Overlooking the importance of optimum manufacturing strains for biological therapeutics can mean that you discover a production problem too late in the development process, putting entire projects at risk of failure – and even the business itself. Fortunately, new technology offers capabilities that can breathe life back into faltering programs.
Off the shelf solutions have risks
During the development of a new biological therapeutic, executives tend to focus on establishing a suitable mechanism of action, and finding a suitable candidate, followed by the design and execution of pre-clinical and clinical development. While a viable means of manufacture is usually recognised as a pre-requisite for any project, in-house expertise in chemistry, manufacturing and controls (CMC) is sometimes limited. Fatefully, this can encourage decision-makers to buy an off-the-shelf solution that is perceived as a safe bet, delegating responsibility to manufacturing specialists.
For projects that are both technically and commercially demanding, opting for a merely adequate strain or an off-the-shelf solution, can be high risk.
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Strain concerns deter investment
Underestimating the value of developing an optimum manufacturing strain carries other potential costs. Due diligence on a promising biological therapeutic project can highlight key issues associated with manufacture that undermine its feasibility. For venture capitalists this can lead to refusing investment of otherwise promising projects, or the realisation post investment that certain investee companies may have fundamental viability issues associated with manufacture. Another high risk scenario is a proposed out-licensing of a product with promising data, only to find in due diligence the exacting standards of big companies for manufacturing viability are not met.
Standard strains limit titre
Titre is the usual focal point when considering the development of a manufacturing strain. For good reason, titre establishes what quantity of protein can be generated upstream in fermenters per capacity unit (litres) of plant. The higher the titre, the lower the cost of goods, the greater the commercial scalability and the less capital expenditure required or plant capacity to be contracted.
This is the first area where established solutions can be fit for purpose – or where problems may arise. Solutions tend to revolve around defined chassis of E.coli, CHO or Pichia pastoris with a defined and established genome. Should this prove less than satisfactory, a limited amount of genetic engineering may be undertaken to seek to improve the titre. Unfortunately, this doesn’t always deliver the hoped-for benefits, even if headline titre is high.
Limited titre raises cost of plant
When the product sells, or is forecast to sell, at a high price, titre may be seen as a luxury rather than essential. However, titre can also require expanding the scale of plant, which can jeopardise the project if large-scale finance is not available to build it, or the timelines are too long. Alternatively, if the strategy is to contract with a contract manufacturing organization for the manufacturing, the requisite capacity of plant may not be accessible.
Net titre matters most
Calculations may suggest the titre is sufficient for gross margin purposes, but if the related manufacturing process involves complex and expensive downstream processing and/or issues of consistency and quality, then the commercial viability of the project may still fail due diligence.
Genetic diversity boosts titre potential
Strains containing a single chassis or those amended by genetic engineering have limited scope to improve titre and meet other manufacturing needs for technical and commercial viability. Such chassis have a fixed genotype with a fixed combination of genetic variants at each gene. The base variations of such genes needed to deliver the specification cannot be established using standard research and strain development methods. Consequently, when the requirements fall outside those deliverable by standard chassis, they struggle to optimise.
Evolutionary approach harnesses the entire genome
QTL Strain Optimisation technology overcomes these shortcomings by using the power of evolution to find the optimum strains using proprietary strain libraries which contain enormous genetic diversity. This can be of critical importance to biotechnology companies but also venture capitalists and CDMOs. Projects that are otherwise not suitable for investment become viable, problem portfolio projects can be transformed, client manufacturing issues can be resolved, and out-licensing or sale transactions that would otherwise risk failing in due diligence, can be completed.
Foresight can save the day
When there is a potential manufacturing problem, it is often the responsibility of more impartial institutional shareholders or contract manufacturing suppliers to raise the alarm. In other cases it may be the client who sees the problem and tasks CDMOs to find alternative solutions that are affordable, deliverable, and that don’t slow development timescales. Success in doing so can secure a lucrative manufacturing supply contract for clinical development and commercial launch.
Summary
Busy biotechnology companies tend to focus on their area of specialism and neglect the manufacture of biologics. A whole industry exists to service these needs, but the capabilities of this industry fit within defined technical constraints. If the product requirements are outside this bandwidth, strains adequate for early stage development may torpedo the project as it advances.
