Considering Whether an FDA-Regulated Product Involves the Application of Nanotechnology Guidance for Industry
DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.
Comments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. Submit electronic comments to http://www.regulations.gov1. All comments should be identified with the docket number (FDA-2010-D-0530) listed in the notice of availability that publishes in the Federal Register.
For questions regarding this draft document contact:
Ritu Nalubola, Ph.D., Office of Policy Office of the Commissioner, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993, 301-796-4830 Ritu.Nalubola@fda.hhs.gov
Or
Carlos Peña, Ph.D., Office of the Chief Scientist, Office of the Commissioner, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993, 301-796-4880 Carlos.Pena@fda.hhs.gov
U.S. Department of Health and Human Services Food and Drug Administration Office of the Commissioner
June 2011
III. DISCUSSION
A. Points to Consider B. Rationale for Elements Within the Points to Consider
1. Engineered material or end product 2. At least one dimension in the nanoscale range (approximately 1 nm to 100 nm) 3. Exhibits properties or phenomena . . . that are attributable to its dimension(s) 4. Size range of up to one micrometer (1,000 nm)
IV. CONCLUSION
Guidance for Industry [1] Considering Whether an FDA-Regulated Product Involves the Application of Nanotechnology
This draft guidance, when finalized, will represent the Food and Drug Administration’s (FDA’s) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the telephone number listed on the title page of this guidance.
I. INTRODUCTION
This guidance is intended for manufacturers, suppliers, importers and other stakeholders. The guidance describes FDA’s current thinking on whether FDA-regulated products [2] contain nanomaterials or otherwise involve the application of nanotechnology.
FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required. II. SCOPE
This guidance document does not establish any regulatory definitions. Rather, it is intended to help industry and others identify when they should consider potential implications for regulatory status, safety, effectiveness, or public health impact that may arise with the application of nanotechnology in FDA-regulated products. Public input on the guidance may also inform the development of any regulatory definitions in the future, as needed.
Nor does this guidance document address the regulatory status of products that contain nanomaterials or otherwise involve the application of nanotechnology, which are currently addressed on a case-by-case basis using FDA’s existing review processes.
The application of nanotechnology may result in product attributes that differ from those of conventionally-manufactured products, and thus may merit examination. However, FDA does not categorically judge all products containing nanomaterials or otherwise involving application of nanotechnology as intrinsically benign or harmful.
In the future, FDA may issue additional guidance documents to address considerations for specific products or classes of products, consistent with the "Principles for Regulation and Oversight of Emerging Technologies"2 released March 11, 2011 as well as the "Policy Principles for the U.S. Decision-Making Concerning Regulation and Oversight of Applications of Nanotechnology and Nanomaterials"3 released on June 9, 2011, that were issued jointly by the Office of Science and Technology Policy, Office of Management and Budget, and the United States Trade Representative. [3] III. DISCUSSION
FDA has not to date established regulatory definitions of “nanotechnology,” “nanoscale” or related terms. [4] However, there are numerous definitions of “nanotechnology.” The term is perhaps most commonly used to refer to the engineering (i.e., deliberate manipulation, manufacture or selection) of materials that have at least one dimension in the size range of approximately 1 to 100 nanometers. For example, the National Nanotechnology Initiative Program defines nanotechnology as “the understanding and control of matter at dimensions between approximately 1 and 100 nanometers, where unique phenomena enable novel applications.” [5] Other factors such as function, shape, charge, the ratio of surface area to volume, or other physical or chemical properties have also been mentioned in various published definitions.
As a first step toward developing FDA’s framework for considering whether FDA-regulated products include nanomaterials or otherwise involve nanotechnology, the agency has developed the points discussed below. Based on FDA's current scientific and technical understanding of nanomaterials and their characteristics, FDA believes that evaluations of safety, effectiveness or public health impact of such products should consider the unique properties and behaviors that nanomaterials may exhibit.
These points to consider are intended to be broadly applicable to all FDA-regulated products, with the understanding that additional guidance may be articulated for specific product areas, as appropriate in the future. A. Points to Consider
At this time, when considering whether an FDA-regulated product contains nanomaterials or otherwise involves the application of nanotechnology, FDA will ask:
1. Whether an engineered material or end product has at least one dimension in the nanoscale range (approximately 1 nm to 100 nm); or 2. Whether an engineered material or end product exhibits properties or phenomena, including physical or chemical properties or biological effects, that are attributable to its dimension(s), even if these dimensions fall outside the nanoscale range, up to one micrometer.
These considerations apply not only to new products, but also may apply when manufacturing changes alter the dimensions, properties, or effects of an FDA-regulated product or any of its components. Additionally, they are subject to change in the future as new information becomes available, and to refinement in future product-specific guidance documents. B. Rationale for Elements within the Points to Consider
1. Engineered material or end product
This term is used to distinguish between products that have been engineered to contain nanoscale materials or involve the application of nanotechnology from those products that contain incidental or background levels of nanomaterials or those that contain materials that naturally occur in the nanoscale range. FDA is particularly interested in the deliberate manipulation and control of particle size to produce specific properties, because the emergence of these new properties or phenomena may warrant further evaluation. This is distinct from the more familiar use of biological or chemical substances that may naturally exist at small scales, including at the nanoscale, such as microorganisms or proteins.
2. At least one dimension in the nanoscale range (approximately 1 nm to 100 nm)
A size range of approximately 1 nm to 100 nm is commonly used in various working definitions or descriptions proposed by the regulatory and scientific community. [6] In this size range, materials can exhibit new or altered physicochemical properties which enable novel applications. [7] Accordingly, a range of approximately 1 nm to 100 nm should be applied as a first reference point in considering whether an FDA-regulated product contains nanomaterials or otherwise involves application of nanotechnology.
3. Exhibits properties or phenomena . . . that are attributable to its dimension(s)
These terms are used because properties and phenomena of materials at the nanoscale enable applications that can the affect safety, effectiveness, performance, quality and, where applicable, public health impact of FDA-regulated products. For example, dimension-dependent properties or phenomena may be used for functional effects such as increased bioavailability, decreased dosage, or increased potency of a drug product [8] , decreased toxicity of a drug product [9] , better detection of pathogens [10] , enhanced protection offered by improved food packaging materials [11] , or improved delivery of a functional ingredient or a nutrient in food [12] . The properties and phenomena may be due to altered chemical, biological, or magnetic properties, altered electrical or optical activity, increased structural integrity, or other unique characteristics of nanoscale materials not normally observed in their larger counterparts. [13] These changes may raise questions about the safety, effectiveness, performance, quality or public health impact of the products. In addition, considerations such as routes of exposure, dosage, and behavior in various biological systems (including specific tissues and organs) are critical for evaluating the wide array of products under FDA’s jurisdiction.
4. Size range of up to one micrometer (1,000 nm)
Materials or end products can also exhibit properties or phenomena attributable to a dimension(s) above the approximate 100 nm range. A reduction in size can lead to properties that are clearly different from those of the conventionally-scaled material although the material or end product itself may not necessarily be within the nanoscale range. Structures such as agglomerates and aggregates are of interest in this context [14] as are coated, functionalized, or hierarchically assembled structures [15] . To account for such materials, some definitions of nanomaterial have applied the 100 nm upper dimension to the internal structure [16] . In the absence of a bright line as to where an upper limit should be set, the agency considers that an upper bound of one micrometer (i.e., 1,000 nm) would serve as a reasonable parameter for screening materials with dimensions beyond the nanoscale range for further examination to determine whether these materials exhibit properties or phenomena attributable to their dimension(s) and relevant to nanotechnology. [17] The agency believes that the one micrometer upper limit in the second point to consider serves both to (1) exclude macro-scaled materials that may have properties attributable to their dimension(s) but are not likely relevant to nanotechnology; and (2) include those materials (such as aggregates, agglomerates, or coated, functionalized, or hierarchically assembled structures) with dimension(s) above 100 nm that may exhibit dimension-dependent properties or phenomena relevant to nanotechnology and distinct from those of macro-scaled materials.
IV. CONCLUSION
There is a critical need to learn more about the potential role and importance of dimensions in the characteristics exhibited by engineered nanomaterials that may be used in producing products regulated by FDA. Premarket review, when required, offers an opportunity to better understand the properties and behavior of products that contain engineered nanomaterials or otherwise involve application of nanotechnology. And where products applying nanotechnology are not subject to premarket review, the agency urges manufacturers to consult with the agency early in the product development process. In this way, any questions related to the regulatory status, safety, effectiveness, or public health impact of these products can be appropriately and adequately addressed.
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