Historic supply chain shortages of cell culture media ingredients have raised costs for biological therapeutics and monoclonal antibodies upon which many biotechnology companies depend – until now. New technologies are reducing the costs of technical development and commercial manufacture for these key medicines by delivering affordable, high quality chemically defined ingredients for cell culture media. The impact on future profit margins and innovation in the sector promises to be significant.
Albumin costs deter innovation
Cell culture is the ‘broth’ that maintains the optimum environment for cell growth and maintenance, whether the cells are the therapy themselves or they are secreting therapeutic proteins. A key component of cell culture media is albumin, a multifunctional protein found in blood serum. Patents and the retention of know-how have historically limited the supply of consistently high-quality pure recombinant albumin. This has driven up the price with indirect consequences for innovation, development cost and biologics’ gross margins.
In recent years, chemically defined media has become the preferred option for regulatory purposes and process optimisation. It has defined components in known concentrations and uses recombinant albumin rather than animal-derived albumin to avoid problems associated with batch-to-batch variability and pathogenic viral and prion contaminants. However, recombinant albumin is in short supply too, which has driven up costs due to the protected patents and know-how of its original developers. Its use has therefore been limited to high-value therapeutics where albumin forms part of the final product, such as childhood vaccines, or increasingly in cell and gene therapy, which often requires specialist forms of albumin.
P. pastoris and rice struggle with quality
The most consistently high-quality and pure recombinant albumin is produced by baker’s yeast, Saccharomyces cerevisiae. However, the technical challenges of developing a manufacturing process capable of delivering scalable, affordable, high-quality pure recombinant albumin from baker’s yeast have deterred new entrants. Instead, manufacturers seeking to meet the supply chain deficit have tended to use Pichia pastoris (another form of yeast) or rice in cell culture media.
Unfortunately, these albumins lack the equivalent approval from the regulatory authorities compared to recombinant albumin from baker’s yeast. They contain proteins from the host species and other contaminants that must be adequately removed from the final products in expensive downstream processing steps. They are more heterogeneous and contain molecular forms not seen in humans, which raises serious immunogenicity concerns. Inconsistent performance can also be an issue owing to variations in the molecular groups needed for their correct function in cell culture media.
New technology optimises albumin production strains
Quantitative Trait Loci (QTL) technology brings the full power of biology to the optimisation of baker’s yeast strains for the manufacture of specific proteins and peptides. This has allowed the know-how barriers of recombinant albumin manufacture to be circumvented. The recombinant albumin resulting from the QTL-optimised production strains of baker’s yeast matches the highest quality on the market while being scalable to manufacture a consistent product at a lower cost.
The recombinant albumin generated by QTL technology avoids the inconsistencies of the alternative existing sources of recombinant albumin while delivering a product from a source that regulators have previously approved as a component of regulated therapeutic products.
Enhancing in-house innovation
The immediate benefit of affordable high-quality recombinant albumin from S. cerevisiae is reduced development costs of new biologics in discovery and an increase in the gross margin of those already on the market. Affordable, high-quality recombinant albumin can significantly boost in-house innovation.
The breadth of discovery activity that can be undertaken for similar budgets can be expanded, catalysing more successful product development and greater prosperity. Specialist formulations of albumin are also optimum for certain biologics, which have previously been unavailable or inaccessible in the supply chain. This provides scope to improve manufacturing processes, extend patents and potentially develop better versions of existing products.
Disrupting an effective monopoly
The costs of cell culture media are not always a high priority for businesses that enjoy the high margins associated with biological therapies. Many businesses prefer not to disturb regulators with changes in substances consumed in regulated manufacturing processes unless absolutely necessary.
However, the effective monopoly of high-quality recombinant albumin and other key components has a price that is paid by the entire sector in terms of lower innovation and productivity. By the same token, undertaking this relatively straightforward switch has commercial benefits that expand beyond profit margin, enabling in-house cell line teams to extend patent cover, increase know-how, boost innovation and potentially develop higher-value products such as bio-betters.