Biopharm

Issues and News Analysis

From SEE Biotech and BioTrek at the University of Wisconsin-Madison

Iowa State University

Public Forum on Pharmaceutical Crops

Regulatory Considerations for Transgenic Plant Veterinary Vaccines

Plants as Bioreactors

Potential for high levels of accumulated recombinant proteins

Glycosylation differences apparently not problematic for at least some proteins

Comparmentalization within the cell

Natural storage stability in certain organs

No contamination from animal byproducts

Ease of delivery: feed not injection, no cold chain requirement

Progression of Transgenic Plant Constructs

1st: Production traits-

Bt corn

Roundup Ready soybeans

2nd: Nutrition-added crops-

Vitamin A rice

lycopene tomato

3rd: Pharmaceuticals, enzymes & biologics-

TGEV corn,

LT-B potato

4th: ?

Types of Plant-Based Biologics

Vaccines

Feed-based for oral mucosal immunization

Whole plant or partial plant

Purified protein

Parenteral subunit or feed additive

Plantibodies

Diagnostic kit components

Antigens, plantibodies

Transgenic Plant Proteins for Animal Vaccines

Rabbit hemorrhagic disease virus

VP60 in potato (injection)

Foot-and-mouth disease virus

VP1 in Arabidopsis (injection)

VP1 in alfalfa (injection, oral)

Transmissible gastroenteritis virus

S protein in Arabidopsis (injection)

S protein in tobacco (injection)

S protein in maize (oral)

Safety Issues

Risk assessment process

Environmental effects

Non-target animals

Pollen drift: spatial & temporal confinement

Accidental release to food/feed facility

Viable/nonviable material

Health risk: toxin, allergen, immunotolerance?

Loss of public confidence in segregation

Factors in Confinement Measures for Corn

1/4 mile separation reduces gene flow>99.5%

Pollen (male) sheds 10-14 days, viable for 3-24 hours

Ear silks (female) receptive for 14 days

1 mile for corn seed production, .5 mile from corn, 21 days from other plantings within .5 to 1 mile of the transgenic plants

Draft Document #1

OSTP, 8/2/02-Proposed Fed. Actions to:

Update field test requirements for biotech-derived plants intended for food/feed use

Establish early food safety assessments for new proteins produced by such plants

Oversight-APHIS, FDA, EPA

Location: http://www.OSTP.gov/html/redregbio.html

Office of Science & Technology Policy Draft

For premarket, experimental use

Level of confinement consistent with risk

Prevent low levels of genes and gene products in commercial seed, commodities, processed food/feed until appropriate safety standards can be met

FDA: website to list all evaluated proteins

USDA: transparency of regulatory process

��Pharm Plant? Regulation

APHIS/BRS: permits for importation, interstate movement, field testing

Inspections: labs, greenhouses, field sites

These plants not to be de-regulated

Field production under Federal oversight

Case-by-case analysis: unique products from differing plants, sometimes using GE?d plant viruses

Draft Document #2

USDA/FDA, 9/12/02-Guidance for Industry

Drugs, biologics, and medical devices derived from bioengineered plants

For use in humans and animals

Locations:

http://www.aphis.usda.gov/vs/cvb/

http://www.fda.gov/cber/guidelines.htm

http://www.fda.gov/ohrms/dockets/default.htm

Guidance Document as it applies to US Vet. Biological Product License

Characterize: rDNA, transformation system, genetic stability, expression (detection assay), tissue distribution

Recommended: genetic

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s (color, leaf pattern), auxotrophic

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, tissue-specific and inducible promoters

Accounting for total yield of seed

Disposal: 9 CFR 114.15, VS Memo 800.56

Manufacturing Procedures

Propagation & purification

Growth conditions & harvest

Transfer & storage conditions

Initial processing, extraction, aseptic processing

Cleaning between harvests

Characterization of the final product, including stability

Production Considerations

Meet EPA, USDA, FDA containment levels

Best if surrounding fields under firm control: their yield cannot go into food/feed chain if temporal & spatial distance not maintained

Outline must state pesticide, herbicide use

Serial: mixed as a batch of representative sampling to demonstrate homogeneity

For whole fruit or vegetable, homogenize for uniform bulk substance: puree, juice, milled grain

Commercial Production

Procedures so no entry into food/feed without FDA or CVB clearances

Identity preservation system

Seeds: shipping to planting

Plants: harvest to product use

Tests to detect the target gene and the protein product in the raw agricultural commodity

Consumer use of a consistent product

Ground into a crude prep (additive), purified, or consumed directly as a food/feed product

Requirements of Oral Vaccines

Purity: within accepted levels for mycotoxins, pesticides, herbicides, soil-borne contaminants, naturally occurring plant toxins, etc.

Safety: overdose study/tolerance but not reversion-to-virulence; field safety trial

Potency: measure, ID protective Ag or Ab in bulk or finished product

Efficacy Requirements

Same as for conventional products

Based on label claim

"prevents infection with (microorganism)"

"for prevention of disease due to (microbe)"

"as an aid in the prevention of (disease)"

"as an aid in the reduction of (disease)"

Requires vaccination/challenge of fully susceptible host animals: sufficient numbers at minimum age on label, potency of efficacy serial established prior to V/C

Labeling of Transgenic Veterinary Biologics

Label claims will need to meet 9 CFR 112 label requirements (adapted)

Directions for use: dosage, frequency, administration, minimum age

Claims for protection

Storage conditions and expiration date

Warnings, cautions, and restrictions

CVB: Biologics Testing

VST Act, 1913: pure, safe, potent, effective

Amended, 1985 by FSA: include distribution of all vet biologics in US & for export

Case-by-case analysis

Target animal safety:

Tolerance induction, reproductive safety, response in young/old, toxin, allergen

Environmental safety:

Use, manufacture, disposal