Regulatory Hurdles for Regulatory Hurdles for NanotechnologyNanotechnology

Regulatory Hurdles for Regulatory Hurdles for NanotechnologyNanotechnology

A tt M M C th Ph D

NanotechnologyNanotechnologyNanotechnologyNanotechnology

Annette M. McCarthy, Ph.D.

Office of Food Additive SafetyCenter for Food Safety and Applied Nutrition (CFSAN)Center for Food Safety and Applied Nutrition (CFSAN)

US FOOD and DRUG ADMINISTRATION

IFTAnaheim, CAJune 5 2009June 5, 2009

Di l iDi l iDi l iDi l iDisclaimerDisclaimerDisclaimerDisclaimer

Th i i d i hi i dThe opinions expressed in this presentation do not necessarily represent any official policies of the US Food and Drug Administration, or of its’ parent organization, the g p gDepartment of Health and Human Services, and should not be considered as changes in regulatory procedures. Any mention of specific companies or products should not bemention of specific companies or products should not be regarded as endorsements.

Current state of affairsCurrent state of affairsCurrent state of affairsCurrent state of affairs

Regulatory authority for food additives is not d b l d dd lexpected to be altered to address nanoscale

particles.Questions that regulators need to ask include:Questions that regulators need to ask include:

What are the appropriate criteria for defining their specifications of identity and purity for determining

f ?safety?What types of toxicity testing protocols are appropriate for establishing safe conditions of use? gDo existing authorizations cover these products?

Guidance for Approval of Food Guidance for Approval of Food Additives and Food Contact Additives and Food Contact

SubstancesSubstances

Guidance for Approval of Food Guidance for Approval of Food Additives and Food Contact Additives and Food Contact

SubstancesSubstancesSubstances Substances Substances Substances

Currently AvailableChemistry Guidance for Direct Food Additive Petitions (March 2009)Chemistry Guidance for Food Contact N ifi i (D b 2007)Notifications (December 2007)

Chemistry Guidance forChemistry Guidance forFood Additive PetitionsFood Additive PetitionsChemistry Guidance forChemistry Guidance forFood Additive PetitionsFood Additive PetitionsFood Additive PetitionsFood Additive PetitionsFood Additive PetitionsFood Additive Petitions

Section III A Identity:Section III.A. Identity:“…If the particle size is important for the additive to achieve its intended technical effect, such that the dditi i d d d i t h iadditive is produced or processed using techniques or

tools that manipulate the particle size and may contain altered particles that are formed as manufacturing by-

d t d t th i ( d di t ib ti )products, data on the size (average and distribution), shape, surface area (average and distribution), surface charge (zeta potential), and morphology of the particles as well as any other size dependent propertiesparticles, as well as any other size-dependent properties (e.g., agglomeration, aggregation, dispersion) should be included, as appropriate.”

Chemistry Guidance forChemistry Guidance forFood Additive PetitionsFood Additive PetitionsChemistry Guidance forChemistry Guidance forFood Additive PetitionsFood Additive PetitionsFood Additive PetitionsFood Additive PetitionsFood Additive PetitionsFood Additive Petitions

S ti III C S ifi ti f Id tit d P itSection III.C. Specifications for Identity and Purity:“…Parameters related to the particle size, shape, and surface properties of the food additive, as appropriate, if particle size is important for the identity and functionality of the additive.”

Section III.E. Intended Technical Effect and Use:"...A clear statement of the intended technical effect(s) of th dditi i f d If t h i l ff t f th dditi ithe additive in food. If technical effect of the additive is related to particle size, the statement should explain how size-dependent properties of the additive affect functionality ( l bilit i it t bilit tib t i l ti(e.g., solubility, viscosity, stability, antibacterial properties, antioxidant properties)."

Chemistry Guidance forChemistry Guidance forFood Contact NotificationsFood Contact Notifications

Chemistry Guidance forChemistry Guidance forFood Contact NotificationsFood Contact NotificationsFood Contact NotificationsFood Contact NotificationsFood Contact NotificationsFood Contact Notifications

Section II A 5 Physical/Chemical Specifications:Section II.A.5. Physical/Chemical Specifications:"...In cases where particle size is important to achieving the technical effect or may relate to toxicity, sponsors h ld d ib ti l i i di t ib ti dshould describe particle size, size distribution, and

morphology, as well as any size-dependent properties.”

Section II.C. Technical Effect:"...If technical effect is dependent on particle size, sponsors should present data that demonstrate thesponsors should present data that demonstrate the specific properties of the particles that make them useful for food-contact applications."

Under Consideration for Under Consideration for RevisionRevision

Under Consideration for Under Consideration for RevisionRevisionRevisionRevisionRevisionRevision

T i l G id f F d C t tToxicology Guidance for Food Contact NotificationsT i l G id f Di t F dToxicology Guidance for Direct Food AdditivesG id f GRAS S b tGuidance for GRAS Substances

*Contact FDA for specific guidance in the interim

Impact on Regulatory StatusImpact on Regulatory StatusImpact on Regulatory StatusImpact on Regulatory StatusImpact on Regulatory StatusImpact on Regulatory StatusImpact on Regulatory StatusImpact on Regulatory Status

1 The majority of food additive regulations do not1- The majority of food additive regulations do not include size-dependent specifications such as particle size, size distribution and morphology.

2- Under section 402 of the Act, it is the responsibility of both the manufacturer and theresponsibility of both the manufacturer and the end user of the food ingredient or food contact substance to ensure that the use of the food ingredient or food contact substance is safe andingredient or food contact substance is safe and lawful.

Impact on Regulatory StatusImpact on Regulatory StatusImpact on Regulatory StatusImpact on Regulatory StatusImpact on Regulatory StatusImpact on Regulatory StatusImpact on Regulatory StatusImpact on Regulatory Status3- Safety of nanoscale versions of compounds3 Safety of nanoscale versions of compounds

can not be demonstrated solely on evidence from conventional scale counterparts due to novel properties and physical characteristicsnovel properties and physical characteristics of nanoscale material.

As a result of these three factors, the regulatory status of nanoscale versions of compounds is frequently questioned.q y q

Guidance for Authorized Guidance for Authorized ProductsProducts

Guidance for Authorized Guidance for Authorized ProductsProductsProductsProductsProductsProducts

Industry has requested that FDA prepare guidance thatIndustry has requested that FDA prepare guidance that clarifies when nanoscale versions of approved food additives are covered by the existing regulations.

FDA is in the process of drafting a guidance document that will address all manufacturingdocument that will address all manufacturing changes including nanotechnology.

FDA hopes to have a draft ready for publication by late 2009 (but it may not be ready until 2010).

Manufacturing ChangesManufacturing ChangesManufacturing ChangesManufacturing ChangesManufacturing ChangesManufacturing ChangesManufacturing ChangesManufacturing Changes

M f t i h i llManufacturing changes, especially nanotechnology, have the potential to substantially alter the identity or toxicitysubstantially alter the identity or toxicity of a compound. Manufacturers may need to re evaluate theManufacturers may need to re-evaluate the safety of the modified product before it is used.used.This evaluation may be informal.

Area of Consideration:Area of Consideration:Impact on IdentityImpact on Identity

Area of Consideration:Area of Consideration:Impact on IdentityImpact on IdentityImpact on IdentityImpact on IdentityImpact on IdentityImpact on Identity

Does the manufacturing change alter:Does the manufacturing change alter:Identity (chemical composition, physical and chemical properties, function, incidental b d )byproducts)PurityIntended Physical or Technical EffectsIntended Physical or Technical Effects

Is the modified product: In compliance with existing specifications or limitationslimitationsProduced and/or used under good manufacturing practices

Area of Consideration:Area of Consideration:Impact on SafetyImpact on Safety

Area of Consideration:Area of Consideration:Impact on SafetyImpact on SafetyImpact on SafetyImpact on SafetyImpact on SafetyImpact on Safety

Is the uptake, absorption and bioavailability of the modified product different than the conventional product?Are new impurities detected at concentrations that are of concern?Are there new toxicology issues that were gynot previously addressed?

Approved Direct or Approved Direct or Indirect Food AdditivesIndirect Food Additives

Approved Direct or Approved Direct or Indirect Food AdditivesIndirect Food AdditivesIndirect Food AdditivesIndirect Food AdditivesIndirect Food AdditivesIndirect Food Additives

The use of the chemical is no longer in compliance with an existing regulation if the change in manufacturing practices altersexisting regulation if the change in manufacturing practices alters the chemical such that:

• the chemical identity and composition are no longer the same as the approved compound,

• the use or intended use is no longer in conformity with the regulationregulation,

• the additive is no longer produced under good manufacturing practices, or a u ac u g p ac ces, o

• the quantity of the additive in food renders it injurious to health.

Analysis currently being done on case by case basis.

Hypothetical ScenarioHypothetical ScenarioHypothetical ScenarioHypothetical ScenarioHypothetical ScenarioHypothetical ScenarioHypothetical ScenarioHypothetical Scenario

Assume that 21 CFR regulates gold particles as a color additive that may be safely used to color externally applied drugs in amounts consistent with good

f i imanufacturing practice.The regulation does not include size specifications

Issues to considerIssues to considerIssues to considerIssues to considerIssues to considerIssues to considerIssues to considerIssues to consider

Reactivity: Gold is inert at a macroscale, can be a catalyst at a nanoscale.The melting point is depressed at the nanoscale.Photoluminescence varies with size.Color varies with sizeColor varies with size.

When is Gold Not Golden?When is Gold Not Golden?When is Gold Not Golden?When is Gold Not Golden?When is Gold Not Golden?When is Gold Not Golden?When is Gold Not Golden?When is Gold Not Golden?

12 nm gold particles look red Other sizes are other colorsg p

Source: http://www.nano.uts.au/pics/au_atoms.jpg

Is Nanoscale Gold Regulated?Is Nanoscale Gold Regulated?Is Nanoscale Gold Regulated?Is Nanoscale Gold Regulated?Is Nanoscale Gold Regulated?Is Nanoscale Gold Regulated?Is Nanoscale Gold Regulated?Is Nanoscale Gold Regulated?

Chemical identity is not the same as macroscalePhysical and chemical properties are alteredTechnical effect may be alteredUptake and absorption may be altered-Uptake and absorption may be altered-more information is needed

Food Contact NotificationsFood Contact NotificationsFood Contact NotificationsFood Contact NotificationsFood Contact NotificationsFood Contact NotificationsFood Contact NotificationsFood Contact Notifications

Under Section 409 (h)(2)(C) of the Act a food contactUnder Section 409 (h)(2)(C) of the Act, a food contact substance approval does not apply to a similar or identical substance manufactured or prepared by a person other than the manufacturer identified in the notificationthe manufacturer identified in the notification.

Any manufacturing change intended to produce nanoscale particles would be considered a significant change, if such particles were not part of the original FCN.

Significant manufacturing changes require a new FCN.

Threshold of RegulationThreshold of RegulationThreshold of RegulationThreshold of RegulationThreshold of RegulationThreshold of RegulationThreshold of RegulationThreshold of Regulation

A i ifi h i f iAny significant change in manufacturing may result in a food additive or food contact substance that is not covered by an existing TORsubstance that is not covered by an existing TOR exemption.New technologies may raise new safety issuesNew technologies may raise new safety issues.An abbreviated review, such as TOR, would generally not be considered suitable in thesegenerally not be considered suitable in these situations.

Generally Recognized as SafeGenerally Recognized as SafeGenerally Recognized as SafeGenerally Recognized as SafeGenerally Recognized as SafeGenerally Recognized as SafeGenerally Recognized as SafeGenerally Recognized as Safe

G ll R i d S f d i tiGenerally Recognized as Safe designation is for the use of substances whose safe

di i f ll bli h d dconditions of use are well established and well recognized among qualified scientists.

Generally Recognized as SafeGenerally Recognized as SafeGenerally Recognized as SafeGenerally Recognized as SafeGenerally Recognized as SafeGenerally Recognized as SafeGenerally Recognized as SafeGenerally Recognized as Safe

G t t i ti i d t t i it fGreater uncertainties in regard to toxicity of nanoscale versions of otherwise GRAS

b k i diffi lsubstances may make it difficult to support a GRAS determination unless there is sufficient toxicity information on the nanoscale version of the compound.

Further Information SourcesFurther Information SourcesFurther Information SourcesFurther Information Sources

Useful Websites

Food and color additives program:Food and color additives program:

http://www.fda.gov/Food/FoodIngredientsPackaging/FoodAdditives/default.htm

GRAS Notification Program:

http://www.fda.gov/Food/FoodIngredientsPackaging/GenerallyRecognizedasSafeGRAS/default.htm

Guidance and reference documents for petitions and notifications:Guidance and reference documents for petitions and notifications:

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

FDA has recently moved many of its web pages.

Visit www.fda.gov to find new locations.