US Regulation of Plant-made Biopharmaceuticals, Part 2

February 1, 2005
Sharon A. Berberich

Rebecca A. Devine

Volume 18, Issue 2

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.

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.

Sharon A. Berberich


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 FDA and USDA issued "Draft Guidance for Industry: Drugs, Biologics, and Medical Devices Derived from Bioengineered Plants for Use in Humans and Animals," in September 2002.34 This guidance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.


The use of agricultural production systems for drugs and biologicals presents some new challenges for FDA and USDA in terms of regulating the crop under what could be called "good agricultural practices." These methods of control are similar to those expected under cGMP for the manufacture of traditional biopharmaceutical drugs. The application of good agricultural practices is necessary to assure that the processes for the growth and harvesting of the crops are properly documented and controlled, that procedures are in place to prevent harmful adulterants from entering the product, and that the crop produced will be contained to the degree necessary to protect the environment and human and animal health. The drug cGMPs apply to the product after harvest. For information on these controls, consult the guidance and regulations on drug GMPs. Some pertinent guidance documents are listed below as references 38 to 47.

Table 2. Issues Addressed in the Guidance for Industry: Drugs, Biologics, and Medical Devices Derived from Bioengineered Plants for Use in Humans and Animals

Confinement. Confinement measures must be developed and validated to ensure that PMB plant material will not be mixed or spread with plant material intended for other uses, such as food or feed. The guidance specifically addresses control of seed stocks, field-grown plants, harvested material, processing facilities, equipment and waste material.

Product Characterization. Product characterization is accomplished by the usual variety of tests for a protein product. Depending on the product being developed and whether or not there is a cell culture derived comparator; the molecular features of the plant-derived material should be carefully examined. Product specifications should be sufficient to address the concerns discussed here.

A plant-derived protein may include post-translational modifications different from those encountered in a cell-culture or prokaryotic cell-culture production system. Different impurities may be present in plant-derived material, posing safety or immunogenicity concerns not found in cell-derived biopharmaceutical products. Comparability to a natural molecule or a molecule produced by other methods that has already been studied in humans may be helpful in assessing the impact of the bioengineered plant production process.

Look carefully at the use of pesticides, infestation by insect contaminants not removed in the harvest process, and the presence of unusual bioburden. Natural bioburden from a plant may be much different than that encountered in traditional cell-culture production techniques and could affect the product if proteases or other impurities interact with the molecule of interest. In addition, some fungal contaminants produce toxic substances and must be prevented from adulterating the plants used to make the PMB.

Preclinical and Clinical Issues. In addition to the usual examination of the active molecule for toxicity, preclinical review of the molecule from the plant should include a review of potential impurities from the plant source. Establish specifications for residual levels of pesticides, herbicides, and fungicides. Evaluate metal toxicants to determine if they are present and whether the host plant stores these metals. Allergenicity should also be evaluated, and tests based on the intended use of the product should be considered.34


The regulatory approval process has inherent risks regardless of the safety, efficacy, and benefits of the product. In the case of PMBs, the level of regulatory risk is unknown and the path to commercialization is somewhat unclear. There are no commercial PMBs on the market today. What is clear is that the process will follow the existing regulatory framework developed for approval of biopharmaceuticals and GE plants. Producers should consult the FDA and USDA guidance documents that are applicable to all biological products in addition to the regulations and guidance used for approval of other GE plants.


See "Internet Resources" for a list of web sites with additional information.

Several PMB products have achieved IND status and are in clinical trials today, so the precedents are being set and the path cleared. Developers of these early products and the primary regulatory agencies, FDA and USDA, are laying the regulatory groundwork for the anticipated growth of PMBs. Public interest groups, non-government organizations, food and feed industry groups, and international regulatory activities are also influencing regulations and PMB industry standards.


The authors would like to acknowledge Steve Ripley and Astrid Szeto of CBER for their help in locating old Federal Register documents used in the article.

Internet Resources

Food and Drug Administration

FDA Center for Drug Evaluation and Research:

FDA Center for Biologics Evaluation and Research:

FDA Center for Veterinary Medicine:

FDA Center for Food Safety and Applied Nutrition:

United States Department of Agriculture

USDA Biotechnology Regulatory Services:

Compilation of Laws Enforced by the FDA

Code of Federal Regulations (Government Printing Office)

Biotechnology Industry Organization

International Academy of Life Sciences


International Service for the Acquisition of Agri-Biotech Applications


References 1-37 are in Part 1. Reference 34 is repeated.

34 FDA. Draft guidance for industry: drugs, biologics, and medical devices derived from bioengineered plants for use in humans and animals. Available at:

38. Rodemeyer M. Pew initiative on food and biotechnology issues in the regulation of genetically engineered plants and animals. Available at:

39. FDA. Points to consider in the manufacture and testing of monoclonal antibody products for human use. Available at:

40. FDA. General principles of process validation. Available at:

41. FDA. Q2B ICH Guidance on the validation of analytical procedures: methodology. Available

42. FDA. Q5B ICH Quality of biotechnological products: analysis of the expression construct used for production of rDNA derived protein products. Available at:

43. FDA. Q5C ICH Quality of biotechnological products: stability testing of biotechnological/biological products. Available

44. FDA. Q6B ICH Specifications: test procedures and acceptance criteria for biotechnological/biological products. Available at:

45. FDA. Draft sterile drug products produced by aseptic processing — current good manufacturing practice. Available at:

46. FDA. Q7A ICH Good manufacturing practice guidance for active pharmaceutical ingredients. Available at:

47. FDA. INDs for phase 2 and phase 3 Studies chemistry, manufacturing, and controls information. Available at:

48. FDA. Submission documentation for sterilization process validation in applications for human and veterinary drug products. Available at:

Sharon A. Berberich is the senior director, licensing & development at Chlorogen, Inc., 893 North Warson Rd., St. Louis, MO 63141, 314.812.8142, fax 314.812.8080,

Rebecca A. Devine, Ph.D. is a consultant, 22 Atwood Ct., Silver Spring MD 20906, 301.871.4300, fax 301.871.4833, She was formerly associate director for policy at CBER and currently serves on the BioPharm International Editorial Advisory Board.