Regulatory Science and Nanotechnology at FDA · Regulatory Science and Nanotechnology at FDA Paul C. Howard, Ph.D. Director, Office of Scientific Coordination, Director, NCTR/ORA

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Regulatory Science and Nanotechnology at FDA

Paul C. Howard, Ph.D.Director, Office of Scientific Coordination,Director, NCTR/ORA Nanotechnology Core FacilityNational Center for Toxicological Research (NCTR),U.S. Food & Drug AdministrationJefferson, Arkansas

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DisclaimerDisclaimer

The contents of this presentation are the responsibility of the speaker, and should not be considered the official position or policy of the U.S. Food & Drug Administration.

Any conclusions or statements should not be considered future policy of the FDA.

The mention of trade names or manufacturers is for clarification and should not be considered as endorsement.

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OUTLINEOUTLINE

- Brief view of FDA

- Regulatory Science

- Nanotechnology Regulatory Science Program

- Program Framework

- Staff Training

- Equipment Core Laboratories

- Cooperative Research Program

- Regulation and Communication

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Nanotechnology: putting size in perspective

www.NNI.gov

http://fusamuy.net84.net

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FDA Mission – Protect the public health by assuring safe and effective medical products and safe foods for humans and animals.

Foods• All interstate domestic

and imported (includingproduce, fish, shellfish,shell eggs, milk) exceptmeat and poultry.

• Bottled water.• Wine (<7% alcohol).• Infant formula

Food Additives• Colors• Food containers

CosmeticsDietary SupplementsAnimal FeedsPharmaceuticals

• Human (safety, efficacy)• Animal (safety, efficacy)

Medical DevicesRadiation Producing DevicesVaccinesBlood Products/ContactTissuesSterilantsTobacco

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• 25% of US domestic spending on products regulated by FDA

• 15% of US food is imported (>10-15%/year)

• ~67% of fruits and vegetables are imported

• >80% of seafood is imported

• Imported foods were ~$85B in 2010

• Food is a global commodity; US FDA involved in national and international regulation, manufacture and inspection

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Food and Drug Administration

Office of Commissioner

Off. Operations

Off. Foods Off. Medical Products & Tobacco

Off. WomensHealth

Off. Counselor

Off. Chief Scientist

Off. Global Regulatory Operations & Policy

Off. Minority Health

Center for Food Safety & Applied Nutrition

Center for Device & Radiological Health

Center for Biologics Evaluation & Research

Center for Drug Evaluation & Research

Center for Tobacco Products

National Center for Toxicological Research

Office of Regulatory Affairs

Center for Veterinary Medicine

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Food and Drug Administration

Office of Commissioner

Off. Operations

Off. Foods Off. Medical Products & Tobacco

Off. WomensHealth

Off. Counselor

Off. Chief Scientist

Off. Global Regulatory Operations & Policy

Off. Minority Health

CFSAN

CDRH

CBER CDER

CTPNCTR

ORA

CVM

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Federal Food, Drug, and Cosmetic ActChapter I--Short TitleChapter II--DefinitionsChapter III--Prohibited Acts and PenaltiesChapter IV--FoodChapter V--Drugs and Devices:

Subchapter A--Drugs and Devices:Sections 501-510: Drugs and DevicesSection 512: New Animal DrugsSections 513-523: Medical Devices

Subchapter B--Drugs for Rare Diseases and ConditionsSubchapter C--Electronic Product Radiation ControlSubchapter D--Dissemination of Treatment InformationSubchapter E--General Provisions Relating to Drugs and DevicesSubchapter F—New Animal Drugs for Minor Use and Minor Species

Chapter VI--CosmeticsChapter VII--General Authority:

Subchapter A--General Administrative ProvisionsSubchapter B--ColorsSubchapter C--FeesSubchapter D--Information and EducationSubchapter E--Environmental Impact ReviewSubchapter F--National Uniformity for Nonprescription Drugs and Preemption for Labeling or Packaging of CosmeticsSubchapter G--Safety Reports

Chapter VIII--Imports and ExportsChapter IX--MiscellaneousAppendix:

Section 107(c) of Drug Amendments of 1962Public Law 88-136; Revolving FundSection 108 of Animal Drug Amendments of 1968Section 5 of Orphan Drug Act

www.fda.govTitle 21 USC Chapter 9

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Federal Food, Drug, and Cosmetic ActChapter I--Short TitleChapter II--DefinitionsChapter III--Prohibited Acts and PenaltiesChapter IV--FoodChapter V--Drugs and Devices:

Subchapter A--Drugs and Devices:Sections 501-510: Drugs and DevicesSection 512: New Animal DrugsSections 513-523: Medical Devices

Subchapter B--Drugs for Rare Diseases and ConditionsSubchapter C--Electronic Product Radiation ControlSubchapter D--Dissemination of Treatment InformationSubchapter E--General Provisions Relating to Drugs and DevicesSubchapter F—New Animal Drugs for Minor Use and Minor Species

Chapter VI--CosmeticsChapter VII--General Authority:

Subchapter A--General Administrative ProvisionsSubchapter B--ColorsSubchapter C--FeesSubchapter D--Information and EducationSubchapter E--Environmental Impact ReviewSubchapter F--National Uniformity for Nonprescription Drugs and Preemption for Labeling or Packaging of CosmeticsSubchapter G--Safety Reports

Chapter VIII--Imports and ExportsChapter IX--MiscellaneousAppendix:

Section 107(c) of Drug Amendments of 1962Public Law 88-136; Revolving FundSection 108 of Animal Drug Amendments of 1968Section 5 of Orphan Drug Act

www.fda.govTitle 21 USC Chapter 9

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21 USC Chapter 9, Subchapter V, Part A Drugs and Devices, Section 355. New Drugs –

(a) Necessity of effective approval of application

No person shall introduce or deliver for introduction into interstate commerce any new drug, unless an approval of an application filed pursuant to subsection (b) or (j) of this section is effective with respect to such drug.

(b) Filing application; contents

(1) Any person may file with the Secretary an application with respect to any drug subject to the provisions of subsection (a) of this section. Such person shall submit to the Secretary as a part of the application (A) full reports of investigations which have been made to show whether or not such drug is safe for use and whether such drug is effective in use; (B) a full list of the articles used as components of such drug; (C) a full statement of the composition of such drug; (D) a full description of the methods used in, and the facilities and controls used for, the manufacture, processing, and packing of such drug; (E) such samples of such drug and of the articles used as components thereof as the Secretary may require; (F) specimens of the labeling proposed to be used f h d d (G) i d d S i 355 f hi

Underlined for emphasis, P Howard

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OUTLINEOUTLINE

- Brief view of FDA



- Program Framework

- Staff Training



- Conclusions

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- Enable major investments and advancesin basic sciences to translate faster into products to benefit consumers - Protect consumers by applying best possible science to support regulatory activities and decision-making

Pre-market reviewPost-market surveillance

- Keep pace with and fully utilize advances in innovation, while also facilitating development of innovative products that benefit consumers and patients

Advancing Regulatory Science

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FDA’s Nanotechnology Regulatory Science Plan

http://www.fda.gov/ScienceResearch/SpecialTopics/Nanotechnology/default.htm

Program Management• Program Administration• Tracking Projects• Coordination• OversightStrategic Partnerships• Domestic (e.g. NNI, NCI/NCL/NIST, NIEHS)• International

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FDA’s Regulatory Science Approach to Nanotechnology

Program Framework

Coordination

StaffTraining

Core LaboratoryFacilities

Collaborative Opportunities for Research Excellence in Science

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Nanotechnology Coordination

OCOC

CBERCBER CDRHCDRH

CDERCDER CFSANCFSAN

CTPCTP CVMCVM

ORAORA NCTRNCTR

National Nanotechnology Initiative

Collaborative, Multi-agency, Cross-cut Program Among 25 Federal agencies, 15 of which have

specific nanotechnology budgets

Funds R&D to advance understanding and control of matter at nanoscale toward:National economic benefit

National and homeland securityImproved quality of life

Internal –Nanotechnology Task Force

External (United States Government) –National Nanotechnology Initiative

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FDA’s Regulatory Science Program in Nanotechnology-Intramural ActivitiesFDA Programmatic

Investment Area 2011 2012 2013 Program

FDA Staff Training

X X X Center Workshops/Seminars

X X X Introduction to Nanotechnology online

X X Applied Courses in Nanotechnology online

X X Hands On Laboratory Course

X Ad hoc Topic Specific/Product Relevant Review Courses

X External Training Opportunities

X FDA Nanotechnology Regulatory Science Research Workshop

FDA Core Facilities

X X X Center Specific Laboratories

X X X NCTR Core Facility

X X White Oak Core Facility

X X FDA Coordination Plan (Safety, Toxicology, Characterization, Manufacturing)

X Public Private Partnerships with External Stakeholders

X Joint funding Laboratory Facility Projects

FDA IntramuralRegulatory Science Research (CORES)

X X X Center Specific Projects

X X X CORES Program

X X External Peer-Review

X Engage Domestic & International Research Opportunities

X Additional Product Specific Regulatory Science Research

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FDA Programmatic

Investment Area

2011 2012 2013 Program

FDA Staff Training

X X X Center Workshops/SeminarsX X X Introduction to Nanotechnology

online X X Applied Courses in

Nanotechnology onlineX X Hands On Laboratory Course


X External Training Opportunities X FDA Nanotechnology Regulatory

Science Research Workshop

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Staff Training and Professional Development

Staff with different needs:- Review Staff- Research Staff- Field Staff- Regulatory Policy Staff

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Staff Training and Professional DevelopmentTitle: Introduction to Nanotechnology Science and Regulation at the U.S. FDA

Module 1 – FDA and Nanotechnology: Materials, Properties, Evaluation, and ApplicationsModule 2 – Nanotechnology: FDA and USG Activities and Perspectives

Location: White Oak Campus

Hours: 16

Speakers: Outside experts, FDA staff experts, and agency representatives

INTRODUCTION TO NANOTECHNOLOGY SCIENCE AND REGULATION AT FDA

Module 1FDA and Nanotechnology: Materials,

Properties, Evaluation, and Applications

September 1st and 14th

1:00 PM-4:30 PM –White Oak Campus

Time: Fall 2011

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Title: Applied Sciences Course in NanotechnologyPart 1 – Characterization & ManufacturingPart 2 – Safety & Toxicology

Location: White Oak CampusHours: 20

Speakers: Outside experts and FDA staff experts

Time: Spring 2012

APPLIED SCIENCES COURSE IN

NANOTECHNOLOGY

Part 1:Characterization &

Manufacturing

March 5th, March 19th, and April 2nd


Manufacturing: Robert Ivkov, Johns Hopkins U.Anjan Nan, Univ. MarylandCarl Simon, NISTAngela Hight Walker, NISTW. Russ Algar, U.S. Naval Res. Lab.Jeffrey Fagan, NIST

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Time: Spring 2012


NANOTECHNOLOGY


Manufacturing



Characterization: Paul Howard, FDA/NCTRVincent Hackley, NISTOlen Stephens, FDA/CDERKevin Lorick, FDA/CDRH

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Time: Spring 2012


NANOTECHNOLOGY


Manufacturing



Safety and Toxicology:Nakissa Sadrieh, FDA/CDERBrian Thrall, PNNLKatherine Tyner, CDER/CDERJim Riviere, N.C. StateNancy Monteiro-Riviere, N.C. StateMarina Dobrovolskaia, NCI/NCLSaber Hussain, WPAFBTao Chen, FDA/NCTRGunter Oberdorster, U. RochesterSyed Ali, FDA/NCTRHamed Laroui, Ga. State U.

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Staff Training and Professional DevelopmentTitle: NCL: Lessons Learned Workshop 2011 at FDA

Location: White Oak CampusHours: 8Speakers: National Cancer Institute, Nanotechnology Characterization Laboratory (NCI/NCL) staff

Title: Hands-On Laboratory Course (I- Size Determination)

Location: NCTR & ORA/ARL Campus (at the Core Facility)

Focus: Physical-Chemical Characterization of Nanomaterials;Part I, Determination of Size

Time: Fall 2011

Time: Summer 2012

Hours: 16

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Upcoming Staff Training at FDA

• Product Specific/Regulatory Review Seminars

• Hands On Laboratory Course• FDA Nanotechnology Regulatory

Science Research Workshop (Public meeting)

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FDA Programmatic

Investment Area

2011 2012 2013 Program

FDA Core Facilities

X X X Center Specific LaboratoriesX X X NCTR Core Facility

X X White Oak Core FacilityX X FDA Coordination Plan (Safety,

Toxicology, Characterization, Manufacturing)



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Important Considerations for Regulating Nanomaterial-Containing Products

• Product safety assessment• Biodistribution• Clearance• Metabolism• Toxicology

• Product quality assessment• Characterization• Quality control• Manufacturing

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Public HealthRisk Management

Risk Assessment

Hazard Identification

Dose Response

Exposure Quantification

Chemical Identification

Absorption, Distribution, Metabolism, Elimination (ADME); PK

Toxicity

Immunotoxicity

Genotoxicity

Carcinogenicity

Human Exposure

Systemic/Organospecific

Risk vs benefit

Risk Assessment/ManagementRisk Assessment/Management

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Important Considerations for Regulating Nanomaterial-Containing Products

• Product safety assessment• Biodistribution• Clearance• Metabolism• Toxicology

• Product quality assessment• Characterization• Quality control• Manufacturing

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Core Laboratory FacilitiesNanotechnology Regulation Requires:

Equipment Personnel Methodologies

+ +

To allow for appropriate: 1) Characterization & Manufacturing Studies and

2) Safety and Biocompatibility Studies

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FDA Nanotechnology Equipment Laboratory Facilities

Purpose: to provide the equipment, expertise, and infrastructure to support nanotechnology regulatory science research within the FDA and collaborating organizations.

Location: two major facilities; White Oak campus, Jefferson AR campus.

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Nanotechnology Core Facility: Nanotechnology Core Facility: Purpose, Purpose, ≥≥ Minimum CharacterizationMinimum Characterization

• Average particle size, and size distribution• Agglomeration and aggregation state• Shape• Chemical composition and purity• Crystal structure (where appropriate)• Surface area• Surface chemistry (reactivity and hydrophobicity)• Surface charge• Stability in bulk• Stability in dosing solutions or test media• UV-Vis, NIR and IR absorbance, fluorescence and

fluorescence quantum yield• Endotoxin content and sterility

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XEndotoxin content and sterilityXXXXXDetection in biological matrices

XSpectral propertiesXXStability in dosing solutions or test media

XXXStability in bulkXSurface charge

XSurface chemistry (reactivity and hydrophobicity)XSurface area

XCrystal structureXXXChemical composition and purity

XShapeXXXXAgglomeration and aggregation stateXXXXAverage particle size, and size distribution

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Equipment Core Facilities Use/Outcomes

• Support the conduct of research to establish methods for use by Agency scientists (e.g. quantification of nanomaterial ionization in vitro and in vivo);

• Provide equipment and expertise to conduct specific measurements or assays for FDA scientists;

• Provide within-Agency expertise for confidential consultations regarding nanomaterial characterization or quantification;

• Provide equipment and expertise to train Agency scientists on measurement techniques for nanomaterials (“hands-on”);

• Maintain equipment for use by Agency scientists and Collaborators on projects;

• Augment other existing equipment at each Center.

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FDA Programmatic

Investment Area

2011 2012 2013 Program

FDA Intramural Regulatory

Science Research (CORES)

X X X Center Specific ProjectsX X X CORES Program continuing




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FDA’s Nanotechnology CORES ProgramCollaborative Opportunities for Research

Excellence in Science• Physico-chemical characterization in FDA-

regulated products• Nonclinical modeling of nanomaterials in FDA-

regulated products• Risk characterization information• Risk assessment• Risk communication

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FDA’s CORES AwardsCenter PI FY11; Title

NCTR Tao Chen

Development and Evaluation of Exposure Dosimetry Methods to Optimize the Standard In Vitro Mammalian Genotoxicity Assays for Engineered Nanomaterials

CBER Jan Simak

In Vitro Evaluation of Effects of Engineered Nanomaterials on Blood Platelets

CFSAN J.J. YinUse of Electron Spin Resonance Spectroscopy (ESR) and Biomarkersof Oxidative Damage to Assess the Safety of Nanomaterials Used in Cosmetics

Center PI FY12; Title

NCTR Tao Chen

Do Engineered Silver Nanomaterials Varying by Size and Coatings Behave Differently than Bulk Silver in their Ability to Induce Genetic Damage?

CBER Jan Simak

In Vitro Evaluation of Effects of Engineered Nanomaterials on Blood Platelets

CDRH B. Dair Biological Evaluation and Safety Assessment of FDA-regulated Products with Nano-engineered Surfaces

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FDA Advances in Nanotechnology

• Science• Regulatory Research• Staff Training & Professional Development• Policy• Communication

40www.fda.gov/ScienceResearch/SpecialTopics/Nanotechnology/defaultwww.fda.gov/ScienceResearch/SpecialTopics/Nanotechnology/default.htm.htm

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Policy (Regulation) Selected FDA Publications Related to Applications of Nanotechnologye.g. Dobrovolskaia et al., Nanoparticle size and surface charge determine effects of PAMAM dendrimers on human platelets in vitro. Mol. Pharm. 9, 382-393, 2012.

www.fda.gov/ScienceResearch/SpecialTopics/Nanotechnology/ucm300632.htm

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Policy (Regulation) Draft Guidance for Industry: Safety of Nanomaterials in Cosmetic Productswww.fda.gov/cosmetics/guidanceComplianceRegulatoryInformation/GuidanceDocuments/ucm300886.htm

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Policy (Regulation) Draft Guidance for Industry: Assessing the Effects of Significant Manufacturing Process Changes, Including Emerging Technologies, on the Safety and Regulatory Status of Food Ingredients and Food Contact Substances, Including Food Ingredients that are Color Additiveswww.fda.gov/cosmetics/GuidanceComplianceRegulatoryInformation/GuidanceDocuments/FoodIngredientsandPackaging/ucm300661.htm

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Policy (Regulation) Draft Guidance: Considering Whether an FDA-Regulated Product Involves the Application of Nanotechnologywww.fda.gov/RegulatoryInformation/Guidances/ucm257698.htm

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Additional Activities

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Communication

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FDA Safety and Innovation Act (FDA-SIA) Legislation Relevant to Nanotechnology

Section 1126 of FDASIA, 21 USC 399e

GENERAL.—The Secretary of Health and Human Services (referred to in this section

as the ‘‘Secretary’’) shall intensify and expand activities related to enhancing scientific

knowledge regarding nanomaterials included or intended for inclusion in products

regulated under the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 301 et seq.) or

other statutes administered by the Food and Drug Administration, to address issues

relevant to the regulation of those products, including the potential toxicology of such

nanomaterials, the potential benefit of new therapies derived from nanotechnology, the

effects of such nanomaterials on biological systems, and the interaction of such

nanomaterials with biological systems.

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FDA’s Regulatory Science Program in Nanotechnology-Intramural ActivitiesFDA Programmatic

Investment Area 2011 2012 2013 Program

FDA Staff Training

X X X Center Workshops/Seminars

X X X Introduction to Nanotechnology online

X X Applied Courses in Nanotechnology online

X X Hands On Laboratory Course


X External Training Opportunities

X FDA Nanotechnology Regulatory Science Research Workshop

FDA Core Facilities

X X X Center Specific Laboratories

X X X NCTR Core Facility

X X White Oak Core Facility

X X FDA Coordination Plan (Safety, Toxicology, Characterization, Manufacturing)



FDA IntramuralRegulatory Science Research (CORES)

X X X Center Specific Projects

X X X CORES Program




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OUTLINEOUTLINE

- Brief view of FDA



- Program Framework

- Staff Training



- Regulation and Communication

REVIEWREVIEW

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Online ResourcesFDA Nanotechnology Websitehttp://www.fda.gov/ScienceResearch/SpecialTopics/Nanotechnology/default.htm

FDA Nanotechnology Regulatory Science Planhttp://www.fda.gov/ScienceResearch/SpecialTopics/Nanotechnology/default.htm

FDA Program Summaries http://www.fda.gov/ScienceResearch/SpecialTopics/Nanotechnology/ucm309672.htm

NNI Strategic Planhttp://www.nano.gov/node/581