Balancing Media Development with Patient Safety - - BioPharm International

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Balancing Media Development with Patient Safety


BioPharm International Supplements


Media Supplementation

Supplementing animal and human cell culture with sera of animal origin still remains a standard practice despite its reputation as an ill-defined, highly variable component. More and more companies are, however, choosing to develop biologics in serum-free conditions. For the manufacture of recombinant therapeutics using bacteria, casein- or meat-derived hydrolysates are frequently used in such fermentations. The trend in this area is to replace casein-derived hydrolysates because most of them are manufactured with animal-origin enzyme systems. Many media suppliers put a significant amount of work into developing hydrolysates produced using non-animal–derived enzyme systems such as vegetable hydrolysates. Quest International (Irvine, CA) was the first to market non-animal–derived protein hydrolysates for serum replacement, maintaining at least the same productivity as when serum was used. Since this breakthrough, a series of non-animal–derived protein hydrolysates have been developed such as the Hy-Pep series, including Hy-Soy, Hy-Rice, Hy-Cotton, Hy-Wheat, Hy-Pea, and Hy-Yest, all developed as serum replacement alternatives. Complementing these is a series of large-scale bulk fermentation hydrolysates. In July 2009, SAFC Biosciences (Lenexa, KS) introduced EX-CELL CD Hydrolysate Fusion, the first chemically defined cell culture supplement based on hydrolysate characterization that promises to match the capabilities of traditional undefined hydrolysate raw materials in CHO, NS0, and Sp2/0 bioprocesses. In November 2009, SAFC Biosciences further introduced EX-CELL ANTIFOAM, a non-animal–origin antifoam to increase consistency, efficiency, and stability of cell culture manufacturing.

Movement to less complex and animal-origin free culture media does not come without its share of problems. The term animal-origin free refers to any component not directly derived from eukaryotic animals (excluding higher plants, fungi, protozoa, and algae) and media suppliers are now being asked to provide certificates of origin of their components ensuring their source is non-animal–derived, and if it is, then it is from a country not affected by the BSE outbreak.

Suppliers of raw materials are under no obligation to provide raw materials free from contaminants, but audits performed by biopharmaceutical companies exercise stringent guidelines and specifications highlighted by the regulatory authorities. Raw materials must be fit for their intended use and show a high degree of consistency between batches. This generally presents no problem because most raw material suppliers adhere to current good manufacturing practices (cGMP) and are ISO 9001:2000 accredited, which is ensuring the relevant SOP documentation is readily available on request.

What Degree of Animal-Free?

The degree to which a product has come into contact with a raw material of animal origin is defined as a level. The primary level indicates that the finished product itself and its associated manufacturing process are free from animal-derived components.

Secondary level classification is the most common, and ensures that raw materials used to manufacture a primary raw material to be used in a manufacturing process are animal-origin free. For example a peptone derived from E. coli grown in a culture containing non-animal–derived components would be classified as secondary level.

The most challenging standard of a component is the tertiary level, requiring that starting raw materials, needed to produce secondary raw materials, are animal-origin free. A raw material can be classified as tertiary level if it contains animal-derived components that are classified as very low risk. This requires an extensive audit trail and because of difficulties in establishing, monitoring, controlling, and maintaining such stringent guidelines, many biopharmaceuticals manufacturers are avoiding tertiary level components and settling with secondary level materials. Even tertiary level components can cause a debate. Should material be classified as tertiary level if it has been at all associated with material of animal origin? Establishing animal-origin–free facilities requires that all of its suppliers provide animal-origin-free products, and that all of their suppliers do the same. Even if one company uses no animal-derived components, there remains a risk of contaminant carryover from the processing steps of its suppliers.9


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