Biological medicines already account for around 10–15% of the current pharmaceutical market and the sector is outperforming the industry as a whole. More than one-fifth of new medicines launched on the world market each year are now biotechnology-derived. According to the latest report from Pharmaceutical Research and Manufacturers of America (PhRMA),1 in the US alone some 452 new medicines for rare diseases, including genetic disorders, neurological conditions, infectious diseases and autoimmune disorders, are being developed by biopharmaceutical companies.
With Big Pharma desperate to fuel its dwindling pipelines, it is looking to be part of this rapidly growing market, but the switch from traditional chemical synthesis-based small molecules to the new biologically-based therapies (biosimilars, mAbs, ADCs, vaccines, gene therapy, recombinent therapeutic proteins, regenerative therapies) requires huge investment in new biotech production facilities.
The production of such novel biologicals is not without challenges. At the recent UK Bioscience Forum, organised by the UK’s BioIndustry Association (BIA) in London, Stephen Ward, COO of the UK’s government-funded Cell Therapy Catapult, outlined some of the major issues that the biotech industry faces in its transition from R&D to commercial products: problems of scale, product characterisation, product release and shelf life, variation of raw materials, and logistics.2
Ward highlighted that the healthcare sector now needs manufacturing innovation to underpin that which has recently taken place in R&D, but with the technology still in its infancy, much of the infrastructure is not yet there.
To produce the next generation of biotech products the industry will need ‘more flexible and larger batch sizes and more decentralised manufacturing
One of the major issues that the industry faces is a lack of production capacity for such products. In a quick overview of the UK’s current manufacturing capability, Ward said there were only 68 MHRA-licensed sites for biological medicine products: 35 are licensed for biopharmaceuticals, 23 are primary manufacturing sites for biopharmaceuticals, and only 12 are manufacturing facilities for cell therapy. Most existing facilities are still producing on a small scale, using labour-intensive practices. To produce the next generation of biotech products the industry will need ‘more flexible and larger batch sizes and more decentralised manufacturing,’ said Ward.
Disposable technology is key
Not only do the procedures carefully created in the lab now have to be replicated in the production environment on a much greater scale, at speed and using more automation, the move from relatively inert, chemically-synthesised powders to living, biological materials (cells, bacteria, yeast etc.) is complex. Biological materials are highly sensitive to their environment, temperature, light, contamination and solvents. This means that a rethink of the traditional robust production processes using stainless steel, which rely on final product sterilisation, is required.
Increasingly disposable equipment and single-use bioreactors are being considered as a viable alternative to conventional stainless steel equipment
One of the main issues has been the lack of scaleable equipment, says market research group Frost & Sullivan,3 but increasingly disposable equipment and single-use bioreactors are being considered as a viable alternative to conventional stainless steel equipment, due to their flexibility, short start-up time and quick changeover between production campaigns. They also remove the need for clean-in-place/sterilise-in-place processes and large volumes of Water for Injection.
Equipment suppliers are looking at providing a full range of products at different scales that provide ease-of-use, quick turnaround and increased flexibility, safety and containment in cGMP operations. Automation is also already underway with a view to shortening steps in the upstream cell line development workflow.
A relatively new area of innovation offered by companies such as Corning is specially developed microcarriers for bioprocess scale-up that increase efficiency, and improve manufacturing results for large-scale vaccine and cell therapy production. The microcarriers are offered with various surface treatments and coatings to enhance cell attachment, helping maximise cell yield and viability.
Researchers today are pressed to more efficiently and effectively scale up their bioprocess production
‘Researchers today are pressed to more efficiently and effectively scale up their bioprocess production,’ says Ken Ludwig, Business Manager, Bioprocess and Cell Therapy, Corning Life Sciences. ‘These newest Corning advancements build on our existing microcarrier product line and all of our scale-up technologies to provide a more advanced and broader range of options to do just that.’
Another technology being used to maximise yields is Near infrared spectroscopy (NIR). This technology is being developed to provide potential real-time control of cells in fermentation, specifically in mammalian cell culture processes and can mean significantly enhanced purity levels and product efficiency.
With regenerative therapies, production and scale-up processes require an even greater rethink, as production methods and quantities are an even greater departure from producing traditional large volume, small molecules. Speakers at the UK Bioscience Forum highlighted that shelf-life, distribution and point of application are quite different from traditional therapies. For example, treatment such as autologous immune enhancement therapy (AIET) involves the implantation, transplantation, infusion or transfer of human cells or tissue back into the individual from whom the cells or tissue were recovered. One major advantage of the treatment is reduced rejection, which means no immunosuppression is required.
Such techniques would theoretically require cells to be harvested near the patient, transported to a main processing centre where they can be handled under cGMP conditions, go through cryopreservation once produced, transported back to the centre near the patient and possibly stored at that centre ready for administration. Within this process there are still many unknowns, such as: does cryopreservation alter cell function in ways not always detected by in vitro assays? If cells are shipped ‘fresh’ are additional release tests required upon receipt? Are autologous therapies best suited to centralised commercial development, or are they better produced locally?
The whole process is service-based, low volume, involves only a small number of patients and must take account of a large amount of cell variability from person to person.
In allogenic cell therapy, where the donor is a different person from the recipient of the cells, the methodology is more interesting for pharmaceutical manufacturers because unmatched allogenic therapies could form the basis of ‘off-the-shelf’ products. For example, there is interest in looking to develop products using this method that could treat conditions such as Crohn's disease and a variety of vascular conditions, giving rise to products with blockbuster potential.
The current reliance on animal-based materials is something that the industry needs to move away from
Discussions at the BioScience Forum highlighted some of the major infrastructure issues that need to be addressed for commercial scale use of such therapies. Chris Mason, Professor of Regenerative Medicine Bioprocessing, UCL, for example, highlighted the fact that currently cell therapy carried out in the R&D lab involves products with a very short shelf life that are intensely laborious and slow to produce using non-GMP processing methods and non-GMP grade research material. He also suggested that the current reliance on animal-based materials is something that the industry needs to move away from.
In addition, the current open processing is not easily scaleable and there are issues of how to apply CMC (content and review of chemistry, manufacturing and control) procedures.
Dealing with living material is different from dealing with antibodies and vaccines
Dr Garry Brooke, Project Manager for cell manufacturing at ReNeuron, said that the sector is still using lab bench flask-based methods that not only need to be scaled up but also require more automation. ‘Dealing with living material is different from dealing with antibodies and vaccines,’ he said, adding that the end product cannot be sterilised using traditional methods. On the other hand, developments in the biotech scenario are already underway, Brooke suggested, adding that there was already a push towards using enclosed systems and bioreactors in place of high level cleanrooms.
The short shelf-life also gives rise to many logistical issues. In initial trials, cell shelf life has been around eight hours – around three of which may be needed for performing the surgical part of the treatment. Freezing may be a future option but will require a safe and suitable supply of liquid nitrogen. Ideally a longer shelf life product is needed to be delivered into surgery. Studies are already underway, however, that suggest that by careful management of parameters such as temperature, for example, shelf life can be increased.
But simple logistical problems can arise: ‘There is no point shipping a product on Saturday or Sunday when there are no surgeons around,’ said Brooke. Many of these issues raise the question of whether the future will be based on a centralised manufacturing model or whether industry should be looking at a model more akin to ‘bedside processing’, using micro-manufacturing facilities at point of care.
A further requirement currently demanded of traditional therapies is product characterisation. If this were also required of stem cells, what properties should be measured and what quality checks need to be embedded throughout the process?
Despite these as yet unresolved issues, investment is growing in this sector and many national governments are keen to help fund projects that will boost their biotech industry capacity. In the UK, for example, ReNeuron has announced that it is to establish a cell manufacturing and development facility in South Wales. Currently based in Guildford, UK, the company recently raised £33m in funding for the move, including £7.8m from the Welsh Government and cash from the Welsh Life Sciences Investment Fund. The exact location has not yet been revealed, but it plans to move its main operations in phases over the next two years and to build a full manufacturing facility and integrate its development work into a stem cell development and manufacturing facility on one site. It will bring the company closer to Cardiff University, a leading centre in the UK for both stem cell and neuroscience research.
Despite these as yet unresolved issues, investment is growing in this sector and many national governments are keen to help fund projects
The UK government is funding a national biologics facility in Darlington – chosen for its close proximity to existing pharmaceutical companies and relevant universities in the north of England, and to the Tees Valley Enterprise Zone. The new centre will help companies of all sizes to develop, prove, demonstrate, scale up and ultimately commercialise new biologics process technologies.
1. Pharmaceutical Research and Manufacturers of America (PhRMA) report published 7 October 2013. http://phrma.org/Medicines-Development-Rare-Diseases#sthash.jNC5hX9a.YXTqTyDq.dpufhttp://phrma.org/Medicines-Development-Rare-Diseases#sthash.jNC5hX9a.dpuf
2. BIA report UK – The strongest bioscience cluster in Europe: State of the Nation
3. Frost & Sullivan insight. 1 October 2103 http://www.frost.com/prod/servlet/press-release.pag?docid=285539591