From Alzheimer’s to Zebrafish: Eclectic Science and Regulatory Stories 74
The US Food and Drug Administration (FDA) defines a botanical drug as a product used
as a drug that contains as ingredients vegetable materials, which may include plant mate-
rials, algae, macroscopic fungi or combinations thereof. Unfortunately, active ingredients
found in botanical products are difficult to characterize, as are the methods to measure
their potency. Moreover, the composition of vegetable materials can vary from season
to season and farm to farm. Most botanical drugs are complex mixtures and may lack a
distinct active ingredient. For these reasons, the agency historically paid little heed to or
generally neglected any form of herbal medicine.1
This philosophy began to change in the late 1990s and culminated in 2004 when FDA
published guidelines for reviewing botanical drug products.2,3 Thus, more than 65 years
elapsed between the enactment of the Federal Food, Drug, and Cosmetic Act and the recogni-
tion that patients may benefit from herbal medicines. Botanical products can take several
developmental pathways in addition to being classified as drugs (see Figure 1). Botanicals
become drugs when they are used to diagnose, cure, mitigate, treat or prevent disease and
are used to affect the structure or function of the body. Botanical drugs may be marketed
in the US under:
• Approved New Drug Applications (NDAs) as an over-the-counter (OTC) drug
(nonprescription) or prescription drug (Rx)
• OTC monographs
The regulatory path to marketing botanical drugs is no more complicated than the path
for any other drug.
The Approval Process
It is apparent that FDA reviewers have adopted a new paradigm to allow approval of
botanical drugs, primarily by establishing acceptable methods of characterizing the
active ingredient(s). For synthetic or highly purified drugs, the characterization is a major
undertaking. The manufacturer must provide a precise description of the composition,
methods of manufacture, specifications and control procedures for both the drug sub-
stance and the drug product. The chemical structure, molecular formula and molecular
weight must be included in the chemistry, manufacturing and controls (CMC) section of
the NDA. Physical and chemical properties, i.e., appearance, taste, odor, crystalline struc-
ture, solubility profile, melting and boiling point ranges, specific gravity, spectroscopic
characteristics and isomeric composition, must be supplied. In addition, proof of structure
including physical and chemical information derived from applicable analyses, such as
mass spectrometry, nuclear magnetic resonance, degradation studies, chromatographic
study methods such as high performance liquid chromatography, gas chromatography,
thin layer chromatography and gas liquid chromatography, infrared spectroscopy, stereo-
chemistry and x-ray diffraction are required. Information on the drug substance’s stability
under defined storage conditions and the method of manufacture, including the analytical
controls used to ensure each batch’s identity, quality and purity are other key parameters.4
Botanical drugs are different from those made synthetically. Botanical drugs have
certain unique characteristics that must be taken into account when the CMC information
is provided in an NDA. Unlike synthetic drugs, botanical drugs’ active ingredients are not
readily identified chemically or easily quantifiable. Fortunately, the active constituents
might not need to be identified if this is shown to be unfeasible.5 In such circumstances,
FDA will rely upon a combination of other tests (e.g., spectroscopic or chromatographic
fingerprints, chemical assay of characteristic markers and biological assay), and controls
for raw materials and in-process methods.
There are a number of critical elements for botanical drug manufacturers to consider.
Strict controls of each plant raw material(s), tight in-process controls, vigorous process vali-
dation and appropriate and adequate plant testing of the drug substance and dosage form
The US Food and Drug Administration (FDA) defines a botanical drug as a product used
as a drug that contains as ingredients vegetable materials, which may include plant mate-
rials, algae, macroscopic fungi or combinations thereof. Unfortunately, active ingredients
found in botanical products are difficult to characterize, as are the methods to measure
their potency. Moreover, the composition of vegetable materials can vary from season
to season and farm to farm. Most botanical drugs are complex mixtures and may lack a
distinct active ingredient. For these reasons, the agency historically paid little heed to or
generally neglected any form of herbal medicine.1
This philosophy began to change in the late 1990s and culminated in 2004 when FDA
published guidelines for reviewing botanical drug products.2,3 Thus, more than 65 years
elapsed between the enactment of the Federal Food, Drug, and Cosmetic Act and the recogni-
tion that patients may benefit from herbal medicines. Botanical products can take several
developmental pathways in addition to being classified as drugs (see Figure 1). Botanicals
become drugs when they are used to diagnose, cure, mitigate, treat or prevent disease and
are used to affect the structure or function of the body. Botanical drugs may be marketed
in the US under:
• Approved New Drug Applications (NDAs) as an over-the-counter (OTC) drug
(nonprescription) or prescription drug (Rx)
• OTC monographs
The regulatory path to marketing botanical drugs is no more complicated than the path
for any other drug.
The Approval Process
It is apparent that FDA reviewers have adopted a new paradigm to allow approval of
botanical drugs, primarily by establishing acceptable methods of characterizing the
active ingredient(s). For synthetic or highly purified drugs, the characterization is a major
undertaking. The manufacturer must provide a precise description of the composition,
methods of manufacture, specifications and control procedures for both the drug sub-
stance and the drug product. The chemical structure, molecular formula and molecular
weight must be included in the chemistry, manufacturing and controls (CMC) section of
the NDA. Physical and chemical properties, i.e., appearance, taste, odor, crystalline struc-
ture, solubility profile, melting and boiling point ranges, specific gravity, spectroscopic
characteristics and isomeric composition, must be supplied. In addition, proof of structure
including physical and chemical information derived from applicable analyses, such as
mass spectrometry, nuclear magnetic resonance, degradation studies, chromatographic
study methods such as high performance liquid chromatography, gas chromatography,
thin layer chromatography and gas liquid chromatography, infrared spectroscopy, stereo-
chemistry and x-ray diffraction are required. Information on the drug substance’s stability
under defined storage conditions and the method of manufacture, including the analytical
controls used to ensure each batch’s identity, quality and purity are other key parameters.4
Botanical drugs are different from those made synthetically. Botanical drugs have
certain unique characteristics that must be taken into account when the CMC information
is provided in an NDA. Unlike synthetic drugs, botanical drugs’ active ingredients are not
readily identified chemically or easily quantifiable. Fortunately, the active constituents
might not need to be identified if this is shown to be unfeasible.5 In such circumstances,
FDA will rely upon a combination of other tests (e.g., spectroscopic or chromatographic
fingerprints, chemical assay of characteristic markers and biological assay), and controls
for raw materials and in-process methods.
There are a number of critical elements for botanical drug manufacturers to consider.
Strict controls of each plant raw material(s), tight in-process controls, vigorous process vali-
dation and appropriate and adequate plant testing of the drug substance and dosage form