by Nick Hutchinson
Last month, speakers from UCB Pharma, Biogen Inc and Amgen were describing next generation processes development – platforms, products and plants during the opening plenary session of the BioProcess International European Summit. The industry, it would appear, is continuing to evolve its approach to manufacturing operations in response to changing market conditions and innovations in production technologies.
In the past, monoclonal antibodies typically made up a significant proportion of company’s pipelines. Recently, however, these pipelines have become more diverse and so the manufacturing networks of large biopharma companies need to be “modality agnostic”. This diversity extends beyond just the type of molecule being produced but also extends into the dosing regime, such that drug product facilities must be suitably adaptable.
Increasing drug potencies and specificities are leading to a downwards trend in the production volume requirements for a given product. However, at the same time, products are nowadays expected to be supplied to global markets rather than a handful of geographical regions. Uncertainly in forecasted demand is growing as firms extend their reach into previously unchartered markets and the industry become more competitive. Biopharmaceutical companies are placing greater emphasis on developing agile manufacturing networks and larger firms see operations functions as a key value driver to be integrated into corporate goals.
From a technology perspective, process sciences have allowed the industry to increase bioreactor titers from less than 1 g/L to 10 g/L. Speakers explained how titers continue to increase and double approximately every six years. This has led to a decrease in the Cost of Goods of a typical biopharmaceutical from around $100,000 g/L to approximately $100/g. Whereas the recovery of biologics during downstream processing was once in the range 20-30%, a company can now reasonably expect their purification yield to exceed 50%.
Firms have invested in process intensification efforts that are now allowing them to operate smaller production facilities. An example of this the use of perfusion technology in the N-1, seed bioreactor. This allows the production bioreactor to be inoculated with a high concentration of viable cells. This kind of approach ensures the capacity is used to gain maximal productivity given production bioreactor are often facility bottlenecks.
Single-use technologies become a more viable option for companies as productivity improvements lead to a decrease in facility size. These are an important innovation that have allowed biomanufacturers to increase the flexibility of their production networks. They significantly limit the risk of product cross-contaminations in multi-product facilities and allow rapid product changeovers, which can increase facility throughput. They are commonly used during the productions of clinical lots but are increasingly being used for the commercial manufacture of biologics. This trend is indicative of the industry’s increasing confidence in the technology and its acceptability by regulatory agencies. Suppliers are evidently being successful at allaying previously held concerns such as possible extractable and leachables, container closure integrity and single-use supply chain assurance.
These so-called ‘flexible facilities’ are allowing firms to bring new products to market very quickly and with lower upfront investment than would be required for a more conventional production plant design. They permit closed-system processing that arguably enhances regulatory compliance. Potentially they can decrease the footprint needed for a facility from 750,000 ft2 to 120,000 ft2 and, although they produce more solid waste, they require less water and generate less carbon dioxide.
Are flexible facilities the solution to the challenges that biomanufacturers face?
Large, 6-pack, stainless steel facilities certainly require significant upfront investment and their construction needs to be started earlier during the clinical development of products. In other words, such facilities need to be constructed while the uncertainty in the product volume requirement is relatively high. If the anticipated market demand does not materialize as forecasted then neither will the return on the invested capital. There is a financial benefit in having the option to delay the investment decision.
Furthermore, having global production centralized to a single-location potentially increases risks should supply from that site be disrupted. Operating smaller, localized facilities on different continents limits the dependency of supply on a single plant.
Nevertheless, large stainless steel facilities do allow biopharmaceuticals to be manufactured with low cost of goods. The speakers at the BioProcess International European Summit highlighted that different manufacturers will adopt different approaches depending on their circumstances. For example, the Neuroscience market segment that Biogen serves demands large volumes of protein. The company, therefore, recognises that it must operate a hybrid model with three different types of facility; flexible facilities, 2k-L facilities and 15k-L facilities.
For the time being at least, hybrid approaches of large and small plants seem to be the best way of creating efficient yet responsive biomanufacturing networks.
Nick Hutchinson is a Technical Content Marketing Manager at Sartorius Stedim Biotech.