferrin, and albumin are now readily available from non-bovine sources. This enhances their overall biological safety but side-steps the issue of eliminating media complexity and subsequently process complexity. Only further raw material development will make such changes easier.

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