This article was prepared by Frost & Sullivan.
Biopharmaceuticals are deemed to be the length and breadth of healthcare in the future; primarily because of the potential benefits they offer over small molecules, such as stronger focus on target diseases, more effective and potent action, their potential to cure diseases, rather than just treating the symptoms and lesser adverse effects. Biopharmaceuticals can take forms of monoclonal antibodies, recombinant proteins, vaccines and regenerative medicines. They find extensive applications in research, therapeutics and diagnostics. As per recent Frost & Sullivan analysis, biologics will continue to outpace overall pharma spending growth and are expected to represent 19-20 percent of the total pharma market value by 2020. The biopharmaceutical industry is estimated to be worth $204.8 billion as of 2015 with the R&D expenditure summing up to $37.3 billion. It is expected to reach US$314.8 billion by 2020, which represents a 9 percent compound annual growth rate (CAGR) between 2015 and 2020. Humira, Enbrel, Remicade, Rituxan, Lantus, Avastin, Herceptin and Prevnar are eight biologic drugs out of the top ten drugs by sales in 2015. These molecules represent a total of US$65.15 billion in market size. Biologics growth is primarily driven by monoclonal antibodies (mAbs) and human insulin, with six out of the top ten drugs by sales in 2015 being mAbs.
Manufacturing of biopharmaceuticals is a capital intensive, complex and highly technical process in comparison to manufacturing of small molecules. Advances in upstream, downstream bioprocessing, lyophilization and process analytical technology as well as the advent of newer technologies such as production of biopharmaceuticals using transgenic plants and animals, stem cells and cloning, which are still at an infancy stage, are likely to have a direct impact on biopharmaceutical contract manufacturers. In particular, attractive opportunities in disposable equipment/single-use bioreactors and perfusion technology are disrupting the traditional model of biologic manufacturers.
Single use technology was first introduced in 1970s in the form of disposable capsules and range of filters. The development of disposable bio-containers started in the early 1980s followed by single-use bags for storage and transport of buffer and media by Hyclone in the 1990s. Finally, large scale tube welders and sterile connectors were introduced in the 2000s. BioProcess System Alliance, was established during the same time to promote the best practices for implementation of SUTs. Disposable equipment/single-use bioreactors are considered a viable alternative to conventional stainless steel equipment in biotech contract manufacturing because of their high degree of flexibility, short start-up time, quick changeover between production campaigns as well as absence of clean-in-place, steam-in-place, and large volumes of water for injection. Single use technologies are specially designed for multi-product contract manufacturing with additional benefits, such as simple transfer of operations between sites, and their ability to easily expand to accommodate larger volumes. They find extensive applications in busy facilities and smaller operations devoid of non-value adding activities. It becomes increasingly important to adopt the work flow, facility design, and scale-up strategies to the features of the disposable equipment, failing which heavy costs are to be incurred. However, usage of single use bioreactors (SUBs) is restricted to operations that do not exceed 2,000 L production scale. At present, disposable equipment are widely implemented for seed bio reactors and storing buffers. Disposables are increasingly gaining acceptance among cell culture engineers and recently, disposable chromatography columns have also been introduced. Therefore, there is a prominent trend among contract manufacturers towards the use of disposable technology, as it helps lower production costs by virtue of their customisable design, enhanced productivity, and significant operational benefits.
Perfusion technology is the ability to culture cells for a longer duration (in months) by continuously feeding fresh media and removing the spent media using either membranes or filters or centrifuge. A high number of cells can be maintained in each cell culture batch by constantly feeding fresh raw materials. Optimum conditions for production are achieved by inducing raw materials and removing waste elements. This technology can be used in tandem with continuous manufacturing processes. As an example, Sanofi is coming up with three 4000L perfusion based bioreactors for their Belgian site. Boehringer Ingelheim is also planning to implement perfusion technology in their Vienna site. Samsung Biologics was the first CMO to provide N-1 perfusion services at large scale. Process analytical technologies are ideal to be used with perfusion system for monitoring quality and critical limits of the involved processes. Since there is no down time, perfusion improves productivity by saving time and rolling out finished products in an uninterrupted fashion. Traditional batch fed technology consists of tanks with a capacity of 10000-25000 litres in which cell cultures run in batches of 7-21 days post which the cultured cells are separated from the cell mass. Yields from batch fed technology are typically in the range of 1-4 gms/ litre depending on clone and antibody. A 50 Litre perfusion bioreactor produces equivalent to 1000L batch fed bioreactor. GE Healthcare’s WAVE bioreactor and iCELL fixed/packed bed bioreactors are some leading products applying this technology. This increased product quality, stability, scalability, cost saving and higher automation levels of production with smaller size of bioreactors is the way forward in biologic manufacturing.
Thus, biopharmaceutical manufacturers continue to focus on gaining efficiency and boosting productivity, through better integration of processes and remaining at the forefront of technology to capture opportunities, survive disruption and emerge as winners.
Unmesh Lal is Program Manager, Life Sciences at Frost & Sullivan.
Unmesh Lal looks back to more than ten years of healthcare industry expertise, comprising of strategy consulting, primarily with global pharmaceutical companies. He has particular expertise in Global Pharmaceutical & Biologics Contract Outsourcing, API manufacturing in India and China, European Oncology and Diabetes market prognosis as well as Pharma sales force effectiveness.