Projections for new and existing biopharmaceutical drugs indicate that demand will soon overwhelm supply.1 New facilities housing cell-culture units can be built, but they require a substantial capital investment and are costly to operate. In response, alternative production systems are being developed. One of the most promising systems incorporates transgenic plants as the expression host.2-5
The plant-made biopharmaceutical (PMB) industry began in the early 1990s, and a few products are now in advanced clinical trials. Some products that have been produced in plants include trypsin, aprotinin, therapeutic monoclonal antibodies, therapeutic enzymes, protective antigens from human pathogens, and blood factors.6,7 The regulatory process has developed alongside this growth. An important document on biotechnology regulation was a 1984 Federal Register Notice (FRN), "Proposal for a Coordinated Framework for Regulation of Biotechnology,"8 in which the government determined that biotechnology products could be regulated effectively under existing statutory authorities and regulations and described those authorities.
This two-part article will guide you through the matrix of federal agencies, laws, and regulations that govern the evaluation, production, and distribution of the final PMB products derived from recombinant plants. Such products fall under the authority of FDA, the US Department of Agriculture (USDA), and the Environmental Protection Agency (EPA), depending upon the nature of the product and its intended use.TECHNICAL BACKGROUND Recombinant organisms are integral to the biomanufacturing industry as a host system for expressing therapeutic and medicinal proteins. Transgenic plant systems promise lower production costs since plants can be grown in a field instead of a cell-culture facility. Also, they provide an alternative production system for proteins that are difficult to express in traditional cell culture.
Using plant-specific transformation techniques, the gene encoding the therapeutic product is inserted into the genome of the host plant. Depending on the techniques and type of plant used, the product may be expressed in the leaves, stems, seeds, fruit, or other plant parts. The recombinant plant is propagated, and a seed bank is established. Subsequent generations of plants are grown from the seed bank to produce plant material expressing the protein, which is harvested and subjected to an extraction and purification process similar to traditional processes with cells or microorganisms.
A PMB is no different than a biopharmaceutical derived from cultured mammalian cells or microorganisms. Existing regulations ensure the safety, purity, and efficacy of a biopharmaceutical regardless of the host expression system. However, with a new host and a new propagation environment (a field or greenhouse which is less controlled than a bioreactor), understanding the differences in development and production is critical for laying the groundwork and defining the regulatory path to commercialization.
PMBs are generally protein products intended for use as human or animal drugs, medical devices, vaccines, diagnostic reagents, and raw biochemical or industrial materials. This article discusses the regulation of biological products for human use as drugs or therapeutics that have been derived from a recombinant plant source. We do not cover traditional "botanical products" as the term is used by FDA in "Guidance for Industry: Botanical Drug Products."9 That document specifically excludes "materials derived from genetically modified botanical species (i.e., by recombinant DNA technology or cloning)."
Biological products from any source are unique and must be handled in a different manner than synthesized chemical drugs in order to assure the safety, purity, and potency of the drug. These products are derived from living systems, are heat labile, are subject to microbial contamination, can be damaged by shear forces, and have the potential to be immunogenic or allergenic.
The source material entering the purification process is likely to be generated in a non-sterile environment (a field or greenhouse) and is exposed to unique environmental factors such as agricultural chemicals, weather, insects, birds, mammals, dirt, pollen from other plants, fungi, and bacteria. Also, there are known and unknown potential contaminants that must be identified and analyzed for potential effect on the end product's quality.
THREE REGULATORY BODIES Because part of the biopharmaceutical manufacturing process takes place outside of a contained facility, a critical component of PMB regulation is a system to avoid inadvertent release of material, to ensure environmental safety, and to protect the integrity of agricultural plant products intended for food and feed. Three US government agencies address these quality and regulatory issues.