Many biological therapeutics rely on Contract Development and Manufacturing Organisations (CDMOs) to develop cell lines for manufacturing and deliver regulated batches for pre-clinical and clinical development programs. However, limited access to a critical ingredient of cell culture media, recombinant albumin, holds back the good work of CMDOs.
Demand for recombinant albumin raises costs
Albumin provides key nutrients to cells within cell culture media. It also preserves the functions of essential growth factors and other media constituents while protecting the therapeutic proteins being manufactured. But the market’s growing preference for chemically defined media has raised demand for recombinant proteins as a replacement for those derived from animal sources such as foetal bovine serum (FBS). The most abundant protein in FBS is albumin.
The highest quality recombinant albumin can be manufactured using baker’s yeast (Saccharomyces cerevisiae), but until recently, its manufacturing process was protected by patents and proprietary know-how. This led to high prices and scarcity of supply because most of the material produced was used in highly-priced medicines, such as those where albumin forms part of the final product, and increasingly in specialist albumin formulations for cell and gene therapy.
The technical challenge of devising a form of recombinant albumin that is consistently high-quality, pure and affordable has driven up the costs of chemically defined media, with repercussions for the entire sector.
Alternative albumin sources fall short
The popularity of chemically defined media with both the market and regulatory authorities is due to better batch-to-batch consistency and no risks from pathogenic viruses and prions. Chemically defined media also make process optimisation more tractable for CDMOs because each media constituent is fully defined.
To meet this demand, alternative sources of recombinant albumin have been created using Pichia pastoris or rice. However, these risk host cell proteins and impurities, potential adverse reactions in patients, high downstream processing and purification costs, and batch-to-batch inconsistencies.
New technology, new solution
Fortunately, new technology allows CDMOs to reduce their costs and devise innovative commercial offerings to command a fair share of the value they create over the lifespan of the products they have been involved in. Quantitative Trait Loci (QTL) technology uses the power of evolution in iterative breeding, in combination with functional genomics, to optimise progeny strains for multiple parameters at the same time.
This enables new baker’s yeast strains to generate consistent, high-quality, pure, affordable recombinant albumin at scale for use in manufacturing. The end product is suitable for inclusion in chemically defined cell culture media and avoids the impurity and infection risks of the alternative sources. The excellent quality control mechanisms present in the baker’s yeast ensure that the recombinant albumin secreted is highly homogeneous, correctly folded and fully functional (Frahm et al. 2014).
Benefits to a CDMO
Reducing the cost of cell culture media clearly helps CDMOs offer more competitively priced cell line development programs during the discovery stage, which may encourage clients to run more of them. It increases the likelihood of products reaching the market, especially as cash resources can be limited in higher-risk programs. This will tend to improve profit margins and expand market share in a competitive market.
Creating better-optimised cell lines and cell culture media provides opportunities for proprietary innovation, enabling CDMOs to gain more upside value from the programs in which they invest their expertise to create scalable efficient manufacturing processes. This discourages clients from switching manufacturing in-house once regulatory approval is obtained.
Future therapies depend on specialist cell culture media
Disrupting the historic monopoly of recombinant albumin supply promises to free CDMOs and many other biological therapeutic businesses from reliance on a few incumbents who generate patented specialist forms for optimum performance of cell culture media in cell and gene therapy. This mitigates the risks of being shut out of key markets of the future, while also bringing benefits to monoclonal antibody projects, which are on the frontline for key indications and also dominate many development pipelines.
