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Biopharming (using crops as drug-producing bioreactors) offers tremendous
economic and health benefits stimulated by improving biotechnology methods.
However, these benefits must be weighed against the potential risks to the
food supply system and the costs of containing pharma crops to meet
zero-tolerance contamination requirements. A combination of strong and
adaptable regulatory oversight with technological innovations is required to
achieve the twin goals of capturing the benefits of biopharming and
safeguarding the food system and the environment. This paper examines the
demand pull driving biopharming and the risk and liabilities to agriculture
and reviews the regulatory and technological responses to the containment
challenge faced by the food industry, June 2005 by Aziz Elbehri.

Introduction

Advances in genetic engineering now make it possible to use crops such as
corn and tobacco as drug factories. Plants used as bioreactors (biopharming)
may soon represent one of the most important developments in US agriculture,
as pharmaceutical and chemical industries use field crops to produce
therapeutic proteins, drugs, and vaccines. Pharmaceutical crops represent a
radical departure from the traditional idea of crops as a source of food,
feed, and fiber. The main driver for pharmaceutical crops comes from the
biotech and pharmaceutical industry, where there is a growing recognition of
the vast economic potential of using plants as platforms for drugs and
therapeutic compounds. However, biopharming also presents unique challenges
for the food and agricultural sector and federal regulators. The challenge
arises from the strict requirement?enforced by federal regulations?that
plants grown for pharmaceutical and industrial compounds (not approved for
food and feed use) must stay clear of the food system under a zero-tolerance
standard. The key issue is whether the economic payoffs from growing
pharmaceutical plants outweigh the costs associated with the risk of food
system contamination.

The objectives of this article are to examine the demand forces from the
biotech industry behind biopharming and to assess the implications for food
and agriculture (i.e., the risks associated with growing these crops in open
fields). The paper also addresses the regulatory and technological responses
to maximize containment effectiveness and minimize contamination risks.

Drug Developments and the Appeal of Plant-Made Pharmaceuticals

The drug development process within the pharmaceutical industry has
experienced a significant transformation over the last two decades, driven
largely by biotechnology advances. Biotechnology played a key role in the
expansion of large-molecule drugs (as opposed to the small-molecule drugs
manufactured by chemical synthesis). Moreover, biotechnology further
stimulated the trend toward biological sources for drugs and therapeutics.
These drugs, known as biologics, include any protein, virus, therapeutic
serum, vaccine, and blood component. Another major impact of biotechnology
was to enable the industry to move beyond simple replication of human
proteins (such as insulin or growth hormones). Rather, new
biopharmaceuticals are genetically engineered proteins targeting some of the
major illnesses in industrial countries, such as cancer, cardiovascular, and
infectious diseases?all critical to an expanding aging population.

In the last two decades, there has been an unprecedented interest in
proteins and antibodies (as opposed to the traditional small-molecule drugs)
stemming from their potential to tackle a whole array of new diseases that
have not been addressed by small-molecule drugs. An advantage of these
large-scale molecule drugs is their ability to target diseases in a very
specific manner, thus maximizing efficacy while minimizing side effects.
Hence, the market share of biologic-derived drugs has been growing at a much
higher rate because of their perceived safety and effectiveness. For an
industry that reached $430 billion of global drug sales, the average
industry growth of small-molecule drugs is around 7-8% over the next decade,
compared to the 15% growth rate for the therapeutic protein segment over the
same period.

Building on developments in genetic engineering since the mid-1970s, the
biopharmaceutical era truly began in early 1980s, starting with the release
of the first transgenic drug, insulin, in 1982. Since then, biotechnology
has had a threefold impact on the manufacture of therapeutic proteins, which
makes up a significant segment of all biologically-derived drugs. There are
currently 84 biopharmaceuticals on the market serving 60 million patients
worldwide for a cumulative market value of $20 billion.

According to the Pharmaceutical Research Medical Association, 500
biopharmaceuticals are estimated to be in clinical trials globally, 378 of
which are in earlier stages (Phase I and II), while 122 are in Phase III or
awaiting FDA approval. Using historical trends for drug approval rates,
industry analysts expect an average of six or seven new large-molecule drugs
to reach the market each year over the next several years. These monoclonal
antibodies, which require a large production capacity, are expected to make
up about a third of all new therapeutics. Building on recent successes and
drug approvals, the strong biotech therapeutics pipeline is creating a
serious supply shortage for drug manufacturing and inducing extended market
disequilibrium, where demand far outstrips supply.

Large-molecule therapeutics, which cannot be produced by chemical synthesis,
are traditionally manufactured either through microbial fermentation or more
commonly via mammalian cell culture. However, it is expected that current
cell culture facilities are unlikely to meet expected demand. There is
already a supply capacity crunch resulting from recently approved monoclonal
antibodies, which are primarily used for chronic diseases that often require
high dosages. These new drugs have stretched the fermentation production to
full capacity. Moreover, this supply-demand imbalance is expected to get
worse in the future, as more biotech therapeutics are approved. For example,
each newly approved monoclonal antibody requires 100,000 kg of production
annually requiring new fermentation capacity to be built. To meet the
expected demand for new drug production, more than three times the current
production capacity may be required. It is estimated that 20-50% of
potential therapeutics industrywide could be delayed due to the lack of
manufacturing capacity.

A striking example of the drug supply shortage is the case of Enbrel?a
biotech drug, introduced by Immunex in 1998, that proved to be highly
successful for treating rheumatoid arthritis, which affects two million
patients in the United States. Enbrel is produced in 10,000-liter
bioreactors of cultured Chinese hamster cells; its success created a supply
shortage starting in 2001. By March 2002, there was a waiting list of 13,000
patients. In response, Immunex began rationing to pharmacies with the goal
of maximizing the number of treated patients. At the same time, Immunex
launched a new production facility in Germany, which will take up to five
years to build and approve at a cost of $450 million. Meanwhile, the supply
shortage is expected to continue into the near future.

The Appeal of Plant-Made Pharmaceuticals

The current interest in pharmaceutical plants can be viewed both as a
response to these supply shortages and as an alternative platform to develop
therapeutics. Although many drug companies are pursuing additional
fermentation capacity to stave off the manufacturing crunch, other drug and
biotech firms are giving serious consideration to alternative platforms,
including transgenic plants and animals, insect cells, and even yeast
cultures. Of these, plant-made pharmaceuticals (PMPs) offer many advantages
over mammalian cell culture methods. First, there is the cost advantage.
Industry estimates of unit costs of therapeutic production with animal cell
bioreactors range from as low as $106/g of antibody to $650/g. The cost of
producing the same amount of therapeutics from plants is estimated to be
four to five times lower than the mammalian cell culture method. As an
illustration, the production of 500 kg of monoclonal antibodies would
require an investment of US$450 million for a mammalian cell culture
fermentation facility and four to seven years to build and approve. By
contrast, the same amount of monoclonal antibodies could be produced on 500
acres of corn using a purification facility costing US$80 million and three
to five years to build and approve. The per-unit (gram) cost is $350-1,200/g
(depending on scale) for mammalian cell culture versus $80-250/g using
pharmaceutical corn.

A second advantage of PMPs is the large production capacity offered by
plants?in particular production scalability, which requires only that new
seeds be developed and that more acres be brought into production to meet
additional demand. A third advantage of PMPs is they are believed to be
inherently safer than recombinant proteins from microorganisms or cells.
PMPs do not carry potentially harmful human or animal viruses into the
drug?a possible limitation for drugs derived from mammalian cell cultures or
animal milk.

Plant-Made Pharmaceuticals and Biopharming: An Emerging Industry

The technology for producing pharmaceuticals from plants has been available
for more than 16 years. The genetic engineering technology, referred to as
the Polymerase Chain Reaction (PCR), makes it possible to isolate the DNA
sequence that codes for a particular protein, reproduce many copies of that
sequence, and ultimately produce considerably larger quantities of
particular proteins. The process of developing and using plants to produce
pharmaceutical compounds consists of identifying the target protein and then
identifying and isolating the gene that codes for the protein. One approach
is to insert the gene into a plant vector, which enables transfer of new DNA
into plant cell. Alternative approaches use electrical discharge or
biolistic particle bombardment to insert the gene into the plant cell. Plant
cells are then grown into callus and then into seed-producing plants. The
seeds are grown in a greenhouse or field, and the protein is purified from
leaf or seed material.

There are more than 20 biotech organizations that specialize in PMPs. Many
of these organizations (companies or universities) have specialized in one
(or more) crop of choice as a platform for therapeutic production. Among
several of the organizations currently active in PMP research and
development is the Missouri-based Chlorogen, Inc., which specializes in
developing PMPs expressed in tobacco, including vaccine for cholera, human
serum albumin, and interferon for hepatitis C, among others. Ventria
Bioscience (California) uses rice to develop PMPs such as lactoferrin and
lysozyme?proteins used for human and animal health applications. Meristem
Therapeutics (France) uses corn to produce gastric lipase (for treating of
cystic fibrosis) and uses gene-modified alfalfa to produce albumin (used in
heart surgery). Another firm, Medicago (Canada), has specialized in
transgenic alfalfa to mass-produce hemoglobin for the growing blood-bank
market. Large Scale Biology Corp. (LSBC) uses the tobacco plant to produce
aprotinin (protease inhibitor), which is traditionally extracted from cow
lungs. Few of these protein therapeutics have yet to reach commercial stage;
many are at various stages of development and clinical testing, ranging from
preclinical stages to advanced or Phase III clinical stage levels.

Field testing of the pharmaceutical (and industrial) crops in the United
States has been taking place since the early 1990s. However, the pace and
number of these field-test trials have accelerated in recent years.
According to APHIS data, more than 325 sites of field trials in the United
States were approved from 1991 to 2004 for pharmaceutical, novel protein,
and industrial enzymes. The number of these trials has grown in the past few
years, particularly in corn, tobacco, soybeans, and rice. Although corn has
dominated as the crop of choice, there has been some drop in corn trials
since 2003 as a result of a move toward nonfood crops for pharmaceutical
trials.

Open-Field Cultivation of Pharma Crops: The Containment Challenge

Genetically engineered crops grown to produce PMPs have little in common
with traditional agriculture. These pharmaceutical crops do not represent a
new wave of value-added agriculture. Rather, these crops represent open-air
bioreactor farming, a component of pharmaceutical and industrial enzyme
manufacturing process. Their cultivation in the field is predicated on the
requirement of total isolation and confinement from the food supply. The
cost structure of pharmaceutical crops is determined mostly by risk
minimization requiring (a) sophisticated risk management to avoid potential
gene outflow and minimize impact on nontarget organisms as well as workers'
health; (b) identity preservation based on a tight closed-loop system to
avoid any possibility of commingling with food supply; and (c) a set of
quality-control procedures with a tight chain of custody to satisfy the
isolation and confinement requirement.

Genetically engineered pharmaceutical-producing crops require a permit from
the United States Department of Agriculture Animal and Plant Health
Inspection Service (USDA APHIS), which must include a containment plan for
the plants during the production, handling, and movement of plants in and
out of the field. APHIS reviews all plans for seed production, timing of
pollination, harvest, crop destruction, shipment, confinement, and the
storage and use of equipment. Field inspections may take place up to five
times during the growing season coinciding with critical times of
production. APHIS issues a field test permit either to an individual company
or research institution who, in turn, may subcontract with growers.
Subcontracting farmers are also required to undergo training in permit
requirements and implementation.

The field confinement measures for pharmaceutical crops vary depending on
the biology of the plant. Self-pollinating crops (e.g., rice, barley), with
their heavy pollen, have isolation distances of 50 to several hundred feet.
Isolation for corn, with its wind-borne, relatively light pollen, is at
least one mile. Confinement guidelines also require a 50-foot fallow zone
around pharma corn. There is also a restriction on growing a food or feed
crop on the same field the following year. Pharma corn grown between one
half and one mile must be planted at least 28 days before or after any other
corn within this distance. (This temporal isolation minimizes the likelihood
of pollen shed overlap and cross-fertilization.) In addition to mandatory
training for personnel, the use of dedicated equipment for planting and
harvesting must be approved by APHIS along with dedicated facilities for
storage of equipment and regulated articles during the season.

The FDA also has domain over human drug and biological products produced
from pharmaceutical plants. The FDA considers pharmaceutical crops to be
outdoor manufacture sites and subject to regulatory scrutiny analogous to
that applied to conventional drug manufacturing facilities. The
manufacturing process, including field production, must follow the current
Good Manufacturing Procedures (GMP) to oversee greenhouse or field
production practices. Basically, the FDA expanded the GMP (traditionally
applied to manufacturing facilities) to the wide-open field for
pharmaceutical crops. The aim is to insure consistent manufacturing
processes and product safety, purity, and potency. Prior to commercial
production of PMPs, the FDA must decide favorably on the safety and efficacy
of the pharmaceutical product, based upon clinical tests, chemistry
manufacturing and control, pharmacology/toxicology information, and an
acceptable inspection of the manufacturing facility.

Overall, the FDA's responsibility extends to the entire manufacture of the
biopharmaceuticals?from production to waste streams?so its role necessarily
complements and overlaps the role of APHIS at the field production stage.
Whereas APHIS regulates the growing and isolation of engineered crops, the
FDA regulates materials, equipment, and manufacturing processes?encompassing
everything from seed stock to packaging.

Federal regulatory rules are constantly evolving in response to advances in
science and technology. These standards have recently been revised.
Moreover, APHIS amended its regulations for genetically engineered plants
that make drugs and industrial compounds, requiring a standard permit for
field testing rather than notification (essentially an expedited permit) as
previously allowed. In 2004, APHIS issued a public notice for proposed rule
changes to its biotechnology regulations. The proposed revisions would
define specific-risk-based categories for field testing for pharmaceutical
and industrial crops and consideration of environmental assessments in the
issuance of field-test permits. At the same time, both APHIS and FDA are
reviewing additional revisions, including specifying appropriate training
standards the use of third-party auditors and standard-setting
organizations.

Biopharming and the Food Industry

Given the potential risks and liabilities associated with accidental
commingling with the food supply, and facing the daunting task of ensuring
near-100% containment, the food and the biotech industries have taken a
precautionary approach to pharmaceutical crops and support for risk-based
regulations. The Prodigene incident case in 2002 illustrates the type of
risks facing the food industry. In Nebraska, during the 2002 growing season,
APHIS inspectors discovered "pharmaceutical" volunteer corn growing in a
soybean field. The corn was from the previous year, when Prodigene had
tested a pharmaceutical corn to produce a swine vaccine. As a result, both
the harvested soybeans (500 bushels) and the entire soybean load of 500,000
bushels in local elevator were quarantined. In another accident in Iowa, the
USDA forced Prodigene to burn 155 acres of conventional corn that may have
cross-pollinated with some of the company's pharmaceutical plants. In both
cases, the infraction was viewed to come from Prodigene's failure to adhere
to permit protocols issued by APHIS. Prodigene was fined US$250,000 and
required to pay approximately $ 3 million for the cleanup costs and disposal
of contaminated corn and soybeans.

Although the quick discovery and resolution of the Prodigene incidence was
credited to the effectiveness of the existing regulations and oversight, the
incidents themselves provided the industry with a precedent for what could
happen in the future as more pharmaceutical crops are grown in open fields.
It is generally agreed that a 100% guarantee of zero contamination may be an
impossible goal to achieve under field growing conditions. This presents the
food industry with several challenges requiring consensual responses. More
immediately, a coalition of food industries seems to favor the inclusion of
food-safety assessment by event prior to issuing a permit. An implication of
such an approach is a better handle on risk in case the containment fails.
In practice, such an approach would tilt the current research and
development away from food crops (such as corn) in favor of nonfood crops
(tobacco). This may explain, in part, the drop in the number of
pharmaceutical corn field trials, beginning in 2003, and the concurrent rise
of tobacco field trials.

In the medium and long term, improved confinement methods may require new
and innovative responses from the biotechnology industry itself. Many
biotech companies are currently pursuing production strategies that combine
both greenhouses and confined facilities with open fields. Other firms use
plants in completely closed facilities or greenhouses. An example is
Medicago, which grows biopharmaceutical alfalfa for therapeutic proteins in
greenhouses. Under this system, the company can produce up to 9 kg/year of
protein with a unit value of $10,000 per gram of protein using one
1,300-square-foot greenhouse.

However, when large quantities of pharmaceutical products are required or
the crops do not grow well in isolated systems, open-field production is
necessary. This tends to favor self-pollinated crops (e.g., soybeans, rice,
or barley) at the expense of open-pollinated crops (corn). There are other
technology-based options to ensure confinement. Among possible solutions is
the use of pharma plants with a "terminator gene" to ensure plant sterility
or engineering plants with visual markers for easy identification. For
wind-pollinated crops like corn, a precautionary practice currently in use
is to manually detassel corn (i.e., remove male flowers) and to plant rows
of nontransgenic corn to supply pollen for pharmaceutical plant and avoid
pollen drift beyond the pharma field. The preferred option from the food
industry perspective is the cultivation of pharma crops in locations that
are far removed from areas where food crops are grown, including possibly
sourcing overseas.

Biopharming and Environmental Impact: Technological Solutions

Pharmaceutical crops may also present risks to the environment which include
potential safety issues linked to contamination with residual pesticides,
herbicides, and toxic plant metabolites. An additional concern is an altered
plant contaminating wild strains and human exposure to plant material
containing potent drugs. There is also the concern that transgenes will
spread in the environment and affect nontarget organisms. However, not all
biopharmaceuticals may be harmful, and many may be considered benign to
nontarget organisms. This is because many biopharmaceuticals are proteins
with little or no biological activity when ingested (e.g., vaccines and
antibodies). Moreover, most proteins are digestible and may pose little
hazard of toxicity. Nevertheless, biopharmaceuticals may be toxic in higher
doses (e.g., anticoagulants, hormones, and enzymes) or may persist longer in
the environment (as in the case of lipophilic drugs).

To limit environmental exposure, several technological solutions are being
pursued. One solution is to induce genes to produce therapeutic proteins
only after harvest. For example, to induce production of the protein
glucocerebrosidase, LSBC uses a nontransgenic tobacco plant cut at a given
height and sprayed under confined conditions with recombinant plant virus.
An alternative LSBC practice involves spraying tobacco plants in the field,
harvesting a few days later, and then purifying the protein. Another
solution is to use chloroplast transformation to limit gene flow. This
approach consists of introducing the gene not in the plant genome per se but
rather in chloroplast DNA, which enables the plant to produce the target
protein but is not transmitted to the seed. This is the approach followed by
Chlorogen for tobacco. Yet another option is to use plant genomes that are
incompatible with nearby related species.

Conclusions

Plant-made pharmaceuticals represent a significant development in the
ongoing biotechnology revolution. But are they inevitable? Certainly
pharmaceutical crops' lower production and capital costs and their greater
production flexibility give them a strong appeal as biofactories for drug
development. However, many scientific, regulatory, and economic hurdles
remain. First, as a new technology, PMPs have yet to fully demonstrate
"proof of concept"; the suitability of green plants for protein manufacture
is still not fully resolved. Although the economics seem compelling, and all
the trends so far point toward feasibility, until these are approved by the
FDA for commercial use, there is still a large segment within the drug
industry that is not yet convinced that plant proteins will be as effective
as animal-based proteins. A second obstacle may come from new technological
developments, which may or may not continue to favor open-field cultivation
compared to confined greenhouse production. A third obstacle is that the
cost advantage of PMPs could change in favor of other production
(expression) platforms with technological improvements in fermentation
processing or with animal-based transgenics (such as the use of milk glands
as the production medium).

Realistically, plants need to be viewed as just one possibility among many
for manufacturing therapeutic proteins. PMPs could evolve along several
paths. They could either dominate specific therapeutic protein markets or
monopolize biogenerics. Overall, plant transgenics will likely be the
favorite expression system with proteins that do not express well in
traditional systems, are given in large doses, or for which production costs
make them too expensive to bring to market.

Pharmaceutical crops may not require large amounts of acreage. The area
needed will depend on the potential demand for the pharmaceutical products.
For example, the production of the antibody against bacteria that cause
tooth decay would require 600 kilograms per year, which can be supplied by a
single large tobacco farm. On the other hand, using tobacco to produce human
serum albumin may require up to 45,000 acres of tobacco to meet world
demand. However, for pharma crops grown in open-field conditions in
proximity to food crops, the challenge of insuring 100% containment will be
daunting. Consequently, one can expect significant spillover effects on
food-crop markets, in the likelihood of contamination, particularly if PMPs
are expressed via food crops such as corn or rice.

For the biotech and drug industry, biopharming offers tremendous economic
and health benefits once the current cycle of product development reaches
the commercialization stage. However, for these benefits to be fully
realized, the central issue of risk to the food industry and the environment
is a critical requirement. Industrial and agricultural investments in
biopharming must weigh the size of economic payoffs from growing
pharmaceuticals against the costs and liabilities within the food supply
system, including the potential loss to export markets. A combination of
strong and adaptable regulatory oversight with technological solutions are
required if the twin goals of realizing the full potential of biopharming
and safeguarding the food system and the environment are to be met.

[www.agbioforum.org]

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