Use of International Standard ISO
`10993-1, "Biological evaluation of
`medical devices - Part 1: Evaluation
`and testing within a risk management
`process"
`
`
`Guidance for Industry and Food and
`Drug Administration Staff
`
`
`
`Document issued on: September 4, 2020
`
`The draft of this document was issued on April 23, 2013.
`
`This document supersedes “Use of International Standard ISO 10993-1,
`"Biological evaluation of medical devices - Part 1: Evaluation and testing
`within a risk management process"” dated June 16, 2016.
`
`For questions about this document, contact the Office of Product Evaluation and Quality
`(OPEQ)/Clinical and Scientific Policy Staff at CDRH.Biocomp@fda.hhs.gov or (301)-796-5701 or
`CBER’s Office of Communication, Outreach and Development (OCOD) at 1-800-835-4709, 240-
`402-8010 or ocod@fda.hhs.gov.
`
`
`
`
`
`U.S. FOOD & DRUG
`
`ADMIN I STRATION
`
`
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Devices and Radiological Health
`Center for Biologics Evaluation and Research
`
`
`Novartis Exhibit 2183.001
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Preface
`
`
`
`Public Comment
`
`You may submit electronic comments and suggestions at any time for Agency consideration to
`https://www.regulations.gov. Submit written comments to the Dockets Management Staff, Food
`and Drug Administration, 5630 Fishers Lane, Room 1061, (HFA-305), Rockville, MD 20852.
`Identify all comments with the docket number FDA-2013-D-0350. Comments may not be acted
`upon by the Agency until the document is next revised or updated.
`
`Additional Copies
`
`CDRH
`Additional copies are available from the Internet. You may also send an e-mail request to
`CDRH-Guidance@fda.hhs.gov to receive a copy of the guidance. Please include the document
`number 1811-R1 and complete title of the guidance in the request.
`
`CBER
`Additional copies are available from the Center for Biologics Evaluation and Research (CBER),
`Office of Communication, Outreach, and Development (OCOD), 10903 New Hampshire Ave.,
`WO71, Room 3128, Silver Spring, MD 20903, or by calling 1-800-835-4709 or 240-402-8010,
`by email, ocod@fda.hhs.gov, or from the Internet at
`https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-
`biologics.
`
`
`
`
`Novartis Exhibit 2183.002
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`IV.
`
`V.
`
`VI.
`
`
`I.
`II.
`III.
`
`Table of Contents
`Introduction ...................................................................................................................................... 4
`Scope ................................................................................................................................................ 6
`Risk Management for Biocompatibility Evaluations ....................................................................... 9
`A.
`Risk Assessment of the Medical Device ............................................................................... 9
`B.
`Identification of Potential Risks .......................................................................................... 10
`C.
`Considering Available Information to Identify and Mitigate Risks .................................... 12
`D.
`Submission and Interpretation ............................................................................................ 16
`ISO 10993 - Part 1 and the FDA-Modified Matrix ........................................................................ 18
`A.
`Evaluation of Local and Systemic Risks ............................................................................. 19
`B.
`FDA Use of ISO 10993-1 ................................................................................................... 20
`C.
`The FDA-Modified Matrix ................................................................................................. 23
`D.
`Endpoint Assessment .......................................................................................................... 24
`General Biocompatibility Testing Considerations ......................................................................... 24
`A.
`Use of Medical Device in Final Finished Form or Representative Test Article ................. 25
`B.
`Testing of In Situ Polymerizing and/or Absorbable Materials ............................................ 25
`C.
`Biological Response Resulting from Device Mechanical Failure ...................................... 26
`D.
`Submicron or Nanotechnology Components ...................................................................... 27
`E.
`Test Article Preparation for Extract Testing ....................................................................... 28
`F.
`Inclusion of Multiple Components or Materials in a Single Test Article ........................... 30
`Test-Specific Considerations ......................................................................................................... 30
`A.
`Cytotoxicity ......................................................................................................................... 30
`B.
`Sensitization ........................................................................................................................ 31
`C.
`Hemocompatibility.............................................................................................................. 33
`D.
`Pyrogenicity ........................................................................................................................ 38
`Implantation ........................................................................................................................ 39
`E.
`F.
`Genotoxicity ........................................................................................................................ 40
`G.
`Carcinogenicity ................................................................................................................... 43
`H.
`Reproductive and Developmental Toxicity ........................................................................ 45
`I.
`Degradation Assessments ................................................................................................... 45
`Chemical Assessment .................................................................................................................... 46
`VII.
`VIII. Labeling Devices as “-Free” .......................................................................................................... 50
`Attachment A: Evaluation Endpoints for Consideration ........................................................................... 51
`Attachment B: Device Master Files for Biocompatibility Evaluations ....................................................... 55
`Attachment C: Summary Biocompatibility Documentation ....................................................................... 57
`Attachment D: Biocompatibility Evaluation Flow Chart ........................................................................... 59
`Attachment E: Contents of a Test Report ................................................................................................... 61
`Attachment F: Component and Device Documentation Examples ............................................................. 63
`A.
`Component Documentation ................................................................................................ 63
`B.
`Device Documentation ........................................................................................................ 63
`C.
`New Processing/Sterilization Changes ............................................................................... 64
`D.
`Formulation Changes .......................................................................................................... 65
`Attachment G: Glossary .............................................................................................................................. 66
`
`
`Novartis Exhibit 2183.003
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Contains Nonbinding Recommendations
`
`Use of International Standard ISO
`10993-1, "Biological evaluation of
`medical devices - Part 1: Evaluation
`and testing within a risk management
`process"
`
`Guidance for Industry and Food and
`Drug Administration Staff
`
`This guidance represents the current thinking of the Food and Drug Administration (FDA or
`Agency) on this topic. It does not establish any rights /or any person and is not binding on
`FDA or the public. You can use an alternative approach ifit satisfies the requirements of the
`applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff
`or Office responsible for this guidance as listed on the title page.
`
`I.
`Introduction
`FDA has developed this guidance document to assist industry in preparing Premarket
`Applications (PMAs), Humanitarian Device Exceptions (HDEs), Investigational Device
`Exemption (IDE) Applications, Premarket Notifications (5 10(k)s), and De Novo requests for
`medical devices that come into direct contact or indirect contact with the human body 1 in order
`to determine the potential for an unacceptable adverse biological response resulting from contact
`of the component materials of the device with the body. The purpose of this guidance is to
`provide further clarification and updated info1mation on the use of International Standard ISO
`10993-1, "Biological evaluation of medical devices - Pait 1: Evaluation and testing within a risk
`
`1 For the purposes of this document, the te1m "human body" refers to either patient tissues or the clinical
`practitioner. For example, masks or gloves intended for protective purposes by clinical practitioners should be
`assessed for biocompatibility. Similarly, medical devices such as implants or skin electrodes also should be
`assessed for biocompatibility.
`
`4
`
`Novartis Exhibit 2183.004
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`management process" to support applications to FDA. This guidance replaces Office of Device
`Evaluation (ODE) Blue Book Memorandum #G95-1 (1995), entitled “Use of International
`Standard ISO-10993, ‘Biological Evaluation of Medical Devices - Part 1: Evaluation and
`Testing.’” This guidance document also incorporates several new considerations, including the
`use of risk-based approaches to determine if biocompatibility testing is needed, chemical
`assessment recommendations, and recommendations for biocompatibility test article preparation
`for devices with submicron or nanotechnology components and for devices made from in situ
`polymerizing and/or absorbable materials, which were not previously discussed in G95-1.
`
`When assessing new devices, the sponsor should specifically state if the device does not have
`any direct or indirect tissue contact,2 and no further biocompatibility information would be
`needed.
`
`When assessing device modifications, the sponsor should specifically state if the modification
`does not result in a change to any direct or indirect tissue-contacting components, and no further
`biocompatibility information would typically be needed. However, if the change could affect
`other parts of the device with direct or indirect contact that were not changed, a biocompatibility
`evaluation should be conducted to assess the potential impact of the change. For example, if a
`new non-contact internal component is added, but it requires the application of heat in order to
`join to another component that has patient contact, the patient-contacting component may be
`impacted by the application of heat such that biocompatibility could be impacted, and should be
`assessed.
`
`For the current edition of the FDA-recognized consensus standard(s) referenced in this
`document, see the FDA Recognized Consensus Standards Database.3
`
`Throughout this guidance document, the terms “we,” “us,” and “our” refer to FDA staff. “You”
`and “your” refers to the sponsor.
`
`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.
`
`
`2 For non-contact devices, there is no direct or indirect contact with the body (e.g., stand alone software), so it would
`be sufficient for the biocompatibility evaluation to confirm that there are no direct or indirect tissue contacting
`components, and no further biocompatibility information is needed. However, for devices with transient contact,
`assessment of biocompatibility risk should be conducted to determine if testing is needed.
`3 Available at https://www.accessdata fda.gov/scripts/cdrh/cfdocs/cfStandards/search.cfm.
`
`Novartis Exhibit 2183.005
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`II. Scope
`The scope of this document and accompanying attachments is limited to the biological
`evaluation of sterile and non-sterile medical devices that come into direct or indirect contact
`with the human body. This document specifically covers the use of ISO 10993-1 but also is
`relevant to other biocompatibility standards (e.g., other parts of the ISO4 10993 series of
`standards, ASTM,5 ICH,6 OECD,7 USP8).
`
`This document discusses the following topics:
`
`
`• use of risk assessments for biocompatibility evaluations for a proposed medical device;
`
`• use of ISO 10993-1 and the FDA-modified matrix (Attachment A) to determine the
`relevant biocompatibility endpoints for an evaluation;
`
`• general biocompatibility testing considerations, including test article preparation;
`
`• specific considerations for the following testing: cytotoxicity, sensitization,
`hemocompatibility, pyrogenicity, implantation, genotoxicity, carcinogenicity,
`reproductive and developmental toxicity, and degradation assessments;
`
`• chemical assessment recommendations;9 and
`
`
`
`
`
`
`
`
`
`• considerations for labeling devices as “-free.”
`
`
`In addition, this guidance includes the following attachments that are intended to serve as
`resources:
`
`
`• Attachment B: Device Master Files (MAFs) for Biocompatibility Evaluations, which
`includes information that we recommend including in an MAF;
`
`4 ISO stands for International Organization for Standardization, an international standards development
`organization. See http://www.iso.org/iso/home.html for more information.
`5 ASTM stands for American Society for Testing and Materials, an international standards development
`organization. See http://www.astm.org/ABOUT/overview.html for more information.
`6 ICH stands for International Conference on Harmonisation, an international standards development organization.
`See http://www.ich.org/about/vision.html for more information.
`7 OECD stands for Organisation for Economic Co-operation and Development, an international standards
`development organization. See http://www.oecd.org/ for more information.
`8 USP stands for U.S. Pharmacopeial Convention, a United States standards development organization. See
`http://www.usp.org/about-usp for more information.
`9 All issues specific to the evaluation of color additives in medical devices included in the draft version of this
`guidance were removed, and the intent is for these items to be addressed in a separate guidance document.
`
`Novartis Exhibit 2183.006
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`• Attachment C: Summary Biocompatibility Documentation, which includes an example
`table that we recommend using to summarize the biocompatibility information used to
`support a submission;
`
`• Attachment D: Biocompatibility Evaluation Flow Chart, which illustrates how to
`proceed with a biocompatibility evaluation;
`
`• Attachment E: Content of a Biocompatibility Test Report, which includes the
`recommended contents of a test report;
`
`• Attachment F: Component and Device Documentation Examples, which outlines
`example documentation language that we recommend using when comparing the
`composition of a test article to the composition of a finished medical device or in
`comparing the composition of a previously legally US-marketed device to the
`composition of a current device; and
`
`
`
`
`
`
`
`• Attachment G: Glossary, which includes terms and definitions used in this guidance.
`
`
`If there are other FDA-recognized consensus standards10 that address biocompatibility issues for
`particular types of devices (e.g., ISO 7405 “Dentistry – Evaluation of biocompatibility of
`medical devices used in dentistry”), the recommendations in the more device-specific standard
`should be followed. In some cases, such as for dental devices, the biocompatibility
`recommendations in the device-specific standard should be used instead of the recommendations
`outlined in ISO 10993-1. In contrast, some device-specific guidances include recommendations
`regarding biocompatibility evaluations, that should be considered in conjunction with ISO
`10993-1. For example, the FDA guidance “Content of Premarket Notifications for Conventional
`and High Permeability Hemodialyzers”11 specifies that subcomponent testing is recommended
`due to the high surface area of the membrane component of a hemodialyzer, and testing of the
`complete device is only recommended if “the extraction conditions (i.e., volume of solvent used
`per surface area of test article) are more rigorous than those recommended in ISO 10993.” In
`this case, if biocompatibility testing of a hemodialyzer is conducted on the final device, FDA
`recommends that the hemodialyzer be filled to capacity with the solvent, resulting in a much
`higher surface area to extract volume ratio, as compared to recommendations from ISO 10993-12
`“Biological evaluation of medical devices – Part 12: Sample preparation and reference
`
`10 Refer to FDA’s “Appropriate Use of Voluntary Consensus Standards in Premarket Submissions for Medical
`Devices: Guidance for Industry and Food and Drug Administration Staff,” available at
`https://www.fda.gov/regulatory-information/search-fda-guidance-documents/appropriate-use-voluntary-consensus-
`standards-premarket-submissions-medical-devices for information regarding the recognition and use of national and
`international consensus standards during the evaluation of premarket submissions for medical devices.
`11 Available at https://www fda.gov/medical-devices/guidance-documents-medical-devices-and-radiation-emitting-
`products/content-premarket-notifications-conventional-and-high-permeability-hemodialyzers-guidance-industry
`
`Novartis Exhibit 2183.007
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`materials.” However, if non-membrane components are tested separately, then use of ISO
`10993-12 recommendations for test article preparation would apply.
`
`Note that if your product is a combination product with a device constituent part,12 the general
`principles of this guidance would apply, although additional or modified testing may13 be
`needed. For example, sample preparation of biologic-device combination products may be
`dependent on the type of product and the endpoint being assessed, and such detailed guidance
`specific to biocompatibility evaluation of combination products are not within the scope of this
`document. As such, we encourage you to discuss combination products with the appropriate
`Center and review division who will initiate proper consultation on combination product-specific
`biocompatibility concerns as appropriate.
`
`We also recognize that an ISO standard is a document that undergoes periodic review and is
`subject to revision. Through the FDA standards recognition process, we provide information
`regarding the extent of recognition of the ISO 10993 series of standards and other
`biocompatibility standards through Supplemental Information Sheets published on the FDA
`website.14 FDA recommends that complete test reports be provided for all tests performed
`because the ISO 10993 series of standards include general methods with multiple options, and in
`some cases do not include acceptance criteria or address assessment of results.15 Therefore,
`when a declaration of conformity is submitted for an FDA-recognized standard in the ISO 10993
`series, a copy of the supplemental information used to support the declaration (e.g., a copy of the
`study test report as described in Attachment E) should also be provided.16 FDA will make
`updates to this guidance document as appropriate, should future revisions to ISO 10993-1 or
`other FDA recognized biocompatibility standards result in significant changes to the
`recommendations in this document.
`
`
`12 Please refer to 21 CFR 3.2(e) for the definition of a combination product.
`13 The term “may” is used here and throughout the document to indicate that the final determination on whether
`additional information should be provided will depend on the specifics of the final device under consideration.
`14 See FDA’s Database on Recognized Consensus Standards and input “10993-1” for the Supplemental Information
`Sheet.
`15 In the case of Abbreviated 510(k)s, a summary of the methods often is needed to ensure that the test was
`conducted in the same way as for a predicate device, and that the same evaluation criteria were used. If it is easier
`for the sponsor to submit a copy of the test report, which is not required by FDA, this would be acceptable. For
`Special 510(k)s, refer to the guidance “The Special 510(k) Program,” available at https://www fda.gov/regulatory-
`information/search-fda-guidance-documents/special-510k-program, for more information about FDA’s
`recommended biocompatibility information that should be included.
`16 Refer to FDA’s “Appropriate Use of Voluntary Consensus Standards in Premarket Submissions for Medical
`Devices: Guidance for Industry and Food and Drug Administration Staff” for information regarding the recognition
`and use of national and international consensus standards, including declarations of conformity to these standards,
`during the evaluation of premarket submissions for medical devices.
`
`Novartis Exhibit 2183.008
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Sponsors are advised to initiate discussions with the appropriate Center and review division prior
`to the initiation of long-term testing of any new device to ensure that, if testing is needed, the
`proper testing will be conducted.
`
`III. Risk Management for Biocompatibility Evaluations
`As stated in ISO 10993-1, the biological evaluation of a medical device (or a material component
`of such) should be conducted within the framework of a risk management process. Such a
`process should generally begin with assessment of the device, including the material
`components, the manufacturing processes, the clinical use of the device including the intended
`anatomical location, and the frequency and duration of exposure. Considering this information,
`the potential risks from a biocompatibility perspective should be identified. Such risks might
`include chemical toxicity, unacceptable biological response to physical characteristics of the
`device, and aspects of manufacturing and processing that could alter the physicochemical
`characteristics of the device, which could lead to changes in the biocompatibility response. Once
`the risks have been identified, the sponsor should assess what information is already available
`regarding those risks and identify the knowledge gaps that remain. Considering the potential
`biological impact, a plan should be developed to address the knowledge gaps either by
`biocompatibility testing or other evaluations that appropriately address the risks. The
`interpretation of the overall biocompatibility evaluation should be considered in the appropriate
`benefit-risk context.
`
`A. Risk Assessment of the Medical Device
`The risk assessment should evaluate the final finished device. The Agency makes a
`clearance or approval decision for a medical device as it is supplied in its final finished
`form. The Agency does not clear or approve individual materials that are used in the
`fabrication of medical devices. Therefore, the risk assessment should evaluate not only
`the materials used in the device, but also the processing of the materials, the
`manufacturing methods (including the sterilization process), and any residuals from
`manufacturing aids used during the process.
`
`The risk assessment should also consider the proposed clinical use of the device,
`including the anatomical location, duration of exposure, and intended use population.
`For example, for pediatric patients with a limited life expectancy, the tolerance for risk
`associated with a permanently implanted medical device may be higher than the tolerance
`for risk from the same device in an otherwise healthy pediatric population. The potential
`exposure duration should also consider which material components of the device have
`direct or indirect contact with tissue, and whether exposure would be a one-time
`exposure, a constant exposure over time, or an intermittent exposure over time that could
`have a cumulative effect. For example, pacemaker pulse generators commonly contain
`internal electronic components made from chemicals that could be toxic to the body, but
`
`Novartis Exhibit 2183.009
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
`appropriate bench testing can demonstrate that the pulse generator is hermetically sealed
`and will limit exposure of those chemicals to the surrounding tissues.
`B. Identification of Potential Risks
`An assessment of potential biocompatibility risk should include not only chemical
`toxicity, but also physical characteristics that might contribute to an unwanted tissue
`response. These characteristics can include surface properties, forces on surrounding
`tissue (e.g., mechanical, thermal, electromagnetic), geometry, and presence of
`particulates, among others. In addition, changes in manufacturing and processing
`parameters can also have an impact on biocompatibility. For example, the original
`processing for an implanted device might include placing the device in an acid bath to
`facilitate passivation of the implant surface. If this passivation process is changed to
`eliminate the acid bath in favor of a different method of passivating the surface, removal
`of the acid bath might unintentionally lead to a smaller reduction in pyrogenic material,
`which could result in pyrogenic reactions (fever) following implantation of the device.
`Another common change that might impact biocompatibility is a change in resin supplier.
`For example, if the new resin supplier does not remove all processing solvents (some of
`which may be known toxic compounds, such as formaldehyde), the final manufactured
`device could cause unexpected toxicities (e.g., cytotoxicity, irritation, sensitization,
`genotoxicity) that were not seen with devices manufactured from the original resin.
`
`Sources of information on potential biocompatibility risks can include, but are not limited
`to, a manufacturer’s previous experience with the same material(s), preferably in the
`same or similar anatomical location; reported experience from other manufacturers using
`the same material in the same or similar anatomical location; information provided by the
`material supplier (e.g., in a master file,17 see Attachment B); chemical or surface analysis
`of the device in its final finished form; and the published literature. In certain situations,
`clinical experience, such as postmarket surveillance information, may be informative.
`For example, for a limited duration, skin-contacting device, patient experience that
`includes information on potential for irritation or sensitization can be useful to the risk
`assessment.
`
`When leveraging data from experience with a particular device for a new device
`submission to FDA, it is important to understand how the tested device compares to the
`device under consideration. In general, the more similar the tested device and device
`under consideration are, including their intended use, the more applicable the risk
`information is likely to be. For example, for a vascular catheter comprised of a certain
`polymer, citing experience with the same polymer in a blood-contacting device will be
`
`17 Additional Information regarding master files for devices is available online at: https://www.fda.gov/medical-
`devices/premarket-approval-pma/master-files.
`
`Novartis Exhibit 2183.0010
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`more applicable than experience with a similar polymer in a device that only contacts
`mucosal membranes. Similarly, experience with device components made using the
`same formulation and processing (e.g., for devices within a product family) will be more
`applicable than experience with device components made by a different manufacturer
`where the formulation and processing are unknown.
`
` A
`
` A
`
` master file for a material, device component, and/or device may be useful if it includes
`information on recommended processing of the material or component and any biological
`testing already performed (see Attachment B). A master file should also contain a risk
`assessment provided by the supplier that includes a discussion of the chemical
`formulation and structure of the material or component and information on how to
`evaluate a device made from that material.
`
`In certain situations, a sponsor may propose to use a material that has known toxicities
`but where the material could be acceptable for the end use. In this case, the risk
`assessment should include consideration of the intended use population that will use (e.g.,
`protective mask for clinician) or be treated with the device and a discussion of potential
`benefits of using the chosen material as well as potential mitigations that have been
`considered (e.g., hermetically sealing).
`
` chemical analysis of the materials used in a device in its final finished form can be
`informative. Chemical analysis can be particularly helpful to demonstrate that chemical
`toxicity testing from a previously cleared or approved medical device is relevant to a
`device under review by the Agency. For example, in some circumstances, a chemical
`analysis can demonstrate that the extractables and leachables in a biocompatibility extract
`have not changed, eliminating the need for additional biocompatibility testing using that
`type of solvent. In addition, chemical analyses can be used to assess the toxicological
`risk of the chemicals that elute from devices. For example, chemical analysis using
`exhaustive extraction techniques (per ISO 10993-12) can also be helpful to evaluate long-
`term toxicity endpoints such as potential carcinogens. Extraction techniques could also
`be used to identify intermediate and final breakdown products in a material that is either
`synthesized in vivo (e.g., in situ polymerizing materials) or intended to be absorbable
`(e.g., degradable materials). However, chemical analysis is usually insufficient to
`identify all of the risks of the device in its final finished form, because it will not consider
`aspects of the finished device such as surface properties (e.g., rough versus polished
`surface) or device geometry that could affect the biological response in certain scenarios
`(e.g., thrombogenicity, implantation). In addition, the outcomes of chemical analyses are
`often sensitive to the parameters of the test. Extraction solvents should be selected to
`optimize compatibility with the device materials and provide information on the types of
`chemicals that are likely to be extracted in clinical use. Solvents that swell the polymer,
`cause the polymer to degrade or dissolve, or interfere with detection of chemicals should
`be used with caution.
`
`Novartis Exhibit 2183.0011
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`Finally, there may be potential hazards that are not addressed by available information.
`In certain cases, such as the addition of a new chemical to a standard formulation,
`individual toxicity information for the added chemical and starting material may be
`insufficient due to the potential for chemical interactions between the material and added
`chemical. Thus, the risk assessment should consider what is known about the additional
`material, the base material, and potential chemical interactions between the two.
`
`C. Considering Available Information to Identify and Mitigate
`Risks
`In order to reduce unnecessary testing, including animal testing,18 FDA recommends that
`sponsors consider all available relevant inform