By 2016, five of the top ten biopharmaceuticals are expected to be monoclonal antibodies (MAbs). Follow-on (biosimilar) versions of these blockbusters will most likely become available in the coming years due to patent expiry and the introduction of legislation for biosimilars. Personalised therapies will further drive the fractionation of the biopharmaceuticals market, thus increasing the need for smaller batch sizes and campaign-based production schemes.
A growing need for flexible, multipurpose and more cost-effective manufacturing will have a significant impact on the design of the production facilities in the future. Demographic and market forces place China in a position to lead the way in the transformation of biopharmaceutical manufacturing.
“Compared with other biopharmaceutical products, MAbs are large proteins that require relatively high doses – and therefore traditionally necessitate high-volume manufacturing facilities,” explains Niels Guldager. “Many biopharmaceutical facilities are still designed as traditional stainless steel facilities with fixed piping and tank layout and large bioreactor volumes. But such facilities require a significant financial investment with total installation costs in the range of USD 100-300 million.”
Recent increases in cell culture yields have led to significantly reduced bioreactor volume requirements, which again has opened the door for single-use manufacturing technologies such as pre-sterilised assemblies of plastic bags, tubing and filters that are only used once and then disposed of. With a concomitant financial investment reduction and simplified installation, single-use technology can be more appealing than stainless steel technology.
“Combining single-use technology and high-yield processes can further reduce the price tag for comparable facilities by 70 to 90 percent. This combination is being pursued in a number of biopharma facilities in China today – the full effect is truly a new biopharma manufacturing paradigm. Maybe the time has come to exit the stainless temples? China is reinventing biotech manufacturing because the future is now in this market”, says Niels Guldager.
Frank Nygaard elaborates on the subject: “Additionally, as products contacting surface are used only once, single use technology runs a much lower risk of batch-to-batch contamination, which is of particular importance in multipurpose facilities. A facility based on single use technology is easy to reconfigure and can therefore be ready for a new product in a matter of days”. This flexibility translates to reduced development timelines and thus accelerated time-tomarket peak. In an increasingly fractionated market the need for speed to secure market shares is more important than initial minimal cost of manufacturing. And with markedly increased cell culture yields, the cost contribution from the manufacturing facility is limited compared with development costs.
This is where the facility lifecycle enters the picture – with single-use technology it becomes possible to optimise facility installations based on anticipated life cycle stages. For instance, the strategy could be to start with just one single-use bioreactor to get material for clinical trials and then upgrade the facility with additional bioreactors later in anticipation of market supply production while clinical trials are taking place. As the next pipeline product must be developed, the facility can change the lifecycle stage back to clinical production and the extra bioreactors can be moved to a market supply expansion facility. Such a strategy becomes possible because single-use technology is so decoupled from the facility building itself.”
“As an interesting side effect, our environmental impact studies show that single-use technology is perhaps 50% less energy intensive than stainless steel manufacturing”, Niels Guldager points out and continues: “It may appear counterintuitive, but the emissions from disposing plastics are more than offset by elimination of the cleaning and sterilisation processes required for reusable technology, basically because heating up many tons of water is extremely energy intensive”. Full implementation of high yield processes and single-use technology results in facilities with a markedly reduced carbon footprint per kg product compared to the stainless steel facilities of the 1990ies. “So to that end you will most likely be going green by going single use, but the high yield process itself is the most important factor”, Niels Guldager concludes. The local aspect should also be factored in. Most facilities are designed for local supply, and a further reduction of carbon footprint by energy optimisation for local climate conditions and using locally available building materials will appear as new facility features.
The need for local biopharma manufacturing capacity is increasing in the fast growing emerging markets as the customer base expands and national initiatives manage the markets. The trend is being amplified by blockbuster patent expiry and the implementation of regulatory legislation for accelerated pathways for biosimilars. Frank Nygaard says: “For biopharmaceuticals, emerging markets are not about low cost manufacturing hubs, but about being on location to get access to the local market. Consequently, many big pharmaceutical companies as well as local manufacturers are investing in new facilities in these countries.” Because of the local focus, it’s a matter of several local facilities instead of one central facility for global supply. Such facilities must clearly meet local manufacturing regulations but also increasingly adhere to global Good Manufacturing Practice (GMP) standards. So here we see two new features of the biopharma facilities of the future. They are adaptable to local conditions and yet comply with global regulations as quality requirements are being harmonised. “A blueprint facility concept that can be established as interesting markets develop will become an important strategic asset for biopharma players with global aspirations”, predicts Frank Nygaard.
Niels Guldager continues: “You can talk of innovative production techniques in the sense that our emerging markets customers are highly innovative and open-minded and therefore capable of leveraging technologies and market dynamics radically. Obviously, the traditional stainless steel production concept may not be the right solution going forward; but while single-use facilities are still regarded as the plants of the future in mature markets, they are fast appearing as a preferred solution to the blooming biopharmaceutical industry in emerging markets.”
In China, new technologies and quality systems are being taken up at a rapid pace, so this emerging market is moving ahead of mature markets. China does not have a specific biosimilar regulatory path today, and any new therapy will need to go through all clinical development phases. This situation favours the development of biobetters or biosuperiors (products that promise additional advantages as opposed to just being similar). The patient population allows for extremely fast clinical trials and therefore fast and cost-effective product development.
“Since full clinical data will be produced, we see the emergence of new business models based on relatively fast initial product registration in China, followed by a strategy to leapfrog back to mature markets and obtain market approval, and perhaps based on a limited additional data set. When that happens, the blueprint facility concept will again be a strategic asset in order to expand capacity for global supply”, says Niels Guldager.
In reality, the important issue is not stainless steel or single-use technology, but rather how technologies can be combined to provide the most productive and costeffective process in a fast and predictable way. “Choosing one or the other technology concept or a hybrid of the two depends on both strategic considerations and feasibility studies of each individual case. The future will change biopharmaceutical manufacturing paradigms from stainless steel to hybrid combinations of single-use and stainless steel and complete single-use facilities. That is clear by now – and we see these opportunities being aggressively explored in China,” states Frank Nygaard. Today new biopharma manufacturing facilities have to be smaller and more flexible, efficient and cost-effective, and able to adapt quickly to changes in market demand. In the end it is not really about technology, but more about product and process know-how to get to the market. “In this respect, single-use technology is a magnificent enabler. For instance, we can now place an entire small-scale clinical production line inside a 100 m2 environment with these technologies. Biotech on demand – the ability to rapidly establish local manufacturing capacity based on new market opportunities – will become an important capability for successful companies in the future. And single-use technology combined with next generation facility design will do just that”, concludes Niels Guldager.