Unlike many traditional specific-use biopharmaceutical facilities that must be constructed as fully functional and uniform
monolithic structures, modular components can be installed rapidly (weeks). This allows for just-in-time capital expenditures
to track the actual need. Modular cleanroom components usually come with validation documentation, are uniform in construction
and finish, and can be serviced (lights, filters) from outside the clean environment. This reduces validation, assembly time,
and operational cost. A lower-cost facility results in smaller depreciation allocated to an operating budget, and this can
greatly decrease the cost-of-goods. Costs associated with upstream quality control, such as in-process testing, environmental
monitoring and testing, component validation and re-validation, are not always subtracted from the upstream cost models when
reviewing transgenic technologies, but they should be.
Other innovative manufacturing approaches such as disposable process materials; outsourced raw material (buffers and media)
production; on-line, time-of-use mixing of buffers from concentrates; and fewer holding steps (tanks and piping) during the
overall manufacturing process can result in significantly lower downstream costs. Other innovations such as the development
of moderate-cost, custom affinity resins can also reduce costs. Many of these cost-saving technologies are difficult to incorporate
into traditional processes due to standardized processes required for licensed products, technology risk avoidance, and simple
inertia. On the other hand, the embryonic stage of transgenic plant protein development is well suited for the incorporation
of innovative technologies, and protein production from tobacco using CTT will benefit from such innovation.
Reduced Regulatory Risk
There is uncertainty about the level of regulatory risk because no plant-made therapeutic has yet been commercialized. The
review process, however, will follow the existing regulatory framework developed for approval of biopharmaceuticals and, separately,
genetically engineered plants. FDA and USDA issued a joint draft guidance document in September 2002, "Drugs, Biologics, and
Medical Devices Derived from Bioengineered Plants for Use in Humans and Animals,"18 providing an interpretation of the regulations and outlining the points to address when requesting product approval.
Confinement is a key concern in the regulation and public acceptance of genetically modified crops, particularly those expressing
pharmaceuticals and industrial proteins in food and feed crops that are not intended to be food or feed. The concern is that
the gene or tissue expressing the protein will escape during field production through pollen movement, seed dispersal, or
germination and growth of plants from released seeds in subsequent growing seasons, and will then co-mingle with food and
In a chloroplast system, the confinement risks are minimized by several inherent properties of the technology and process.
Tobacco chloroplasts are maternally inherited, thereby mitigating the risk of gene transfer via pollen to other tobacco or
compatible wild species. Because leaves are used for processing, only seed used for proliferation is required, and the seed
set is so prolific (up to one million seeds per plant) that sufficient amounts can be produced in enclosed greenhouses, eliminating
pollen and seed disbursal. In addition, leaf material is harvested prior to flowering and seed set — which eliminates the
potential for pollen movement, seed dispersal, or growth from the released seeds.
With regard to contamination of food or feed, tobacco is not grown for human food or animal feed, so it is unlikely that co-mingling
would occur. Physical isolation from tobacco grown for smoking is easily achieved because tobacco is grown only in limited
geographic areas, and with such a high-yielding system, commercial quantities of protein can be produced from a small acreage,
resulting in lower overall environmental exposure. These inherent properties of tobacco cultivation contribute to a low regulatory
risk and lead to enhanced public acceptance.3,18,19
1. Global Industry Analysts, Inc. Global Marketing Data Compendium; Rockville MD. 2003.
2. Palmer JD. Comparative organization of chloroplast genomes. Annu. Rev. Genet. 1985; 19:325-354.
3. Daniell H, Ruiz ON, Dhingra A. Chloroplast genetic engineering to improve agronomic traits. Methods in Molecular Biology 2004; 286:111-137.
4. Kumar S, Dhingra A, Daniell H. Manipulation of gene expression facilitates cotton plastid transformation of cotton by
somatic embryogenesis & maternal inheritance of transgenes. Plant Mol. Biol. 2004; in press.
5. Ruf S, Hermann M, Berger IJ, Carrer H, Bock R. Stable genetic transformation of tomato plastids and expression of a foreign
protein in fruit. Nat Biotechnol. 2001; 19:870-5.