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`
`INTERNATIONAL
`STANDARD
`
`ISO
`11137-2
`
`First edition
`2006-04-15
`
`Corrected version
`2006-08-01
`
`Sterilization of health care products -
`Radiation -
`Part 2:
`Establishing the sterilization dose
`
`Irradiation -
`Sterilisation des produits de sante -
`Partie 2: Etablissement de la dose sterilisante
`
`Reference number
`ISO 11137-22006(E)
`
`© 1SO2006
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`ISO 11137-2:2006(E)
`
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`© ISO 2006
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`
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`ISO 11137-2:2006(E)
`
`Contents
`
`Page
`
`4.1
`4.2
`4.3
`
`4.4
`4.5
`
`5
`5.1
`5.2
`5.3
`5.4
`5.5
`6
`7
`7.1
`7.2
`
`7.3
`
`7.4
`
`Foreword............................................................................................................................................................. v
`Introduction ....................................................................................................................................................... vi
`1
`Scope ......................................................................................................................................................1
`2
`Normative references ............................................................................................................................1
`3
`Abbreviations, terms and definitions ..................................................................................................1
`3.1
`Abbreviations .........................................................................................................................................1
`3.2
`Terms ......................................................................................................................................................3
`4
`Definition and maintenance of product families for dose setting, dose substantiation and
`sterilization dose auditing ....................................................................................................................4
`General....................................................................................................................................................4
`Defining product families......................................................................................................................4
`Designation of product to represent a product family for performance of a verification
`dose experiment or sterilization dose audit .......................................................................................5
`Maintaining product families ................................................................................................................6
`Effect of failure of establishment of sterilization dose or of a sterilization dose audit on a
`product family ........................................................................................................................................7
`Selection and testing of product for establishing and verifying the sterilization dose .................7
`Nature of product...................................................................................................................................7
`Sample item portion (SIP) .....................................................................................................................8
`Manner of sampling ...............................................................................................................................8
`Microbiological testing..........................................................................................................................9
`Irradiation ...............................................................................................................................................9
`Methods of dose establishment ...........................................................................................................9
`Method 1: dose setting using bioburden information .....................................................................10
`Rationale...............................................................................................................................................10
`Procedure for Method 1 for product with an average bioburden W 1,0 for multiple
`production batches..............................................................................................................................11
`Procedure for Method 1 for product with an average bioburden W 1,0 for a single
`production batch..................................................................................................................................16
`Procedure for Method 1 for product with an average bioburden in the range 0,1 to 0,9 for
`multiple or single production batches...............................................................................................18
`Method 2: Dose setting using fraction positive information from incremental dosing to
`determine an extrapolation factor......................................................................................................18
`Rationale...............................................................................................................................................18
`Procedure for Method 2A....................................................................................................................19
`Procedure for Method 2B....................................................................................................................22
`Method VDmax — Substantiation of 25 kGy or 15 kGy as the sterilization dose...........................25
`Rationale...............................................................................................................................................25
`25 for multiple production batches ...................................................26
`Procedure for Method VDmax
`25 for a single production batch .......................................................29
`Procedure for Method VDmax
`15 for multiple production batches ...................................................30
`Procedure for Method VDmax
`15 for a single production batch .......................................................33
`Procedure for Method VDmax
`Auditing sterilization dose..................................................................................................................34
`Purpose and frequency.......................................................................................................................34
`
`8
`
`8.1
`8.2
`8.3
`9
`9.1
`9.2
`9.3
`9.4
`9.5
`
`10
`10.1
`
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`
`10.2
`10.3
`
`Procedure for auditing a sterilization dose established using Method 1 or Method 2 ................ 35
`Procedure for auditing a sterilization dose substantiated using VDmax ....................................... 37
`Worked examples................................................................................................................................ 41
`11
`11.1 Worked examples for Method 1......................................................................................................... 41
`11.2 Worked examples for Method 2......................................................................................................... 44
`11.3 Worked examples for Method VDmax ................................................................................................ 53
`11.4 Worked example of a sterilization dose audit for a dose established using Method 1, the
`findings from which necessitated augmentation of the sterilization dose ................................... 55
`11.5 Worked example of a sterilization dose audit for a dose established using Method 2A, the
`findings from which necessitated augmentation of the sterilization dose ................................... 56
`11.6 Worked example of a sterilization dose audit for a sterilization dose substantiated using
`25................................................................................................................................... 58
`Method VDmax
`Bibliography ..................................................................................................................................................... 59
`
`
`iv
`
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`ISO 11137-2:2006(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 11137-2 was prepared by Technical Committee ISO/TC 198, Sterilization of health care products.
`
`This first edition, together with ISO 11137-1 and ISO 11137-3, cancels and replaces ISO 11137:1995.
`
`ISO 11137 consists of the following parts, under the general title Sterilization of health care products —
`Radiation:
`
` Part 1: Requirements for development, validation and routine control of a sterilization process for medical
`devices
`
` Part 2: Establishing the sterilization dose
`
` Part 3: Guidance on dosimetric aspects
`
`This corrected version of ISO 11137-2:2006 incorporates changes in the following subclauses:
`
`4.3.1.3, 5.1.1, 7.1, 7.2.3.2, 7.3.4.2, 7.4, 8.1, 8.2.3.1.1, 8.2.3.3.1, 8.2.6.3, 8.3.3.3.1, 8.3.6.3, 9.2.3.2,
`9.2.4, 9.3.4.2, 9.3.5, 9.3.6.2, 9.4.1.2, 9.4.3.2, 9.4.5.2, 9.5.2.2, 9.5.4.2, 9.5.6.2, 10.2.5.2, 10.2.6.1,
`10.3.3.2, 10.3.6.4.2, 11.3.
`
`
`
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`ISO 11137-2:2006(E)
`
`Introduction
`
`This part of ISO 11137 describes methods that may be used to establish the sterilization dose in accordance
`with one of the two approaches specified in 8.2 of ISO 11137-1:2006. The methods used in these approaches
`are:
`
`a) dose setting to obtain a product-specific dose;
`
`b) dose substantiation to verify a preselected dose of 25 kGy or 15 kGy.
`
`The basis of the dose setting methods described in this part of ISO 11137 (Methods 1 and 2) owe much to the
`ideas first propounded by Tallentire (Tallentire, 1973 [17]; Tallentire, Dwyer and Ley, 1971 [18]; Tallentire and
`Khan, 1978 [19]). Subsequently, standardized protocols were developed (Davis et al., 1981 [8]; Davis,
`Strawderman and Whitby, 1984 [9]) which formed the basis of the dose setting methods detailed in the AAMI
`Recommended Practice for Sterilization by Gamma Radiation (AAMI 1984, 1991 [4], [6]).
`
`Methods 1 and 2 and the associated sterilization dose audit procedures use data derived from the inactivation
`of the microbial population in its natural state on product. The methods are based on a probability model for
`the inactivation of microbial populations. The probability model, as applied to bioburden made up of a mixture
`of various microbial species, assumes that each such species has its own unique D10 value. In the model, the
`probability that an item will possess a surviving microorganism after exposure to a given dose of radiation is
`defined in terms of the initial number of microorganisms on the item prior to irradiation and the D10 values of
`the microorganisms. The methods involve performance of tests of sterility on product items that have received
`doses of radiation lower than the sterilization dose. The outcome of these tests is used to predict the dose
`needed to achieve a predetermined sterility assurance level, SAL.
`
`Methods 1 and 2 may also be used to substantiate 25 kGy if, on performing a dose setting exercise, the
`derived sterilization dose for an SAL of 10–6 is u 25 kGy. The basis of the method devised specifically for
`substantiation of 25 kGy, Method VDmax, was put forward by Kowalski and Tallentire (1999) [14]. Subsequent
`evaluations involving computational techniques demonstrated that the underlying principles were soundly
`based (Kowalski, Aoshuang and Tallentire, 2000) [13] and field trials confirmed that Method VDmax is effective
`in substantiating 25 kGy for a wide variety of medical devices manufactured and assembled in different ways
`(Kowalski et al., 2002) [16].
`
`A standardized procedure for the use of VDmax for substantiation of a sterilization dose of 25 kGy has been
`published in the AAMI Technical Information Report Sterilization of health care products — Radiation
`sterilization — Substantiation of 25 kGy as a sterilization dose — Method VDmax (AAMI TIR27:2001) [5], a text
`on which the method described herein is largely based. Method VDmax is founded on dose setting Method 1
`and, as such, it possesses the high level of conservativeness characteristic of Method 1. In a similar manner
`to the dose setting methods, it involves performance of tests of sterility on product items that have received a
`dose of radiation lower than the sterilization dose. The outcomes of these tests are used to substantiate that
`25 kGy achieves an SAL of 10–6.
`
`To link the use of VDmax for the substantiation of a particular preselected sterilization dose, the numerical
`value of the latter, expressed in kGy, is included as a superscript to the VDmax symbol. Thus, for
`25.
`substantiation of a sterilization dose of 25 kGy the method is designated VDmax
`
`15 is based on the same principles as Method VDmax
`25 described above. The test procedure is
`Method VDmax
`25, but VDmax
`15 is limited to product with average bioburden u 1,5. The outcomes
`the same as Method VDmax
`of these tests are used to substantiate that 15 kGy achieves a sterility assurance level of 10–6.
`
`This part of ISO 11137 also describes methods that may be used to carry out sterilization dose audits in
`accordance with ISO 11137-1:2006, Clause 12. Following establishment of the sterilization dose, sterilization
`dose audits are performed routinely to confirm that the sterilization dose continues to achieve the desired SAL.
`
`vi
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`INTERNATIONAL STANDARD
`
`ISO 11137-2:2006(E)
`
`
`
`Sterilization of health care products — Radiation —
`
`Part 2:
`Establishing the sterilization dose
`
`1 Scope
`
`This part of ISO 11137 specifies methods of determining the minimum dose needed to achieve a specified
`requirement for sterility and methods to substantiate the use of 25 kGy or 15 kGy as the sterilization dose to
`achieve a sterility assurance level, SAL, of 10–6. This part of ISO 11137 also specifies methods of dose
`auditing in order to demonstrate the continued effectiveness of the sterilization dose.
`
`This part of ISO 11137 defines product families for dose establishment and dose auditing.
`
`2 Normative references
`
`The following referenced 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 11137-1:2006, Sterilization of health care products — Radiation — Part 1: Requirements for the
`development, validation and routine control of a sterilization process for medical devices
`
`ISO 11737-1, Sterilization of medical devices — Microbiological methods — Part 1: Determination of the
`population of microorganisms on product
`
`ISO 11737-2, Sterilization of medical devices — Microbiological methods — Part 2: Test of sterility performed
`in the validation of a sterilization process
`
`ISO 13485, Medical devices — Quality management systems — Requirements for regulatory purposes
`
`3 Abbreviations, terms and definitions
`
`For purposes of this document, the terms and definitions given in ISO 11137-1 and the following apply.
`
`3.1 Abbreviations
`
`3.1.1
`A
`dose to adjust the median ffp dose downwards, to the FFP dose
`
`3.1.2
`CD*
`number of positive tests of sterility obtained from tests performed individually on 100 product items irradiated
`in a Method 2 verification dose experiment
`
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`
`3.1.3
`d *
`dose derived from an incremental dose experiment performed on product items drawn from a given production
`batch
`
`3.1.4
`D*
`initial estimate of the dose to provide an SAL of 10–2 for the test items
`
`NOTE
`
`Generally, it is the median of the 3 d * values derived for a given product.
`
`3.1.5
`D**
`final estimate of the dose to provide an SAL of 10–2 for the test items, which is used in the calculation of the
`sterilization dose
`
`3.1.6
`DD*
`dose delivered in a Method 2 verification dose experiment
`
`3.1.7
`DS
`estimate of D10 value of microorganisms present on product after exposure to DD*
`
`3.1.8
`D value
`D10 value
`time or dose required to achieve inactivation of 90 % of a population of the test microorganism under stated
`conditions
`
`[ISO/TS 11139:2006]
`
`NOTE
`
`For the purposes of this document, D10 applies to the radiation dose only and not to time.
`
`3.1.9
`first fraction positive dose
`ffp
`lowest dose of an incremental dose series, applied to product items drawn from a given production batch, at
`which at least one of the associated 20 tests of sterility is negative
`
`3.1.10
`First Fraction Positive dose
`FFP
`dose at which 19 positives out of the 20 tests of sterility are expected to occur, calculated by subtracting A
`from the median of 3 ffp doses
`
`3.1.11
`First No Positive dose
`FNP
`estimate of the dose to provide an SAL of 10–2 for the test items, which is used in the calculation of DS
`
`3.1.12
`15
`VDmax
`maximal verification dose for a given bioburden, consistent with the attainment of an SAL of 10–6 at a
`specified sterilization dose of 15 kGy
`
`3.1.13
`25
`VDmax
`maximal verification dose for a given bioburden, consistent with the attainment of an SAL of 10–6 at a
`specified sterilization dose of 25 kGy
`
`2
`
`
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`ISO 11137-2:2006(E)
`
`3.2 Terms
`
`3.2.1
`batch
`defined quantity of product, intended or purported to be uniform in character and quality, which has been
`produced during a defined cycle of manufacture
`
`[ISO/TS 11139:2006]
`
`3.2.2
`bioburden
`population of viable microorganisms on or in product and/or sterile barrier system
`
`[ISO/TS 11139:2006]
`
`3.2.3
`false positive
`test result interpreted as growth arising from the product, or portions thereof, tested when either growth
`resulted from extraneous microbial contamination or turbidity occurred from interaction between the product,
`or portions thereof, and the test medium
`
`3.2.4
`fraction positive
`quotient in which the number of positive tests of sterility is given by the numerator and the number of tests
`performed is given by the denominator
`
`3.2.5
`incremental dose
`dose within a series of doses applied to a number of product, or portions thereof, and used in a dose setting
`method to obtain or confirm the sterilization dose
`
`3.2.6
`negative test of sterility
`test result for which there is no detectable microbial growth from product, or portion thereof, subjected to a test
`of sterility
`
`3.2.7
`packaging system
`combination of the sterile barrier system and protective packaging
`
`[ISO/TS 11139:2006]
`
`3.2.8
`positive test of sterility
`test result for which there is detectable microbial growth from product, or portion thereof, subjected to a test of
`sterility
`
`3.2.9
`sample item portion
`SIP
`defined portion of a health care product that is tested
`
`3.2.10
`sterile barrier system
`minimum package that prevents ingress of microorganisms and allows aseptic presentation of product at the
`point of use
`
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`
`3.2.11
`sterility assurance level
`SAL
`probability of a single viable microorganism occurring on an item after sterilization
`
`[ISO/TS 11139:2006]
`
`The term sterility assurance level takes a quantitative value, generally 10–6 or 10–3. When applying this
`NOTE
`quantitative value to assurance of sterility, an SAL of 10–6 has a lower value but provides a greater assurance of sterility
`than an SAL of 10–3.
`
`3.2.12
`sterilization dose audit
`exercise undertaken to confirm the appropriateness of an established sterilization dose
`
`3.2.13
`verification dose
`dose of radiation predicted to give a predetermined SAL W 10–2 used in establishing the sterilization dose
`
`4 Definition and maintenance of product families for dose setting, dose
`substantiation and sterilization dose auditing
`
`4.1 General
`
`The establishment of a sterilization dose and the carrying out of sterilization dose audits are activities that are
`part of process definition (see Clause 8 of ISO 11137-1:2006) and maintaining process effectiveness
`(see Clause 12 of ISO 11137-1:2006). For these activities, product may be grouped into families; definition of
`product families is based principally on the number and types of microorganism present on or in product (the
`bioburden). The type of microorganism is indicative of its resistance to radiation. Variables such as density
`and product configuration within its packaging system are not considered in the establishment of these
`product families because they are not factors that influence bioburden.
`
`In using product families in establishing the sterilization dose and for sterilization dose auditing, it is important
`to be aware of risks such as reduction in the ability to detect an inadvertent change within the manufacturing
`process that influences the effectiveness of sterilization. Furthermore, the use of a single product to represent
`the product family might not detect changes that occur in other members of the product family. The risk
`associated with a reduction in ability to detect changes in other members of the product family should be
`evaluated and a plan for maintaining product families developed and implemented before proceeding.
`
`NOTE
`
`See ISO 14971 for guidance related to risk management.
`
`4.2 Defining product families
`
`4.2.1 The criteria for defining a product family shall be documented. Product shall be assessed against
`these criteria and the similarities between potential product family members considered. Consideration shall
`include all product-related variables that affect bioburden, including, but not limited to:
`
`a) nature and sources of raw materials, including the effect, if any, of raw materials that might be sourced
`from more than one location;
`
`b) components;
`
`c) product design and size;
`
`d) manufacturing process;
`
`e) manufacturing equipment;
`
`4
`
`
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`ISO 11137-2:2006(E)
`
`f) manufacturing environment;
`
`g) manufacturing location.
`
`The outcome of the assessment and considerations shall be recorded (see 4.1.2 of ISO 11137-1:2006).
`
`4.2.2 Product shall only be included in a product family if it is demonstrated that the product-related
`variables (see 4.2.1) are similar and under control.
`
`4.2.3 To include product within a product family, it shall be demonstrated that bioburden comprises similar
`numbers and types of microorganisms.
`
`Inclusion of product from more than one manufacturing location in a product family shall be
`4.2.4
`specifically justified and recorded (see 4.1.2 of ISO 11137-1:2006). Consideration shall be given to the effect
`on bioburden of:
`
`a) geographic and/or climatic differences between locations;
`
`b) any differences in the control of the manufacturing processes or environment;
`
`c) sources of raw materials and processing adjuvants (e.g. water).
`
`4.3 Designation of product to represent a product family for performance of a verification
`dose experiment or sterilization dose audit
`
`4.3.1 Product to represent a product family
`
`The number and types of microorganism on or in product shall be used as the basis for selecting
`4.3.1.1
`product to represent a product family.
`
`4.3.1.2
`
`A product family shall be represented by:
`
`a)
`
`the master product (see 4.3.2)
`
`or
`
`b) an equivalent product (see 4.3.3)
`
`or
`
`c) a simulated product (see 4.3.4).
`
`A formal, documented assessment shall be undertaken to decide which of the three potential
`4.3.1.3
`representative products in 4.3.1.2 is appropriate. In this assessment, consideration shall be given to the
`following:
`
`a) numbers of microorganisms comprising the bioburden;
`
`b)
`
`types of microorganism comprising the bioburden;
`
`c)
`
`the environment in which the microorganisms occur;
`
`d) size of product;
`
`e) number of components;
`
`f)
`
`complexity of product;
`
`g) degree of automation during manufacture;
`
`h) manufacturing environment.
`
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