Moving to the Next Level in Biomanufacturing - Pharmaceutical Technology

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PharmTech Europe

Moving to the Next Level in Biomanufacturing
Growth in the market for monoclonal antibodies, recombinant proteins, and vaccines creates new opportunities for drug companies and suppliers.

Pharmaceutical Technology
Volume 34, Issue 4, pp. 64-70

The supply side

Aptamers: a potential bridge between monoclonal antibodies and small molecules
Greater interest in biologics is creating opportunity on the supply side. The market for biopharmaceutical contract manufacturing was estimated at $2.6 billion in 2009, and long-term growth prospects remain strong through 2014, according to a 2009 study by the research firm High Tech Business Decisions. Although contractor capacity utilization was slightly lower in 2009 compared with recent levels, the decline in utilization was believed to be temporary resulting from a combination of previous investment in capacity, improved expression yields, and a slowdown in biotechnology investments because of the downturn in financial markets. During the next few years, demand is expected to grow as new biopharmaceuticals move through the clinical pipeline and become commercial products. Demand for biopharmaceutical contract manufacturing services is expected to grow 16% annually through 2014 as biopharmaceutical business models shift toward more outsourcing of production and some large pharmaceutical companies elect not to expand their internal capacities. Moreover, other productivity gains such as better expression systems, more efficient cell lines, and improved media present new opportunities, said the firm in a June 2009 press release.

Nigel Darby, vice-president of biotechnologies at GE Healthcare Life Sciences (Uppsala, Sweden), pointed to improvement in yield in an recent interview with Pharmaceutical Technology (4). Darby was also a speaker at a biologics forum, The Rapid Evolution of Biomanufacturing and the New Supplier Reality organized by the Drug, Chemical, and Associated Technologies Association.

He pointed out in the interview that cell-culture productivity expressed as product titer has increased to a level of 2-4 g/L in established production processes and to 4-6 g/L in preclinical and some clinical manufacturing processes. "This is a combined effect: optimized expression systems turn the cells into more efficient production systems and culture-media developments, including the feed strategy, lead to significantly increased cell density in the bioreactor," he said. "Cells would be capable of even higher yields up to 10 g/L, but this benefit, more often than not, comes with 50–70% prolonged culture time and deletes part of the productivity gains made with high titers." Furthermore, longer culture times can reduce the flexibility in production scheduling and may thus limit the benefits of cell-culture optimization.

Production strategies

Producing proteins more efficiently is an ongoing goal by pharmaceutical companies, their suppliers, and academia. As a case in point, Merck & Co. (Whitehouse, NJ) acquired the biotechnology firm GlyoFi (Lebanon, NH) for $400 million in 2006 to gain access to the company's proprietary technology for producing recombinantly engineered yeast strains capable of specific human glycosylation at high fidelity. The company's recombinant yeast-based approach seeks to overcome limitations in manufacturing methods based on mammalian-cell culture that do not allow for the control of glycosylation and so produce a mixture of different glycoforms, some of which are more active than others and some of which may have no activity at all. By expressing a given protein in different glycoengineered yeast strains, a library of glycoproteins, all with an identical peptide backbone but with different sugars attached to them, can be generated. This process allows drug developers to identify the glycoform with the highest therapeutic potency. Because many therapeutic characteristics such as pharmacokinetic stability, bioavailability, immunogenicity, and tissue-specific targeting are affected by sugar attachment, the technology can be broadly applied to all glycoproteins, including growth factors, fusion proteins, and mABs, according to the company.

Sugar-engineered technology. In September 2009, the biotechnology company Seattle Genetics (Bothell, WA) launched its sugar-engineered antibody (SEA) technology, an approach to increase the potency of mAbs. The SEA technology consists of modified sugars that inhibit the incorporation of fucose into the carbohydrate chains of mAbs, resulting in enhanced antibody-dependent cellular cytotoxicity (ADCC) activity in preclinical models. The company says that the modified sugars can be readily added to standard cell-culture media without affecting manufacturing processes while still maintaining yields and reproducible product quality. The technology can be applied to existing cell lines without cell-line reengineering. In model systems, the technology has been shown to be applicable across a range of antibodies and antibody-producing cell lines.

Seattle Genetics filed a patent application covering its SEA technology and intends to use the technology in its internal early-stage pipeline and in external collaborations. The development of mAbs possessing enhanced effector function is an emerging area of therapeutic research. The company estimates that there are at least 10 ADCC-enhanced antibodies in clinical trials using a variety of technologies.

Bacterial methods for producing eukaryotic N-glycoproteins . Researchers recently reported a new method that may provide a general platform for producing eukaryotic N-glycoproteins, which would offer an efficient way to customize glycoproteins such as mAbs. The method involves producing homogeneous eukaryotic N-glycoproteins that involves the engineering and functional transfer of the Campylobacter jejuni glycosylation machinery in Escherichia coli to express glycosylated proteins with GlcNAc-Asn linkage. The bacterial glycans were subsequently trimmed and remodeled in vitro by enzymatic transglycosylation to fulfill an eukaryotic N-glycoslyation. Although homogenous N-glycoproteins can be made via chemical synthesis or engineered yeast, the new method uses a bacterial system to produce the homogeneous eukaryotic N-linked glycoproteins, which offer the potential of reducing some of the challenges found in chemical and yeast-engineered approaches (5, 6).


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