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
Biotherapeutics—including recombinant proteins, monoclonal antibodies, and nucleic-acid-based drugs—represent the largest
growth sector in the pharmaceutical industry, with a market size estimated at $33 billion and projected to reach $70 billion
by the end of the decade. Of the 31 therapeutic proteins approved since 2003, 17 are manufactured using mammalian cell lines.1 Mammalian cell culture is the method of choice for manufacturing large complex proteins, especially those requiring posttranslational
modifications, such as glycosylation.
Traditionally, a range of animal-derived protein products—including fetal calf serum, peptones derived from acid or enzyme,
hydrolysates of casein, gelatin, meat, egg, lactalbumin, and bovine serum albumin (BSA) or human serum albumin (HSA)—have
been used for mammalian cell culture media for research and commercial-scale manufacturing of biopharmaceuticals. These ingredients,
together with supplements such as human holo transferrin and insulin-like growth factors (IGF), are added to promote cell
growth, survival, and optimized productivity.
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
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:
- evidence of select sourcing of animals
- testing for the presence of adventitious agents
- inactivation or removal treatments for contaminating agents.
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:
- source animals and their origin
- the nature of animal-derived material used and cross-contamination procedures
- systems in place for ensuring product consistency and traceability.
Today the use of animal-derived materials in pharmaceutical production places an increasingly onerous burden on product manufacturers
to comply with established requirements.