Biopharm

Issues and News Analysis

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

FDA Perspective on Drugs and Biologics Produced in Bioengineered Plants

Keith O. Webber, Ph.D.

Director
Division of Monoclonal Antibodies
OTRR/CBER/FDA
Public Forum
Iowa State University

The Food and Drug Administration

The FDA is authorized to:

Ensure safety to the U.S. food supply.

Ensure the safety, purity, potency, and efficacy of the nationês drugs, biological products, and medical devices.

Ensure the safety of clinical trial subjects.

Statutes--Regulations&Guidance

Federal regulatory authority is a 3-tiered system.

Statutes: THE LAW--passed by Congress and signed by President.

Regulations: details of the law--written by the Agency and approved by the Executive Branch.

Guidance: the Agencyês interpretation of the Regulations

The Statutes

The Public Health Service Act

42 U.S.C. 262 et seq.

Applies to biological products

The Food, Drug, and Cosmetic Act

21 U.S.C. 301 et seq.

Applies to "traditional drugs"

The Statutes

The Virus, Serum, and Toxins Act

21 U.S.C. 151 et seq.

applies to veterinary biological products

administered by USDA/APHIS/CVB

The Regulations--21 CFR

21 CFR Part 25:

Environmental Impact Considerations

21 CFR Parts 210, 211, 225, and 226:

Good Manufacturing Practices for Drugs and Biologics

21 CFR Parts 312 and 314:

IND, DMF, and NDA Regulations

21 CFR Parts 500, 510, 515, and 558:

Animal Drug Regulations

21 CFR Parts 600, 601, 610:

Biological Product Regulations

21 CFR Parts 812 and 814:

Medical Device Regulations

Introduction

GUIDANCE FOR INDUSTRY

Drugs, Biologics, and Medical Devices Derived From Bioengineered Plants For Use in Humans and Animals Draft- Not for Implementation

This guidance document represents the agencies' current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA, USDA, or the public. An alternative approach may be used if such approach satisfies the requirements of applicable statutes and regulations.

Committee

Scope of the Guidance

Bioengineered plants or plant materials to produce biological products, including intermediates, protein drugs, medical devices, new animal drugs, and veterinary biologics regulated by FDA or USDA e.g., recombinant vaccines and therapeutics

What is a "bioengineered pharmaceutical plant"?

Any plant manipulated by recombinant DNA technology to express a gene encoding a biological or drug product.

What types of submissions are covered by the Guidance?

Biologic License Application (BLA),

New Drug Application (NDA),

New Animal drug Application (NADA),

Premarket Approval (PMA),

Investigational New Drug (IND),

Investigational Device Exemptions (IDE), or 510 (k)

Veterinary Biological Product License Application (VBPLA)

Scope

What role does the USDA/APHIS/BRS play?

Biotechnology Regulatory Services Division (BRS) oversees the importation and interstate movement of bioengineered pharmaceutical plants and infectious plant vectors as well as the release of these entities into the environment.

The FDA Perspective

Our primary concern is with the continued safety, purity, potency, and strength of our product.

The Biologics Perspective

Biological products are complex "entities".

They are almost always a mixture of components:

Product-related components

Product-related contaminants

Process-related contaminants

The "product" is dependent on the process.

Therefore, the process should be well-controlled.

Manufacturing Processes

Seed Bank Production & Storage

Planting

Cultivating

Harvesting

Storage

Extraction

Purification

Formulation

Filling

Analytical Methods

Host Plant Characterization

The following should be addressed:

The potential for the plant to express an allergenic or toxic compound.

The method of plant propagation

The measures necessary to ensure confinement

If it is a food crop species, the measures to ensure than non-food (or non-feed) material will not get into food or feed

Host and Source Plant Characterization

Identify narrowest taxonomic grouping applicable.

Is it an annual, perennial, or biennial?

Timing of sexual maturity and duration of flowering

Seed production and harvesting

Recognized practices for maintaining seed stock purity

Levels of any toxins, anti-nutrients, and allergens known to be produced by the plant species

Is it known to accumulate heavy metals?

Is it of a species used for food or feed?

The DNA Construct

Physical map of the contruct(s) illustrating the position of each functional component

The origin and function of all component parts of the construct, including antibiotic- or herbicide-resistance genes, promoters, and enhancers

The nucleotide sequence of the intended insert

Any changes in codons to reflect more acceptable codon usage

Master and Working Seed Bank

Describe:

The method of production,

The results of analytical tests used to characterize it,

The size of the bank,

The storage conditions,

Data demonstrating its viability and stability.

Characterization of Transformants

For stable transformation systems:

Describe the gene transfer method in detail,

Report the number of copies of the gene inserted, the number of integration sites

Demonstrate if complete or partial copies are inserted

Determine the nucleotide sequence of the insert from DNA or mRNA retrieved from the stably-transfected plants

Transient Transfection Systems

Regarding the recombinant virus vector:

Provide the taxonomic name of the virus

Is it a DNA or RNA virus?

Is it associated with any satellite or helper viruses?

What is the natural host range of the virus?

How the virus is transmitted?

Describe any vector-mediated transmission

Describe any reported synergistic or transcapsidation interactions with other viruses

Describe the protocol for cloning of recombinant virus

Describe the protocol for purification of the virus

Describe the preparation of the Master Plasmid Bank (MPB), if one is used

Describe the storage conditions and data demonstrating stability of the MPB

Describe the protocol for the preparation of infectious nucleic acid from plasmid

Provide data characterizing the infectious nucleic acid with respect to its identity with the parental genome.

Genetic Stability

To demonstrate genetic stability:

Segregation analysis for the trait of interest,

A molecular characterization of the genomic insert (e.g., Southern analysis)

Analysis of expression of the intended product

Provide data demonstrating that the inheritance and expression of the new traits are stable over the number of generations that you plan to use during manufacturing.

For plants that are infertile or for which it is difficult to produce seed (such as vegetatively propagated male-sterile potatoes), you should provide data to demonstrate that the trait is stably maintained and expressed during vegetative propagation over a number of cycles that is appropriate to the crop.

Tissue Distribution of Expression Products

For all inserted coding regions, provide data demonstrating whether the protein is or is not produced as intended in the expected tissues.

If the gene is inducible, you should provide quantitative data characterizing the distribution of the product in the major plant titues (e.g., leaves, roots, stalks, seeds) under uninduced and induced conditions

Envrionmental Considerations

Authorization from APHIS/BRS is required prior to the interstate movement, importation, and field release of bioengineered pharmaceutical plants.

A copy of the letter from APHIS/BRS granting your permit should be submitted in your application.

National Environmental Policy Act

You should consider the potential environmental impact of all aspects of the manufacturing process, including but not limited to transport of seeds and plants, planting, growing, harvesting, processing, purifying, packaging, storage and disposal.

If you believe that your activities are categorically excluded by 7 CFR 372.5(c) , 21 CFR 25.31, or 25.33 from the requirement to submit an environmental assessment, you should state this in your application.

Confinement Measures

Regardless of whether the bioengineered pharmaceutical plants are grown and/or processed by you or on a contractual basis by other persons, manufacturing controls are your responsibility.

You should implement controls and procedures to ensure that pharmaceutical-plant material is used only for its intended purpose.

If the plant species is used for food or feed, consider using:

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s (e.g., a novel color or leaf pattern)

Using tissue specific promoters

Using an inducible promoter

Measures should be in place to ensure that there is no inadvertent mixing of the bioengineered pharmaceutical plant with plant material intended for food or feed (including inadvertent mixing with seeds for food or feed crops).

We strongly recommend that you have tests available that can detect the presence of the target gene and the protein product in raw agricultural commodities.

Control over Seed Stocks:

Label them in accordance with APHIS Permit

Accounting

Of the total yield of seed when seed banks are produced

Of the amount and disposition of any withdrawals from the seed bank

Store seed stocks in aliquots of appropriate volume to allow reasonably accurate accounting

Control of Harvested Material

During transport, containers of harvested material should be clearly labeled indicating that the material is not to be used for food or feed.

Reconciliation of the quantities of material leaving the growing facility and arriving at the processing facility should be made.

Control at Processing Facilities

Bioengineered pharmaceutical plants or plant materials should not unintentionally mix with other plant products, particularly those used as food or feed.

Source plant materials should not be processed in facilities that also are used for the production of food or feed, such as grain mills, without prior consultation with USDA/APHIS/BRS and FDA.

Control of Waste Material

Waste material should be treated to inactivate the regulated product prior to disposal.

Disposal should conform to local and state regulations.

Manufacturing Processes

Seed Bank Production & Storage

Planting

Cultivating

Harvesting

Storage

Extraction

Purification

Formulation

Filling

Analytical Methods

Design to prevent contamination and cross-contamination during harvest and processing of source material.

Quality control of starting material.

Flow of product, equipment & personnel.

Environmental monitoring, as appropriate

Growth Conditions

Establish specifications & procedures for:

Soil composition

Irrigation

Fertilizers

Pesticides

Induction of expression

Inoculation with viral vectors

Harvesting

Written procedures to cover:

Timing

Health of plants

Harvesting process

Identification of equipment

Cleaning of equipment

Transport and storage of harvest

Written procedures to cover:

C

ontainment to keep vermin out

Time and temperature limits

Monitor quality of stored material

Identification of containers

Cleaning of containers

Extraction & Purification

Written Procedures

Validate methods

Environmental monitoring

Control bioburden

Product Characterization

Analogous to other biological products

Purity

Potency

Strength

Molecular weight

Aggregation

Charge characteristics

Post-translational modifications

Special Issues for Unpurified Products (e.g., whole or processed veggies)

Batch uniformity

Consistency of dose

Allergenicity

Packaging

Stability

Contacts

Human biologics:

Keith Webber, Ph.D., at 301-827-0850 (CBER)

Human drugs:

Yuan Yuan Chiu, Ph.D., at 301-827-5918 (CDER)

Animal drugs:

Wendelyn Warren, Ph.D., at 301-827-6978 (CVM)

Veterinary biologics:

Patricia L. Foley, D.V.M., Ph.D., at 515-232-5785 (USDA/APHIS/CVB)

Submit comments to:

Dockets Management Branch (HFA-305)
Food and Drug Administration
5600 Fishers Lane, Rm. 1061
Rockville, MD 20852

You should identify all comments with docket number

02D-0324