Probiotics: Safety Issues
Francis B Palumbo, PhD, Esq.
University of Maryland
School of Pharmacy
Center on Drugs & Public Policy
Drug
• Must be safe and effective
• Effectiveness demonstrated by
substantial evidence (i.e. well
controlled clinical trials)
• Safety data compiled
throughout the clinical trials
process.
Drug
• Post market safety data
collected via Medwatch and
entered into FDA’s AERS.
• Safety continually evaluated.
Conventional Foods
• “Ordinarily injurious to health”
standard
– Standard for adulteration of food
caused by naturally occurring
substances.
– Less rigorous safety standard than
for added substances.
Food Shall be Deemed to
be Adulterated
• If it bears or contains any
poisonous or deleterious
substance which may render it
injurious to health, but if not an
added substance it will not be
adulterated if the quantity of
substance does not ordinarily
render it injurious to health.
Food Shall be Deemed to
be Adulterated
• If it bears or contains
– any added poisonous or
deleterious substance that is
unsafe within the meaning of
section 406 FDCA (tolerances for
poisonous ingredients).
– Pesticide residue
– Unsafe food additive or unsafe
new animal drug
Food Shall be Deemed to
be Adulterated
• Consists in whole or part of any
filthy, putrid, or decomposed
substances, or if it is otherwise unfit
for food.
• Prepared, packed or held under
unsanitary conditions
• Others
GMPs & Foods?
• The food industry, however, does
observe the concept of GMPs and
FDA has promulgated several
regulations establishing current GMPs
in the manufacturing, packing, or
holding of human food (21 C.F.R. §
110)
Enforcement Actions &
GMPs
• In enforcement actions, FDA usually
does not rely on the food GMP
regulations as creating legally binding
requirements against the food
industry
• Instead, FDA uses evidence gathered
during factory inspections to prove a
direct violation of the Food Drug &
Cosmetic Act.
Dietary Supplements
• Under DSHEA, manufacturer is
responsible for ensuring that the DS
is safe before it is marketed.
• FDA can take action if product is
adulterated or misbranded.
Dietary Supplement
Adulteration
• The dietary supplement failed the general food
safety standard in that the product bears any
poisonous or deleterious substance which may
render it injurious to health.
• if it presents a significant or unreasonable risk of
illness or injury under conditions of use
recommended or suggested in the labeling or,
under ordinary conditions of use if no conditions of
use are suggested or recommended in the labeling.
Dietary Supplement
Adulteration
• if it is a new dietary ingredient for which
there is inadequate information to provide
reasonable assurance that such ingredient
does not present a significant or
unreasonable risk of illness or injury.
Dietary Supplement
Adulteration
• if the Secretary (of HHS) declares it to pose
an imminent hazard to public health
• if it contains a food additive (not a dietary
ingredient) that is unapproved for such
use, is not generally recognized as safe or
is otherwise adulterated
Dietary Supplement
Adulteration
• if it failed to meet current good
manufacturing practices
• Dietary supplement manufacturers
follow the general food GMPs
Food Additives
• A manufacturer wishing to market a new
ingredient in a conventional food can
– Make a self determination of GRAS
– File a notification with FDA asking that
they not object to the self
determination, or
– File a food additive petition supported
by extensive toxicology testing
Generally Recognized as
Safe (GRAS)
• Any substance that is intentionally added
to food is a food additive and is subject to
premarket review and approval by FDA,
unless the substance is generally
recognized, among qualified experts, as
having been adequately shown to be safe
under the conditions of its intended use, or
unless the use of the substance is
otherwise excluded from the definition of a
food additive.
GRAS
• the use of a food substance may
be GRAS either through
scientific procedures or, for a
substance used in food before
1958, through experience based
on common use in food.
GRAS
• Under 21 CFR 170.30(b), general recognition of
safety through scientific procedures requires the
same quantity and quality of scientific evidence as
is required to obtain approval of the substance as a
food additive and ordinarily is based upon published
studies, which may be corroborated by unpublished
studies and other data and information.
• Under 21 CFR 170.30(c) and 170.3(f), general
recognition of safety through experience based on
common use in foods requires a substantial history
of consumption for food use by a significant number
of consumers.
GRAS Notification
• Information about the identity &
properties of the substance & a
discussion of the notifier’s
reasons that the substance is
GRAS
• Information is generally
chemical, toxicological and, if
applicable, microbiological in
nature
Food Additive Petition
• Chemical composition, substances used in
preparation, etc.
• Amount & proposed use
• Data that it will have intended effect
• Methods to determine amount of additive
in food
• Safety reports
Food Additive-Safety
Standard
• General two-part food additives
standard:
– Legislative history- whether
substance is hazardous to the
health of man or animal
– Must be “reasonable certainty”
that no harm will result
The Delaney Clause
The Food Additives Amendment –
Delaney Clause:
• Asserts that “no additive shall be deemed
to be safe if it is found to induce cancer
when ingested by man or animal, or if it is
found after tests which are appropriate for
the evaluation of the safety of food
additives, to induce cancer in man or
animal …”
Tests Showing Safety of a
Food Additives
• FDA has summarized in its Redbook the
various types of testing that may be
required to show that a particular use of
a food additive is safe
• Depending on the food additive and its
intended use, the data required to
demonstrate safety vary depending on
the additive’s chemical structure,
projected human exposure, and current
knowledge about its safety
Tests Showing Safety of a
Food Additives – Cont’d
• As long as the tests conducted do not
show that the additive “induce[s]
cancer” (thereby invoking the Delaney
Clause), FDA will review the data and
then determine the level at which the
additive does not cause an adverse
effect
• Then, FDA will apply a safety factor to
that number (21 C.F.R. § 170.22)
Food Additives
Toxicity Testing
• NOEL: No-Observed-Effect Level
– Highest exposure that does not
produce an adverse effect
Safety Factor
• Safety Factor: used to account
for differences between humans
and animals
– Generally, a safety factor of 100 is
used to apply animal test data to
man
• May be modified based on
subpopulation (e.g. children where it
might be increased)
Hazard Analysis & Critical
Control Points and Principles
(HACCP)
• a management system in which food
safety is targeted through review &
control of biological, chemical, and
physical hazards from raw material
production, procurement and handling, to
manufacturing, distribution and
consumption of the end product
• designed for use in all areas of the food
industry – (growing, harvesting,
processing, manufacturing, distributing,
and merchandising)
Genetically Modified
Organisms & Food
• The FDA uses the term genetic modification
to refer to all forms of breeding -- both
modern, e.g. genetic engineering, and
conventional
• Bioengineered foods and food ingredients
(including food additives) must adhere to the
same standards of safety and adulteration
provisions under the FDCA
• GMO products must be as safe as the
traditional foods/food additives in the market
Genetic Modification as
Food Additives
• FDA considers the existing
statutory authority and
regulations to be fully adequate
to ensure the safety of new
food ingredients and foods
derived from new varieties of
plants , regardless of the
process by which they are
produced.
Food Safety Modernization
Act - 2011
• Gives FDA much greater oversight over the food
industry, including requiring facilities to register
every two years, to develop new food safety plans,
and to provide the agency with test results
• Gives greater incentives to the industry and
importers to implement strong food safety programs
• Gives FDA the power to mandate recalls
• Requires FDA to develop by this coming April a
consumer-friendly website to help identify food that
is subject to a recall
• Requires grocery stores to provide notices about
recalls to customers when they are shopping