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FDA Perspective on FDA Perspective on Nanomaterial-Nanomaterial-

Containing Containing ProductsProducts

Nakissa Sadrieh, Ph.D.Nakissa Sadrieh, Ph.D.Associate Director for Research Associate Director for Research

Policy and Implementation Policy and Implementation Office of Pharmaceutical Science, Office of Pharmaceutical Science,

CDER, FDACDER, FDA

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FDA MissionFDA Mission

Not only to protect, but also Not only to protect, but also to advance the public health to advance the public health by assuring safe and effective by assuring safe and effective medical products and safe medical products and safe foods for humans and foods for humans and animals.animals.

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FDA’s Critical Path FDA’s Critical Path InitiativeInitiative

Initiative to help reduce existing Initiative to help reduce existing hurdles in medical product design hurdles in medical product design and development.and development.

Initiative rooted in taking advantage Initiative rooted in taking advantage of innovative science and of innovative science and technologies to reach technologies to reach commercialization of medical commercialization of medical products.products.

Nanotechnology is an element under Nanotechnology is an element under evaluation in FDA’s Critical Path evaluation in FDA’s Critical Path Initiative.Initiative.

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Coordination of Policy on Coordination of Policy on Nanomaterials With Nanomaterials With Other Government Other Government

AgenciesAgencies FDA is a member of the Nanoscale Science FDA is a member of the Nanoscale Science and Engineering Technology (NSET) and Engineering Technology (NSET) Subcommittee of the National Science and Subcommittee of the National Science and Technology Council (NSTC) Committee on Technology Council (NSTC) Committee on Technology.Technology.

FDA co-chairs with NIOSH the NSET FDA co-chairs with NIOSH the NSET Working Group on Nanomaterials Working Group on Nanomaterials Environmental and Health Implications Environmental and Health Implications (NEHI) to define new test methods to (NEHI) to define new test methods to assess safety of these products.assess safety of these products.

FDA contributes to the evaluation of the FDA contributes to the evaluation of the toxicity of materials supported by NIEHS toxicity of materials supported by NIEHS and NTP.and NTP.

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FDA Activities in FDA Activities in NanotechnologyNanotechnology

Office of Science and Health Coordination Office of Science and Health Coordination (within OC) coordinates regular (within OC) coordinates regular discussions within Agency.discussions within Agency.

Individual Centers have regular Individual Centers have regular discussion groups within each Center.discussion groups within each Center.– Purpose of these meetings is to insure Purpose of these meetings is to insure

awareness of policies that may be developing awareness of policies that may be developing within the Agency and to educate staff and within the Agency and to educate staff and policy makers on scientific progress in policy makers on scientific progress in nanotechnology.nanotechnology.

FDA-NCI Clinical Proteomics ProgramFDA-NCI Clinical Proteomics Program Interagency Oncology Task Force, Interagency Oncology Task Force,

Nanotechnology subcommittee, featuring Nanotechnology subcommittee, featuring collaboration between FDA-NCI-NIST collaboration between FDA-NCI-NIST

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Current FDA Definition Current FDA Definition for Nanotechnology for Nanotechnology

FDA calls it "nanotechnology" only if it FDA calls it "nanotechnology" only if it involves involves allall of the following: of the following:– 1. Research and technology development, or 1. Research and technology development, or

products regulated by FDA, that are at the products regulated by FDA, that are at the atomic, molecular or macromolecular levels, atomic, molecular or macromolecular levels, andand where at least one dimension, that affects the where at least one dimension, that affects the functional behavior of the product, is in the functional behavior of the product, is in the length scale range of approximately 1-100 length scale range of approximately 1-100 nanometers.nanometers.

– 2. Creating and using structures, devices and 2. Creating and using structures, devices and systems that have novel properties and systems that have novel properties and functions functions becausebecause of their small and/or of their small and/or intermediate size.intermediate size.

– 3. Ability to control or manipulate at the atomic 3. Ability to control or manipulate at the atomic scale. scale.

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FDA-Regulated Products FDA-Regulated Products Expected to be Impacted Expected to be Impacted

by Nanotechnologyby Nanotechnology DrugsDrugs Drug delivery systemsDrug delivery systems Medical devicesMedical devices VaccinesVaccines Biotechnology productsBiotechnology products CosmeticsCosmetics Gene and protein deliveryGene and protein delivery Combination tissue/deviceCombination tissue/device

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HistoricallyHistorically

FDA has approved many products FDA has approved many products with particulate materials in the with particulate materials in the nanosize range.nanosize range.

Most drugs are expected to go Most drugs are expected to go through a nanosize phase during the through a nanosize phase during the process of absorption in the body.process of absorption in the body.

There have been no safety concerns There have been no safety concerns reported in the past because of reported in the past because of particle size. particle size.

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General Concerns General Concerns about Nanotechnology about Nanotechnology

ProductsProducts Examples of concerns Examples of concerns

regarding:regarding:– SafetySafety– Quality of Quality of

material/characterizationmaterial/characterization– Environmental Environmental

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Safety ConcernsSafety Concerns

As particle size gets smaller, there As particle size gets smaller, there may be size-specific effects on may be size-specific effects on activity, such as:activity, such as:– Will nanoparticles gain access to Will nanoparticles gain access to

tissues and cells that normally would tissues and cells that normally would be bypassed by larger particles?be bypassed by larger particles?

– Once nanoparticles enter tissues, how Once nanoparticles enter tissues, how long do they remain there and how are long do they remain there and how are they cleared?they cleared?

– If nanoparticles enter cells, what If nanoparticles enter cells, what effects do they have on cellular and effects do they have on cellular and tissue functions? Might there be tissue functions? Might there be different effects in different cells types?different effects in different cells types?

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Safety Concerns Safety Concerns (Cont’d)(Cont’d)

What are the differences in the ADME profile What are the differences in the ADME profile of nanoparticles versus larger particles?of nanoparticles versus larger particles?

What preclinical screening tests would be What preclinical screening tests would be useful to identify potential risks (in vitro or useful to identify potential risks (in vitro or in vivo)?in vivo)?

Can new technologies such as “omics” help Can new technologies such as “omics” help identify potential toxicities and how can identify potential toxicities and how can these methodologies complement current these methodologies complement current testing requirements?testing requirements?

Can nanoparticles gain access to the Can nanoparticles gain access to the systemic circulation from dermal exposure? systemic circulation from dermal exposure? If nanoparticles enter skin cells, is there an If nanoparticles enter skin cells, is there an effect on cellular functions? This would be effect on cellular functions? This would be relevant to drugs and cosmetics.relevant to drugs and cosmetics.

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Characterization Characterization ConcernsConcerns

What are the forms in which particles are What are the forms in which particles are presented to host, cells and organelles?presented to host, cells and organelles?

What are the critical physical and chemical What are the critical physical and chemical properties, including residual solvents, properties, including residual solvents, processing variables, impurities and processing variables, impurities and excipients?excipients?

What are the standard tools used for this What are the standard tools used for this characterization? characterization?

What are validated assays to detect and What are validated assays to detect and quantify nanoparticles in tissues, medical quantify nanoparticles in tissues, medical products, foods and processing equipment?products, foods and processing equipment?

How do physical characteristics impact How do physical characteristics impact product quality and performance?product quality and performance?

How do we determine long and short-term How do we determine long and short-term stability of nanomaterials?stability of nanomaterials?

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Environmental Environmental ConcernsConcerns

Can nanoparticles be released into Can nanoparticles be released into the environment following human the environment following human and animal use?and animal use?

What methodologies would identify What methodologies would identify the nature, and quantify the extent, the nature, and quantify the extent, of nanoparticle release in the of nanoparticle release in the environment?environment?

What might be the environmental What might be the environmental impact on other species (animals, impact on other species (animals, fish, plants, microorganisms)?fish, plants, microorganisms)?

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Crucial Hurdles for Crucial Hurdles for NanotechnologyNanotechnology

Safety assessmentSafety assessment– Adequacy of current toxicologic screens for Adequacy of current toxicologic screens for

nanoscale materials.nanoscale materials.– Potential for novel, unanticipated reactions.Potential for novel, unanticipated reactions.– Environmental consequences of medical use.Environmental consequences of medical use.

EfficacyEfficacy– No experience with clinical testing.No experience with clinical testing.

IndustrializationIndustrialization– Understanding the physical and chemical Understanding the physical and chemical

parameters that are crucial to product parameters that are crucial to product performance.performance.

– Developing test methods and specifications to Developing test methods and specifications to control product/process.control product/process.

– Scale-up to mass production.Scale-up to mass production.– Lack of reference material, standards and Lack of reference material, standards and

manufacturing standardization.manufacturing standardization.

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Standard Test Methods Standard Test Methods for Biological Response for Biological Response

Including ParticlesIncluding Particles Guidelines for evaluating biological Guidelines for evaluating biological

safety for medical devices is based on safety for medical devices is based on application of voluntary standards application of voluntary standards – ASTM F 748 (F1903 in vitro and F1904 in ASTM F 748 (F1903 in vitro and F1904 in

vivo, for particles)vivo, for particles)– ISO 10993, Part 1 ISO 10993, Part 1

None of the standards are specific for None of the standards are specific for nanoparticles. nanoparticles.

Additional standard test methods may Additional standard test methods may need to be developed for nanoparticles.need to be developed for nanoparticles.

No existing standards for testing No existing standards for testing particles for drugs and biologics.particles for drugs and biologics.

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Current Preclinical Tests Current Preclinical Tests for Safety Evaluationfor Safety Evaluation

PharmacologyPharmacology Safety pharmacologySafety pharmacology Toxicology (including clinical pathology Toxicology (including clinical pathology

and histopathologic analysis)and histopathologic analysis) ADMEADME GenotoxicityGenotoxicity Developmental toxicityDevelopmental toxicity ImmunotoxicityImmunotoxicity CarcinogenicityCarcinogenicity Other Other

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Adequacy of Current Adequacy of Current Preclinical Screening Preclinical Screening

System?System? Existing battery of preclinical tests is Existing battery of preclinical tests is

currently believed to be adequate.currently believed to be adequate. Why?Why?

– High dose multiples usedHigh dose multiples used– At least 2 animal species usedAt least 2 animal species used– Extensive histopathology on most organsExtensive histopathology on most organs– Functional tests (cardiac, neurologic, Functional tests (cardiac, neurologic,

respiratory, reproductive, immune respiratory, reproductive, immune system, etc/…)system, etc/…)

– Extended treatment periods (up to 2 Extended treatment periods (up to 2 years for carcinogenicity studies)years for carcinogenicity studies)

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FDA Research in FDA Research in NanotechnologyNanotechnology

Examples of research in Examples of research in

– CDERCDER– CBERCBER– NCTRNCTR– CFSANCFSAN

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Examples of CDER Examples of CDER Research in Research in

NanotechnologyNanotechnology Particle size determination in Particle size determination in

marketed sunscreens with TiO2 and marketed sunscreens with TiO2 and ZnO nanoparticles.ZnO nanoparticles.

Development of in vitro assays to Development of in vitro assays to assess toxicity of selected assess toxicity of selected nanoparticles (collaboration with nanoparticles (collaboration with CDRH).CDRH).

Manufacture of nanoformulations Manufacture of nanoformulations and characterization of physical and and characterization of physical and chemical properties.chemical properties.

2020

Examples of CDER Examples of CDER Research in Research in

Nanotechnology (Cont’d)Nanotechnology (Cont’d) Evaluation of excipient effects on Evaluation of excipient effects on

nanotechnology products.nanotechnology products. Evaluation of the effects of Evaluation of the effects of

preparation methodology, process preparation methodology, process and formulation variables on and formulation variables on nanotechnology product nanotechnology product characteristics (including characteristics (including mathematical modeling of variables).mathematical modeling of variables).

Evaluate the stability and pre-clinical Evaluate the stability and pre-clinical bioavailability of certain selected bioavailability of certain selected nanotechnology products.nanotechnology products.

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Examples of CBER Examples of CBER Research in Research in

NanotechnologyNanotechnology FDA-NCI Clinical Proteomics ProgramFDA-NCI Clinical Proteomics Program

– Interagency Agreement with NCI. Interagency Agreement with NCI. Nanotechnology collaboration to Nanotechnology collaboration to evaluate and analyze clinical material evaluate and analyze clinical material from eventual NCI-based from eventual NCI-based nanotechnology applications.nanotechnology applications.

Developing novel protein microarray Developing novel protein microarray based phosphoproteomic endpoint based phosphoproteomic endpoint analysis of analysis of in vivoin vivo nanoparticle nanoparticle toxicity screening.toxicity screening.

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Examples of CBER Examples of CBER Research in Research in

Nanotechnology (Cont’d)Nanotechnology (Cont’d) Assessing nanoparticle ADME- animal Assessing nanoparticle ADME- animal

imaging studies combined with laser imaging studies combined with laser capture microdissection.capture microdissection.

Developing nanoporous filtering Developing nanoporous filtering devices for disease biomarker devices for disease biomarker discovery.discovery.

Developing and manufacturing Developing and manufacturing nanoparticle biomarker “harvesting” nanoparticle biomarker “harvesting” agents- combined with mass agents- combined with mass spectrometry based profiling.spectrometry based profiling.

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Examples of CFSAN Examples of CFSAN Research in Research in

Nanotechnology for Nanotechnology for CosmeticsCosmeticsCollaboration with NCTR/NTP/Rice U.:Collaboration with NCTR/NTP/Rice U.:

Evaluating the effects of varying Evaluating the effects of varying nano-size on the penetration of nano-size on the penetration of quantum dots through human and quantum dots through human and pig skin.pig skin.

Evaluating the penetration of TiO2 Evaluating the penetration of TiO2 and ZnO nanoparticles through and ZnO nanoparticles through human skin.human skin.

Evaluating the photocytotoxicity of Evaluating the photocytotoxicity of TiOTiO2 2 nanoparticles using human nanoparticles using human skin fibroblasts.skin fibroblasts.

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Examples of NCTR Examples of NCTR Research in Research in

NanotechnologyNanotechnology Evaluating the effect of size and coating Evaluating the effect of size and coating

on dermal penetration of quantum dots on dermal penetration of quantum dots in skin of hairless mice (collaboration in skin of hairless mice (collaboration with NTP and Rice University)with NTP and Rice University)

Evaluating the toxicology of nanoscale Evaluating the toxicology of nanoscale TiOTiO22 and ZnO: market survey (size and and ZnO: market survey (size and coating); dermal penetration coating); dermal penetration in vitroin vitro & & in mice and pigs; PK and in mice and pigs; PK and toxicogenomics in mice; phototoxicity toxicogenomics in mice; phototoxicity in in vitrovitro & mice; photocarcinogenicity in & mice; photocarcinogenicity in mice (collaboration with NTP, CFSAN mice (collaboration with NTP, CFSAN and Rice University)and Rice University)

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Two Most Frequently Two Most Frequently Asked Questions:Asked Questions:

Who (which Center) will Who (which Center) will review nanotechnology review nanotechnology products?products?

What will be the requirements What will be the requirements for nanotechnology products?for nanotechnology products?

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Who Will Review Who Will Review Nanotechnology Nanotechnology

Applications?Applications? Office of Combination Office of Combination

Products will coordinate the Products will coordinate the regulatory framework for regulatory framework for nanotechnology products.nanotechnology products.

An FDA Center will be An FDA Center will be designated with the primary designated with the primary responsibility for review.responsibility for review.

However, consultations from However, consultations from other Centers will be sought.other Centers will be sought.

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What are the Testing What are the Testing Requirements for Requirements for Nanotechnology Nanotechnology

Products?Products? As new toxicological risks that derive As new toxicological risks that derive

from nanomaterials are identified, from nanomaterials are identified, new tests will be required.new tests will be required.

Industry and academia need to plan Industry and academia need to plan and conduct the research to identify and conduct the research to identify potential risks and to develop potential risks and to develop adequate characterization adequate characterization methodologies.methodologies.

FDA can help in this process.FDA can help in this process.

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FDA Nanotechnology FDA Nanotechnology WebsiteWebsite

For links to individual Centers, For links to individual Centers, published guidance documents published guidance documents and other relevant information and other relevant information on nanotechnology activities at on nanotechnology activities at FDA:FDA:

– www.FDA.GOV/NANOTECHNOLOGYwww.FDA.GOV/NANOTECHNOLOGY