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Speed of response, small-scale manufacturing and process flexibility will become increasingly important.
The strategic focus of debate about the long-term development of biologics manufacturing is shifting away from its traditional emphasis on stainless steel and increasingly considering the softer issues of people and technology. Avecia's Dr. Stephen Taylor now discusses that as short campaigns of ever more complex, personalized biotech-drugs become an increased part of the product mix, so technology will grow as the third challenge in biomanufacturing.
Dr. Stephen Taylor
In exploring the factors necessary to secure long-term growth of a biomanufacturing industry, the three critical requirements of assets, people and technology loom large.
In recent years most of the focus has been on 'liters of fermentation capacity' — assessment of existing capacity and that under construction with comparison to projected market need. This rather imperfect analysis, based on assumptions about clinical success of products in the global pipeline, generated concerns that lack of capacity would constrain market growth of new products. This view was largely driven by the surge in the numbers of monoclonal antibodies in development and which require very large-scale cell culture biologics capacity. However, recent emphasis in biomanufacturing has moved steadily away from measuring outright investment in stainless steel.
Essentially, this is because it is now recognized that capacity supply and demand have moved into reasonable balance. They seem likely to remain so, with a number of new and expanded manufacturing facilities in North America and Europe being brought online — albeit though there are first signs of potentially unutilized capacity. These new facilities are the result of investment decisions made in 2001 and 2002, when concerns resulting from Enbrel capacity not keeping pace with demand, with associated loss of sales, first surfaced.
Accordingly, increasing attention and media coverage have been devoted to the industry's second challenge — the current and future supply constraints of people and industry-wide competition to secure the brightest and best. The lack of skilled people able to work in biomanufacturing — and, moreover, interested and keen to do so — has been and remains a concern for almost every business either setting up or expanding existing biologics operations.
Addressing this major challenge, which is recognizable in so many science-based industries, requires long-term action across the education community and at both national and corporate business levels. In the UK, the plan to establish a national bioprocessing network that will improve interaction between the manufacturing operations of the biotech industry and the academic training and development base is to be applauded and supported.
Through this mechanism the future leaders of our industry will receive inspiration, encouragement and training by exposure to real-life business operating experience. The UK has clearly identified that if it can get the people issues right at a national level and ensure availability of high-quality staff, then business investment and growth of operations should follow. In a similar vein, the recently announced national bioprocessing training institute in Ireland is also a positive step, aimed specifically at the people challenge — and in a country that has received considerable investment in capacity but where the people challenges threaten sustainable growth.
Capacity and people are of course the big drivers, but they have perhaps tended to obscure the third challenge which is now lifting above the horizon. That is the imperative for continued investment of time, money and human inventiveness in enhanced manufacturing technologies.
In one respect, technology is an obvious part of the story. That is, in the context of the growing market and competitive pressure to reduce development timelines and ensure that when new biologics do reach the market, they are economically viable as medicines and profitable to the companies developing them. If we consider some of the conflicting demands on drug development this need is clear. These demands include:
A focus on increased process and facility productivity is therefore both inevitable and necessary. There are a whole range of technical objectives that are part of the development process. Measures such as antibody titre, process yield, the number of stages of purification and capital investment are but a few of the typical targets for any development program. However, there is perhaps a less well recognized effect of the listed demands above that should influence strategic process research. That is the likely growth of personalized medicines. This is now starting to emerge because:
Whilst we should not overestimate the timescale by which this will start to impact — simply because of the very long timescale associated with drug development — it does seem reasonable to assume that our targeting of new drugs to populations where they have an effect will increasingly become a reality. The consequence of such a trend may well be a demand for smaller volumes of more customized biologic medicines — an effect that would erode much of the benefit that large-scale manufacture brings in ultimate production cost.
Thus the pressures on technology not only relate to improved manufacturing productivity and development time, but also to the need to create smarter manufacturing operations able to switch more easily between products and processes — and doing so without compromising on efficacy or patient safety. Speed of response, small-scale manufacturing and process flexibility will become increasingly important. Clearly, this would also place even greater demands and dependency on the skills of the workforce.
Despite these big issues faced by the biotech industry, it is worth reviewing the key global numbers for biologic products in 2004, since these help to illustrate the likely future scale of changing manufacturing needs. Today there are about 60 biologics with licensed status. Assuming only a modest survival rate through trials, another 50 could join them by 2010. The new arrivals would come from a combination of the nearly 400 biopharmaceuticals currently in trials and further 600 in pre-clinical development. There also remain at least 200 diseases (unmet needs) to be challenged so the growth in need is hardly an issue.
And while there are clear differences in mood, emphasis and financial attitudes characterising healthcare biotech in the US and Europe, the overall picture is one of growth and returning confidence after two very difficult years for the industry's self-esteem.
As Ernst & Young recently reported to a New York meeting, 2003 saw an increase in pharma biotech revenues of more than 22 percent; FDA approvals up by 25 percent and product sales of US $28 billion, marking the biggest revenue increase in the industry's history. Its 2004 Global Biotech Report put it like this: "... the stage is set for a tremendous increase in new products...the focus is on the end game, new drugs for patients. This recovery is about real products."
Accordingly, we can reasonably expect many more drugs in terms of absolute numbers, but probably within a gradually changing product mix, with quite possibly relatively fewer blockbusters.
Arguably, the rapid growth in monoclonal antibodies in development has tended to overshadow many of the other changes and needs that are relevant to biomanufacturing. This rather unique sector of the market offers substantial treatment options and with successful products such as Enbrel and Herceptin it has attracted continued major investment.
Purification strategies for antibodies tend to be straightforward and similar but cell growth and volumetric productivity remain rather limiting, thus technology advance has tended to address gene expression and process titre which now regularly achieves over 1 gram per liter. With mainstream diseases such as cancer and arthritis the target, manufacturing operations even early in the product lifecycle are normally based on multiple 10,000 to 20,000 liter batch vessels, underpinning 100s kilos per annum scale production. But away from the antibody sector there are some rather different needs.
There is now a clear trend in the industry towards a strategy of seeking early licensing of biologics targeted to small-volume orphan indications. Around 160 submissions have received Orphan Medical Product designation over the last three years with 90 percent of them from small bioscience companies. This strategy should help biotech companies achieve the milestone of an early biologics license in a cash-constrained environment. Simultaneously though, it also has a major impact on biomanufacturing by reducing many of the benefits and efficiencies of scale. Thus all of the costs of manufacture, facility compliance and product licensing are loaded onto relatively small volumes of product - will this compound the global concerns about biologic pricing?
This growing emphasis on short manufacturing campaigns calls for a highly flexible manufacturing regime, characterized by the ability to make continual fast changeovers between individual product runs that may be as low as only 2 to 3 batches per campaign. This creates very real pressures in terms of cleaning efficiency and ultimate asset utilization, where 24/7 manufacturing may no longer be a realistic business goal.
The scale-up and manufacturing challenges of the changing product mix notably apply to the contract manufacturing sector, which is taking a significant and growing share of a rapidly diversifying customer base. However, if it is to truly deliver the promise of helping the biotechnology industry bring effective, safe and affordable medicines to market — and deliver profitable activity in the process — this sector must meet a further challenge.
Many aspects of our manufacturing processes are crying out for more innovation and with CMOs growing as the recognized leaders in biomanufacturing, they must drive delivery, working with the regulators to help the industry through a discernable reluctance to adopt new technologies and operating strategies.
CMOs should take the lead in creating streamlined methods for process development, building flexibility into processes to enable effective operations across a range of scales, intensifying stages such as protein re-folding and developing innovative procedures for fast facility turn-around between campaigns and products. Disposables technology will certainly have a place, but with its associated high consumables, cost may not always be the best solution. Continued innovation at the interface of science and engineering is needed and the CMO sector must rise to the leadership challenge.
While 'stainless steel' capacity issues will, periodically, re-occupy center stage in response to market forces and everyone will seek the top talent and the right people balance, it is in process technologies that the healthcare biotech production leaders will most likely compete for differentiation and supremacy.
It's not hard to see technology as the focus for the next real arms race in biomanufacturing. Meanwhile, we must not forget that the ultimate aim of this strategic contest is to speed up development and contain and reduce the cost of goods because, in the final analysis, making more and better drugs and treatments affordable for, and beneficial to, patients is the real driver for what we do every day.
This article was first published in Contract Services Europe (November 2004, 14-17) and is reproduced with kind permission.
Dr. Stephen Taylor is the general manager at Avecia Biotechnology, P.O. Box 2, Belasis Avenue, Billingham TS23 1YN, UK, 44.1642.363.511, fax 44.1642.364.463, firstname.lastname@example.org , www.avecia.com