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Regulatory Science Aspects of Products 

Containing Nanoscale Materials

Subhas G. Malghan, PhD

Office of Science and Engineering Laboratories

Center for Devices and Radiological Health

Food and Drug Administration

Presentation at the

Nanotechnology Partnership Forum 

National Institute of Standards and Technology 

Gaithersburg, Maryland 

September 13, 2010
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Outline

What does CDRH (FDA) do in regulation of 

devices containing nanoscale materials:

1. Regulatory pathways of translating devices 

to the clinic 

2. Regulatory science challenges/issues 
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FDA Mission

FDA is responsible for protecting the public health by 

assuring the safety, efficacy, and security of human and 

veterinary drugs, biological products, medical devices, our 

nation’s food supply, cosmetics, and products that emit 

radiation. 

FDA is also responsible for advancing the public health by:

- helping to speed innovations that make 

medicines and foods more effective, safer, and more 

affordable; and 

- helping the public get the accurate, sciencebased information they need to use medicines and foods to 

improve their health. 
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U.S. Food and Drug Administration (FDA)

Center for 

Devices and 

Radiological 

Health,

CDRH

National 

Center for 

Toxicological 

Research,

NCTR

Office of 

Regulatory 

Affairs,

ORA

Center for 

Biologics 

Evaluation and 

Research,

CBER

Center for 

Veterinary 

Medicine,

CVM

Center for 

Food Safety 

and Applied

Nutrition, 

CFSAN

Center for 

Drug 

Evaluation and 

Research, 

CDER

Center for 

Tobacco 

Products,

CTP 
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Office of In Vitro 

Diagnostic Device

Evaluation 

& Safety

Office of

Compliance

Office of Device

Evaluation

Office of 

Science & 

Engineering 

Laboratories

Office of 

Communication, 

Education, &

Radiation 

Programs

Office of 

Surveillance & 

Biometrics

Office of 

Management

Operations

Office of the Center Director

CDRH Organization
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Medical devices are classified and regulated according to their degree of 

risk to the public

Class I Class II - 510(k)

Class III - PMA

De Novo HDE

Medical Device ClassificationRisk-Based Paradigm
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Medical Devices Classification

Based on level of regulation necessary to protect the public

• Class I

- General Controls (GC)

• Class II

- Special Controls + GC

- premarket notification (510(k)

• Class III

- Premarket Approval

General Controls include:

- Prohibition against adulterated or misbranded devices

- Premarket notification (510(k)) requirements

- Banned devices

- Good Manufacturing Practices (GMPs)

- Listing of device types

- Record keeping

- Repair, replacement, refund

Special Controls include:

-Labeling

- Guidance

- Tracking

- Design Controls

- Performance Standards 

- Postmarket Surveillance

- Most complex, highest risk

- Establish safety and effectiveness

- Bench - Animal – Human testing

- May include post-approval study requirements
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Three Steps to Obtaining Marketing 

Clearance from CDRH

STEP ONE

• Ensure the product is a medical device, meets the definition of a 

medical device in section 201(h) of the FD&C Act. 

STEP TWO

• Classify Your Device, i.e., determine which one of the three classes the 

device may fall into.

• CDRH Classification identifies the level of regulatory control necessary 

to assure the safety and effectiveness of a medical device. 

• Classification of the device will identify, unless exempt, the marketing 

process. 

• Manufacturer must obtain FDA clearance/approval for marketing.
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Three Steps to Obtaining Marketing 

Clearance from CDRH (cont)

STEP THREE

• Select the appropriate marketing application.

• Develop data and/or information necessary 

to submit a marketing application, and to 

obtain FDA clearance to market. 

• Develop clinical performance data to obtain 

clearance to market. 

• Conduct trial in accord with FDA's 

Investigational Device Exemption (IDE)

regulation.
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Other Requirements Besides Marketing 

Clearance (cont.)

• Postmarket Surveillance Requirements Require 

Compliance with:

- Quality System Regs (Good Manufacturing Practices, GMPs) 

+ The QS regulation covers the design, packaging, 

labeling and manufacturing of a medical device.

- Medical Device Reporting (MDR) Regs 

+ The MDR regulation is an adverse event reporting 

program.
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We discussed

• Role of FDA and Centers

• Regulatory pathways of bringing devices 

to market
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Basis for Regulation of Nanotechnology

• Current regulations are flexible so as to incorporate 

new emerging fields such as nanotechnology. For 

example:

- Medical device regulations are based on risk management, 

and 

- This risk management approach is in principle suitable to 

address all kinds of risks, including risks associated with 

medical devices manufactured using nanoscale materials. 

• Similar analysis may be made for other FDA regulated 

products

• Additional steps may be needed in the future
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Regulatory Landscape 

I. Regulatory Science

Characterization and mechanistic 

understanding of nanoscale 

materials behavior from physical, 

chemical and biological aspects

II. Regulations

Current regulations are 

adequate to ensure safety 

and efficacy

III. Issues

- Does the product contain 

nanoscale materials

- When does the presence of 

nanoscale materials change the 

product classification

IV. Review process

Case-by-case versus classbased review
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Regulatory Science

Driving Forces

1. Mechanistic understanding of 

nanoscale materials behavior 

from physical, chemical and 

biological aspects

2. The dynamic nature of 

nanoscale materials in 

biological systems

3. Advancing our knowledge 

regarding the characterization 

of nanoscale materials 

4. Minimum level of 

characterization needed

Specific activities

• Characterization methods

• Mechanisms of transport, and 

mechanisms of 

accumulation, degradation, 

and release and data

• In-vitro and in-vivo behavior

• ADME, biocompatibility and 

toxicity

• Guidance preparation

• Standards development
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Schematic of potential NP-bioconjugate components and configurations:

A. Biomolecule interacting with NP core; B. Biomolecule interacting with NP core via intermediate ligands; 

C. Biomolecule interacting with NP shell layer that surrounds the NP core; D. Biomolecule interacting with 

NP shell layer—NP core via intermediate ligands; E. Porous NP core containing entrapped biomolecules; 

E. Porous/hollow NP core containing entrapped biomolecules surrounded by a NP shell layer; F. NP core 

smaller than much larger biomolecule; G. NP core smaller than much larger biomolecule attached via 

intermediate ligands. (H) NP core (or NP core/NP shell structures) particles smaller in size than

the much larger biomolecule attached via intermediate ligands. Ref. Techniques for the Characterization of NanoparticleBioconjugates; Kim E. Sapsford, et al.
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Characterization and Use of consensus 

standards in review of nanotechnology products

• Sponsors required to produce a range of 

characterization data to gain better 

understanding of safety and efficacy issues

1. Physical 

2. Chemical

3. Biological 

Minimum level 

of characterization
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Characterization Data

1. Physical properties evaluation determines physical characteristics of 

materials used in the device. 

- Size distribution, aggregation, methods and standards used, 

repeatability 

- Aspect ratio of particles

- Specific surface area 

- Stability as a function of storage time

2. Chemical and surface chemical properties evaluation describe the material 

and its "potential" to undergo chemical change or reaction by virtue of its 

composition. 

- Overall Composition 

- Impurities, especially those that may affect its behavior

- Surface charge and surface properties
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Characterization Data (cont.)

3. Biological properties evaluation determines potential toxicity resulting 

from contact of materials in the device with the body. 

• The device material has the potential to produce adverse local or 

systemic effects; therefore, evaluation of a new device requires data 

from systematic testing to ensure that the benefits exceed any potential 

risks. 

- proof of efficacy 

- sterility and depyrogenation

- toxicity and biocompatibility 

• An appropriate set of tests include those in ISO-10993 

- Interference of nanoscale particles 
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Examples of tests included in ISO-10993

• toxicity (acute, sub-chronic 

and chronic)

• irritation to skin, eyes and 

mucosal surfaces

• sensitization

• hemocompatibility 

• effects on reproduction 

and developmental

• genotoxicity

• carcinogenicity 

• neurotoxicity

• immunotoxicity 

• inflammation (ASTM F04)

• cytotoxicity (ASTM F04)

“Ultimately, the specific clinical application and the materials used in 

the manufacture of the device determine the appropriateness of 

tests.”
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Summary

• Primary Focus

- Protecting public health and promoting nanotechnology

• Challenges remain in nanotechnology

- Mechanistic understanding, methods, standards, data 

• Gaps remain in developing test methods and standards

- Identification and assessment of nanoscale materials in products

+ characterization methods

+ biocompatibility and toxicity assessment 
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More information available at

FDA Websites

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

http://www.fda.gov/Training/CDRHLearn/default.htm

Overview of Regulatory Requirements: Medical Devices

Quality System Regulation 21 CFR Part 820 Basic Introduction

Device Establishment Registration and Listing

Overview of the Premarket Notification Process – 510(k)

Bioresearch Monitoring (BIMO)

http://www.fda.gov/cdrh/devadvice/

http://www.fda.gov/cder/drug/default.htm

Investigational New Drug Application (21 CFR Part 312)

Applications for FDA Approval of a Biologic License (21 CFR Part 601

http://www.fda.gov/ScienceResearchSpecialTopics/Nanotechnology/default.htm