The US Food and Drug Administration (FDA) and the Department of Agriculture have erected a series of barriers to protect humans from exposure to the fatal agent linked to bovine spongiform encephalopathy (BSE), and measures announced by the FDA in January 2007 build on those barriers. With its heavy reliance on mammalian cell-based expression systems, and with the problem of serum-free versus protein-free versus productivity, the biopharmaceutical industry continues to need chemically undefined or defined supplements of animal and human origin. To move toward avoidance of animal- or human-derived materials used during biopharmaceutical manufacturing, the industry is increasingly looking at alternative raw materials and is investigating the benefits of non-mammalian expression systems that offer simpler and chemically defined growth conditions. New recombinant raw ingredients are becoming more readily available and have been developed specifically for use in large-scale mammalian cell culture. Animal-free microbial expression systems have made such products possible, and these may themselves offer solutions to some regulatory and productivity issues the biopharmaceutical industry faces.
MAMMALIAN PROTEIN EXPRESSION
REGULATORY REQUIREMENTS FOR THE PRODUCTION OF PHARMACEUTICALS
Due to the threat of contamination from bovine materials infected with BSE and the threat of transmission of variant Creutzfeldt-Jakob disease (vCJD) from HSA, regulatory authorities worldwide have issued guidelines that govern the use of animal-derived materials in pharmaceutical products. For example, both the European Medicines Agency (EMEA)2 and the Center for Biologics Evaluation and Research (CBER) of the US Food and Drug Administration (FDA)3 have issued guidelines for the controlled use of animal-derived materials for pharmaceuticals from sources with a risk of BSE or vCJD infection.
In addition to existing guidance, in January 2007 the FDA announced further proposals to prohibit the use of certain bovine materials as ingredients in some medical products or as elements of product manufacturing. These proposals are the latest in a series of BSE safeguards that would bar material that harbors the highest concentrations of this fatal agent in infected cattle.
To ensure that companies comply with these prohibitions, the FDA proposes that records be kept to demonstrate that any bovine material used as an ingredient in these medical products or as part of their manufacturing process should meet FDA requirements. This proposal is in addition to measures that companies must already take to reduce risks from serum-derived products, including:
Current efforts in the US to minimize the risk of BSE infection from pharmaceuticals are in line with those in place in the EU since 2003.4 These US regulations require manufacturers of medicinal products to undertake and document extensive risk assessments on all animal-derived materials used in any aspect of pharmaceutical production, including in the preparation of active substances, excipients, adjuvants, and raw starting and packaging materials. Those assessments should be based on:
Today the use of animal-derived materials in pharmaceutical production places an increasingly onerous burden on product manufacturers to comply with established requirements.