Probiotics: Safety Probiotics: Safety IssuesIssues

Francis B Palumbo, PhD, Esq.

University of MarylandSchool of Pharmacy

Center on Drugs & Public Policy

DrugDrug

• Must be safe and effective• Effectiveness demonstrated

by substantial evidence (i.e. well controlled clinical trials)

• Safety data compiled throughout the clinical trials process.

DrugDrug

• Post market safety data collected via Medwatch and entered into FDA’s AERS.

• Safety continually evaluated.

Conventional FoodsConventional 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 Food Shall be Deemed to be Adulteratedto 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 Food Shall be Deemed to be Adulteratedto 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 Food Shall be Deemed to be Adulteratedto 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?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 & Enforcement Actions & GMPsGMPs

• 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 SupplementsDietary 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 Dietary Supplement AdulterationAdulteration

• 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 Dietary Supplement AdulterationAdulteration

• 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 Dietary Supplement AdulterationAdulteration

• 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 Dietary Supplement AdulterationAdulteration

• if it failed to meet current good manufacturing practices

• Dietary supplement manufacturers follow the general food GMPs

Food AdditivesFood 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 Generally Recognized as Safe (GRAS)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.

GRASGRAS

• 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.

GRASGRAS

• 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 NotificationGRAS 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 PetitionFood 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 Food Additive-Safety StandardStandard

• 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 ClauseThe 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 Tests Showing Safety of a Food Additivesof 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 Tests Showing Safety of a Food Additives – of a Food Additives –

Cont’dCont’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 Food Additives Toxicity TestingToxicity Testing

• NOEL: No-Observed-Effect Level– Highest exposure that does

not produce an adverse effect

Safety FactorSafety 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 Hazard Analysis & Critical Control Points and Control Points and Principles (HACCP)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 Genetically Modified Organisms & Food 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 Genetic Modification as Food AdditivesFood 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 Food Safety Modernization Act - Modernization Act -

20112011

• 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