Drug Products,
Including Biological
Products, that Contain
Nanomaterials
Guidance for Industry
DRAFT GUIDANCEThis guidance document is being distributed for comment purposes only.
Comments and suggestions regarding this draft document should be submitted within 90 days of
publication in the Federal Register of the notice announcing the availability of the draft
guidance. Submit electronic comments to https://www.regulations.gov. Submit writtencomments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630
Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with thedocket number listed in the notice of availability that publishes in the Federal Register.
For questions regarding this draft document contact (CDER) Katherine Tyner 301-796-0085, or(CBER) Office of Communication, Outreach and Development, 800-835-4709 or 240-402-8010.

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
December 2017
Pharmaceutical Quality/CMC
17050 draft

Drug Products,
Including Biological
Products, that Contain
Nanomaterials
Guidance for Industry
Additional copies are available from:
Office of Communications, Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor
Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353
Email: druginfo@fda.hhs.gov
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

and/orOffice of Communication, Outreach and Development
Center for Biologics Evaluation and Research
Food and Drug Administration
10903 New Hampshire Ave., Bldg. 71, Room 3128
Silver Spring, MD 20993
Phone: 800-835-4709 or 240-402-8010
Email: ocod@fda.hhs.gov
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
December 2017
Pharmaceutical Quality/CMC

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TABLE OF CONTENTSI.

INTRODUCTION............................................................................................................. 1II.

SCOPE ............................................................................................................................... 2

III.

RISK-BASED FRAMEWORK: POTENTIAL RISK FACTORS FOR
PRODUCTS CONTAINING NANOMATERIALS ...................................................... 5IV.

QUALITY: CHEMISTRY, MANUFACTURING, AND CONTROLS ...................... 6A.

Description of the Nanomaterial(s) in the Drug Product ........................................................... 6

B.

Nanomaterial Quality Attributes and Structural Characterization ......................................... 7

C.

Nanomaterial Physicochemical Characterization Methods ....................................................... 9

D.

Dissolution/In Vitro Drug Release Methods for Quality Testing ............................................ 10

E.

Manufacturing Process and In-Process Controls ..................................................................... 11

F.

Excipients ...................................................................................................................................... 12
1. Function ......................................................................................................................................... 12
2. Safety.............................................................................................................................................. 13

G.

Stability ......................................................................................................................................... 13

H.

Postmarket CMC Changes.......................................................................................................... 14V.

NONCLINICAL STUDIES FOR DRUG PRODUCTS .............................................. 15A.

General Applicability of Existing Guidance .............................................................................. 15

B.

Absorption, Distribution, Metabolism, and Excretion (ADME) Considerations................... 15

C.

Risk Considerations for Specific Routes of Administration .................................................... 15
1. Topically Applied Products............................................................................................................ 15
2. Subcutaneous Administration ........................................................................................................ 16
3. Inhalation ....................................................................................................................................... 16
4. Intravenous Products ..................................................................................................................... 16
5. Oral Products ................................................................................................................................ 16

D.

Testing of Representative Nanomaterial.................................................................................... 16

E.

Bridging Toxicology from a Drug Product not Containing Nanomaterials to a
Drug Product Containing Nanomaterials .................................................................................. 17

VI.

CLINICAL DEVELOPMENT ...................................................................................... 17A.

505(b)(2) Submissions .................................................................................................................. 17
1. General Considerations ................................................................................................................. 17
2. Clinical Studies .............................................................................................................................. 19B.

505(j) Submissions ....................................................................................................................... 20C.

351(k) Submissions ...................................................................................................................... 23

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D.

Bioanalytical Methods ................................................................................................................. 23

E.

In Vitro Tests With Human Biomaterials.................................................................................. 23

F.

Immunogenicity ........................................................................................................................... 24

VII.

ENVIRONMENTAL IMPACT CONSIDERATIONS .............................................. 24

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Drug Products, Including Biological Products,that Contain Nanomaterials 1
Guidance for Industry 2

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This draft guidance, when finalized, will represent the current thinking of the Food and Drug
Administration (FDA or Agency) on this topic. It does not create any rights for any person and is notbinding on FDA or the public. You can use an alternative approach if it satisfies the requirements of theapplicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible
for this guidance as listed on the title page.

I.

INTRODUCTION

Nanotechnology can be used in a broad array of FDA-regulated products, such as human drug
products, including those that are biological products. 3 Nanotechnology may be used to create
drug products in which nanomaterials (as explained in section II of this document), serve avariety of functions, for example as active ingredients, carriers loaded with an active ingredient,
or inactive ingredients. The inclusion of such materials may result in product attributes thatdiffer from those of products that do not contain such materials, and thus may merit particularexamination. This document provides guidance on the development of human drug products,
including those that are biological products, in which a nanomaterial is present in the finisheddosage form.
Note that FDA does not categorically judge all products containing nanomaterials or otherwise
involving the use of nanotechnology as intrinsically benign or harmful. Rather, for all products(nanotechnology-derived or otherwise), FDA considers the characteristics of the product and its
safety and effectiveness for its use. FDA issued a guidance document to industry on theagency’s considerations related to nanotechnology applications in FDA-regulated products

1This guidance document is one of several FDA guidance documents related to FDA-regulated products that may
involve the use of nanotechnology. The use of the term “nanomaterial” in this document, as in other FDA guidance
documents, does not constitute the establishment of a regulatory definition. Rather, we use this term for ease ofreference only. See section II of this document for additional discussion.
2
This guidance has been prepared by the CDER Nanotechnology Working Group in the Center for Drug Evaluation
and Research (CDER) with participation from the Center for Biologics Evaluation and Research (CBER) at the
Food and Drug Administration.
3
Refers specifically to those drug products that are biological products under 42 USC 262(i) and subject to licensure
under section 351(a) or (k) of the PHS Act (42 U.S.C. 262(a) or (k)). See 42 U.S.C. 262(j). According to 42 USC
262(i), the term “biological product” means a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood
component or derivative, allergenic product, protein (except any chemically synthesized polypeptide), or analogous
product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound),applicable to the prevention, treatment, or cure of a disease or condition of human beings.

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(referred to as “FDA’s nanotechnology considerations guidance”). 4 FDA’s consideration of theuse of nanomaterials in drug products, including those that are biological products, in thisdocument is consistent with FDA’s nanotechnology considerations guidance, and with thebroader federal guidance on regulatory oversight of emerging technologies 5 andnanotechnology. 6
In general, FDA’s guidance documents 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 document provides guidance on the development of human drug products, including thosethat are biological products, in which a nanomaterial (as explained in this section) is present in
the finished dosage form. This guidance focuses on considerations relevant to FDA’s regulationof these drug products under the Federal Food, Drug, & Cosmetic Act (FD&C Act) and Public
Health Service Act (PHS Act), and includes recommendations for applicants and sponsors ofinvestigational, premarket, and postmarket submissions for these products. 7
For purposes of this guidance:•

The term “drug product” or “drug products” hereafter refers to any human drug productor products in finished dosage form, including those that are also biological products,
unless otherwise specified.
o The term “biological products” refers specifically to those drug products that are
biological products under 42 USC 262(i) and subject to licensure under section
351(a) or (k) of the PHS Act (42 U.S.C. 262(a) or (k)). See 42 U.S.C. 262(j).

4

See FDA’s guidance for industry Considering Whether an FDA-Regulated Product Involves the Application of
Nanotechnology. For the most recent version of a guidance, check the FDA guidance web page at:https://www.fda.gov/scienceresearch/specialtopics/nanotechnology/default.htm.
5
Office of Science and Technology Policy, Office of Management and Budget, and the United States Trade
Representative. Principles for Regulation and Oversight of Emerging Technologies, March 2011; available online
at:https://obamawhitehouse.archives.gov/sites/default/files/omb/inforeg/for-agencies/Principles-for-Regulation-andOversight-of-Emerging-Technologies-new.pdf.
6
Office of Science and Technology Policy, Office of Management and Budget, and the United States Trade
Representative. Policy Principles for the U.S. Decision-Making Concerning Regulation and Oversight ofApplications of Nanotechnology and Nanomaterials, June 2011; available online at:https://obamawhitehouse.archives.gov/sites/default/files/omb/inforeg/for-agencies/nanotechnology-regulation-andoversight-principles.pdf.
7This guidance also includes recommendations regarding NEPA, as relevant to potential FDA regulatory decisions
on these drug products, but does not comprehensively address considerations that may be advisable to addresscompliance with legal obligations under other authorities, including those related to protection of occupationalsafety and health.

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o The term “drug product” also encompasses the drug or biologic constituent part ofa combination product, as defined in FDA regulations at 21 CFR 3.2(e). 8•

FDA has not established regulatory definitions of “nanotechnology,” “nanomaterial,”“nanoscale,” or other related terms. As described in FDA’s nanotechnology
considerations guidance (issued in June 2014), at this time, when considering whether an
FDA-regulated product involves the application of nanotechnology, FDA will ask:o (1) whether a material or end product is engineered to have at least one external
dimension, or an internal or surface structure, in the nanoscale range(approximately 1 nm to 100 nm).
In addition, because materials or end products can also exhibit related properties or
phenomena attributable to a dimension(s) outside the nanoscale range of approximately 1
nm to 100 nm that are relevant to evaluations of safety, effectiveness, performance,
quality, public health impact, or regulatory status of products, we will also ask:o (2) whether a material or end product is engineered to exhibit properties or
phenomena, including physical or chemical properties or biological effects, thatare attributable to its dimension(s), even if these dimensions fall outside thenanoscale range, up to one micrometer (1,000 nm).
We will apply these considerations broadly to all FDA-regulated products, including
products within the scope of this guidance.
For the purpose of this guidance only, we use the term “nanomaterial” generally to referto materials falling within either point 1 or 2 above. The use of this term in this manneris consistent with its use in the FDA’s nanotechnology considerations guidance. In
addition, use of this term in this document is for the purpose of communicating FDA’s
current thinking elaborated in this document only.

•

The term “application” refers to Investigational New Drug (IND) applications, New Drug
Applications (NDAs), Biological License Applications (BLAs), Abbreviated New Drug
Applications (ANDAs), and Drug Master Files (DMF), including any referenced DMF,
unless noted otherwise.

This draft guidance does not apply to biological products composed of proteins, cells, viruses,
nucleic acids, or other biological materials that naturally occur at particle sizes ranging up to 1
micrometer (1000 nm), such as gene therapy or vaccine products, unless a material that has been
deliberately manipulated to have dimensions between 1-100 nm or to exhibit dimensiondependent properties or phenomena up to 1 micrometer, is also present in the product (e.g., as acarrier or an inactive ingredient). This draft guidance also does not apply to drug products thatincidentally contain or may contain particles in the nanoscale range due to conventional
manufacture or storage, in alignment with FDA’s nanotechnology considerations guidance. 98If the classification of a product as a drug, device, biological product, or combination product is unclear or indispute, sponsors can contact the Office of Combination Products for assistance. See, e.g., guidance for industry and
FDA staff Classification of Products as Drugs and Devices and Additional Product Classification Issues.
9
However, evaluations of conventionally-manufactured drug products may include a consideration of effects, if any,of such incidental presence of particles in the nanoscale range on the safety or effectiveness of the product.

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This draft guidance also does not apply to products not regulated by FDA as human drugs, forexample, those regulated solely as drugs for animals, devices, foods, or cosmetic products.
This draft guidance discusses both general principles and specific considerations for thedevelopment of drug products containing nanomaterials, including considerations forestablishing the equivalence of such products with other drugs. Considerations for quality,
nonclinical, and clinical studies are discussed as they relate to drug products containing
nanomaterials throughout product development and production. This draft guidance also
includes recommendations on the specific content of applications for products containing
nanomaterials where the nanomaterial is present in the finished dosage form.
Nonprescription drug products marketed under FDA’s over-the-counter (OTC) drug monographsystem (OTC monograph drugs) are not subject to premarket review and approval of productspecific marketing applications. Instead, among other requirements, such products must satisfy
the conditions established in the applicable monograph (such as permitted active ingredients,
dosage forms, and dosage strengths), must contain only safe and suitable inactive ingredients,and must be manufactured according to current good manufacturing practices. 10 If nanomaterials
are present in a finished OTC drug product marketed under the OTC monograph system, its
manufacturer is responsible for ensuring that the resulting product satisfies all applicable legal
requirements. We therefore encourage monograph drug manufacturers to consider the generalprinciples and specific considerations laid out in this draft guidance concerning drug
development, safety evaluation, and quality considerations, and to consult with FDA to facilitate
a mutual understanding of the specific scientific and regulatory issues for these products.
This guidance does not limit or classify the types of nanomaterials that can be used in drug
products. Rather, it is focused on the deliberate and purposeful manipulation and control ofdimensions to produce specific physicochemical properties which may warrant further evaluation
with regards to safety, effectiveness, performance, and quality.
FDA does not address, or presuppose, what ultimate regulatory outcome, if any, will result for aparticular drug product that contains nanomaterials. Issues such as the safety, effectiveness,
public health impact, or the regulatory status of drug products that contain nanomaterials are
currently addressed on a case-by-case basis using FDA’s existing review processes. Current
CDER and CBER guidance documents and requirements for the evaluation and maintenance ofquality, safety, and efficacy, apply to drug products containing nanomaterials that otherwise fallwithin their scopes. As such, this guidance should be viewed as supplementary to otherguidances for drug products. In addition, the Agency may continue to develop guidance
addressing certain specific commonly-used types of nanomaterials, e.g., some liposomes, 11 tobetter address the challenges in evaluating and characterizing the quality and performance ofdrug products that incorporate them.

10

21 CFR 330.1; see generally 21 CFR part 330.
See FDA’s draft guidance for industry Liposome Drug Products. When final, this guidance will represent the
FDA’s current thinking on this topic.
11

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III.

RISK-BASED FRAMEWORK: POTENTIAL RISK FACTORS FOR PRODUCTSCONTAINING NANOMATERIALS 12

There is great diversity in drug products containing nanomaterials including route ofadministration, indication, function of the nanomaterial, structural complexity, and maturity ofthe technology (including manufacturing processes, analytical techniques, and product design).
In some instances, nanomaterials may take on different chemical, physical, or biologicalproperties than their larger-scale counterparts that may impact quality, safety, or efficacy. For
example, 13•

Nanomaterials may have enhanced rates of dissolution and may improve bioavailability(BA) compared to the same material that is not manufactured to be a nanomaterial. In
addition, after entry into the systemic circulation, nanomaterials can affect the
distribution, the exposure-response profile, and the residence time of an active ingredient.
These changes may be partly due to the interaction of nanomaterials with multiple plasma
proteins resulting in the formation of a protein corona. The bound plasma proteins may
endow nanomaterials with new biological properties. Through endocytosis thenanomaterial-protein complex can be taken up by tissue cells. Elimination of thenanomaterial-protein complex occurs mainly through phagocytosis by macrophages ofthe mononuclear phagocyte system, predominantly in the liver and spleen. Thus,
nanomaterials enable targeting of active ingredients to specific sites but at the same timethey may become targets of the complement and mononuclear phagocyte systems. Smallhydrophilic nanomaterials may be eliminated by the kidney.

•

Nanomaterials can be passively and/or actively targeted to different sites within the body.
For example, passive targeting to different organs (e.g., liver) may be accomplishedbased on size or charge, while active targeting of tumors typically requires attachment ofspecific molecules (e.g., ligands, monoclonal antibodies, small molecules) to the surfaceof nanomaterials that are recognized by receptors on cancer cells.

Compared to other products, further understanding may be needed regarding the interactions ofnanomaterials with biological systems. These interactions include, but are not limited to, theimpact of intrinsic (e.g., disease, age, sex) and extrinsic factors (e.g., co-administered drugs) on
exposure and response, the role of enzymes and transporters in their disposition, and theirimmunogenic potential.
This guidance is based on the premise that adequate (1) characterization of the nanomaterial, and(2) understanding of a nanomaterial’s intended use and application, and how the nanomaterial
attributes relate to product quality, safety, and efficacy, is a suitable framework for evaluating
12
As explained in section II of this document, we use the term “nanomaterial” in this document for ease ofreference. See FDA’s guidance for industry Considering Whether an FDA-Regulated Product Involves the
Application of Nanotechnology for more information.
13
Tyner, KM et al. WIREs Nanomed Nanobiotechnol 2015. doi: 10.1002/wnan.1338; Tyner, KM et al. The AAPS
Journal 2017. doi: 10.1208/s12248-017-0084-6; Cruz, CN et al. The AAPS Journal 2013. doi: 10.1208/s12248-0139466-6; Palombo M, et al. Annu Rev Pharmacol Toxicol. 2014doi: 10.1146/annurev-pharmtox-010611-134615.

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potential risk(s) associated with drug products containing nanomaterials. We propose a riskbased approach focusing on the following risk factors, which are further addressed in thisguidance. Note this list is not comprehensive and other risk factors may need to be evaluatedduring product development. Development of drug products containing nanomaterials entails
continual reduction of residual uncertainty throughout a product’s lifecycle.
Factors for Assessment of the Nanomaterial:

IV.

•

Adequacy of characterization of the material structure and its function.

•

Complexity of the material structure.

•

Understanding of the mechanism by which the physicochemical properties of the material
impact its biological effects (e.g., effect of particle size on pharmacokinetic parameters).

•

Understanding the in vivo release mechanism based on the material physicochemical
properties.

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Predictability of in vivo release based upon established in vitro release methods.

•

Physical and chemical stability.

•

Maturity of the nanotechnology (including manufacturing and analytical methods).

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Potential impact of manufacturing changes, including in-process controls and therobustness of the control strategy on critical quality attributes of the drug product.

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Physical state of the material upon administration.

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Route of administration.

•

Dissolution, bioavailability, distribution, biodegradation, accumulation and theirpredictability based on physicochemical parameters and animal studies.

QUALITY: CHEMISTRY, MANUFACTURING, AND CONTROLSA.

Description of the Nanomaterial(s) in the Drug ProductA description of nanomaterials in the drug product should be included in the application, as partof the sections on product composition and description (e.g., common technical document (CTD)
3.2.P.2.1). The description of the nanomaterial should include information that sufficiently
describes the product (e.g., size, charge, morphology, composition, and complexation) at a levelappropriate for the stage of product development. At the IND stage, sufficient description of thenanomaterial is necessary to ensure safety during use in clinical trials as well as to collectsufficient data to bridge early development batches to late stage clinical trial material and the6Contains Nonbinding Recommendations
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14,15

proposed commercial material.
Sufficient description of the nanomaterial in an ANDA,
NDA, or BLA allows for control over the material properties to ensure consistent quality of the
drug product. A narrative description and a complementary diagram of the structure being
described should be included. The description of the nanomaterial structure is particularly
important for more complex structures involving multiple components or compartments (e.g.,layers, core-shell structures), ligands, and coatings. Providing only an ingredient list may not be
sufficient to explain the resulting structure of the nanomaterial after assembly, formulation,
and/or processing.
In addition to the description of the nanomaterial structure, a description of the functionality of
the nanomaterial should be included (e.g., used for solubilization of the active ingredient, as acarrier, as the active ingredient, for targeting and delivery).
FDA acknowledges that as product development progresses, more information will become
available on the structure and function of the nanomaterial. For example, approximate values fornanomaterial particle size or coating thickness may be provided in the description portion during
early stages of development. However, as the product enters late stage development (e.g.,
pivotal clinical and safety trials), the description of the material and understanding of thematerial functionality should be revised, as applicable, and supported with characterization dataaccordingly.
Generally, information on the structure of a specific nanomaterial can also be referenced with anappropriate letter of authorization to other applications or to a drug master file, as appropriate.
However, as with any product, the applicant is responsible for the quality of all ingredients, 16
including nanomaterials used in the product, which may be challenging for highly complex
structures.
B.

Nanomaterial Quality Attributes and Structural Characterization

As with any formulation, a full description of the physical and chemical characteristics of the
drug substance must be provided, 17 including proper characterization of identity, strength,
stability, and quality of the product. The nanomaterial’s critical quality attributes (CQAs) should
be determined with regard to its function and potential impact on product performance. The
nanomaterial properties that can impact product performance should be defined along with thepotential risks due to changes in those properties, whether as final product quality attributes or asintermediate material attributes. The applicant should utilize risk assessments that link the
structure-function relationship of the nanomaterial to attributes that need to be examined during
development and controlled if changes are made during development of the final productformulation or manufacturing process.
14

See FDA’s guidance for industry Content and Format of Investigational New Drug Applications (INDs) for Phase
1 Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-derived Products.
15
See FDA’s guidance for industry INDs for Phase 2 and Phase 3 Studies Chemistry, Manufacturing, and Controls
Information.
16
See 21 CFR 314.50(d)(1)(ii)(a); 21 CFR 314.94(a)(9) (requiring, among other things, an ANDA to contain theinformation required under 2 CFR 314.50(d)(1)); 21 CFR 601.2.
17
Ibid.

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As with most aspects of the drug product development process, the specific CQAs for ananomaterial will be product-specific and will most likely include a combination of attributes
that are specific to the nanomaterial (e.g., particle size distribution and physical stability) andthose that are not necessarily nanomaterial-specific (e.g., impurities). The sponsor should justify
the level of nanomaterial characterization based on the impact of its quality attributes on thefunction of the drug product as well as the general knowledge of the nanomaterial published in
the literature. The CQAs need not be an exhaustive catalogue of quality attributes, but shouldcapture attributes that potentially impact the quality, safety, or efficacy of the final product.
The following attributes should be described and measured 18 for any nanomaterial in a drug
product:•

Chemical composition;•

Average particle size;•

Particle size distribution (PSD) (description of d10, d50, d90 or polydispersity;modality);•

General shape and morphology (aspect ratio); and•Stability, both physical (e.g. aggregation and agglomeration or separation) and chemical.

Additional quality attributes may also apply to nanomaterials in drug products, depending on theparticular drug product (e.g., route of administration), its indication, and patient population.
Examples can include, but are not limited to:•

Assay and distribution of any active ingredient associated with the nanomaterial and free
in solution (e.g., surface bound or liposome encapsulated versus free active ingredient);•

Structural attributes that relate to function (e.g., lamellarity, core-shell structure);•

Surface properties (e.g., surface area, surface charge, chemical reactivity, ligands,hydrophobicity, and roughness);•

Coating properties, including how coatings are bound to the nanomaterial;•

Porosity (if it relates to a function, e.g., capacity to load a drug);•

Particle concentration;•

In vitro release;18

The methodology, sampling and testing frequency, and acceptance criteria for these attributes will depend on thecontrol strategy considerations (review and inspection) for each product. Drug products containing nanomaterials
should include information in the submission regarding the characterization and understanding of these attributes.

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•

Crystal form;•

Impurities; and•Sterility and endotoxin levels. 19
C.

Nanomaterial Physicochemical Characterization Methods

Some standardized methods for nanomaterial characterization exist or are currently being
developed (e.g., ISO 22412:2017, ASTM E2859-11(2017)). As with any method used in supportof an application, adequacy for a standardized method should be demonstrated and justified forthe product being tested (e.g., the particle size range or the presentation of the sample). In
addition, corresponding validation and verification and related protocols should be provided as
per FDA’s guidance on methods validation. 20
Sponsors should consider the following factors when selecting and using specificcharacterization methods:•

Method suitability: Sponsors should ask: (1) Is the method capable of detecting andcharacterizing the material in the size range of interest (e.g., laser diffraction versus lightscattering, or various forms of microscopy)? (2) Does the methodology require a sample
preparation that may significantly alter the nanomaterial attribute being measured during
analysis (e.g., dilution, drying, or sonication)? (3) Can the analytical equipment haveunintended interactions with the nanomaterial (e.g., filters)?

•

Complementary methods: In some cases, several different analytical techniques may beavailable to characterize a given material attribute, for example particle size ormorphology. Due to inherent differences in analytical techniques for measuring a given
attribute, different instruments may provide different endpoint measurements. To address
technique-related differences, we recommend the use of complementary methods whenmeasuring material attributes that have been established as critical (e.g., use bothdynamic light scattering and transmission electron microscopy for size). In addition, adescription of what is being measured should also be provided (e.g., hydrodynamic radius
versus projected radius, ensemble versus single particle results) in order to account forpotential differences. If different techniques are needed -at different stages of processing(e.g., in-process, on final product release, and on stability), justification and any
correlation of the measurement should be discussed. The analysis of raw data also needs
to take into account the behavior of nanomaterials (e.g., diffusion).
Sampling: Whenever possible, testing of the nanomaterial should be performed in a statethat is most representative of the process stage being evaluated (e.g., in-process, isolated

19
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See FDA’s guidance for industry Pyrogen and Endotoxins Testing: Questions and Answers.
See FDA’s guidance for industry Analytical Procedures and Methods Validation for Drugs and Biologics.

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intermediate, final formulation, during storage, and in-use conditions), taking into
consideration how each process stage may impact quality.
•

Sample preparation: Diluting or drying out a formulation or sample for analysis may
produce substantial changes in the nanomaterial such that it is no longer representative of
the nanomaterial contained in the final product. Therefore, any change made to thematerial from the original sample aliquot should be evaluated for relevance to theattribute being measured. Filtration steps may also confound results. Nanomaterials may
interact with the filter medium, causing a loss of sample. Alternatively, in some methods
a filtration step may lead to an erroneous conclusion that all material passing through thefilter is in a dissolved state, because nanomaterials may pass through filters whileremaining discrete entities (e.g., as nanocrystals instead of dissolved molecules).
Therefore, the sample preparation steps for a nanomaterial should be adequately
controlled to ensure these steps do not substantially change the product from its intended
state.

In addition to the specific points above, additional general considerations for analysis include:•

Shape assumptions in analysis (e.g., assuming a sphere).

•Sufficient sample size (number of samples analyzed to ensure adequate statistical rigor).

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Appropriate reporting of results (e.g., cumulant analysis or distribution analysis;
intensity, volume, or number weighted distributions; number or histogram for dynamic
light scattering data).

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Appropriate use of viscosity in particle size measurements (e.g., dynamic viscosity orapparent viscosity).

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Sample preparation protocols (e.g., microscopy).
D.

Dissolution/In Vitro Drug Release Methods for Quality Testing

A fully validated dissolution/in vitro release method is one of the control tools to ensure that
quality and clinical performance are maintained throughout the lifecycle of the drug product.
For example, in vitro release methods may aid in the characterization of liposome integrity, andin quantifying free versus encapsulated drug. Like drug products without nanomaterials, drug
products containing nanomaterials should have dissolution/in vitro release methods capable ofdiscriminating formulation and manufacturing differences which may impact the clinicalperformance of the drug product. In general, the dissolution/in vitro release testing should be
conducted with the drug products manufactured under target conditions and compared to drug
products that are intentionally manufactured with meaningful variations in formulation andmanufacturing parameters, such as particle size, drug loading, types and/or amounts of inactive
ingredients. Ideally, the dissolution/in vitro release method should be able to discriminate
batches that are not bioequivalent to the pivotal clinical batch, which will have demonstrated
efficacy and safety. Detailed descriptions of the proposed dissolution/in vitro release test and the10

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developmental parameters (selection of equipment/apparatus, media, agitation/rotation speed,
pH, sink conditions, surfactant type and concentration) should be included in the submission.
Drug release profiles should be complete; that is, drug release should reach a plateau (nosignificant increase over three consecutive time points) and achieve at least 85 percent release of
the labeled amount of active ingredient(s), or, if not complete, the application should provide
additional data to explain the reasons for incomplete release. As mentioned above, in vitro
methods involving filtration that are used for testing during development and quality control(e.g., dissolution and assay) may need to be revised for appropriate use in the formulations
containing nanomaterials. For example, using current United States Pharmacopeia (USP)
dissolution methods that require filtration may lead to misinterpretation of results.
Due to the complex nature of some drug products containing nanomaterials, a sponsor may bemotivated to develop a novel in vitro release/dissolution method for its product. If a sponsor
develops novel drug release/dissolution methods, we recommend consultation with the Agency
regarding feasibility, scientific rationale, and method validation to ensure that such a method isreproducible, reliable, and sensitive to variations in the product’s formulation and manufacturing
processes.
E.

Manufacturing Process and In-Process Controls

All drugs , including both active ingredients and finished drug products that containnanomaterials, must be manufactured in accordance with current good manufacturing practice(CGMPs) as set forth in section 501(a)(2)(B) of the Food, Drug, and Cosmetic Act (FD&C Act).
In addition, the CGMP regulations in 21 CFR parts 210, 211, & 212, and the regulations in 21
CFR parts 600-680, as applicable, apply to finished drug products, including drugs subject to
OTC monograph regulations. (See 21 CFR 330.1(a).) The variety of nanomaterials and theiruses in drug products continue to grow. A comprehensive body of knowledge of nanomaterial
attributes and the effects of these attributes on the quality and manufacturing process of drug
products does not currently exist. Building a knowledge base to better understand potential risks
to product safety, identity, strength, quality and purity characteristics during manufacturing ofdrug products containing nanomaterials is essential to establishing robust control strategies andimplementing effective process validation protocols. It is, therefore, critical that the applicant
apply manufacturing experience and increased understanding of potential risks to improve boththe manufacturing process and associated control strategy over time.
Nanomaterials are engineered and manufactured to elicit novel product properties and clinicaloutcomes. The quality, safety, or efficacy of drug products containing nanomaterials can,however, be very sensitive to process conditions and production scales. Moreover,environmental controls should be established early in the development stage to prevent crosscontamination. This type of process and scale dependency, coupled with inherent polydispersityof some nanomaterials, makes it a priority to assess the risk to quality associated with thenanomaterial attributes, and develop adequate detectability of both nanomaterial and process
failures at the development stage. As such, the earlier that CQAs can be identified during
development, the more quickly in-process controls can be designed and implemented in the
manufacturing process. A well-disciplined design control approach can generate key process
knowledge, especially for those areas where, in the absence of comprehensive understanding,11

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variability is not predictable, scale effects are unknown, and where results cannot be extrapolated
or interpolated to demonstrate safety and efficacy.
A different shape or size of a nanomaterial could be considered a batch consistency issue if it
impacts the quality, safety, or efficacy of the product. In addition, nanomaterial carriers (i.e., acarrier that is a nanomaterial) that are empty or have missing or incomplete surface coatings
could be considered an impurity and may need to be quantified.
For drug products containing nanomaterials, changes in analytical methods, manufacturing
process, scale, and manufacturing sites may make the bridging of early development lots to largecommercial scale lots difficult. It is important to ensure that a sufficient amount of product isretained from all batches to allow any future analysis by updated or complementary methods.
This will help to establish a bridge between developmental and commercial batches. Thisapplies to stability samples as well as stable process intermediates.
F.

Excipients
1.

Function

Nanomaterials can be present as excipients in drug products and may serve specific functions toensure or enhance desired product attributes. For the purposes of this guidance, an excipient is
any inactive ingredient that is intentionally added to a therapeutic or diagnostic product, but thatis not intended to exert therapeutic effect(s) at the intended dosage, although it may act toimprove product delivery (e.g., enhance absorption or control release of the drug substance). For
example, nanomaterial excipients can be used as adjuvants for vaccines or for delivery ofantigens or genetic material. Excipients (e.g., polymers, targeting agents, coating agents, andlipids) are also used as matrices to assemble structures or to stabilize more complex
nanomaterials. The material attributes of these excipients are a critical element of the control
strategy relating to product performance. For example, the purity of lipids used in a liposome or
the molecular weight distribution of the polymers used in nanomaterial drug delivery systems
may be critical. Therefore, nanomaterial excipient properties need to be fully characterizedbased on their functionality and intended use. Proper controls, including test methods andacceptance criteria, a description of material source, and grade should be defined in an
application, with justification for how those acceptance criteria enable the product to meet its
desired quality target product profile. Changes in the grade and source of nanomaterial
excipients during development should be addressed with regard to how these changes may
impact the safety or efficacy of the product.
Some nanomaterials (whether as primary particles or in an agglomerated or aggregated state) arecommonly used as excipients (e.g., diluents, surfactants, glidants, emulsifiers, and lubricants), to
improve processability and formulation performance. As a general matter, nanomaterial
excipients with documented prior human exposure under circumstances relevant to the proposeduse (including the same route of administration, dosage forms, function, and maximum potency)
can be adequately described in terms of the excipient’s overall function and control specification,
the same as other commonly used excipients. These common nanomaterials may represent a low

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risk to product safety and efficacy; however, excipient functionality may still be important for
overall product quality.
2.

SafetyThe incorporation of an excipient into a nanomaterial structure or reducing the size of an
excipient below 1 micrometer (1000 nm) may have implications for the safety and/or efficacy of
the finished product. Current FDA guidance on evaluating the safety of new excipients 21 applies
when a common excipient is deliberately modified into a nanomaterial. An adequate safety
evaluation should be provided when the nanomaterial’s safety is not fully demonstrated byexisting safety data with respect to level of exposure, duration of exposure, and route ofadministration. In the event that a common excipient has been deliberately modified to be ananomaterial or incorporated into a nanomaterial, we recommend that you consult with the
Agency regarding any impact on potential exposure to and safety of the material.
G.

Stability

Current FDA guidance documents related to the extent of stability data and testing conditions to
support drug product applications 22 applies to drug products containing nanomaterials. The
determination of container closure system suitability, storage conditions, shelf life, and in-use
conditions for a drug product containing nanomaterials will be based on chemical and physicalstability of that product, as justified by data, consistent with current FDA guidance on this issue.
In particular, when assessing the stability of the drug product, the developer should consider
potential factors impacting the product performance, including interactions of nanomaterial
properties, prior to reaching the patient. The study of the stability of nanomaterials in products
should involve the evaluation of physical and chemical changes in the material during handlingand storage. There are particular risk factors that are more specific to the physical stability ofnanomaterials. Stress stability studies can be useful in elucidating changes and pathways of
those changes in the nanomaterials. Stability issues that impact nanomaterial properties may
include, but are not limited to:•Changes to particle size and size distribution.

•

Changes to particle morphology.

•

Self-association (agglomeration/aggregation).

•

Change in surface charge (e.g., zeta potential).

•

Changes in dissolution/release rate of active ingredient.

21

See FDA’s guidance for industry Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients.
See FDA’s guidances for industry ICH Q1A(R2) Stability Testing of New Drug Substances and Products; ICH
Q5C Quality of Biotechnological Products: Stability Testing of Biotechnological/Biological Products; ANDAs:
Stability Testing of Drug Substances and Products; and ANDAs: Stability Testing of Drug Substances and Products,
Questions and Answers.

22

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•

Drug leakage from a nanomaterial carrier.

•Degradation of particle (e.g., removal/exchange of surface ligands).

•

Interaction with formulation or container closure (e.g., compatibility, denaturing ofproteins).

•

Changes to reconstitution properties of the product.

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Changes in the solid state (e.g., crystal structure).

In addition, if the drug product must be diluted prior to use, the dilution medium may affectsurface charge and/or particle size, altering colloidal stability of nanomaterials and triggering
release of the active ingredient. In-use stability studies at clinically relevant concentrations andunder relevant storage conditions may also be requested. Such studies may evaluate
nanomaterial interactions with surfaces in the primary package, since these can result in changes
to CQAs. Note that stability issues during storage can include interaction with the storage
container, contact with administration or delivery devices (e.g. syringe walls, catheters), anddispersion media.
H.

Postmarket CMC Changes

Additional risk factors may arise when making a major or moderate change 23 to drug products
containing certain nanomaterials after approval. The comparison between a drug product before
a change and after a change may require physicochemical comparison of CQAs and may requirein vivo bioequivalence (BE) studies, depending on the impact of the change and the type of
product. 24 As stated above, retention of samples from pivotal batches through development toenable bridging between manufacturing process changes, scale-up, and site transfers may be a23

See 21 CFR 314.70(b) &(c) (classifying as major changes and moderate changes, respectively, changes in the
drug substance, drug product, production process, quality controls, equipment, or facilities that have substantial
potential (for major changes) or moderate potential (for moderate changes) “to have an adverse effect on theidentity, strength, quality, purity, or potency of the drug product as these factors may relate to the safety oreffectiveness of the drug product”). Such changes require supplemental applications prior to implementation. See 21
CFR 314.97 (changes to approved ANDAs also subject to 21 CFR 314.70, see also 601.12 (regulation defining andgoverning changes to licensed biological products).
24
For general information/examples of change categories, see the following FDA guidances for industry SUPACMR: Modified Release Solid Oral Dosage Forms: Scale-Up and Postapproval Changes: Chemistry, Manufacturing,and Controls; In Vitro Dissolution Testing and In Vivo Bioequivalence Documentation; and SUPAC-SS: Nonsterile
Semisolid Dosage Forms: Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls; In Vitro
Release Testing and In Vivo Bioequivalence Documentation; and Immediate Release Solid Oral Dosage Forms
Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls, In Vitro Dissolution Testing, and In
Vivo Bioequivalence Documentation; and ICH Q5E Comparability of Biotechnological/Biological Products Subject
to Changes in Their Manufacturing Process.

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suitable strategy. For manufacturing changes that may affect the bioequivalence of certain drug
products containing nanomaterials, please refer to section VI of this guidance.

V.

NONCLINICAL STUDIES FOR DRUG PRODUCTS
A.

General Applicability of Existing Guidance

All existing International Conference on Harmonization (ICH) guidance addressing nonclinicalsafety of drug products and their components is generally applicable to drug products containing
nanomaterials. New drug products that contain nanomaterials should be thoroughly tested as forany new drug product. However, depending on the water solubility of the component or
aggregation under in vitro conditions, some in vitro assays may not be appropriate, or theconditions under which these assays are conducted might need to be adjusted.
B.

Absorption, Distribution, Metabolism, and Excretion (ADME)
Considerations

Components that are nonbiodegradable can accumulate and persist longer than biodegradable
components and can consequently produce effects related to chronic exposure to thesecomponents. A nanomaterial can sometimes cross biological barriers in greater amounts than thelarger particle size version. This can lead to increased safety concerns in some cases, such asincreased penetration of the blood-brain barrier, or the placenta. 25 If a drug product contains
nanomaterials as excipients, including excipients that function as drug carriers, the biologicalfate of the carriers and their potential impact on safety may need to be determined in addition to
those of the active ingredient.
To conduct biodistribution studies of nanomaterials, it may be necessary for the material to belabeled in some manner (e.g., radiolabeled, fluorescence). Data should be collected
demonstrating that the label does not substantially affect the biodistribution of the nanomaterial.
C.

Risk Considerations for Specific Routes of Administration

The following route-specific issues should be considered when assessing the safety of a drug
product containing nanomaterials, and may warrant special assessment in addition to thenonclinical studies normally conducted in support of drug product development.
1.

Topically Applied Products

Increased hair follicle penetration or distribution to local lymph nodes is a possibility fornanomaterials. 26 In addition, nanomaterials can interact with sunlight differently than larger size
25
Pietroiusti, A et al. Small 2013. doi: 10.1002/smll.201201463; Landsiedel, R et al. Arch Toxicol. 2012. doi:
10.1007/s00204-012-0858-7; Hubbs, AF et al. Toxicol Pathol. 2011 Feb;39(2):301-24. doi:
10.1177/0192623310390705.
26
Gulson, B et al. Arch Toxicol 2015. DOI 10.1007/s00204-015-1564-z.; Almeida, JP et al. Nanomedicine (Lond).
doi: 10.2217/nnm.11.79.

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particles and this can impact the interaction of light with the skin. Penetration of a nanomaterial
through the skin in human patients can be impacted by the condition of the skin (e.g., intact,damaged, diseased). The evaluation of effects and exposures achieved in the nonclinical studies
should consider this impact.
2.

Subcutaneous Administration

Materials introduced below the stratum corneum can possess an increased sensitization potential
compared to some other (e.g., dermal) routes. It has been reported that nanomaterials injectedsubcutaneously can enhance sensitization to other allergens. 27 The biological fate of non-soluble
nanomaterials should be considered.
3.

Inhalation

Local/respiratory toxicity of nanomaterials can differ from larger particles, as can lungdeposition, distribution in respiratory tissues, and systemic BA. 28 The biological fate(accumulation/translocation) of non-soluble carrier nanomaterials should be considered.
4.

Intravenous Products

Drug products containing nanomaterials can have a different tissue distribution of the active
ingredient and a different half-life compared to the same drug products without nanomaterials.
Changes in hemocompatability can occur. 29
5.

Oral Products

For orally administered drug products, use of nanomaterial ingredients is often intended toincrease bioavailability of the active ingredient. Other than possible local effects and anincreased absorbed dose (which should be detected with existing methods), if the oral toxicology
studies with a micrometer scale material were adequate, new effects are not expected for soluble
drugs. If an insoluble nanomaterial is included in an oral product, toxicology studies should takethis into consideration and include assessment of tissues where such materials might accumulate.
D.

Testing of Representative Nanomaterial

Before toxicity studies are conducted with a drug product containing nanomaterials, it isimportant to know that the nanomaterial has been made reproducibly and that it is representativeof the nanomaterial to which humans will be exposed. The different factors, vehicles, and media
that affect the aggregation and surface properties of the drug, in vitro and in vivo, should beunderstood. Appropriately validated analytical methods should be used to characterize the test
articles used in nonclinical studies. These analytical methods should include methods suitable
27
Dobrovolskaia, MA et al. Nat Nanotechnol 2007. doi: 10.1038/nnano.2007.223; Ilinskaya, AN et al. Toxicol Appl
Pharmacol 2016. doi: 10.1016/j.taap.2016.01.005; Smith, AR et al. Curr Allergy Asthma Rep. 2017
doi: 10.1007/s11882-017-0674-5.
28
Stone, V et al. Environ Health Perspect. 2016. doi: 10.1289/EHP424.
29
See footnote 11.

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for the unique properties of nanomaterials, as discussed elsewhere in this guidance (section IV),
when test articles contain nanomaterials.
Generally, nonclinical evaluations of the kind typically conducted to support development of any
drug product will be adequate to assess drug products containing nanomaterials when the clinicalmaterial is tested in the nonclinical studies. However, as noted above, some in vitro assays may
not be appropriate for drugs that contain nanomaterials, or the conditions under which theseassays are conducted might need to be adjusted in order to obtain accurate results.
E.

Bridging Toxicology from a Drug Product not Containing Nanomaterials to a
Drug Product Containing Nanomaterials

When a previously-approved drug product is modified to include a nanomaterial (active
ingredient or inactive ingredient), ADME and a bridging toxicology study can often be
appropriate and sufficient to allow reliance on previous nonclinical information assuming otherregulatory requirements are met. Consideration should be given to how the change may affectdrug ADME and what potential impact any change may have on toxicity, e.g., increased
penetration through the placenta (refer to section V.B). Additional studies can be warranted ifchanges suggest the possibility of an altered effect in a particular tissue. In some cases, when thenanomaterial is not the active ingredient, assessment of its contribution to any observed toxicity
can be useful in interpreting such bridging studies. Therefore, inclusion of treatment groups with
only the nanomaterial should be considered.

VI.

CLINICAL DEVELOPMENT

The clinical development of drug products containing nanomaterials should follow all policies
and guidances relevant to clinical safety and efficacy studies as they pertain to development of
IND, NDA, ANDA, and BLA submissions. This section addresses the particular topic of clinicaldevelopment of drug products containing nanomaterials developed using a reference product,e.g., along the 505(b)(2), 505(j), and 351(k) pathways.
A.

505(b)(2) Submissions
1.

General Considerations

From a pharmacokinetic-pharmacodynamic (PK-PD) point of view, drug products that containnanomaterials can be differentiated into two different types: (1) those where the nanomaterial isthe active ingredient, or (2) those where the nanomaterial carries the active ingredientsolubilized, conjugated, associated, or encapsulated for delivery. For the first type,determination of PK and PD is focused on the active ingredient as the nanomaterial. For thesecond type, determination of PK and PD is focused on the released active ingredient and the PKof the carrier. An example for the first category is a stabilized nanocrystal suspension.
Examples of the second category include liposomes, polymeric nanoparticles, and dendrimers.
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loaded active ingredient (e.g., immunogenicity) and could also affect the safety and effectivenessof the drug product.
The disposition and exposure-response relationship of an active ingredient formulated as ananomaterial (whether a nanomaterial itself or within a nanomaterial carrier) may not be thesame as for a drug product that does not contain nanomaterials. Nanomaterial carriers candeliver the active ingredient to the target tissue by various routes, such as the endocytic route or
via enhanced permeation retention (EPR) effect. Consequently, the tenet for products containing
the same active ingredient, i.e., that equivalent active ingredient exposure in plasma ensuresequivalent therapeutic performance, may not hold for proposed drug products containing
nanomaterials relative to a reference drug product that does not contain nanomaterials. In somecases, demonstration of BE between a proposed product containing nanomaterials and areferenced product (whether or not the referenced drug product also contains nanomaterials) may
not be sufficient to bridge the proposed product to the referenced product. Additional
nonclinical and clinical evidence may be required to demonstrate comparable disposition andexposure-response relationship for the active ingredient between a proposed product containing
nanomaterials and a referenced product. For example, if the goal of a development program fora drug product containing nanomaterials developed along the 505(b)(2) path is to demonstrate noclinically meaningful difference in disposition and exposure-response relationship relative to thereference product, the magnitude of the development program depends on the amount ofevidence required to support this demonstration or bridge.
In development programs attempting to bridge the performance of a drug product containing
nanomaterials to a referenced drug product, FDA recommends that sponsors apply a risk-based
approach to determine if the product in development will exhibit clinically significant changes in
exposure, safety, and/or effectiveness relative to the referenced product. The risks of a drug
product exhibiting such clinically significant changes may vary; factors that can influence thatrisk include certain characteristics of the nanomaterial contained within the drug product, routeof administration, and frequency of use. With medium and high risk drug products containing
nanomaterials, the residual uncertainty about equivalent exposure indicating equivalent
therapeutic performance is greater than with low risk drug products containing nanomaterials.
To reduce the residual uncertainty with medium and high risk drug products containing
nanomaterials, the exposure-response profile may have to be explored. In addition, a particulardrug product may be considered higher or lower risk for bridging based on other clinical orsafety information. Such considerations should be demonstrated in development programs
attempting to bridge the performance of a drug product containing nanomaterials to a referenced
drug product.
Below, we present examples that are meant to be illustrative of the risk categories, derived fromthe Agency’s preliminary thinking and experience with drug products containing nanomaterials.
Note that these examples are not comprehensive.
•Low risk to exhibit clinically significant changes in exposure, safety, and/or effectiveness
relative to the referenced product: For example, drug products containing nanomaterials
that revert to their molecular constituents immediately after administration are likely topresent low risk, whether these drug products are administered by oral, topical, and18

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parenteral routes. Examples include oral nanocrystals and some intravenous lipid
nanoparticles.
•

Medium risk to exhibit clinically significant changes in exposure, safety, and/or
effectiveness relative to the referenced product: For example, drug products containing
non-targeted nanomaterials intended for systemic action that are administered parentallyare likely to present medium risk. Examples include drug products with known or
predictable active ingredient release characteristics.

•

High risk to exhibit clinically significant changes in exposure, safety, and/or effectiveness
relative to the referenced product: For example, drug products containing targeted
nanomaterials intended for systemic action and that are administered intravenously arelikely to present high risk. Examples include drug products with complex and difficult topredict active ingredient release characteristics.
2.

Clinical Studies

In the clinical development of drug products that follow a 505(b)(2) approval pathway and are
low risk, demonstration of BE between the proposed and the referenced product based on acomparative plasma PK may be generally sufficient to bridge. Products in the medium and highrisk categories should initially include single and multiple dose studies assessing PK, PD, andtolerability to characterize the proposed product. These studies should be followed by a single
dose BE study comparing the proposed and the referenced product. For orally administerednanomaterials, a single dose fed BE study is also necessary to provide a sufficient bridge.
For medium and high risk drug products containing nanomaterials, demonstration of BE between
the proposed and the referenced product alone may not be enough to ensure therapeutic
equivalence, and additional evidence for comparability of disposition and exposure-response
relationship of the active ingredient across test and referenced products may be necessary. The
extent of evidence needed to demonstrate comparable therapeutic performance in addition to BEwith the referenced product is potentially greatest for high risk products.
For medium and high risk drug products containing nanomaterials that are proposed to bebioequivalent to the referenced drug product, a single dose comparative ADME study canprovide additional assurance of similarity of disposition of the active ingredient with thereferenced product. However, ADME studies may not be able to detect discrete but clinicallysignificant differences between products in rate and extent of release of the active ingredient into
the target tissues. Single and multiple dose studies examining the PK and PD characteristics ofthe proposed product and the referenced product may be better suited because they allow an
exploration of the exposure-response relationship. Both therapeutic- and toxicity-related PD
biomarkers, ideally related to clinical outcomes, should be selected in these studies. Recognitionof a difference in the exposure-response relationship between the proposed drug productcontaining nanomaterials and the referenced product may be facilitated if the selected PD
biomarkers vary over the blood/plasma concentration range of interest and exhibit a reasonably
rapid onset and offset of the response.

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If PD biomarkers suitable for establishing comparative exposure-response relationships are notavailable, the development program of drug products containing nanomaterials may have toinclude comparative safety and effectiveness studies. Specific safety or effectiveness concerns
regarding the referenced drug product and its pharmacological class also may necessitate
additional comparative clinical safety and effectiveness data for drug products containing
nanomaterials. Clinical studies may be designed to demonstrate that the proposed drug productcontaining nanomaterials does not have decreased activity compared to the referenced product,
as decreased activity usually would preclude approval. Alternatively, a superiority design may
be used if the sponsor wishes to make a superiority claim over the referenced product. A study
employing a sequential test in which non-inferiority is tested first and superiority is tested second
may be a useful design if a sponsor believes its drug product containing nanomaterials provides
an efficacy advantage over the listed product. This study should be based on a pre-specified
non-inferiority margin that is scientifically justified and adequate to enable the detection ofclinically meaningful differences in effectiveness and safety between the proposed product andthe referenced product.
A sponsor may use endpoints that are different from those in the referenced product’s clinical
trials if they are scientifically justified. For example, response rate may be an appropriate
endpoint for a non-inferiority trial in the oncology setting where the referenced product wasapproved based on a progression-free survival endpoint. Certain endpoints that are effectively
PD biomarkers, as discussed above, also may be acceptable.
The sponsor of a proposed drug product containing nanomaterials may seek approval only forindications that have been previously approved for the referenced product, unless new clinical
trials to demonstrate safety and efficacy are conducted in the proposed new indication.
Furthermore, extrapolation to other indications for the listed product also will necessitate newcomparative clinical studies.
B.

505(j) Submissions

An applicant may seek approval of a generic product that references a drug product containing
nanomaterials by submitting an ANDA under section 505(j) of the FD&C Act. An ANDA
applicant must demonstrate, among other things, that the generic drug product is bioequivalent to
the reference listed drug (RLD) (section 505(j)(2)(A)(iv) of the FD&C Act). 30 In addition, an
ANDA must contain sufficient information to show that the proposed generic drug has the sameactive ingredient(s), previously approved conditions of use, route of administration, dosage form,
strength, and (with certain exceptions) labeling as the RLD (section 505(j)(2)(A) and (j)(4) of the
FD&C Act). Like all generic drug products, generic drug products containing nanomaterials
meet the following general criteria: (1) they are approved as safe and effective, (2) they arepharmaceutically equivalent, (3) they are bioequivalent, (4) they are adequately labeled, and (5)30Under the FD&C Act, “[a] drug shall be considered to be bioequivalent to a listed drug if . . . the rate and extent ofabsorption of the drug do not show a significant difference from the rate and extent of absorption of the listed drug
when administered at the same molar does of the therapeutic ingredient under similar experimental conditions ineither a single dose or multiple doses.” See section 505(j)(8)(B)(i); see also implementing regulations at 21 CFRpart 320.

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they are manufactured in compliance with CGMP regulations. 31 BE studies are conducted withthe goal of demonstrating the generic drug has the same rate and extent of absorption at thetarget site as the RLD (21 CFR 320.1(e) and (f), 320.21(b)(1)). Nanomaterials range from
simple nanocrystals, organic nanomaterials (e.g., liposome, polymeric nanoparticle) andinorganic nanomaterials (e.g., gold nanoparticles), to complex-structure integrated nanoparticles(e.g., core-shell, surface modified nanoparticles). Any critical structural change in the multiple
components of nanomaterial-based products can influence the bioequivalence, pharmacology,
and toxicology profiles. Due to the diversity of nanomaterial formulation, drug releasemechanisms, and unique bio-distribution, evidence of comparable PK parameters inblood/plasma in conventional BE studies alone may or may not be sufficient to establish BE of
the generic and the RLD depending on the route of administration and nanomaterials employed.
For orally-administered drug products containing nanomaterials that have relatively low risk, PK
studies in blood/plasma and bioequivalence criteria generally are considered sufficient todemonstrate BE between the generic and the RLD. ANDA applicants using for their generic druga nanocrystal similar to that used in the RLD can refer to FDA’s draft guidance for industry on
Bioequivalence Studies with Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA 32
for advice on BE study design. Generally, both fasted and fed BE studies are recommended todemonstrate BE of orally administered drug products.
ANDAs referencing oral drug products using nanotechnology to improve BA for poorly watersoluble drugs need not use that particular nanotechnology or any nanotechnology, but may use
alternative strategies to achieve the same BA enhancement. There are a number of effective
technologies that exist to improve drug BA, including the use of amorphous solid dispersions,introduction of surfactants or co-solvents, and others. If the ANDA applicant uses a different
type of nanomaterial than the RLD (e.g., nanocrystal versus nanomaterials other thannanocrystals) that may potentially affect nanoparticle distribution in the GI tract, additional
characterization and evidence supporting non-specific drug uptake by Peyer’s patch or other GI
tissues, should be provided.
For parenteral products containing nanomaterials, the applicant should demonstrate that thegeneric product contains the same active and inactive ingredients as the RLD (i.e., isqualitatively the same (Q1)) in the same concentration (i.e., is quantitatively the same (Q2)) as
the RLD. 33 In general, the generic applicant should conduct in vivo BE studies, demonstratecomparable size and distribution of nanomaterials based on population BE criteria, anddemonstrate sameness in a wide range of physicochemical properties.
There are significant challenges to demonstrating Q1 and Q2 sameness as well as BE between ageneric parenteral drug product containing nanomaterials and its RLD. Firstly, the active
ingredients of some nanomaterials are generally heterogeneous mixtures which may require
31

Orange Book, Preface, Section 1.2 (pg. vii).
When final, this guidance will represent the FDA’s current thinking on this topic.
33
Differences in preservatives, buffers, or antioxidants may be permitted provided that the applicant identifies andcharacterizes these differences and provides information demonstrating that the differences do not affect the safety
or efficacy profile of the proposed generic drug product. See 21 CFR 314.94(a)(9)(iii).
32

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considerable characterization to demonstrate drug substance sameness. Some critical excipientsfor the formation of nanomaterials are also complex. Secondly, the manufacturing processes forcertain nanomaterials are complicated and involve lengthy steps. Thirdly, after administration,
the drug substance often exists in multiple forms, e.g., free drug 34 or nanomaterial-associateddrug, both in systemic circulation and at the target site. Therefore, it is critical to identify themost therapeutically relevant moiety for establishing BE. Furthermore, drug levels in systemic
circulation may not always reflect drug concentration at the target site. As a result, in mostcases, evidence of comparable PK parameters in blood/plasma in conventional BE studies alone
may not be sufficient to satisfy the requirements for generic drug approval.
As for the most therapeutically relevant moiety for establishing BE, the ANDA applicant isadvised to provide concentration-time curves for all clinically relevant entities (e.g., free drug
and nanomaterial-associated drug) relating to the drug release from nanoparticles, in order toenable an accurate assessment of the PK of the generic product. The PK of both the free drug
and nanomaterial-associated drug in the blood/plasma needs to be equivalent between the genericand the RLD, based on adequate and validated bio-analytical methods.
For generic parenteral drug products containing nanomaterials, since comparable PK parametersin blood/plasma alone may not be sufficient, additional measures such as comparative
physicochemical testing would be needed to correlate the blood/plasma PK to its availability at
the site of action. These physicochemical characterizations include particle morphology, particle
size and distribution, surface property, free and nanomaterial-associated drug, and others. Thesein vitro characterizations should be conducted on at least three different batches of each of thegeneric and referenced drug products and analyzed by appropriate statistical methods (e.g.,
population equivalence for particle size distribution).
In general, an ANDA applicant is responsible for providing sufficient scientific evidence basedon a comprehensive in vivo PK evaluation and in vitro physicochemical characterization todemonstrate the equivalence between generic and referenced nanomaterials. In addition,
comprehensive characterization of the RLD and understanding of the fundamental chemistry
used to form the active ingredient is needed to demonstrate equivalence. For the active
ingredient, FDA considers an active ingredient in a generic drug product to be the same as that of
the RLD if it meets the same standards for identity. The standards are based on USP standards
or an evaluation of current data and other relevant scientific information, including
characteristics of the RLD and scientific experience and expertise. Therefore, comprehensive
characterizations of the RLD and understanding of the fundamental chemistry used to form theactive ingredient would be needed for FDA to make its evaluation to establish appropriate
standards. 35

34

As used in this guidance, free drug is drug not associated with a nanomaterial or nanomaterial carrier. Free drug
may have been released from a nanomaterial carrier or never associated with a nanomaterial or nanomaterial carrier.
Although not used in this sense in this guidance, in other contexts, “free drug” may refer to non-protein bound drugin the blood (PK).
35
See FDA’s draft guidance for industry Bioanalytical Method Validation. When final, this guidance will represent
the FDA’s current thinking on this topic.

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The potential multi-component structure of drug products containing nanomaterials allows great
flexibility of drug delivery designs. Due to the complexity and diversity of materials, structures,and functionalities of nanomaterials, the Office of Generic Drugs (OGD) currently examines
nanoparticle-based parenteral drug products and develops product-specific BE guidance on a
product-by-product basis. 36 A number of product-specific guidances, including BE
recommendations for doxorubicin hydrochloride liposomal injection, sodium ferric gluconate
colloidal complex, and others have been published.
C.

351(k) Submissions

The development of a biosimilar to a reference biological product containing nanomaterials
should follow current guidance on biosimilars. 37 The contribution of the nanomaterial to productsafety, purity, and potency would be assessed as part of the product development and thedemonstration of biosimilarity or interchangeability. Sponsors are encouraged to contact FDA
early during the development of biosimilars containing nanomaterials.
D.

Bioanalytical Methods

All clinically relevant entities, i.e., parent drug and major active metabolites, if possible, shouldbe measured in the appropriate biologic matrices after administration of products containing
nanomaterials. In general, total, free, and nanomaterial-associated drug should be measured
separately or indirectly derived. This may require separation of free and nanomaterial-associateddrug prior to detection or simultaneous analysis. The concentrations of free parent drug andmajor active metabolite(s) may be low. The use of validated, specific, and highly sensitive
methods is recommended.
E.

In Vitro Tests With Human Biomaterials

Stability and Biocompatibility: The impact of human plasma and blood on the stability ofnanomaterials intended for systemic activity and the biocompatibility of nanomaterial with bloodand serum should be examined.
Because of significant differences between products containing nanomaterials and otherproducts, the methods for the test procedures listed below may have to be appropriately adapted
to provide reliable results with products containing nanomaterials.
Plasma Protein Binding: Nanomaterials entering the blood circulation interact with multiple
plasma proteins in a process lasting over several hours, which ultimately results in the formationof a protein corona. The goal of this study, therefore, is to determine the major binding proteins
involved in the formation of the corona over time and the percentage of bound nanomaterial overthe incubation time.

36

See Product-Specific Recommendations for Generic Drug Development at
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm075207.htm.
37
See a sortable listing of Biosimilarity guidances athttps://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/guidances/ucm290967.htm.

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In Vitro Clearance and Metabolism: Phagocytes play a major role in the clearance ofsystemically administered nanomaterials. The uptake of nanomaterials may expose phagocytes
to high concentrations of the active component. Therefore, in vitro exposure of cultured humanphagocytes to nanomaterials may be useful in evaluating potential cytotoxicity. Small molecule
active ingredients released from carriers are metabolized primarily by Phase 1 and Phase 2
enzymes or eliminated unchanged in the urine. The interaction of active ingredients that arenanomaterials and intact nanomaterial carriers with enzymes is thought to be limited, but somedissociated monomers such as block copolymers, PEG, and lipids may affect the function ofcytochrome P450 enzymes and gastrointestinal transporters. Therefore, experimental evidence
supporting or rejecting this notion should be provided.
F.

Immunogenicity

There is a potential for nanomaterials to exert an immunogenic effect depending on a patient’s
immunologic status, prior history, route/dose/frequency of drug administration, and uniquecharacteristics of the administered nanomaterial. 38 It is recommended that applicants use a riskbased approach to evaluate and mitigate adverse immune responses that may be associated withadministration of products containing nanomaterials that could affect safety and efficacy. The
risks for immunogenicity will need to be assessed on a case-by-case basis and considered at theearliest stage of product development as well as throughout the remainder of the productlifecycle depending on the potential severity of immune responses and the likelihood of theiroccurrence. Immunogenicity risks should similarly be assessed prior to implementing changes tothe process and/or product (e.g., product and/or process optimization) depending on the extent ofsuch changes and the level of risk for invoking immune responses. For generalrecommendations regarding how to evaluate and mitigate risks associated with adverse immune
responses the applicants should consult FDA guidance for industry Immunogenicity Assessment
for Therapeutic Protein Products and the ICH guidance S8 Immunotoxicity Studies for Human
Pharmaceuticals for sample approaches. Immunogenicity risk assessments of biologicalproducts that have a non-biologic nanomaterial component should consider that the nanomaterial
component may possess adjuvant properties. Consequently, biological products with ananomaterial component may have different immunogenic characteristics compared to the
biologic alone that may warrant specific examination.

VII.

ENVIRONMENTAL IMPACT CONSIDERATIONSThe National Environmental Policy Act (NEPA) requires Federal agencies to assess theenvironmental impact of Agency actions and to ensure that the interested and affected public is
informed of environmental analyses. FDA requires applicants to submit an Environmental
Assessment (EA) or a claim of categorical exclusion when requesting Agency action on a drugor biologic application (21 CFR 25.15(a); see also, FDA’s guidance for industry Environmental
Assessment of Human Drug and Biologics Applications). In light of the current, evolving stateof scientific knowledge regarding the impact of nanomaterials in the environment, CDER and
CBER intend to use a case-by case-approach at this time to determine whether drug products that
contain nanomaterials qualify for an existing categorical exclusion or whether an EA is required.
38

See footnote 27.

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In accordance with FDA regulations, if an EA is submitted, CDER or CBER will evaluate theinformation contained in the EA to determine whether it is accurate and objective, whether the
proposed action may significantly affect the quality of the human environment, and whether an
Environmental Impact Statement (EIS) will be prepared. If significant effects requiring the
preparation of an EIS are identified, FDA will prepare an EIS for the action pursuant to its
procedures (21 CFR 25.15(b)). If significant effects requiring the preparation of an EIS are not
identified, resulting in a decision not to prepare an EIS, FDA will prepare a Finding of No
Significant Impact, in accordance with 21 CFR 25.41.
To assist the Agency in our decision-making and help avoid late cycle information requests, we
advise industry to notify the FDA early in the development process of their intent to either claim
a categorical exclusion or submit an EA. Information supporting the criteria for the selectedcategorical exclusion and a statement of “no extraordinary circumstances” (see 21 CFR 25.21)
should be provided. For example, the applicant could provide information demonstrating
negligible release of the nanomaterial into the environment (e.g., dosing, ADME, partitioning
and biodegradation data) or information demonstrating that the nanomaterial would not be
expected to produce toxicity in aquatic and terrestrial organisms at expected levels of exposure.
As needed, the Agency may request additional information to support a conclusion that approvalof the application would not significantly affect the quality of the human environment. If FDA
determines that extraordinary circumstances exist, the applicant will be required to submit an EA
that assesses the exposure, fate, and effects of the nanomaterial(s) in the environment. If FDA
determines that the proposed action may significantly affect the quality of the humanenvironment and, therefore, prepares an EIS, FDA may request additional information from theapplicant to assist in preparation of such an analysis. Impacts on the environment may occur atvarious stages of the product lifecycle, including manufacture, storage, patient use, and disposal.
FDA may provide additional guidance as needed and as our knowledge of and experience withnanomaterials increases.

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