Future challenges in biomanufacturing
Outsourcing is one of the biggest global trends in the biopharmaceutical industry. It is taking more and more specific know-how to master the challenges posed by manufacturing of biologics, which include rising price and cost pressures, the need for high flexibility, and the ever-shifting (and in most cases
growing) regulatory requirements for biomanufacturing. This article will give you an overview of how a contract manufacturing organisation (CMO) with many years of experience in manufacturing several classes of biopharmaceuticals is positioning itself to face these challenges.
In the maturing biopharmaceutical industry today, there is increasing competition to innovative pipelines from me-too products, biobetters and biosimilars. The pressure on the cost of goods (COG) is therefore increasing. And to reduce COG, each manufacturing facility needs to meet the specific requirements for a new project regarding the technical instrumentation even before the project enters its initial stages. This will reduce investment and later depreciation, which impact negatively on costs. At the same time, it is important to be able to maintain as much flexibility as possible in order to comply with upcoming regulatory requirements. Thus CMOs need to invest constantly in the development and establishment of new manufacturing technologies and the necessary equipment.
Implementation of new
At Richter-Helm, the investment in new technology does not focus only on adding new (greater) manufacturing scales, although this is often a first reaction to COG pressure. Many firms consider
decreasing costs by increasing scale.
But a good alternative to simple scale-up is the implementation of new process technologies that can achieve higher yields, while at the same time improving quality or process robustness – at least for certain processing steps. Over the past few years, the biomanufacturing industry has made substantial improvements in expression and fermentation technologies. In terms of microbial production, innovative E. coli expression systems combined with high density fermentation regimes can lead to yields up to 20g of the target protein per litre of fermentation broth – as was recently accomplished by Richter-Helm for a fusion protein process.
In addition to high product yields, in many cases it is also important to find the appropriate expression system for high-quality products that show no or only low expression rates in E. coli. In these cases, the use of other bacterial expression hosts such as Bacillus or Pseudomonas strains can help. Pichia pastoris technology is another option for dealing with even more complex proteins such as enzymes or antibody fragments. A multipurpose facility for manufacturing biopharmaceuticals therefore needs to be equipped to take advantage of all these expression systems in order to be able to reduce upfront investment costs from the outset.
New expression systems lead to high primary product yields, and these need to be dealt with in purification processes. Thus optimisation of the downstream processes is also necessary. A recent study showed that the implementation of EBA technology can reduce total process cost by up to 56%. Other new purification technologies that can be implemented include multicolumn counter current solvent gradient purification (MCSGP), which reduces the loss of product in chromatography steps.
An ongoing trend in biopharmaceutical product development is the covalent modification of proteins by chemical or enzymatic cross linking (e.g. PEGylation, HESylation, Polyasialation) to increase the half-life of those products in humans. These technologies therefore need to be accessible in a multipurpose facility as well.
Expert project management
Of course, all of the technologies mentioned above also need to be scalable. For a CMO to offer customers the option of going from bench to market with a single manufacturer, it is important to offer more than one scale. For instance, at Richter-Helm three different manufacturing scales are available (lab, pilot, large) to implement each project at the best matching scale while limiting costs for large equipment or a higher number of batches (Fig. 1).
But a CMO does not only need sufficient technical capabilities to serve the future needs of its customers. Professional project execution is also a major success factor. It is extremely important for a CMO to be prepared for the fact that different customers have different requirements, as they range from small start-ups to big pharma. The project approach, for example regarding the regulatory consultancy required, will be extremely dependent on the customer’s situation (Fig. 2). Project management that ensures close collaboration and communication between all parties is becoming increasingly important, driven by the trend towards long-lasting partnerships and strategic alliances between developers and manufacturers.D
 Kaiser et al., Steigerung von Qualität und Ausbeute in der Wirkstoffproduktion; Laborwelt 11 (3), 18-22, 2010
 May, Pohlmeyer; Improving Process Economy with Expanded-Bed Adsorption Technology, BioProcess International, January 2011
Dr. Kai Pohlmeyer
Dr.-Ing. Philipp Göpel
Richter-Helm BioTec GmbH & Co. KG
20097 Hamburg, Germany
Tel.: +49 40 2375-0