Bright outlook for biologics

Dr Iain Crowder, strategy manager for Avecia Biotechnology, examines the issues facing biologics-based medicines, such as capacity and demand expectations and the need to enhance productivity if these exciting new drugs are to pass the vital cost-of-goods test

First approved for sale in the early 1980s, many biologics are protein-based medicines - where biological substances or their derivatives are made through the application of bioprocess technology, rather than isolated from natural materials. There are now more than 70 such products on the international market, used to treat conditions such as leukaemia, diabetes, multiple sclerosis and growth defects. They account for about 25% of all new drug approvals, with some 400 in clinical trials and at least that many again in pre-clinical studies.

A couple of years ago, final form biologics represented only US$15-16bn - or 5% - of the $320bn. global healthcare market. But comfortable double-digit growth, running well ahead of pharma's more pedestrian 6-7%, indicates launched biologics sales of perhaps $30bn by 2005. This growth will be fuelled by a combination of recent market launches of new products; new formulations and delivery mechanisms for existing products (which extend their life cycles), and new approvals for products presently in late stage clinical trials.

However, this growth can be supported only by manufacturing capacity increasing at the same pace. Although there is general widespread availability of early clinical manufacturing at relatively small scale, analysis of requirements at large scale for late stage clinical and licensed products suggests that there is a capacity deficit. So for in-house (captive) and contract manufacturers alike, as well as those companies developing the products of the future, these projections indicate a major challenge over the next few years.

For biologics production the two dominant expression technology platforms are microbial fermentation and mammalian cell culture. Historically, both platforms have been applied in approximate parity, though the large numbers of monoclonal antibodies entering development in recent years - as well as some of the newer experimental therapeutics - suggests that presently the demand for cell culture is greater. However, both platforms figure strongly in announced plans for biologics capacity expansion.

genetic engineering

Examples of specific microbial-derived biologics include Neupogen (filgastim) and Betaseron (interferon β-1b). Leading mammalian-derived biopharmaceuticals include Enbrel (etanercept) and Epogen (epoetin a), and monoclonals such as Rituxan (ritaximab), Synagis (palivizumab) and Herceptin (trastuzumab).

Microbial fermentation involves applying advanced techniques of genetic engineering to strains of yeast or bacteria, causing them to generate large amounts of desired protein when grown in fermenters. Expression through mammalian cell culture is the preferred 'upstream' approach when glycosylation of the protein is required for functional and therapeutic efficacy. In some instances - for example, the production of monoclonal antibodies - microbial fermentation is not an option because of this reason, though micro-organisms are capable of manufacturing antibody fragments, a relatively recent area of interest.

Other technologies being used for expression of therapeutic proteins include transgenic animals and plants, although as yet no product from either of these approaches has received marketing approval.

Both recombinant microbial fermentation and mammalian cell culture are well-established technologies in historical as well as regulatory terms, having been associated with expression of biologics for about 30 years. Without doubt, microbial fermentation is the manufacturing technology of choice because the expression systems are more productive, cycle times are much shorter, capital costs are generally lower and these and other factors lead towards a lower cost of goods. However, the choice may be predetermined depending on the functional requirement of glycosylation.

technological synergies

There are important synergies between these manufacturing technologies - notably in molecular biology, separation, purification and analytical sciences. To exploit these fully, most leading manufacturers work across both technology platforms.

Applying its deep knowledge of cell-based technologies, Avecia completed a development stage move into mammalian cell culture during 2002 to complement its leading position in microbial fermentation. The company will start work this year on a cGMP cell culture pilot facility, also at Billingham, to manufacture materials for Phase I and Phase II clinical trials.

Manufacturing of biologics has emerged from the former exclusive in-house preserve of major pharma and the larger biotechs to include a strongly growing contract sector. Since the early-mid '90s, changes in the regulatory climate, notably the rationalisation of licensing into one Biologics License Application, and recognition of the greater ability to characterise products and thus demonstrate process robustness and comparability between plants, have facilitated the emergence of the contract manufacturing sector. Its growth has been driven by the huge increase in numbers of drugs in development by biotechnology companies and their particular need to maximise flexibility of approach and minimise risk. Outsourcing of development and manufacturing has consequently become an established business model for many of these companies.

That isn't to downplay the continuing importance of in-house capacity, as presently the vast majority of licensed product manufacturing is captively held. But add up projected figures for development and launched product biologics and the important future role of contract manufacturing becomes clear.

Presently, the contract manufacturing market for clinical trials materials is valued at more than $700m (not including the substantial market for other manufacturing-related services such as testing), but this is forecast to double by the end of 2005. With contract manufacturing playing an increasingly strategic role and more licensed products seeking second, or even third, suppliers, the overall market for manufacture of clinical and licensed products could easily reach $2bn in this timeframe.

'capacity crunch'

Even allowing for substantial investment in captive (in-house) manufacturing, demand on this scale is going to take a great deal of new contract capacity - probably twice that presently available in microbial manufacturing and nearly three times that in cell culture. This explains the significant expansions already announced by Avecia, BioChemie, Boehringer Ingelheim, Cambrex, DioSynth, DSM and Lonza.

The shiny new tankage announced across the industry to date doesn't add up to forecast demand, but neither is a 'stainless steel arms race' the only countermeasure to the threat of undercapacity, which is presently a real commercial risk for those companies developing biologics. Part of the longer-term solution to this expected 'capacity crunch' lies in maximising productivity of all the installed and planned stainless steel. This offers substantial potential to bring down 'cost of goods' and improve the affordability of new biologics medicines to increasingly budget-conscious healthcare providers.

Maximising productivity from manufacturing assets is critical in terms of being in production for as much of the year as possible. This requires fast turnaround and clean-down procedures, especially so when operating multi-product facilities, and minimising shutdown for modification and maintenance.

Of course, achieving high productivity is in large part governed by plant design and operating efficiency; however, improved expression levels in the bioreactor matched to intensive product recovery across the whole process can reduce the need for large capacity tanks and, importantly, the number of batches required - thereby saving both time and cost. With their generally much lower bioreactor titres and longer cycle times, as well as more expensive media and intensive capital, it is unsurprising that mammalian cell culture processes are typically much more expensive to operate than microbial processes.

Biopharma manufacturing processes are essentially in two stages: expression of the desired molecule, where the greatest opportunities for productivity gains can often be found; and separation and purification.

Opportunities for productivity gains via expression include optimising vectors, host strains, media and conditions in the bioreactor. Perhaps one of the best-known examples of substantially raising productivity is the development and scale-up of MedImmune's humanised monoclonal antibody Synagis.

Addressing the chronic large-scale capacity shortage in 1998/99, MedImmune decided to focus on improving its process yield to reduce capacity requirements. Optimising media nutrients and feeding strategy saw a four-fold increase in productivity, now delivering >3g/l in the bioreactor, enabling much of its product requirement to be delivered from smaller bioreactors.

In microbial fermentation, Avecia's proprietary E.coli-based expression system pPOP offers potential for major impact on cost of goods. By changing expression vector to pPOP where appropriate, Avecia has demonstrated >20% reduction in cost of goods at large scale.

Using statistical experimental design and advanced chemometrics early on in development reaps longer-term benefits. To arrive at a process that meets anticipated cost of goods and thereby facilitates market entry and penetration should the product be licensed, it is essential that these aspects of expression are considered early on.

Similarly, optimising downstream product recovery presents additional opportunity to improve cost of goods. However, to maximise overall process efficiency a holistic approach is needed from the outset, whereby downstream processing is directly matched with performance in the bioreactor. Above all, the key recognition in chasing the potential productivity gains is a constant and conscious awareness that: 'the process is the product'.

hard pressed

Even on a 'middle case', the number of biologics entering clinical tests and surviving all the way through the trials pipeline to launch is set for dramatic increase over the next few years. Manufacturing capacity to meet demand will remain hard pressed, even with significant further investment by in-house and contract manufacturers alike. To relieve some of this pressure, and to simultaneously meet the cost-of-goods challenge, there must be major and sustained emphasis on productivity at every stage of the development process.

Enhanced expression levels and improved process productivity and efficiency can be the 'smart munitions' in biotech manufacturing. Protein-based therapeutics are increasingly seeking utility in chronic therapy areas where there is direct competition with small molecules. Especially in these price-sensitive indications, cost-of-goods is a major factor in determining market penetration and indeed potential access to new areas of opportunity. Securing all the attainable benefits requires a holistic approach to process development at a very early stage, based on strong science and deep experience to commercialise new technologies and technology combinations.

In the contract manufacturing sector, success with biologics is likely to be achieved by players flexible enough to partner equally with big pharma and with biotech, and with technology development capability that can span the whole length of the biopharma pipeline, from clinical trials to drug launch and long-term market supply.

The growing numbers of pharma/biotech partnerships and product licensing deals are increasing the complexity of commercial relationships. Understanding and managing such complexities successfully as a manufacturing partner may well depend on the experience and flexibility found only within the top flight of contract manufacturers.