INTERNATIONAL
`STANDARD
`
`ISO
`10993-1
`
`Fourth edition
`2009-10-15
`
`Biological evaluation of medical
`devices-
`Part 1:
`Evaluation and testing within a risk
`management process
`
`Evaluation biologique des dispositifs medicaux -
`
`Partie 1: Evaluation et essais au sein d'un process us de gestion
`du risque
`
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`
`Reference number
`ISO 10993-1:2009(E)
`
`© ISO 2009
`
`Novartis Exhibit 2181.001
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`ISO 10993-1:2009(E)
`
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` ISO 2009
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`© ISO 2009 – All rights reserved
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`

`ISO 10993-1:2009(E)
`
`Contents
`
`Page
`
`Foreword ............................................................................................................................................................iv
`Introduction........................................................................................................................................................vi
`1
`Scope......................................................................................................................................................1
`2
`Normative references............................................................................................................................1
`3
`Terms and definitions ...........................................................................................................................2
`4
`General principles applying to biological evaluation of medical devices.......................................3
`5
`Categorization of medical devices ......................................................................................................6
`5.1
`General ...................................................................................................................................................6
`5.2
`Categorization by nature of body contact ..........................................................................................6
`5.3
`Categorization by duration of contact.................................................................................................7
`6
`Biological evaluation process..............................................................................................................8
`6.1
`Material characterization ......................................................................................................................8
`6.2
`Biological evaluation tests ...................................................................................................................8
`7
`Interpretation of biological evaluation data and overall biological safety assessment ..............14
`Annex A (informative) Biological evaluation tests ........................................................................................15
`Annex B (informative) Guidance on the risk management process............................................................16
`Annex C (informative) Suggested procedure for literature review ..............................................................19
`Bibliography......................................................................................................................................................21
`
`
`© ISO 2009 – All rights reserved
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`iii
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`

`

`ISO 10993-1:2009(E)
`
`Foreword
`
`ISO (the International Organization for Standardization) is a worldwide federation of national standards bodies
`(ISO member bodies). The work of preparing International Standards is normally carried out through ISO
`technical committees. Each member body interested in a subject for which a technical committee has been
`established has the right to be represented on that committee. International organizations, governmental and
`non-governmental, in liaison with ISO, also take part in the work. ISO collaborates closely with the
`International Electrotechnical Commission (IEC) on all matters of electrotechnical standardization.
`
`International Standards are drafted in accordance with the rules given in the ISO/IEC Directives, Part 2.
`
`The main task of technical committees is to prepare International Standards. Draft International Standards
`adopted by the technical committees are circulated to the member bodies for voting. Publication as an
`International Standard requires approval by at least 75 % of the member bodies casting a vote.
`
`Attention is drawn to the possibility that some of the elements of this document may be the subject of patent
`rights. ISO shall not be held responsible for identifying any or all such patent rights.
`
`ISO 10993-1 was prepared by Technical Committee ISO/TC 194, Biological evaluation of medical devices.
`
`This fourth edition cancels and replaces the third edition (ISO 10993-1:2003), which has been technically
`revised.
`
`ISO 10993 consists of the following parts, under the general title Biological evaluation of medical devices:
`
`Part 1: Evaluation and testing within a risk management process
`
`Part 2: Animal welfare requirements
`
`Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity
`
`Part 4: Selection of tests for interactions with blood
`
`Part 5: Tests for in vitro cytotoxicity
`
`Part 6: Tests for local effects after implantation
`
`Part 7: Ethylene oxide sterilization residuals
`
`Part 9: Framework for identification and quantification of potential degradation products
`
`Part 10: Tests for irritation and skin sensitization
`
`Part 11: Tests for systemic toxicity
`
`Part 12: Sample preparation and reference materials
`
`Part 13: Identification and quantification of degradation products from polymeric medical devices
`
`Part 14: Identification and quantification of degradation products from ceramics
`
`Part 15: Identification and quantification of degradation products from metals and alloys
`
`© ISO 2009 – All rights reserved
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`iv
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`Novartis Exhibit 2181.004
`Regeneron v. Novartis, IPR2021-00816
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`

`

`ISO 10993-1:2009(E)
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`⎯
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`Part 16: Toxicokinetic study design for degradation products and leachables
`
`Part 17: Establishment of allowable limits for leachable substances
`
`Part 18: Chemical characterization of materials
`
`Part 19: Physico-chemical, morphological and topographical characterization of materials (Technical
`Specification)
`
`Part 20: Principles and methods
`Specification)
`
`for
`
`immunotoxicology
`
`testing of medical devices (Technical
`
`Future parts will deal with other relevant aspects of biological evaluation.
`
`© ISO 2009 – All rights reserved
`
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`
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`
`

`

`ISO 10993-1:2009(E)
`
`Introduction
`
`The primary aim of this part of ISO 10993 is the protection of humans from potential biological risks arising
`from the use of medical devices. It is compiled from numerous International and National Standards and
`Guidelines concerning the biological evaluation of medical devices. It is intended to be a guidance document
`for the biological evaluation of medical devices within a risk management process, as part of the overall
`evaluation and development of each device. This approach combines the review and evaluation of existing
`data from all sources with, where necessary, the selection and application of additional tests, thus enabling a
`full evaluation to be made of the biological responses to each medical device, relevant to its safety in use. It
`must be appreciated that the term “medical device” is wide-ranging and, at one extreme, consists of a single
`material, which may exist in more than one physical form, and at the other extreme, of a complex instrument
`or piece of apparatus, consisting of numerous components made of more than one material.
`
`ISO 10993 addresses the determination of the effects of medical devices on tissues, mostly in a general way,
`rather than in a specific device-type situation. Thus, for a complete biological safety evaluation, it classifies
`medical devices according to the nature and duration of their anticipated contact with human tissues when in
`use and indicates, in matrices, the biological data sets that are thought to be relevant in the consideration of
`each device category.
`
`The range of biological hazards is wide and complex. The tissue interaction with a constituent material alone
`cannot be considered in isolation from the overall device design. Thus, in designing a device, the choice of the
`best material with respect to its tissue interaction might result in a less functional device, tissue interaction
`being only one of a number of characteristics to be considered in making that choice. Where a material is
`intended to interact with tissue in order to perform its function, the biological evaluation needs to address this.
`
`Tissue interactions that are regarded as adverse, caused by a material in one application, might not be
`regarded as such in a different situation. Biological testing is based upon, among other things, in vitro and ex
`vivo test methods and upon animal models, so that the anticipated behaviour when a device is used in
`humans can be adjudged only with caution, as it cannot be unequivocally concluded that the same tissue
`reactions will also occur in this species. In addition, differences in the manner of response to the same
`material among individuals indicate that some patients can have adverse reactions, even to well-established
`materials.
`
`The role of this part of ISO 10993 is to serve as a framework in which to plan a biological evaluation which, as
`scientific knowledge advances our understanding of the basic mechanisms of tissue responses, minimizes the
`number and exposure of test animals by giving preference to chemical constituent testing and in vitro models,
`in situations where these methods yield equally relevant information to that obtained from in vivo models.
`
`It is not intended that ISO 10993 provide a rigid set of test methods, including pass/fail criteria, as this might
`result in either an unnecessary constraint on the development and use of novel medical devices, or a false
`sense of security in the general use of medical devices. Where a particular application warrants it, experts in
`the product or in the area of application concerned can choose to establish specific tests and criteria,
`described in a product-specific vertical standard.
`
`This part of ISO 10993 is intended for use by professionals, appropriately qualified by training and experience,
`who are able to interpret its requirements and judge the outcome of the evaluation for each medical device,
`taking into consideration all the factors relevant to the device, its intended use and the current knowledge of
`the medical device provided by review of the scientific literature and previous clinical experience.
`
`Annex A contains an informative table that is generally helpful in identifying biological data sets recommended
`in the evaluation of medical devices, according to their category of body contact and duration of clinical
`exposure. Annex B contains guidance for the application of the risk management process to medical devices
`which encompasses biological evaluation.
`
`
`
`vi
`
`
`© ISO 2009 – All rights reserved
`
`Novartis Exhibit 2181.006
`Regeneron v. Novartis, IPR2021-00816
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`

`

`INTERNATIONAL STANDARD
`
`
`ISO 10993-1:2009(E)
`
`Biological evaluation of medical devices —
`Part 1:
`Evaluation and testing within a risk management process
`
`1 Scope
`
`This part of ISO 10993 describes:
`
`⎯
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`⎯
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`⎯
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`⎯
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`⎯
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`⎯
`
`the general principles governing the biological evaluation of medical devices within a risk management
`process;
`
`the general categorization of devices based on the nature and duration of their contact with the body;
`
`the evaluation of existing relevant data from all sources;
`
`the identification of gaps in the available data set on the basis of a risk analysis;
`
`the identification of additional data sets necessary to analyse the biological safety of the medical device;
`
`the assessment of the biological safety of the medical device.
`
`This part of ISO 10993 does not cover testing of materials and devices that do not come into direct or indirect
`contact with the patient's body, nor does it cover biological hazards arising from any mechanical failure. Other
`parts of ISO 10993 cover specific tests, as indicated in the Foreword.
`
`2 Normative references
`
`The following documents are indispensable for the application of this document. For dated references, only
`the edition cited applies. For undated references, the latest edition of the referenced document (including any
`amendments) applies.
`
`ISO 10993-2, Biological evaluation of medical devices — Part 2: Animal welfare requirements
`
`ISO 10993-3, Biological evaluation of medical devices — Part 3: Tests for genotoxicity, carcinogenicity and
`reproductive toxicity
`
`ISO 10993-4, Biological evaluation of medical devices — Part 4: Selection of tests for interaction with blood
`
`ISO 10993-5, Biological evaluation of medical devices — Part 5: Tests for in vitro cytotoxicity
`
`ISO 10993-6, Biological evaluation of medical devices — Part 6: Tests for local effects after implantation
`
`ISO 10993-7, Biological evaluation of medical devices — Part 7: Ethylene oxide sterilization residuals
`
`ISO 10993-9, Biological evaluation of medical devices — Part 9: Framework for identification and
`quantification of potential degradation products
`
`ISO 10993-10, Biological evaluation of medical devices — Part 10: Tests for irritation and skin sensitization
`
`© ISO 2009 – All rights reserved
`
`1
`
`
`Novartis Exhibit 2181.007
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`ISO 10993-1:2009(E)
`
`ISO 10993-11, Biological evaluation of medical devices — Part 11: Tests for systemic toxicity
`
`ISO 10993-12, Biological evaluation of medical devices — Part 12: Sample preparation and reference
`materials
`
`ISO 10993-13, Biological evaluation of medical devices — Part 13: Identification and quantification of
`degradation products from polymeric medical devices
`
`ISO 10993-14, Biological evaluation of medical devices — Part 14: Identification and quantification of
`degradation products from ceramics
`
`ISO 10993-15, Biological evaluation of medical devices — Part 15: Identification and quantification of
`degradation products from metals and alloys
`
`ISO 10993-16, Biological evaluation of medical devices — Part 16: Toxicokinetic study design for degradation
`products and leachables
`
`ISO 10993-17, Biological evaluation of medical devices — Part 17: Establishment of allowable limits for
`leachable substances
`
`ISO 10993-18:2005, Biological evaluation of medical devices — Part 18: Chemical characterization of
`materials
`
`ISO/TS 10993-19, Biological evaluation of medical devices — Part 19: Physico-chemical, morphological and
`topographical characterization of materials
`
`ISO/TS 10993-20, Biological evaluation of medical devices — Part 20: Principles and methods for
`immunotoxicology testing of medical devices
`
`ISO 14971, Medical Devices — Application of risk management to medical devices
`
`3 Terms and definitions
`
`For the purposes of this document, the following terms and definitions apply.
`
`3.1
`medical device
`any instrument, apparatus, implement, machine, appliance, implant, in vitro reagent or calibrator, software,
`material or other similar or related article, intended by the manufacturer to be used, alone or in combination,
`for human beings for one or more of the specific purpose(s) of:
`⎯ diagnosis, prevention, monitoring, treatment or alleviation of disease,
`⎯ diagnosis, monitoring, treatment, alleviation of or compensation for an injury,
`⎯
`investigation, replacement, modification, or support of the anatomy or of a physiological process,
`⎯ supporting or sustaining life,
`⎯ control of conception,
`⎯ disinfection of medical devices,
`⎯ providing information for medical purposes by means of in vitro examination of specimens derived from
`the human body,
`
`and which does not achieve its primary intended action in or on the human body by pharmacological,
`immunological or metabolic means, but which may be assisted in its function by such means
`
`NOTE 1
`
`This definition has been developed by the Global Harmonization Task Force (GHTF).
`
`[ISO 13485:2003, definition 3.7]
`
`2
`
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`© ISO 2009 – All rights reserved
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`

`ISO 10993-1:2009(E)
`
`Products which might be considered to be medical devices in some jurisdictions but for which there is not yet
`NOTE 2
`a harmonized approach, are:
`
`1) aids for disabled/handicapped people;
`
`2) devices for the treatment/diagnosis of diseases and injuries in animals;
`
`3) accessories for medical devices (see Note 4);
`
`4) disinfection substances;
`
`5) devices incorporating animal and human tissues, which might meet the requirements of the above definition but
`are subject to different controls.
`
`Accessories intended specifically by manufacturers to be used together with a “parent” medical device to
`NOTE 3
`enable that medical device to achieve its intended purpose, should be subject to ISO 10993.
`
`NOTE 4 Medical devices are different from drugs/biologics, and their biological evaluation requires a different approach.
`
`NOTE 5 Medical devices can include dental devices.
`
`3.2
`material
`any synthetic or natural polymer, metal, alloy, ceramic or other non-viable substance, including tissue
`rendered non-viable, used as a medical device or any part thereof
`
`3.3
`final product
`medical device in its “as-used” state, as defined by the manufacturer's specification or labelling
`
`3.4
`chemical constituent
`any synthetic or natural substance that is used in a process for manufacturing materials and/or medical
`devices, such as additives (antioxidants, UV stabilizers, dyestuff, etc.), processing aids (solvents, lubricants,
`antifoaming agents, etc.)
`
`3.5
`data set
`information from a variety of sources necessary to characterize the biological response of a device
`
`4 General principles applying to biological evaluation of medical devices
`
`4.1 The biological evaluation of any material or medical device intended for use in humans shall form part
`of a structured biological evaluation programme within a risk management process in accordance with
`ISO 14971, as set out in Figure 1. Annex B provides guidance on this process. The biological evaluation shall
`be planned, carried out, and documented by knowledgeable and experienced professionals. See Annex C for
`how to perform a literature review of existing data.
`
`The risk management plan should identify aspects of the biological evaluation requiring specific technical
`competencies and shall identify the person(s) responsible for the biological safety evaluation.
`
`include documented,
`The evaluation programme shall
`advantages/disadvantages and relevance of:
`
`informed decisions
`
`that assess
`
`the
`
`a)
`
`the physical and chemical characteristics of the various candidate materials;
`
`NOTE
`reference.
`
`Where this information is already documented within the risk management for the device it can be included by
`
`© ISO 2009 – All rights reserved
`
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`
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`

`

`ISO 10993-1:2009(E)
`
`b) any history of clinical use or human exposure data;
`
`c) any existing toxicology and other biological safety data on product and component materials, breakdown
`products and metabolites;
`
`d)
`
`test procedures.
`
`Evaluation may include both a study of relevant preclinical and clinical experience and actual testing. Such an
`evaluation might result in the conclusion that no testing is needed if the material has a demonstrable safe
`history of use in a specified role and physical form that is equivalent to that of the device under design.
`
`4.2
`In the selection of materials to be used in device manufacture, the first consideration shall be fitness for
`purpose with regard to characteristics and properties of the material, which include chemical, toxicological,
`physical, electrical, morphological and mechanical properties.
`
`4.3 The following shall be taken into account for their relevance to the overall biological evaluation of the
`device:
`
`a)
`
`the material(s) of manufacture;
`
`b)
`
`intended additives, process contaminants and residues (see ISO 10993-7 for ethylene oxide residues);
`
`c)
`
`leachable substances (see ISO 10993-17);
`
`d) degradation products (see ISO 10993-9, for general principles and 10993-13, 10993-14 and 10993-15 for
`degradation products from polymers, ceramics and metals, respectively);
`
`e) other components and their interactions in the final product;
`
`f)
`
`the performance and characteristics of the final product;
`
`g) physical characteristics of the final product, including but not limited to, porosity, particle size, shape and
`surface morphology.
`
`Identification of material chemical constituents and consideration of chemical characterization
`(see ISO 10993-18) shall precede any biological testing (see Figure 1).
`
`Physical effects of the device shall be considered if they impact the biocompatibility (see ISO/TS 10993-19).
`
`For implanted devices, in addition to systemic effects, local effects should also be considered for risk
`evaluation.
`
`4.4 The choice of tests and the data required in a biological evaluation, and their interpretation, shall take
`into account the chemical composition of the materials, including the conditions of exposure as well as the
`nature, degree, frequency and duration of exposure of the medical device or its constituents to the body,
`enabling the categorization of devices to facilitate the selection of appropriate tests (see Clause 5). The rigour
`necessary in the biological evaluation is principally determined by the nature, degree, duration and frequency
`of the exposure and the hazards identified for the material.
`
`4.5 All known possible biological hazards shall be taken into account for every material and final product,
`but this does not imply that testing for all possible hazards will be necessary or practical (see Clauses 5 and 6).
`Test results cannot guarantee freedom from potential biological hazards, thus biological investigations shall be
`followed by careful observations for unexpected adverse reactions or events in humans during clinical use of
`the device.
`
`The range of possible biological hazards is wide and can include short-term effects such as acute toxicity,
`irritation to the skin, eye and mucosal surfaces, haemolysis and thrombogenicity, as well as long-term or
`specific toxic effects such as subchronic and chronic toxic effects, sensitization, allergy, genotoxicity,
`carcinogenicity (tumorigenicity) and effects on reproduction including teratogenicity.
`
`4
`
`
`© ISO 2009 – All rights reserved
`
`Novartis Exhibit 2181.0010
`Regeneron v. Novartis, IPR2021-00816
`
`

`

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`Novartis Exhibit 2181.0011
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`ISO 10993-1:2009(E)
`
`4.6 Selection of any in vitro or in vivo tests shall be based on end-use applications. All tests shall be
`conducted according to recognised current/valid best laboratory/quality practices, for example Good
`Laboratory Practice (GLP) or ISO/IEC 17025, where applicable, and the data shall be evaluated by competent,
`informed professionals.
`
`In vitro test methods, which are appropriately validated, reasonably and practically available, reliable and
`reproducible shall be considered for use in preference to in vivo tests. Whenever possible, in vitro screening
`shall be carried out before in vivo tests are commenced. Test data, complete to the extent that an independent
`analysis could be made, shall be retained.
`
`4.7 The materials or final product shall be re-evaluated if any of the following occurs:
`
`a) any change in the source or in the specification of the materials used in the manufacture of the product;
`
`b) any change in the formulation, processing, primary packaging or sterilization of the product;
`
`c) any change in the manufacturer's instructions or expectations concerning storage, e.g. changes in shelf
`life and/or transport;
`
`d) any change in the intended use of the product;
`
`e) any evidence that the product may produce adverse effects when used in humans.
`
`4.8 The biological evaluation shall take into account the nature and mobility of the chemical constituents in
`the materials used to manufacture the device and other information, other non-clinical tests, clinical studies,
`and post-market experience for an overall assessment.
`
`5 Categorization of medical devices
`
`5.1 General
`
`Medical devices shall be categorized according to the nature and duration of body contact as described in 5.2
`and 5.3. The categorization of medical devices facilitates identification of appropriate data sets (see Annex A).
`
`The evaluation of any device that does not fall into one of the categories described shall follow the general
`principles contained in this part of ISO 10993. Certain devices might fall into more than one category, in which
`case evaluation appropriate to each category shall be carried out.
`
`5.2 Categorization by nature of body contact
`
`5.2.1 Surface-contacting devices
`
`These include medical devices in contact with the following.
`
`a) Skin
`
`⎯ devices that contact intact skin surfaces only.
`
`EXAMPLES Electrodes, external prostheses, fixation tapes, compression bandages and monitors of various types.
`
`b) Mucosal membranes
`
`⎯ devices that contact intact mucosal membranes.
`
`EXAMPLES Contact lenses, urinary catheters, intravaginal and intra-intestinal devices (stomach tubes, sigmoidoscopes,
`colonoscopes, gastroscopes), endotracheal tubes, bronchoscopes, some dental prostheses and orthodontic devices.
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`6
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`© ISO 2009 – All rights reserved
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`Novartis Exhibit 2181.0012
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`ISO 10993-1:2009(E)
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`c) Breached or compromised surfaces
`
`⎯ devices that contact breached or otherwise compromised body surfaces.
`
`EXAMPLES Dressings or healing devices and occlusive patches, for ulcers, burns and granulation tissue.
`
`5.2.2 External communicating devices
`
`External communicating devices shall be categorized according to their contact with the following application
`sites:
`
`a) Blood path, indirect
`
`⎯ devices that contact the blood path at one point and serve as a conduit for entry into the vascular
`system.
`
`EXAMPLES Solution administration sets, extension sets, transfer sets and blood administration sets.
`
`b) Tissue/bone/dentin
`
`⎯ devices that contact tissue, bone or pulp/dentin systems.
`
`EXAMPLES Laparoscopes, arthroscopes, draining systems, dental cements, dental filling materials and skin staples.
`
`c) Circulating blood
`
`⎯ devices that contact circulating blood.
`
`Intravascular catheters, temporary pacemaker electrodes, oxygenators, extracorporal oxygenator tubing
`EXAMPLES
`and accessories, dialysers, dialysis tubing and accessories, haemoadsorbents and immunoadsorbents.
`
`5.2.3
`
`Implant devices
`
`Implant devices shall be categorized according to their contact with the following application sites:
`
`a) Tissue/bone
`
`⎯ devices principally contacting bone.
`
`EXAMPLES Orthopaedic pins, plates, replacement joints, bone prostheses, bone cements and intra-osseous devices.
`
`⎯ devices principally contacting tissue and tissue fluid.
`
`EXAMPLES Pacemakers, drug supply devices, neuromuscular sensors and simulators, replacement tendons, breast
`implants, artificial larynxes, subperiosteal implants, ligation clips and intra-uterine devices.
`
`b) Blood
`
`⎯ devices principally contacting blood.
`
`EXAMPLES Pacemaker electrodes, artificial arteriovenous fistulae, heart valves, vascular grafts, internal drug-delivery
`catheters and ventricular assist devices.
`
`5.3 Categorization by duration of contact
`
`Medical devices shall be categorized according to the anticipated duration of contact as follows.
`
`a) Limited exposure (A) – devices whose cumulative single, multiple or repeated use or contact is up to 24 h.
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`© ISO 2009 – All rights reserved
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`7
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`Novartis Exhibit 2181.0013
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`ISO 10993-1:2009(E)
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`b) Prolonged exposure (B) – devices whose cumulative single, multiple or repeated long-term use or contact
`is likely to exceed 24 h but not 30 d.
`
`c) Permanent contact (C) – devices whose cumulative single, multiple or repeated long-term use or contact
`exceeds 30 d.
`
`If a material or device can be placed in more than one duration category, the more rigorous testing and/or
`evaluation considerations shall apply. With multiple exposures to the device, the decision into which category
`a device is placed shall take into account the potential cumulative effect, bearing in mind the period of time
`over which these exposures occur. If a device is intended to change during its lifetime, as those that are
`polymerized and/or biodegraded in situ, separate evaluations shall be conducted for the different device states.
`For example, for a biodegradable glue intended to polymerize in situ, the different device states would include
`starting components, intermediate reaction products, the fully polymerized material and degradation products.
`
`6 Biological evaluation process
`
`6.1 Material characterization
`
`Material characterization is a crucial first step in the biological evaluation process. The extent of chemical
`characterization required depends on what pre-clinical and clinical safety and toxicological data exist, and on
`the nature and duration of body contact with the medical device; but, as a minimum, the characterization shall
`address the constituent chemicals of the device and possible residual process aids or additives used in its
`manufacture. Material characterization is described in ISO 10993-18 and ISO/TS 10993-19.
`
`Figure 1 indicates how the different steps in the chemical characterization process