BY JOHN WILLIAMSON
WASHINGTON, D.C. – A growing interest in plant-made pharmaceuticals (PMPs), where crop plants become “factories” that manufacture therapeutic proteins extracted and used as the active pharmaceutical ingredient (API) in many medicines, is generating a new round of enthusiasm-and controversy.
While the Biotechnology Industry Organization (www.bio.org) notes the active ingredient in many protein medicines on the market or in the pipeline can be produced in crop plants more efficiently and economically than by using current microbial or cell culture technologies, the promise is being countered by concerns about using bioengineered food crops for the production of products not intended to be in foods for the general public or for livestock.
Because the technology is relatively new, recent concern has focused on crops used in field trials for PMPs, and the possibility of contaminating food or feed crops through cross-pollination or out-crossing. Another concern is the danger that the PMP feedstock can come in contact with human or animal food or feedstock.
The Food Products Association (www.fpa-food.org) has expressed some of these concerns in recent comments filed with the U.S. Department of Agriculture (USDA). The USDA, its Animal and Plant Health Inspection Service (APHIS), and the Food and Drug Administration (FDA) are in charge of processes required to participate in PMP studies, from seed to the pharmaceutical company.
PMPs are the result of genetic alteration of crops, such as corn, rice and tobacco, to produce therapeutic proteins, which are extracted and used as the API in many medicines.
Dr. Jeffrey Barach, FPA’s vice president of special projects, says, “We would like to see more emphasis on restricting field trials, seed development and production in major food crop areas. For example, disallowing PMP corn or PMP rice in a major corn belt or commercial rice area seems sensible to us and to most everyone-except the developers and the USDA.”
Barach adds, “We would like more emphasis and a more robust system of Good Agricultural Practices (GAPs) put in place. We would like more government surveillance to ensure compliance during the production and transport phase, and also we see value in development of third-party monitoring programs.”
Rachel Lattimore, a Washington-based member of Arent Fox PLLC (www.arentfox.com), who focuses on biotechnology and broader environmental and food safety issues, responds, “We must recognize that the permitting processes for PMPs and PMIPs are thorough, and their production is highly regulated. PMPs and PMIPs are produced and processed in a closed-loop system outside the commercial food channel. Moreover, multiple containment strategies are used to keep this plant material from entering the food channel. There is a chain of custody from seed development extending through to the pharmaceutical company.”
Concerning out-crossing (cross-pollination), Lattimore notes that spacing and temporal rules governing PMP and PMIP plants provide a “belt-and-suspender” protection level. “Cross-pollination only has the potential to happen when sexually compatible plants are in proximity to each other and are flowering at the same time,” she says.
But Dr. Barach counters, “Much of the field-trial containment requirements (distance restrictions and planting times) are based on classical studies on pollen drift. We lack good information and studies on pollen and seed dispersal by floodwater, high winds, insects, birds and rodents. Current studies do not model for or predict possible unusual events such as these. Instead, they focus on the average and not the extreme. We are concerned about the exceptions beyond the norm that may result in spread of pollen or seeds.”
Franco Di-Giovanni, an air dispersal modeler with Mississauga, Ontario-based AirZone Inc. (www.airzoneone.com), suggests a solution for pollen dispersed in the air: “Short-term pollen drift data (measured at only a few sites or over a few years) are unreliable because of weather and climate changes from site-to-site and year-to-year. To establish [the] worst-case scenario that is essential for studies of this type, we need to take a page from the Environmental Protection Agency’s air pollution studies and impact assessment methods. It’s a valid comparison because airborne particulate can be likened to pollen flow, and models apply.”
Safe, but not foolproof
Di-Giovanni says the Canadian Food Inspection Agency, which is the equivalent of the USDA’s APHIS section, sponsored work by AirZone to apply air pollution models to wheat out-crossing. “In a short period of time, using supercomputers, we simulated pollen flow and gene flow across nine sites in Canada’s wheat-growing regions, replicating 30 years of pollen- and gene-flow data,” he reports. “This is the type of work that should be done to add to the weight of evidence in controlling out-crossing because it enables an estimation of worst-case pollen drift and pollen drift variability. But it should be used together with field trials and not totally replace them.”
Andrew Baum, president and CEO of SemBioSys Genetics Inc. (www.sembiosys.com), a Calgary, Alberta PMP producer, adds, “To the issue of whether the industry is taking proper precautions in the growth and transport of PMPs, the question is: ‘Is somebody paying the right level of attention?’”
Baum says, “We at SemBioSys think so. The approval processes are rigorous in order to get into this business, and the rules are dutifully enforced throughout the entire process. There is a tremendous amount of regulatory oversight, which we support and facilitate. That said, no process is completely foolproof.”
He cautions, “In my opinion, anyone who promotes a ‘fail-safe’ system in this area is stretching reality. Because we live in a world of reality, we apply good science and work closely with government agencies in Canada and the U.S., and with trade associations such as BIO, by following containment process guidelines. We reach out to the food industry to address their concerns. But it is more than that: We have a moral, ethical, legal and business interest in maintaining compliance with these standards.”
In the end, however, Baum says, “We believe that the PMP industry is regulated appropriately, and the science we apply to the issue of containment is sound.”
PMPs and cleanrooms
With PMPs holding promise of being a new source of more affordable medicines that can be produced on a much larger scale than conventional biopharmaceutical production systems, cleanroom use could also be dramatically impacted. For example, Sacramento, California-based Ventria Bioscience (www.ventria.com) has a PMP production system that, according to CEO Scott Deeter, allows for the production of thousands of kilograms of protein at 10 percent of the capital cost required for mammalian cell production systems.
If such expectations are met, biotech cleanrooms will be gearing up for increased production.
R. Barry Holtz, PhD, president and CEO of InterveXion Therapeutics (www.intervexion.com), says, “PMPs will require the same attention to cGMP compliance as any other process. In my experience, in cancer vaccine preparation, cleanrooms were required to prepare parenteral doses of vaccine under cGMP compliance for injectable drugs. Plant growth is regulated by USDA and there are also compliance requirements for growing recombinantly modified plants in greenhouses.”