Biotechnology as an integrated science has given rich dividends in terms of products for human health, agriculture and industrial use. A number of protein based therapeutics and vaccines have emerged as a result of genetic manipulation of animal, plant and microbial systems. High yielding, pest resistant and more nutritious genetically modified crops are available -- thanks to the advent of biotechnological tools.

There is no stopping to this branch of science as novel and so far un-thoughtful ideas are dawning to the scientists and being researched upon, both by the private and the public sectors. At the same time, fiddling with nature has its own limitations and is beset with risks. As newer solutions are sought, newer regulations to safeguard the biosphere and environment have to be laid.

Most of the biopharmaceuticals are proteins and proteins cannot be chemically synthesized, hence, these are produced using mammalian & microbial cell cultures and plants. Having experienced the limitations of the fermentation system for producing biological drug or biopharmaceuticals, some of the world leaders in the field of biodrugs have gone ahead to use plants as the producers of these molecules. Such plants come under the category of industrial plants and biopharmaceuticals produced by them known as - Plant Made Pharmaceuticals or PMPs in short.

Plant-Made Pharmaceuticals (PMPs) are a category of pharmaceutical proteins such as monoclonal antibodies, enzymes, and blood proteins produced in live plants for their ultimate use as therapeutic agents to treat life-threatening diseases. Crops such as corn, tobacco, potato, sugarcane, rice, alfalfa, safflower and soybean are genetically altered to yield proteins with purity and activity equivalent to those produced by other manufacturing systems, with advantages that include large volume production capacity, reduced capital requirements, and freedom from potential viral and animal protein contamination. A number of novel and complex proteins, which are difficult to produce in mammalian cell cultures, could also be made in plants. The proteins are then extracted, refined and used in pharmaceuticals usually as active pharmaceutical ingredients.

The obvious choice of plants for PMPs is the GM food crops. The scientists have a good understanding of genetics, agronomics and environmental impact of GM crops, the information gathered during their development and field trials come handy in developing methods for confinement, safety, regulation and management of crops grown for PMPs. At the same time, these crops are different from GM crops. In GM crops, beneficial traits such as higher yield, better nutrition and resistance to disease are introduced in the crops grown for food, feed and fiber, i.e. "golden rice", which is rich in pro-Vitamin A. PMP research does not deal with value-added commodity agriculture. Protein-producing plants are actually "production factories" and are a step towards pharmaceutical manufacturing process. PMPs also differ from edible vaccines, as these are not meant to administer via food or food chain.

Therapeutic proteins for diseases such as cancer, HIV, heart disease, diabetes, Alzheimer's, kidney diseases, cystic fibrosis, multiple sclerosis, spinal cord injuries, Hepatitis C, Herpes, rheumatoid arthritis, iron deficiency etc. are aimed to be produced through plants. Companies working on plant-made pharmaceutical technology include Biolex, Ceres, Chlorogen, Dow AgroSciences, Epicyte, Medicago, Meristem Therapeutics, Monsanto Protein Technologies, Planet Biotechnology, ProdiGene, SemBioSys, Syngenta and Ventria Bioscience. The current status on PMPs is given in Table.

Plant-Made Pharmaceuticals in Clinical Trials

Plant-Made Pharmaceuticals Expected Soon in Clinical Trials

A number of biopharma companies in India are taking initiatives to work on PMPs or import this technology. The efforts are laudable but it is pertinent to see whether regulatory systems are in place to deal with safety issues involved in crops producing PMPs. Currently, still on biogenerics and in early stages of transgenics through licensing and sub-licensing, PMP technology making inroads may raise newer safety concerns specially in the wake of milieu when bio-companies are hoarsing aloud for a single window clearance or an independent regulatory body.

It is worthwhile to note here that the currently the country follows a three-tier system for biosafety as per the Environmental Protection Act, 1986 and the guidelines issued thereof in 1989. These guidelines are in accordance to the Cartegena Protocol on Biosafety as well. Yet, it is not certain that the same biosafety regulations could be applied to the crops producing medicines. Bringing in new technology of PMP at this point of time, without understanding the logical reasons or science behind strict regulations imposed in countries where PMP technology is functional may backfire. It is, therefore, pertinent to look at the multi-agency and interwoven regulatory systems that have been established for PMPs elsewhere in the world, specially in US where the technology has taken a firm footing.

US follows an integrated, multi-agency regulatory system for all its biotechnological products. For PMPs, initial regulations are same as for other genetically modified systems, however field trials are federally controlled. Following agencies are involved for regulation of crops producing medicines:
-- Food and Drug Administration (FDA)
-- U.S. Department of Agriculture (USDA)
-- USDA's Animal and Plant Health Inspection Service (APHIS) under the Biotechnology Regulatory Services (BRS),
-- FDA Center for Biologics Evaluation and Research (CBER),
-- FDA Center for Drug Evaluation and Research (CDER)
-- FDA Center for Food Supply and Applied Nutrition (CFSAN), and
-- FDA Center for Veterinary Medicine

Plant-made pharmaceuticals (PMP) technology needs more stringent regulatory mechanisms than GM crops. The central points of regulations in case of PMPs are:
-- Issuing of the permit by the federal Government after R&D and limited confined trials
-- Confinement measures
-- Training for growers, and
-- Penalty Clause

Issue of the permit
USDA's Animal and Plant Health Inspection Service (APHIS) is the central body granting permits for field trials of crops for pharmaceutical protein production. APHIS requires companies to obtain permits for field trials and grants permit on a case-by-case basis. In general, it takes approximately 120 days from the time the permit application is received until the permit is either denied or issued.
-- Prior to issuing a test permit, APHIS reviews all plans for seed production, timing of pollination, harvest, crop destruction, shipment, confinement and the storage and use of equipment.
-- Permits are then issued for the importation, interstate movement and field-testing of the plants.
-- APHIS or state officials inspect records, facilities (including laboratories and greenhouses), and each field site is inspected at least five times in the growing season, with those inspections corresponding to critical times in production, such as pre-planting site location evaluation, planting, mid-season, harvesting and post-harvesting.
-- A sample inspection plan might include five site visits made during the growing season, with an additional two inspections to assess any potential volunteer plants in the following year.
-- Records also are required for all activities specified by the permit, including planting dates of regulated and adjacent crops if applicable, and dates of bagging and assessment.
-- APHIS will use these records to oversee and audit the field tests.
-- Permit reporting requires field test reports six months after field test termination. Interim reports also may be required.
-- Additionally, APHIS must be notified by phone within 24 hours of an unusual occurrence or suspicion of a breach of confinement, followed by a written report within five business days.

Confinement measures
PMPs need special requirements of confinement to prevent commingling with food or feed crops, the environment, humans and non-target organisms. Hence, these plants are grown and processed separately from food and feed crops in a well-defined system of "confinement". Unlike food industry, which follows Hazard Analysis and Critical Control Point (HACCP) principles, PMP industry has based its risk assessment on Containment Analysis and Critical Control Point (CACCP), which takes into account the:
-- crop,
-- specific protein being expressed,
-- spatial setting defining the distance between plots for plants producing pharmaceutical proteins and conventional crops used for food and feed,
-- Temporal setting defining the time separating the flowering and pollination between plants producing pharmaceutical proteins and nearby conventional crops of the same or related species,
-- location of the intended production area,
-- agronomic and crop handling practices,
-- perimeter fallow zone around the field test site,
-- Special confinement conditions for crops such as corn

Training
For PMPs, only a few select growers are identified, trained and supervised to grow these prescription plants. The annual training of contract growers and all other individuals involved with the development and production of PMPs is an APHIS regulatory requirement. An APHIS-approved training program ensures personnel are prepared to successfully implement and comply with all permit conditions.

Availability of Seeds
The seeds are available from the authorized manufacturer and cannot be purchased off the shelf at a local seed store.

Penalty Clause
APHIS conducts a full-scale investigation governed by the Plant Protection Act that provides for both criminal and civil penalties against the erring company or individuals. In case, the permit is violated:
-- there is a civil penalty of up to US $250,000 per violation and/or imprisonment for up to five years, or US $500,000 per adjudication, and may result in having their permits revoked.
-- the transgenic plants can be subjected to remedial measures, including disposal, to protect the environment or public health,;
-- if the owner fails to take such action, APHIS can take the action and recover the cost of the action from the owner.

It may be of interest that despite US Federal Government's strict guidelines based purely on science, some companies have faltered and penalized. Case of ProdiGene is of special relevance in this context. Though there is a perception that no separate regulations are required in case Indian biotech companies plan to move into the era of next generation of medicines, there is need, both for the biotech companies and regulators to understand and discuss the logic behind sticker regulations in case of plants producing medicines than genetically modified food crops. If need be, proper guidelines for this technology at the federal level need to be formulated to be at par with the international guidelines.

(Concluded)

The author is Director, Department of Biotechnology Ministry of Science and Technology, New Delhi

(Views expressed in this article are those of the author and not necessarily of the organization she works for)