US Regulation of Plant-made Biopharmaceuticals, Part 2 - The evaluation, production, and distribution of therapeutic products derived from recombinant plants are regulated under existing laws administ

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US Regulation of Plant-made Biopharmaceuticals, Part 2
The evaluation, production, and distribution of therapeutic products derived from recombinant plants are regulated under existing laws administered by FDA, USDA, and EPA.


BioPharm International



Sharon A. Berberich
In the first part of this feature (Jan. 2005) we discussed the technical background and the role that FDA, US Department of Agriculture (USDA), and Environmental Protection Agency (EPA) play in setting the rules for accepting plant-made biopharmaceuticals (PMBs). We now continue by discussing how producers will be able to take products to market.

GUIDANCE FOR INDUSTRY There are six important issues to consider when filing an Investigational New Drug (IND) Application for a PMB. We will examine them here.

Agency Overlap. FDA and USDA issued "Draft Guidance for Industry: Drugs, Biologics, and Medical Devices Derived from Bioengineered Plants for Use in Humans and Animals," in September 2002.34 This guidance resulted from collaboration between FDA and USDA and outlines the regulatory expectations for products derived from bioengineered plants. It describes the division of authority between the two agencies and also provides technical guidance on the use and characterization of the plants and the products produced from them. The document is still in draft form but provides an idea of FDA and USDA concerns. Issues addressed in the guidance are shown in Table 2. (Table 1 is in Part 1). Note the high degree of overlap between FDA and USDA issues.


Host and Source Plant Characterization. When choosing the plant production systems, just as in choosing a mammalian cell culture system, it is essential to assure the system is appropriate for its use. In choosing the plant type and the tissue used for purification of the PMB, the developer must address concerns regarding the presence of potentially toxic or allergenic substances. In addition, if the plant host is also used for production of food or feed, the developer must consider confinement of the PMB material and the potential impact of unfavorable public opinion regarding the production system. One must consider the type of product and its end use (oral or parenteral) and the potential routes of exposure for different plant hosts and source tissues. The guidance document contains a list of specific criteria to be considered in choosing a host plant and recommends certain characterization data for the engineered source plants, including suitability of the vectors, transfection or transformation method, copy number and stability of the inserted DNA.34

Seed Banking. The fundamental requirements for preparing and maintaining a master seed bank (MSB) and a working seed bank (WSB) are applied to PMB products. Characterization data will be specific to each MSB or WSB and will include parameters such as uniformity, bioburden, storage conditions, gene content and stability, phenotype or genotype stability, and viability data.

A difference between an MSB for cultured cells and one for plants is that seed cannot be frozen in liquid nitrogen vials. Seed must be stored at a temperature and humidity that will maintain viability. Depending on the type of plant, viability may be reduced over time (4-10 years, depending upon the seed) below production specifications. Therefore, new MSBs must be generated and characterized on a regular basis. Another difference is the ability to generate starting material for PMB purification from one generation of the host, compared to multiple generations for cell culture and fermentation. Again, the type of data needed to characterize and verify consistency of the MSBs and WSBs for plants should be appropriate for the system and ensure the consistency and safety of the final PMB product.


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