One of the most significant challenges facing the Bio-Pharm industry in recent years has been how to reduce development timelines and cost; billons of dollars have been invested in this area, with significant success. This has included the adoption of high throughput screening technologies, rapid single stage scale up of manufacturing process and, not least, the widespread adoption of single use technologies in development and manufacturing facilities for the production on antibody based products as highlighted in Amgen’s recent investment in Singapore. In an industry that is often perceived as being “highly conservative” and risk adverse, these changes show that “where there is a will there is a way”, and the industry can be highly innovative if the benefits are high enough.
The impact of this has been to establish new norms for the development times and costs for new products and manufacturing approaches adopted. This raises the question of how we deal with those products produced by production routes that fall outside of this new “norm”, which cannot be produced using highly developed platform processes and produced in flexible single use facilities. Not least amongst the products that fall into this category are those produced using microbial production platforms; smaller non-glycosylated proteins addressing new therapeutic targets via microbial production routes. Within development groups, microbial production routes are perceived as “low cost”; cloning occurs in days and products can be produced in weeks within the lab, fermentations are short and performed with low cost media, they must be cheap to produce? However, we then start to hit a few roadblocks.
Tradition has it that these products are produced at scale as intracellular inclusion bodies by high density fermentation, recovered by large scale continuous centrifugation and high pressure homogenisation and complex “refolding” approaches and then purified by de-novo large scale chromatography approaches including HPLC. Each process has to be developed on a de-novo basis, going through multiple scale-up steps ahead of clinical production in complex, inflexible production facilities and, as with all ne-novo developments, it carries a high risk of failure. The problem is that whilst this approach may have been acceptable 25 years ago, it falls along way outside current expectations and starts to become an unattractive production route for new therapeutics.
This poses the question of how the bio-process community should address this dilemma? The first issue is that technology and production approaches have remained largely unchanged for the last 25 years with limited investment in R&D or production facilities; the second is that the mechanical limitations of single use systems means that many traditional operations now have single use options available. From my perspective this creates a significant opportunity for innovation from a scientific and engineering perspective; we see companies developing new “scaffold” based product types that allow for the development of “platform” based production routes. The real challenge is how we seek to drive out the cost, complexity and risks associated with these production routes. How we seek to make these approaches more suited to the capabilities of single use systems and how single use suppliers can develop their offerings to meet the processing needs of microbial products.
We are starting to see significant developments with regards to synthetic biology approaches, to the development of engineered production strains in academic labs with refolding and secretory capabilities and suppliers such as GE and Thermo Fisher, developing bio-reactors capable of growing microbial cultures, but there is still some way to go. However, the real driver for this will be the industry working with both groups to champion these developments to allow for the adoption of the innovations to overcome current road blocks and help bring these production routes back into favour and meet the needs of drug development groups over the coming years.
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Pharma IQ: Making Tomorrow's Medicines
Tony will be presenting at the Disposable Solutions for Biomanufacturing Asia conference, 2-4 December 2014; find out more and arrange your meeting with Tony in Singapore.