Gloria Mao, PhD

Senior Scientist

Technical Regulatory Affairs

Amway of Australia and Malaysia

2012

Ensuring the Safety of

Nutrition Products

Nutrition Products Products used to supplement a diet and to maintain, enhance and

improve the healthy function of the human body

Wide variety of sources of ingredients

Foods, herbs, animals, microorganisms, minerals

Complex Compositions

An ingredient can be a single compound or mixture of compounds

Whole material or processed to isolate compounds

Naturally Derived

Many are naturally formed/grown

Composition and quality varies for the same ingredient

Synthetically Derived

Synthetic versions are same or similar to natural compounds

New ingredients continually being discovered and developed for human uses

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Ensuring Safe Nutrition Products

Safety evaluations and determining maximum safe levels of ingredients use the same scientific principles as evaluating the safety of any substance Focus on foods, botanicals and vitamin/minerals

Unique challenges

Models that have been used and modified

Considerations for evaluating multi-ingredient products

Role of the manufacturer- Responsibility to ensure safety of their product Integrated Safety Program

Assessment of safety of ingredients and products

Quality Assurance

Research and Development

Monitor and Respond to Adverse Events

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Safety Assessment

Safety Assessment process involves

Identification of the nature of the substance

Summary of the available data on relevant exposures

Identification of any safety concern

Determination of safe usage conditions and safe levels of exposure in humans

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Safety Assessments

There are several authoritative organizations with guidance documents on how to conduct a safety assessment on botanical or food ingredients

Scientific organizations (ILSI, WHO)

Regulatory agencies

Examples of completed safety assessments

(US NTP, JECFA)

Similar in content

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Sources of Safety Information

Raw Material Supplier

Identification, feedstock, processing methods, characteristics

Non-published studies

Publicly available literature

Web-based search

Research studies in scientific journals, reports from scientific organizations and government agencies

Reference books

Lay-person sources

Manufacturer generated information

Analytical chemistry, assays

Research and Development- in vitro studies, clinical studies, consumer preference studies

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Evaluating Ingredients-botanicals/other

Information relevant to determine ingredient identification, characterization and standardization as much as is available

Source:

Identity, Scientific name, common names

Part(s) of plant used

Geographic origin

Growth conditions:

Wild or cultivated, harvesting process

Methods of preparation:

extraction, solvents

Purity criteria (micro, heavy metals, residual solvents, etc)

Level and nature of excipients

Specifications

Standard reference (pharmacopeia)

Identity tests

Tests to determine constituents and quantity relevant for beneficial effects

Tests to determine inherent constituents of toxicological relevance

Standardization criteria

Plant-extract ratio

Chemical/Active/Marker identification and level/range

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Evaluating Ingredients-example of specifications

Description :

Extract obtained from raspberry leaf.

Botanical name : Rubus spp.

Plant part used: leaf

Extraction solvent:

ethanol x%/water x%

Extract ratio: x/1

Composition :

Natural extract , excipients, etc...

Specifications : Sensory quality :

Aspect : powder/liquid, etc Color : white/brown, etc Flavor : characteristic

Analytical quality :

Identification : TLC conform Ellagic acid content : > x % Loss on drying : < x % Particle size : 100% through x mesh Residual ethanol content : < x %

Microbiological quality : Total plate count : < x cfu/g Yeasts and molds : < x cfu/g

R E D R A S P B E R R Y with x % E L L A G I C A C I D

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Evaluating Ingredients Information for evaluating safety

History of Use

How has it been used- food, medicine, other?

How long has it been in use historically?

If used as food, what is the estimated dietary exposure of the ingredient via product and habitual diet, taking into account geographical/cultural variation?

Potential/reported pharmacological activity

What has been the serving size/daily intake/doses

Preparation, target population(s)

Information on health/adverse effects

Known warnings (precautions, contraindications, interactions)

Regulatorily allowed intakes

Vitamins and minerals have published estimates of maximum safe levels and/or upper limits for supplements

Information regarding allowed levels of ingredient may be obtained from positive lists or monographs

Countries may also have guidance on ingredients’ daily dose, duration and required cautionary statements

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Evaluating Ingredients Information for evaluating safety (continued)

Human Studies

Clinical studies

Epidemiology studies

Case reports

In most cases, these studies are not specifically used to test safety in humans. They are designed instead for clinical/efficacy outcomes. These studies are useful sources of safety information if they document identity of exposure, dose-response, whether any adverse effects occurred, highest observed safe dose, duration of intake, etc.

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Evaluating Ingredients Information for evaluating safety (continued)

Toxicology Studies

A safe intake level for human consumption may be estimated through extrapolation from the animal data

In some instances, human data are adequate to demonstrate safety up to certain intake levels, but extrapolation from well-conducted preclinical toxicology studies with animals may suggest much higher safe levels for human consumption

In such instances, both the human data on observed safe use and the animal data on extrapolated safe levels should be cited and the human data take preference.

Protocol and design for the conduct of toxicological studies have become standardized

International guidelines have been developed to achieve consistency in experimental techniques

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US FDA Redbook

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http://www.fda.gov/Food/GuidanceComplianceRegulatoryInformation/GuidanceDocuments/FoodIngredientsandPackaging/Redbook/default.htm

OECD Testing Guidelines http://www.oecd-ilibrary.org/environment/oecd-guidelines-for-the-testing-of-chemicals-section-4-health-effects_20745788

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Evaluating Ingredients Information for evaluating safety (continued)

Analytical

Chemical identification may be undertaken to characterize botanicals.

Scientific evidence for risk can be obtained by considering if the plant constituents are compounds with established toxicity or are closely related in structure to compounds with established toxicity.

In-vitro

Validated in-vitro studies (proven to predict a specific effect in animals and/or humans with reasonable certainty) can be indicators of risk to human health.

There needs to be comparable exposure in humans and the in-vitro effects must correlate with a specific adverse health effect in humans or animals.

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Safety Assessment After review of the information, the safety assessment should be conducted.

Ingredient materials and doses are not necessarily the same in the information to the product and the identity and quantitative differences must be taken into account.

Assumptions or limits to evaluating the data should be stated

The safety assessment should identify:

Any risks associated with intake/exposure

Acceptable daily intake

Contraindications

Interactions

If the ingredient is important or commonly used, there may be existing evaluations by an authoritative group of scientists, such the Joint Expert Committee on Food Additives (JECFA) or a GRAS Panel (a panel of experts convened to examine whether the substance is “Generally Recognized as Safe” under national or international guidelines).

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JECFA

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http://www.inchem.org/pages/jecfa.html

Safety Assessment How data is evaluated is dependent on what information is available

CASE 1: Identification of a risk (genuine toxicological risk as compared to a nuisance such as gastrointestinal distress), assessment of the dose-response relationship, consideration of uncertainty, and determination of the acceptable daily intake that is not only safe but includes a reasonable margin of safety.

or

CASE 2: If no data exist that establish adverse effects in humans, the highest observed intake level (HOI) with sufficient scientific evidence of safety at that intake becomes the acceptable daily intake

or

CASE 3: If no scientific evidence is available related to safety of high intakes by humans, then animal data may be used to determine acceptable daily intake with appropriate extrapolation

or

CASE 4: If no scientific clinical or animal data exist, a compelling pattern of history of safe intake as components of foods commonly consumed by humans is used as the acceptable daily intake

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Acceptable Daily Intake (ADI)

ADI is an estimate of the amount of a [substance] that can be ingested daily over a lifetime without appreciable health risk

1. Determination of No Observed Adverse Effect Level

2. Determine of Safety Factors

3. Calculate the Acceptable Daily Intake

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NOAEL

The No Observable Adverse Effect Level (NOAEL) is the greatest dose of an agent that causes no detectable adverse alteration of morphology, function, growth, development or lifespan of the target.

The NOAEL from animal studies is used to determine the allowable daily intake for humans

To extrapolate to humans, safety factors are used to give a margin of safety to estimate a safe dose for humans

The objective is to establish a large margin of safety to ensure protection to humans.

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Use of Safety Factors Safety factors are used to extrapolate from animals to an average human and from average humans to potentially sensitive sub-populations (example: SFs=10 for each extrapolation)

SF2 Margin of Safety (MOS) SF1

SPECIES DIFFERENCES

HUMAN VARIABILITY

SF2=10 SF1=10

x =

20 10 100 10 = x

Margin of Safety

MOS < 100 if there is a substantial number of clinical studies or human population studies that examined safety outcomes; UF=1

MOS = 100 if there are animal study data with determined NOAELs for acute and chronic toxicity, based on credible scientific studies

MOS > 100 ingredient is intended for “at-risk” human population (i.e. children) or data is incomplete

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ADI = NOAEL

SAFETY FACTOR (100)

Data indicating no toxicity CASE 2: If no data exist that establish adverse effects in humans, the highest

observed intake level (HOI) with sufficient scientific evidence of safety at that intake becomes the acceptable daily intake

The January 2006 FAO-WHO report on risk assessment defined a Highest Observed Intake (HOI) as estimate of safe level when no toxicity has been observed

Very similar to CRN/IADSA Observed Safe Level (OSL) method and UK EVM’s unnamed method for some nutrients

CASE 4: If no scientific clinical or animal data exist, a compelling pattern of history of safe intake as components of foods commonly consumed by humans is used as the acceptable daily intake

Food Equivalent method

The chemical identity of the supplemental form is the same, or less than, as that found in foods.

The intake level, frequency of intake and duration of use are similar to that that occurred through food consumption.

The population on which the history of use is based had sufficient health care to provide a good chance of observing any adverse effects.

No established pattern of adverse effects has credibly related to intake of the substance.

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Safety Assessment Outcomes Safe for use

At wide range of doses or

Within these specific restrictions…..

CODEX 2001: Reasonable certainty of no harm results in consumption

Or

Insufficient Info to Determine Safety

List specific items needed to be able to evaluate

Or

Unsafe at any dose

List why it is unsafe

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Product Safety Assessment

Components of a Product Safety Assessment

Description of the finished product

Safety summaries of all active ingredients

Relevant studies (clinical, consumer preference), if any, with the finished product

Describe any interactions, contraindications

Possible side effects

Cautionary statement

Previous marketing experience of the finished product

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Product Safety Assessment-template example

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Safety of Chemical Mixtures Opinion on Toxicity and Assessment of Chemical Mixtures by the

three independent non-food Scientific Committees of the EU Commission SCCS, SCHER and SCENHIR

Based on the analysis of the available scientific literature, their conclusions are that:

(1) Under certain conditions, chemicals may act jointly in a way that the overall level of toxicity is being affected;

(2) Chemicals with common modes of action may act jointly to produce combination effects that are larger than the effects of each mixture component applied singly. These effects can be described by dose/ concentration addition;

(3) For chemicals acting independently, no robust evidence is available that exposure to a mixture of such substances is of health concern if the individual chemicals are present at or below their zero-effect levels;

(4) Interactions (including antagonism, potentiation, synergies) usually occur at medium or high dose levels (relative to the lowest effect levels). At low exposure levels, they are either not occurring or toxicologically insignificant;

(5) In view of the almost infinite number of possible combinations of chemicals to which humans and environmental species are exposed, some form of initial filter to allow a focus on mixtures of potential concern is necessary. Several criteria for such screening are offered;

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http://ec.europa.eu/health/scientific_committees/environmental_risks/docs/scher_o_150.pdf

Mixtures of potential concern A potential for a toxicologically significant synergistic effect should be

considered under the following conditions:

Can one or more components significantly enhance the uptake of other components?

Can one or more components inhibit significantly the excretion/clearance of other components?

Do one or more of the components exert their toxic action via the formation of an active metabolite(s) and may one or more of the components induce the drug metabolising enzymes that may be involved in the formation of these active metabolites?

Can two or more components act on different enzymes in an important metabolic pathway?

Can two or more components act on different elements of cellular protection mechanisms or cellular repair mechanisms?

Testing for Interactions In vivo toxicity testing and clinical studies are inadequate for testing for interactions.

Interactions are unlikely to be detected because they rare, it is not known what targets to study and is dependent on test subject physiology.

In vitro predictive models for drugs are still in development and it is not known whether are applicable to nutrition products.

Methods combine mechanistically based toxicology studies with statistical modelling to determine interactions.

Studies to determine potential interactions may be investigated for new drugs, but are not typically conducted unless there is a known potential risk

Even so, these drug studies are designed to screen specific metabolic pathways and may or may not be applicable to nutrition ingredients.

Testing for interactions at this stage is not effective and not feasible.

Safety of Multi-Ingredient Products History of use shows that risk from multi-ingredient nutritional products is low

Post-market serious adverse effect reports with nutritional products are rare

Explanation:

Ingredient amounts are below risk (ADI) levels or at food equivalent levels

Adverse events are independent (not the same causal pathway)

For chemicals acting independently, no robust evidence is available that exposure to a mixture of such substances is of health concern if the individual chemicals are present at or below their zero-effect levels;

Evaluation of interactions is warranted under the following conditions:

When there are common mechanisms of toxicity

When there are reports, such as in monographs, of potential interactions.

Safety of Multi-Ingredient Products Risk Management practices

Warning labels to reduce possible interactions with medicines

“Individuals taking medicine or under doctor supervision should seek medical advice before taking.”

Monographs cite possible and theoretical interactions

The Natural Standard: “Most herbs and supplements have not been thoroughly tested for interactions with other herbs, supplements, drugs, or foods. The interactions listed below are based on reports in scientific publications, laboratory experiments, or traditional use. You should always read product labels. If you have a medical condition, or are taking other drugs, herbs, or supplements, you should speak with a qualified healthcare provider before starting a new therapy.”

Monograph information regarding interactions

Canadian monographs, EFSA database

Internet sites that have searchable databases: www.drugs.com, www.drugdigest.org, www.medscape.com

Health Canada

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Monograph for Gingko biloba http://www.hc-sc.gc.ca/dhp-mps/prodnatur/applications/licen-rod/monograph/mono_ginko_biloba-eng.php

Safety of Vitamins and Minerals Expert Risk Assessments for Vitamins and Minerals:

Risk assessments and estimates for upper limits of safety (ULs) for vitamins and minerals have been evaluated by expert organizations

Some countries or regions have regulated maximum limits (MLs) for V/M in foods or supplements

Some differences in ULs and MLs. Dependent on which risks were used for the NOAEL or the target population specific exposures or needs.

ULs or MLs published by:

Government or scientific organizations

US Food and Nutrition Board

EC Scientific Committee on Food

UK Expert Group on Vitamins and Minerals

Japan, China, etc.

Industry

CRN Vitamin and Mineral Safety, 2nd Edition, 2004

IADSA Safety of Vitamin and Mineral Supplements, 2004

ERNA

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ASEAN Model for Maximum Levels General Principles for Establishing Maximum Levels of Vitamins and Minerals in Health

Supplements

Developed for the normal healthy adult population

Risk Assessment involves the derivation of upper limit (UL) of a vitamin or mineral (WHO Model)

Risk Management involves managing the risk of population for total exposure to vitamins and minerals (ERNA Model)

If there is no basis for a UL because there is no evidence of adverse effects for that particular vitamin or mineral, the Highest Observed Intake (HOI) is used.

There is no scientific basis for the use of RDA/RDIs in establishing ULs. The RDA/RDI is a measurement of nutritional adequacy and not a measurement of health risk due to excess intake.

ULs are based on data already established by EFSA, EVM and IOM

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WHO Model

Determining MLs for Vit/Min Following the derivation of ULs, the nutrients are divided into three groups according to the risk of

population intakes exceeding the UL.

-Group A is for nutrients that do not have reported adverse effects and there is no risk of excessive population intakes causing human health problems

-Group B and C are for nutrients with reported adverse effects.

Group B is for nutrients with a low risk of intakes exceeding the UL

Group C is for nutrients with a potential risk of intakes exceeding the UL

MHI is the mean of highest intakes of a nutrient from foods (e.g. at 95 or 97.5 percentile)

Formulas used to establish ASEAN Maximum Level in health supplements:

ML of Group A nutrients = HOI ÷ UF – MHI

--For nutrients that have no established hazards at high intakes, their maximum intake levels with sufficient evidence of safety (observed safe level) may be used to establish ASEAN ML--

ML of Group B nutrients = UL – MHI

ML of Group C nutrients = UL – MHI

Special effort must be taken in the derivation of the ASEAN ML for Group C nutrients to minimize the chance of exceeding UL. In addition, appropriate risk communication can be instituted for certain Group C nutrients on a case-by-case basis if necessary.

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ASEAN Max Levels in Supplements

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Exemption Clause Despite the establishment of the ASEAN MLs of vitamins and minerals, Member States may consider exemption in their countries under special circumstances such as national requirements based on country assessment/consumption survey or product type classification. Such exemption with reasons should however be made known to other Member States

Thank You

Discussion

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