The biopharmaceutical contract manufacturing (CMO) industry has experienced a significant improvement in the average expression levels for both mammalian cell culture and microbial fermentation, according to the “Biopharmaceutical Contract Manufacturing 2009: Expanding Markets, New Capacities and Improved Performance” report recently published by HighTech Business Decisions.
The industry study with directors from 29 biopharmaceutical CMOs and 48 pharmaceutical and biotechnology companies showed that expression yield has improved significantly over the last two years. Firms attribute much of the increase to use of high-expression systems and continuous process improvement.
Improvements in efficiency and increased productivity resulting from new technologies have helped CMOs gain new customers. For example, Oxford-Emergent Tuberculosis Consortium, a joint venture between the University of Oxford and Emergent BioSolutions, signed a commercial license agreement in May with ProBioGen to explore production of the MVA85A TB vaccine using ProBioGen’s AGE1.CR.pIX® cell line.
Companies cite improvements in media, overall process, and cell-line development as examples of methods that will further improve yields. However, increased titers and improved expression yields have created pressure on downstream processing. In addition to capacity concerns, the downstream processing bottleneck is consistently cited by pharmaceutical and biotechnology companies as one of the top three biomanufacturing challenges.
Many CMOs are addressing the downstream processing bottleneck by implementing membrane chromatography, high-performance liquid chromatography (HPLC), protein crystallization for protein purification, wider adoption of disposables, and use of process analytical tools (PAT).
Reducing Need for Chromatography
NPro Autoprotease Fusion Technology (NAFT) is a new technology being implemented by Sandoz Biopharmaceuticals. According to Friedrich Nachtmann, Ph.D., head biotech cooperations, “NAFT is a novel expression system yielding inclusion bodies of a fusion protein that consists of an autoprotease portion and the target protein or peptide. The autoprotease part cleaves off after renaturation, providing high yield of correctly processed target protein or peptide.”
Rentschler Biotechnologie is working on research projects dealing with protein crystallization for industrial protein purification. Professor Roland Wagner, svp of development, said that “crystallization of proteins is commonly used for determination of the 3-D structure of proteins. However, proteins in crystalline state are of high purity and usually more stable than dissolved ones. Therefore, the method is expected to be beneficial for the rapid purification and stabilization of pharmaceutical proteins.”
Also increasing its use of crystallization is Boehringer Ingelheim, which is continuously expanding its protein purification toolbox. Vitomir Vucenovic, Ph.D., senior manager of enabling technologies, the corporate division biopharmaceuticals, explained, “depending on a protein’s nature, we are able to crystallize, wash, and resolve the protein again, thereby reducing chromatography steps and overall time.”