INTERNATIONAL
`STANDARD
`
`ISO
`11608-1
`
`First edition
`2000-12-15
`
`Pen-injectors for medical use -
`Part 1:
`Pen-injectors - Requirements and test
`methods
`
`Stylos-injecteurs a usage medical -
`Partie 1: Stylos-injecteurs - Exigences et methodes d'essai
`
`~ ~1S01
`
`=-~-=
`-
`- -
`-
`-
`~~====~~
`
`Reference number
`ISO 11608-1 :2000(E)
`
`©1SO2000
`
`Copyright International Organization for Standardization
`Provided by IHS Markit under license with ANSI
`No reproduction or networking pennitted without license from IHS
`
`Order Number. W2108280
`Sold to:PHILIP BARAHONA [224858100001] - PHILIP.BARAHONA@WEILCOM,
`Not for Resale,2018-00-02 18:42:04 UTC
`
`Sanofi Exhibit 2131.001
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`ISO 11608-1 :2000(E)
`
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`Sanofi Exhibit 2131.002
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`ISO 11608-1:2000(E)
`
`Contents
`
`Page
`
`Foreword ..................................................................................................................................................................... iv
`
`Introduction ................................................................................................................................................................. v
`
`1
`
`2
`3
`
`4
`5
`6
`6.1
`6.2
`6.3
`7
`7.1
`7.2
`7.3
`7.4
`7.5
`8
`9
`9.1
`9.2
`10
`10.1
`10.2
`10.3
`11 I
`11.1
`11.2
`11.~
`12,,:
`
`Scope .............................................................................................................................................................. 1
`
`Normative references .................................................................................................................................... 1
`Terms and definitions ................................................................................................................................... 1
`
`Symbols and abbreviations .......................................................................................................................... 3
`General requirements .................................................................................................................................... 4
`Test conditions .............................................................................................................................................. 5
`Standard atmosphere .................................................................................................................................... 5
`Cool atmosphere ............................................................................................................................................ 5
`Hot atmosphere .............................................................................................................................................. 5
`Preconditioning of pen-injectors ................................................................................................................. 6
`Preconditioning in dry heat atmosphere ..................................................................................................... 6
`Preconditioning in cold storage atmosphere ............................................................................................. 6
`Preconditioning in cyclical atmosphere ...................................................................................................... 6
`Preconditioning by free fall .......................................................................................................................... 6
`Preconditioning by vibration for pen-injectors with electronic components ......................................... 7
`Reagent and apparatus ................................................................................................................................. 7
`Determination of dose accuracy .................................................................................................................. 7
`Dose accuracy ................................................................................................................................................ 7
`Dose accuracy requirements ...................................................................................................................... 12
`Freedom from defects ................................................................................................................................. 14
`Defects after being subjected to cyclical preconditioning ...................................................................... 14
`Freedom from defects after being subjected to vibration ....................................................................... 14
`Freedom from defects after being subjected to free fall ......................................................................... 14
`Determination of electromagnetic compatibility ...................................................................................... 14
`Electromagnetic compatibility (EMC) ........................................................................................................ 14
`Electrostatic discharge ............................................................................................................................... 15
`Radiated radio frequency (RF) fields ......................................................................................................... 15
`Visual inspection ......................................................................................................................................... 15
`
`Functional inspection .................................................................................................................................. 16
`13
`Replaceable cartridge ................................................................................................................................. 16
`13.1
`Nonreplaceable cartridge ............................................................................................................................ 16
`13.2
`Accuracy ....................................................................................................................................................... 16
`13.3
`Test report .................................................................................................................................................... 16
`14
`Information supplied by the manufacturer ............................................................................................... 16
`15
`General .......................................................................................................................................................... 16
`15.1
`15.2 Marking ......................................................................................................................................................... 17
`15.3
`Instructions for use ..................................................................................................................................... 17
`
`Annex A (informative) Two-sided tolerance limit factors (k) ................................................................................ 19
`Bibliography .............................................................................................................................................................. 25
`
`Copyright ,n1e..®i~Q.QQ.ro.4U~~eserved
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`
`iii
`
`Sanofi Exhibit 2131.003
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`ISO 11608-1 :2000(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 3.
`
`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.
`
`Atteniion is drawn to the possibility that some of the elements of this part of ISO 11608 may be the subject of
`pater-it rights. ISO shall not be held responsible for identifying any or all such patent rights.
`
`International Standard ISO 11608-1 was prepared by Technical Committee ISO/TC 84, Medical devices for
`injections.
`
`i
`ISO 11608 consists of the following parts, under the general title Pen-injectors for medical use:
`
`Part 1: Pen-injectors - Requirements and test methods
`
`Part 2: Needles - Requirements and test methods
`
`Part 3: Finished cartridges - Requirements and test methods
`
`Annex A of this part of ISO 11608 is for information only.
`
`Copyright 1AM'mational Organization for Standardization
`Provided by IHS Markit under license with ANSI
`No reproduction or networking pennitted without license from IHS
`
`© ISO 2000-AII rights reserved
`orc1e,Number.w21002ao
`Sold to:PHILIP BARAHONA [224858100001] - PHILIP.BARAHONA@WEILCOM,
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`Sanofi Exhibit 2131.004
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`ISO 11608-1:2000(E)
`
`Introduction
`
`It provides performance
`This part of ISO 11608 covers pen-injectors primarily intended for human use.
`requirements regarding essential aspects, so that variations of design are not unnecessarily restricted.
`
`The devices described in this part of ISO 11608 are designed to be used with devices described in ISO 11608-2
`and ISO 11608-3.
`
`It is recognized that interchangeability of the components (pen-injector, needle and cartridge) is desirable for some
`medicinal products and to be avoided for other medicinal products, and that future design may change the current
`concepts. Therefore, ISO 11608-2 and ISO 11608-3 encourage interchangeability by establishing certain specific
`requirements for interchangeable needles (Type A) and interchangeable cartridges (Type A) respectively.
`
`Performance requirements are imposed on both Type A (interchangeable) and non-Type A needles and cartridges.
`Additional dimensional requirements are imposed on Type A needles and cartridges and hereby indirectly on pen(cid:173)
`injectors intended for either Type A needles and/or Type A cartridges.
`
`Information as to whether the components are interchangeable (Type A) or not should be given on the unit
`container.
`
`The sampling plans for inspection selected for this part of ISO 11608 are intended to verify, at a high confidence
`level, the manufacturer's ability to manufacture one "lot" of pen-injectors that conforms to the critical product
`attributes. The sampling plans for inspection do not replace the more general manufacturing quality systems that
`appear in standards on quality systems, e.g. the ISO 9000 series.
`
`~aterials to be used for the construction are not specified, as their selection to some extent will depend upon the
`design, the intended use and the process of manufacture by individual manufacturers. All materials should be
`~esistant to the medicinal product intended to be injected with the pen-injector.
`
`In some countries national regulations exist, and their requirements may supersede or complement this part of
`1'so 11608.
`
`Copyright ,n1e..®i~Q.QQ.ro.4U~~eserved
`Provided by IHS Markit under license with ANSI
`No reproduction or networking pennitted without license from IHS
`
`Order Number. W2108280
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`Not for Resale,2018-00-02 18:42:04 UTC
`
`V
`
`Sanofi Exhibit 2131.005
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`Copyright International Organization for Standardization
`Provided by IHS Markit under license with ANSI
`No reproduction or networking pennitted without license from IHS
`
`Order Number. W2108280
`Sold to:PHILIP BARAHONA [224858100001] - PHILIP.BARAHONA@WEILCOM,
`Not for Resale,2018-00-02 18:42:04 UTC
`
`Sanofi Exhibit 2131.006
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`INTERNATIONAL STANDARD
`
`ISO 11608-1 : 2000(E)
`
`Pen-injectors for medical use -
`
`Part 1:
`Pen-injectors - Requirements and test methods
`
`1 Scope
`
`This part of ISO 11608 specifies requirements and test methods for pen-injectors intended to be used with needles
`and with replaceable or non-replaceable prefilled cartridges.
`
`This part of ISO 11608 is also applicable to pen-injectors which are not electrically driven, but are equipped with
`electronic components.
`
`This part of ISO 11608 is not applicable to high-pressure injectors and electrically driven injectors.
`
`2 Normative references
`
`The following normative documents contain provisions which, through reference in this text, constitute provisions of
`this part of ISO 11608. For dated references, subsequent amendments to, or revisions of, any of these publications
`do not apply. However, parties to agreements based on this part of ISO 11608 are encouraged to investigate the
`possibility of applying the most recent editions of the normative documents indicated below. For undated
`references, the latest edition of the normative document referred to applies. Members of ISO and IEC maintain
`registers of currently valid International Standards.
`
`ISO 11608-2:2000, Pen-injectors for medical use - Part 2: Needles - Requirements and test methods.
`
`ISO 11608-3:2000, Pen-injectors for medical use - Part 3: Finished cartridges - Requirements and test methods.
`
`IEC 60068-2-6:1995, Environmental testing- Part 2: Tests. Test Fe: Vibration (sinusoidal).
`
`IEC 60068-2-6:1995, Corr. 1.
`
`IEC 60068-2-30:1980, Environmental testing - Part 2: Tests. Test Db and guidance: Damp heat, cyclic (12 + 12-
`hour cycle).
`
`IEC 60068-2-30, Amendment No. 1:1985.
`
`.i
`IEC 61000-4-2:1999, Electromagnetic compatibility (EMC) - Part 4-2: Testing and measurement techniques;....
`Electrostatic discharge immunity test.
`·
`
`IEC 61000-4-3:1998, Electromagnetic compatibility (EMC) - Part 4-3: Testing and measurement techniques~
`Radiated, radio-frequency, electromagnetic field immunity test.
`}
`
`3 Terms and definitions
`
`For the purposes of this part of ISO 11608, the following terms and definitions apply.
`
`Copyright ,n1e..®i~Q.QQ.ro.4U~~eserved
`Provided by IHS Markit under license with ANSI
`No reproduction or networking pennitted without license from IHS
`
`Order Number. W2108280
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`Not for Resale,2018-00-02 18:42:04 UTC
`
`1
`
`Sanofi Exhibit 2131.007
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`ISO 11608-1 :2000(E)
`
`The nomenclature of some components of pen-injectors is illustrated in Figure 1.
`
`3.1
`pen-injector
`medical device intended for parenteral administration by injection of medicinal products from a multidose cartridge
`
`NOTE
`
`The doses may be pre-set by manufacturer or user.
`
`3.2
`connector
`mechanical arrangement allowing the connection between the needle and the cartridge
`
`3.3
`cartridge
`primary container for the medicinal product
`
`3.4
`injection mechanism
`m~chanism which performs the parenteral injection of the pre-set dose
`
`3.5
`re~ase mechanism
`m~chanism which initiates the parenteral injection of the pre-set dose
`3.6
`injection stroke
`that portion of a parenteral injection involving movement of the injection mechanism following initiation by the
`release mechanism
`
`It does not include the subsequent relaxation of the system components required for the complete injection of the
`NOTE
`pre-set dose.
`
`3.7
`mechanism holder
`part of the body of the injector containing the injection mechanisms
`
`3.8
`selector
`mechanism which allows pre-setting of a dose
`
`3.9
`increment
`smallest possible difference to be selected between two dose amounts
`
`3.10
`indicator
`means by which the amount of pre-set dose is shown
`
`3.11
`residual scale
`graduated scale which indicates the remainder of medicinal product in the cartridge
`
`3.12
`dose accuracy
`accuracy with which the pen-injector delivers a pre-set dose of medicinal products
`
`3.13
`cap
`part of the pen-injector intended to protect the system
`
`Copyright 12mational Organization for Standardization
`Provided by IHS Markit under license with ANSI
`No reproduction or networking pennitted without license from IHS
`
`© ISO 2000-AII rights reserved
`orc1e,Num1>er.w21002ao
`Sold to:PHILIP BARAHONA [224858100001] - PHILIP.BARAHONA@WEILCOM,
`Not for Resale,2018-00-02 18:42:04 UTC
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`Sanofi Exhibit 2131.008
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`ISO 11608-1:2000(E)
`
`3.14
`pre-setting
`procedure by which individual amounts of medicinal product can be selected for injection by the user
`
`3.15
`unit container
`package intended for customer use
`
`3.16
`Type A
`classification of needles and cartridges for pen-injectors which fulfil certain specific requirements providing
`interchangeability
`
`3.17
`non-Type A
`classification of needles and cartridges which are not classified as Type A
`
`1 2 3 4
`
`5
`
`6
`
`1
`
`11 l
`
`8
`
`Key
`
`1 Cap
`2
`Injection system
`3 Connector
`4 Residual scale
`5 Window
`6 Cartridge holder
`7 Mechanism holder
`8 Release mechanism
`
`Figure 1 - Schematic presentation of a pen-injector
`
`4 Symbols and abbreviations
`
`Vset
`
`One of the three pre-set doses (expressed as a volume, in millilitres) used in determining the dose
`accuracy for a given pen-injector. Vset is defined as one of the following:
`
`a) minimum dose (V58t = Vmin) (specified in the instructions for use);
`
`b) maximum dose (Vset = Vmax) (specified in the instructions for use);
`
`c) midpoint dose (V58t = Vmid), where Vmid is defined as the injector setting closest to (Vmin + Vmax)/2.
`
`NOTE Recommended doses as specified in the instruction for use may differ from those doses that can be set.
`
`Vmeas
`
`The volumetric measurement value for a given Vset
`
`Gmeas
`
`The gravimetric measurement value for a given Vset
`
`Copyright ,n1e..®i~Q.QQ.ro.4U~~eserved
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`Order Number. W2108280
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`3
`
`Sanofi Exhibit 2131.009
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`ISO 11608-1 :2000(E)
`
`p
`
`p
`
`Y
`
`R
`
`n
`
`x
`
`s
`
`k
`
`a
`
`p
`
`TP
`
`U
`
`L
`
`Density, expressed in grams per millilitre
`
`Probability content
`
`Number of pens required for a given test
`
`Number of replicates required for a given test. A replicate is a random sequence of V min• V mid• and V max.
`There are six possible replicates.
`
`Number of measurements (V meas) to be made for each Vset
`
`The sample mean; when based on a random sample, an estimate of the true mean:
`
`x= LVmeasln
`
`The sample standard deviation; when based on a random sample, an estimate of the true standard
`deviation:
`
`s = L(Vmeas -x)2/(n-1)
`[
`]
`
`1/2
`
`Tolerance Limit Factor, determined from the confidence level (95 %), probability content (p) and the
`number of accuracy measurements (n) conducted at each dose setting
`
`Absolute error (millilitres) used to define the upper and lower specification limits for a pre-set dose in
`absolute terms
`
`Relative error (%) used to define the upper and lower specification limits for a pre-set dose in relative
`terms
`
`The transition point volume (millilitres) at which the definition of the upper and lower specification limits for
`Vset changes from absolute terms to relative terms:
`
`TP = (100 X a)/ p
`
`Upper specification limit for a given Vset
`
`Lower specification limit for a given Vset
`
`5 General requirements
`
`When the pen-injector is ready for injection, the cartridge holder shall allow visibility of the deliverable volume. It
`shall be possible to determine whether sufficient medicinal product remains in order to administer the maximum
`pre-settable dose.
`
`The pen-injector shall be designed such that it is able to deliver the labelled volume from the cartridge for which it is
`designed.
`
`The pen-injector shall be designed such that the last dose delivered from a cartridge satisfies requirements for
`dose accuracy.
`
`The pen-injector shall indicate the pre-set dose.
`
`The pen-injector shall indicate, at least by visual means, that it is ready for injection. There shall be an indication of
`the pre-setting procedure by tactile or audible means, or both.
`
`Copyright l'mational Organization for Standardization
`Provided by IHS Markit under license with ANSI
`No reproduction or networking pennitted without license from IHS
`
`© ISO 2000-AII rights reserved
`orc1e,Number.w21002ao
`Sold to:PHILIP BARAHONA [224858100001] - PHILIP.BARAHONA@WEILCOM,
`Not for Resale,2018-00-02 18:42:04 UTC
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`Sanofi Exhibit 2131.010
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`ISO 11608-1:2000(E)
`
`The state of the pen-injector, when ready to deliver a dose, shall be different to its state when the dose has been
`delivered. The difference shall be visible.
`
`The pen-injector shall indicate, by visual, audible or tactile means or any combination of these, that the injection
`stroke has been completed.
`
`If the pen-injector is designed for variable doses, it shall be so designed that it is impossible to deliver a second
`dose after delivery of the first dose without a second pre-setting.
`
`The pen-injector shall be so designed that it:
`
`does not allow a larger dose to be pre-set than is left in the cartridge; or
`
`does not allow dose delivery if the pre-set amount exceeds the amount of medicinal product left in the
`cartridge; or
`
`indicates the amount of medicinal product delivered; or
`
`indicates the amount of medicinal product not delivered of the pre-set dose.
`
`The pen-injector shall be designed to function with a needle fulfilling the specifications of ISO 11608-2.
`
`If the pen-injector is designed to function with a single-compartment cartridge, it shall be designed to function with a
`cartridge fulfilling the specifications of ISO 11608-3.
`
`6 Test conditions
`
`6.1 Standard atmosphere
`
`Unless otherwise specified, measurements shall be performed in the following atmosphere:
`
`temperature:
`
`from 18 °C to 28 °C;
`
`relative humidity: from 25 % RH to 75 % RH;
`
`after having been subjected to storage for at least 4 h in this atmosphere.
`
`6.2 Cool atmosphere
`
`The assembled pen-injector with the cartridge and needle is placed in a test chamber for at least 4 h in the
`following cool atmosphere:
`
`-
`
`temperature: (5 ± 3) °C.
`
`6.3 Hot atmosphere
`
`The assembled pen-injector with the cartridge and needle is placed in a test chamber for at least 4 h in the
`following hot atmosphere:
`
`temperature:
`
`(40 ± 2) °C;
`
`relative humidity:
`
`(50 ± 10) % RH.
`
`Copyright ,n1e..®i~Q.QQ.ro.4U~~eserved
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`Sanofi Exhibit 2131.011
`Mylan v. Sanofi
`IPR2018-01675
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`

`

`ISO 11608-1 :2000(E)
`
`7 Preconditioning of pen-injectors
`
`7 .1 Preconditioning in dry heat atmosphere
`
`The pen-injector without the cartridge and needle is placed in a test chamber for at least 96 h in the following hot
`atmosphere:
`
`temperature:
`
`(70 ± 2) °C;
`
`relative humidity:
`
`(50 ± 10) % RH.
`
`7 .2 Preconditioning in cold storage atmosphere
`
`The pen-injector without the cartridge and needle is placed in a test chamber for at least 96 h in the following cold
`atmosphere:
`
`-
`
`temperature:
`
`(-40 ± 3) °C.
`
`7.3 Preconditioning in cyclical atmosphere
`
`The pen-injector with the cartridge and without the needle is placed in a test chamber. Conditioning in accordance
`with IEC 60068-2-30 is carried out as follows:
`
`variant 1 (see IEC 60068-2-30, Figure 2a);
`
`upper temperature:
`
`(55 ± 2) °C; and
`
`6 cycles.
`
`NOTE
`
`The relevant clauses of IEC 60068-2-30:1980 are: clauses 3, 6 and 8.
`
`7 .4 Preconditioning by free fall
`
`Prepare the pen-injector according to the instructions for use with a new cartridge and proceed as follows:
`
`a) Pen-injectors with replaceable cartridges
`
`1) Expel the air.
`
`2) Take off the needle and put on the cap.
`
`3) Drop each pen-injector three times by free fall from a height of 1 000 mm onto the test surface (see 8.3),
`once horizontally and twice vertically, the pen-injector being rotated 180° between the two vertical drops.
`Care shall be taken that the pen-injector is released in a non-turbulent way.
`
`4)
`
`If a cartridge breaks such that it is obvious to the user, replace the cartridge and continue until all three
`drops have been performed.
`
`b) Pen-injectors with non-replaceable cartridges
`
`) ) Expel the air.
`
`';2)
`
`Take off the needle and put on the cap.
`
`3) Drop the pen-injectors by free fall from a height of 1 000 mm onto the test surface (see 8.3) in accordance
`with i), ii) and iii), as follows:
`
`Copyright 1fimauonal Organization for Standardization
`Provided by IHS Markit under license with ANSI
`No reproduction or networking pennitted without license from IHS
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`© ISO 2000-AII rights reserved
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`Sanofi Exhibit 2131.012
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`IPR2018-01675
`
`

`

`ISO 11608-1:2000(E)
`
`i) Horizontal
`
`Drop a minimum of 10 new pen-injectors in a non-turbulent way. If a cartridge breaks such that it is
`obvious to the user, exclude the pen-injector from further testing.
`
`ii) Vertical A
`
`Drop a minimum of 10 new pen-injectors in a non-turbulent way. If a cartridge breaks such that it is
`obvious to the user, exclude the pen-injector from further testing.
`
`iii) Vertical B [180° from orientation ii)]
`
`Drop a minimum of 10 new pen-injectors in a non-turbulent way. If a cartridge breaks such that it is
`obvious to the user, exclude the pen-injector from further testing.
`
`7.5 Preconditioning by vibration for pen-injectors with electronic components
`
`Vibrate the pen-injector with its cartridge and needle in each of three axes in accordance with IEC 60068-2-6 and
`Table 1.
`
`Ta~le 1 -Vibration amplitudes with lower cross-over frequency: IEC 60068-2-6:1995, Table IV and Figure 1
`
`Frequency range
`
`3 Hzto 8 Hz
`
`8 Hzto 300 Hz
`
`Displacement/Acceleration
`(peak value)
`
`Number of sweeps a
`per direction
`
`7,5mm
`
`2g
`
`4
`
`4
`
`a The sweep speed shall be 1 octave per minute.
`
`8 Reagent and apparatus
`
`Test liquid, i.e. the original medicinal product intended to be injected by the pen-injector or a liquid which
`8.1
`gives the same results.
`
`8.2 Balance, with a maximum tolerance of 1 % of the minimum dose delivery.
`
`8.3 Test surface, smooth, hard, rigid steel of 3 mm thickness backed by wood of between 10 mm and 19 mm
`thickness.
`
`8.4 Needle connector for connecting the needle to a tube.
`
`9 Determination of dose accuracy
`
`9.1 Dose accuracy
`
`9.1.1 General
`
`Dose accuracy is determined by selecting and testing a variable number of pen-injectors. The number of pen(cid:173)
`injectors depends upon the cartridge and accuracy requirements for a given test. Assuming that the accuracy
`measurements are normally distributed and that each measurement is independent, the following method enables
`accuracy measurements to be used as the basis for determining a statistical tolerance interval for three dose
`settings (the minimum, midpoint and maximum dose settings for a given pen-injector), i.e. an interval such that
`there is a fixed probability (confidence level) that the interval will contain at least a proportion (p, probability content)
`
`Copyright ,n1e..®i~Q.QQ.ro.4U~~eserved
`Provided by IHS Markit under license with ANSI
`No reproduction or networking pennitted without license from IHS
`
`Order Number. W2108280
`Sold to:PHILIP BARAHONA [224858100001] - PHILIP.BARAHONA@WEILCOM,
`Not for Resale,2018-00-02 18:42:04 UTC
`
`7
`
`Sanofi Exhibit 2131.013
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`ISO 11608-1 :2000(E)
`
`of the true population from which the sample is taken. The statistical tolerance interval is two-sided, and the limits
`of the interval are called "statistical tolerance limits" or "natural limits of the process".
`
`To pass the dose accuracy requirement, there shall be a 95 % confidence that at leastp of all doses delivered will
`fall within the proposed upper and lower specification limits for the three dose settings.
`
`The two-sided statistical tolerance interval is calculated using the mean ( x) plus or minus the standard deviation
`(s) multiplied by a tolerance limit factor (k):
`
`x±k•s
`
`where
`
`x is the mean of the sample;
`
`k
`
`s
`
`is the tolerance limit factor;
`
`is the standard deviation of the sample.
`
`The factor is determined based upon the confidence level (95 %), probability content (p), and the number of
`measurements (n) taken for each of the three dose settings. ISO 3207:1975111, Table 8, lists the tolerance limit
`factors for the construction of two-sided statistical tolerance intervals when the true population mean and standard
`deviation are not known. Annex A contains a more comprehensive two-sided tolerance limit for the 95 %
`confidence level.
`
`9.1.2 Accuracy assessment (expressed in millilitres)
`
`If Vset ~ TP, then:
`
`U= Vset + a;
`
`L= Vset-a,
`
`If Vset > TP, then:
`
`U = Vset + (JJ · VseV / 100;
`
`L = Vset - (/J · Vset) / 100.
`
`A pen-injector population's accuracy satisfies the requirements when, for a given Vset, the following are fulfilled:
`
`x + (k · s) ~ U; and
`
`x -(k · s) ~L.
`
`9.1.3 Example of accuracy limit calculation
`
`In the following an example of calculation (volumes expressed as millilitres) is given for a single-compartment
`cartridge:
`
`Vmin = 0,02 ml;
`
`Vmid = 0, 16 ml;
`
`Vmax = 0,30 ml;
`
`Copyright 1lmational Organization for Standardization
`Provided by IHS Markit under license with ANSI
`No reproduction or networking pennitted without license from IHS
`
`© ISO 2000-AII rights reserved
`orc1e,Number.w21002ao
`Sold to:PHILIP BARAHONA [224858100001] - PHILIP.BARAHONA@WEILCOM,
`Not for Resale,2018-00-02 18:42:04 UTC
`
`Sanofi Exhibit 2131.014
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`ISO 11608-1:2000(E)
`
`and:
`
`a= 0,01 ml;
`
`/3= 5 %;
`
`then:
`
`For V min :::;; TP:
`
`For V mid ::,;; TP:
`
`TP = (100 x 0,01 ml)/5
`
`= 0,20 ml;
`
`U= (0,02 + 0,01) ml
`L = (0,02 - 0,01) ml
`
`U= (0,16 + 0,01) ml
`
`L = (0, 16 - 0,01) ml
`
`= 0,030 ml;
`
`= 0,010 ml;
`
`= 0,170 ml;
`
`= 0,150 ml;
`
`For Vmax > TP:
`
`U = 0,30 ml + (5 x 0,30 ml)/100
`
`= 0,315 ml;
`
`L = 0,30 ml