PMPs — If Not Now, When?

Biopharmaceutical companies are developing clever technologies for plant made pharmaceuticals (PMPs). When will the promise for the future turn into reality?

Brandon J. Price, Ph.D

Transgenic plants will eventually be adopted as manufacturing vehicles for biopharmaceutical products. The timing is dictated by the need to overcome several hurdles. The promise of PMPs, like most new technologies, precedes the practical reality.

The two common arguments in favor of PMPs are reduction in manufactured costs and lack of human-infectious viral contaminants. Novel mammalian-cell expression systems and improved processes are pushing cell-culture productivity into the gram per liter range on a consistent basis. A ten-fold increase in expression level effectively turns a 1,000 L bioreactor into a 10,000 L bioreactor.

Freedom from viral contaminants is a potentially powerful advantage. However, for PMPs to be accepted by the market, industry needs to focus on the hurdles and not the advantages.

The first and foremost hurdle, at least among experienced biomanufacturers, is the regulatory unknown (also known as the fear of "being first"). There are draft FDA/USDA and EMEA documents focused on PMPs, and dozens of products in development. The major achievement for transgenic systems, whether animal or plant, that paves the regulatory pathway for all will be approval of the first product. This could happen as early as March 2005, with EMEA approval of GTC Biotherapeutics' ATryn, a recombinant human thrombin expressed in the milk of goats.

Secondly, it is not clear that total manufacturing costs will be reduced multi-fold, as often claimed. Capital requirements for the upstream part of a kilogram-level biomanufacturing facility will be reduced from the $100+ million range to perhaps the $10+ million range. A significant portion of the manufacturing costs, though, ranging from 30-60% depending upon the product, resides in downstream purification — a part of the biomanufacturing process not likely to be greatly influenced by the type of feed stream.

Thirdly, and perhaps most importantly, there are issues regarding the public's (and industry's) perception of growing transgenic plants in open, unconfined spaces. Concern with the likelihood for gene flow among transgenic plants and their non-transgenic neighbors, along with the potential for transgenic "contaminants" appearing in the food chain, have led to strict recommendations from the USDA on buffer zones between transgenic and neighboring crops and, in some instances, moving them to locations far removed from traditional growing areas. Perhaps elimination of the gene flow issue will only be achieved by isolation in totally confined spaces such as greenhouses or underground mines. Mines, if comparable in capital and operational costs to greenhouses, might offer the best bet, since this involves a completely controlled environment — free of environmental pests and weather and seasonal issues — that can actually increase the annual amount of biomass generated per acre.

Turning the issues into advantages will really drive adoption of PMPs into the mainstream of biomanufacturing. Someone will be "first" with a regulatory approval. Underground growth chambers will achieve economic parity.

One remarkable potential advantage remains to be fully exploited; namely, the ability to genetically manipulate plants to perform post-translational modifications and, so, to control important structures such as glycans. Already, offending sugar residues (xylose and fucose) can be removed in planta. Terminal galactose residues on glycans, typical of Mabs (not natively produced in plants) have been engineered into a variety of plant species. The ability to produce a protein with structures that more closely mimic the human molecule or, perhaps, improve upon the human molecule, will be what ultimately gives PMPs their place in the biomanufacturing sun.

Brandon J. Price, Ph.D. is vice president, Biotechnology Services at Cardinal Health, P.O. Box 13341, Research Triangle Park, NC, 919.465.8149, Fax: 919.481.4908. brandon.j.price@cardinal.com