EN ISO 11608-1:2012

SLOVENSKI STANDARD
11-september-2012
1DGRPHãþD
SIST EN ISO 11608-1:2001
Peresa za injiciranje za uporabo v medicini - Zahteve in preskusne metode - 1. del:
Peresa za injiciranje (ISO 11608-1:2012)
Needle-based injection systems for medical use - Requirements and test methods - Part
1: Needle-based injection systems (ISO 11608-1:2012)
Nadelbasierte Injektionssysteme zur medizinischen Verwendung - Anforderungen und
Prüfverfahren - Teil 1: Nadelbasierte Injektionssysteme (ISO 11608-1:2012)
Systèmes d'injection à aiguille pour usage médical - Exigences et méthodes d'essai -
Partie 1: Systèmes d'injection à aiguille (ISO 11608-1:2012)
Ta slovenski standard je istoveten z: EN ISO 11608-1:2012
ICS:
11.040.25 Injekcijske brizge, igle in Syringes, needles an
katetri catheters
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.

EUROPEAN STANDARD
EN ISO 11608-1
NORME EUROPÉENNE
EUROPÄISCHE NORM
April 2012
ICS 11.040.25 Supersedes EN ISO 11608-1:2000
English Version
Needle-based injection systems for medical use - Requirements
and test methods - Part 1: Needle-based injection systems (ISO
11608-1:2012)
Systèmes d'injection à aiguille pour usage médical - Nadelbasierte Injektionssysteme zur medizinischen
Exigences et méthodes d'essai - Partie 1: Systèmes Verwendung - Anforderungen und Prüfverfahren - Teil 1:
d'injection à aiguille (ISO 11608-1:2012) Nadelbasierte Injektionssysteme (ISO 11608-1:2012)
This European Standard was approved by CEN on 31 March 2012.

CEN members are bound to comply with the CEN/CENELEC Internal Regulations which stipulate the conditions for giving this European
Standard the status of a national standard without any alteration. Up-to-date lists and bibliographical references concerning such national
standards may be obtained on application to the CEN-CENELEC Management Centre or to any CEN member.

This European Standard exists in three official versions (English, French, German). A version in any other language made by translation
under the responsibility of a CEN member into its own language and notified to the CEN-CENELEC Management Centre has the same
status as the official versions.

CEN members are the national standards bodies of Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia,
Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland,
Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland, Turkey and United Kingdom.

EUROPEAN COMMITTEE FOR STANDARDIZATION
COMITÉ EUROPÉEN DE NORMALISATION

EUROPÄISCHES KOMITEE FÜR NORMUNG

Management Centre: Avenue Marnix 17, B-1000 Brussels
© 2012 CEN All rights of exploitation in any form and by any means reserved Ref. No. EN ISO 11608-1:2012: E
worldwide for CEN national Members.

Contents Page
Foreword .3
Foreword
This document (EN ISO 11608-1:2012) has been prepared by Technical Committee ISO/TC 84 "Devices for
administration of medicinal products and intravascular catheters" in collaboration with Technical Committee
CEN/TC 205 “Non-active medical devices” the secretariat of which is held by DIN.
This European Standard shall be given the status of a national standard, either by publication of an identical
text or by endorsement, at the latest by October 2012, and conflicting national standards shall be withdrawn at
the latest by October 2012.
Attention is drawn to the possibility that some of the elements of this document may be the subject of patent
rights. CEN [and/or CENELEC] shall not be held responsible for identifying any or all such patent rights.
This document supersedes EN ISO 11608-1:2000.
According to the CEN/CENELEC Internal Regulations, the national standards organizations of the following
countries are bound to implement this European Standard: Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech
Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia,
Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain,
Sweden, Switzerland, Turkey and the United Kingdom.
Endorsement notice
The text of ISO 11608-1:2012 has been approved by CEN as a EN ISO 11608-1:2012 without any
modification.
INTERNATIONAL ISO
STANDARD 11608-1
Second edition
2012-04-01
Needle-based injection systems for medical
use — Requirements and test methods —
Part 1:
Needle-based injection systems
Systèmes d’injection à aiguille pour usage médical — Exigences et
méthodes d’essai —
Partie 1: Systèmes d’injection à aiguille
Reference number
ISO 11608-1:2012(E)
©
ISO 2012
ISO 11608-1:2012(E)
All rights reserved. Unless otherwise specified, no part of this publication may be reproduced or utilized in any form or by any means,
electronic or mechanical, including photocopying and microfilm, without permission in writing from either ISO at the address below or ISO’s
member body in the country of the requester.
ISO copyright office
Case postale 56 • CH-1211 Geneva 20
Tel. + 41 22 749 01 11
Fax + 41 22 749 09 47
E-mail copyright@iso.org
Web www.iso.org
Published in Switzerland
ii © ISO 2012 – All rights reserved

ISO 11608-1:2012(E)
Contents Page
Foreword .iv
Introduction . v
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 2
4 Symbols and abbreviated terms . 3
5 Requirements . 4
5.1 General . 4
5.2 System designations . 4
5.3 Risk analysis requirements . 5
5.4 Uncertainty of measurement and conformance with specifications . 5
5.5 General design requirements . 5
6 Reagent and apparatus . 7
6.1 General . 7
6.2 Test liquid . 7
6.3 Balance . 7
6.4 Test surface for free-fall testing . 7
7 Determination of dose accuracy . 7
7.1 General . 7
7.2 Dosing regions . 8
7.3 Dose settings . 8
7.4 Assessment . 9
8 Preparation and operation of NISs .12
9 Test matrix .12
10 Test descriptions .15
10.1 General .15
10.2 Cool, standard and warm atmosphere testing .15
10.3 Last-dose testing (system designations A and C only) .16
10.4 Life-cycle testing (systems designations A and B only) — Pre-conditioning .16
10.5 Free-fall testing .16
10.6 Dry-heat and cold-storage testing — Pre-conditioning .18
10.7 Damp-heat testing (system designations A and B only) — Pre-conditioning .18
10.8 Cyclical testing (system designations A and B only) — Pre-conditioning .18
10.9 Vibration testing — Pre-conditioning .18
10.10 Electromagnetic compatibility (EMC) (systems with electronics only) .19
11 Inspection .20
11.1 Visual inspection .20
11.2 Container inspection .20
11.3 Dose accuracy acceptance criteria .20
12 Test report .21
13 Information supplied by the manufacturer .22
13.1 General .22
13.2 Marking .22
13.3 Instructions for use .23
Annex A (informative) Dose replicates, accuracy and testing rationale .25
Annex B (normative) One- and two-sided tolerance limit factors, k .29
Bibliography .40
ISO 11608-1:2012(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 11608-1 was prepared by Technical Committee ISO/TC 84, Devices for administration of medicinal
products and intravascular catheters.
This second edition cancels and replaces the first edition (ISO 11608-1:2000), which has been technically revised.
ISO 11608 consists of the following parts, under the general title Needle-based injection systems for medical
use — Requirements and test methods:
— Part 1: Needle-based injection systems
— Part 2: Needles
— Part 3: Finished containers
— Part 4: Requirements and test methods for electronic and electromechanical pen-injectors
— Part 5: Automated functions
iv © ISO 2012 – All rights reserved

ISO 11608-1:2012(E)
Introduction
This part of ISO 11608 covers needle-based injection systems (referred to as NISs) primarily intended for
human use. It provides performance requirements regarding essential aspects so that variations of design are
not unnecessarily restricted.
This part of ISO 11608 should be used in conjunction with the other parts of ISO 11608.
The first edition of this part of ISO 11608 introduced the concept of interchangeability and the labelling
designations “Type A” (i.e. interchangeable) and “non-Type A” for needles and container systems. Since its
promulgation, experience has shown that the complexity of these systems makes it very difficult to ensure
functional compatibility as defined in the different parts of this International Standard, particularly when products
are made by different manufacturers. Based on this experience, it is believed that the Type A designation does
not represent adequate guidance to the user in making decisions on the compatibility of needles and containers
with specific needle-based injector systems. As such, the labelling designation “Type A” has been removed.
The design requirements related to system function have been maintained as a guide to assist manufacturers
during the design phase, supporting the achievement of cross-platform compatibility. However, these design
requirements are an insufficient replacement for system testing of the components and, where possible, direct
communication and/or quality agreements between system component manufacturers. Therefore, given the
patient convenience benefits associated with cross-platform compatibility, manufacturers of needles, containers
and needle-based injectors shall label their products with the specific system components that have been
tested and demonstrated to be functionally compatible.
The sampling plans for inspection selected for this part of ISO 11608 are intended to verify the design at a high
confidence level. The sampling plans for inspection do not replace the more general manufacturing quality
systems that appear in standards on quality systems, for example the ISO 9000 series and ISO 13485.
Materials to be used for construction are not specified, as their selection will depend on the design, the intended
use and the process of manufacture used by individual manufacturers.
There are other international and national standards and guidance publications and, in some countries, national
regulations that are applicable to medical devices and pharmaceuticals. Their requirements might supersede
or complement this part of ISO 11608. Developers and manufacturers of NISs are encouraged to investigate
and determine whether there are any other requirements relevant to the safety or marketability of their products.
Manufacturers are expected to follow a risk-based approach during the design, development and manufacture
of the product. Given the specific medicinal product and intended use, this might result in product-specific
requirements and test methods that differ from what is outlined in this part of ISO 11608.
INTERNATIONAL STANDARD ISO 11608-1:2012(E)
Needle-based injection systems for medical use —
Requirements and test methods —
Part 1:
Needle-based injection systems
1 Scope
This part of ISO 11608 specifies requirements and test methods for needle-based injection systems (NISs)
intended to be used with needles and with replaceable or non-replaceable containers. Containers covered in
this part of ISO 11608 include single- and multi-dose syringe-based and cartridge-based systems, filled either
by the manufacturer or by the end-user.
Additional guidance for NISs equipped with electronic or electromechanical components and NISs equipped
with automated functions is given in ISO 11608-4 and ISO 11608-5 respectively.
Needle-free injectors, and requirements relating to methods or equipment associated with end-user filling of
containers, are outside the scope of this part of ISO 11608.
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 10993-1, Biological evaluation of medical devices — Part 1: Evaluation and testing within a risk
management process
ISO 11608 (all parts), Needle-based injection systems for medical use — Requirements and test methods
ISO 13485:2003, Medical devices — Quality management systems — Requirements for regulatory purposes
ISO 14253-1, Geometrical Product Specifications (GPS) — Inspection by measurement of workpieces and
measuring equipment — Part 1: Decision rules for proving conformance or non-conformance with specifications
ISO 14971, Medical devices — Application of risk management to medical devices
ISO/IEC Guide 98-3, Uncertainty of measurement — Part 3: Guide to the expression of uncertainty in
measurement (GUM:1995)
IEC 60068-2-6:2007, Environmental testing — Part 2-6: Tests — Test Fc: Vibration (sinusoidal)
IEC 60068-2-30:2005, Environmental testing — Part 2-30: Tests — Test Db: Damp heat, cyclic (12 + 12 h cycle)
IEC 60601-1-2:2007, Medical electrical equipment — Part 1-2: General requirements for basic safety and
essential performance — Collateral standard: Electromagnetic compatibility — Requirements and tests
IEC 62366, Medical devices — Application of usability engineering to medical devices
ISO 11608-1:2012(E)
3 Terms and definitions
For the purposes of this document, the following terms and definitions apply.
3.1
cap
part of the NIS intended to protect the injector and its contents
3.2
container
primary packaging that contains the medicinal product for injection (either single-compartment or multi-compartment)
3.3
dose delivery efficiency
ratio of expelled dose to fill volume
NOTE 1 Dose delivery efficiency is expressed as a percentage.
NOTE 2 Delivery efficiency can be used to evaluate dose accuracy for NISs designed to fully empty single-dose
containers filled by the user.
3.4
dialling resolution
smallest possible increment to be selected between dose amounts
3.5
dose accuracy
accuracy with which the NIS delivers a pre-set dose of medicinal product
3.6
“dose delivered” indication
dose number shown in the dose window indicating the amount of medicinal product delivered
NOTE 1 This applies to variable multi-dose NISs that allow the setting of a dose greater than the remaining volume.
NOTE 2 If the dose window indicates the amount of medicinal product yet to be delivered, then the “dose delivered”
indication can be determined as the intended dose minus the indication of medicinal product yet to be delivered.
3.7
manufacturer-filled
container supplied to the user pre-filled by the manufacturer of medicinal products
NOTE This medicinal product can be in liquid form or lyophilized with diluent in the same container.
3.8
minimum deliverable dose
minimum dose that is ensured by the manufacturer to be delivered in a single-dose manufacturer-filled NIS
designed to fully empty the container
3.9
NIS
needle-based injection system
injection system intended for parenteral administration by injection of medicinal products using a needle and a
multi-dose or single-dose container
NOTE This term may also be referred to as “system” or “injector” in this part of ISO 11608.
3.10
pre-setting
procedure by which individual amounts of medicinal product can be selected for injection by the user
NOTE The doses may be pre-set by the manufacturer or the user.
2 © ISO 2012 – All rights reserved

ISO 11608-1:2012(E)
3.11
residual scale
graduated scale which indicates the remainder of medicinal product in the container
3.12
user packaging
what is provided to the user with one or a collection of devices of the same item and from the same manufacturing
batch, including the directions for use
3.13
user-filled
container that is filled or reconstituted (if in lyophilized form) by the user from a separate medicinal product or
diluent container
4 Symbols and abbreviated terms
NIS Needle-based injection system.
V One of the three pre-set doses (expressed as a volume, in millilitres) used in determining the dose
set
accuracy for a given NIS. V is defined as one of the following:
set
a)  minimum dose (V = V ) (specified in the instructions for use);
set min
b)  maximum dose (V = V ) (specified in the instructions for use);
set max
c)  midpoint dose (V = V ), where V is defined as the injector setting closest to (V + V )/2.
set mid mid min max
NOTE 1 Recommended doses as specified in the instructions for use may differ from the pre-set doses used

for determining the dose accuracy.
NOTE 2 System designations B1 and D1 define V to be equal to the manufacturer-filled or user-filled
set
volumes. System designations B2 and D2 define V to be equal to a single pre-set dose representing a portion
set
of the manufacturer-filled or user-filled volumes. In the case of last-dose accuracy assessments for system
designations A and C, V is equal to V , the TP, or dose error (evaluated over a range of doses within a
set mid
specified percentage of the TP).
V The volumetric measurement value for a given V , expressed in millilitres.
meas set
G The gravimetric measurement value for a given V , expressed in grams.
meas set
r Density, expressed in grams per millilitre.
p Probability content.
Y Number of pens required for a given test.
R Number of replicates required for a given test. A replicate is a random sequence of V , V , and
min mid
V . There are six possible replicates.
max
n
Number of measurements, V , to be made for each V .
meas set
x
The sample mean; when based on a random sample, an estimate of the true mean:

xV= /n
∑ meas
.
s The sample standard deviation; when based on a random sample, an estimate of the true standard
deviation:
12/
 
sV=−()xn/( −1)
∑ meas
 
.
ISO 11608-1:2012(E)
k k value, or tolerance limit factor, determined from the confidence level (95 %), probability content, p,
and number of accuracy measurements, n, conducted at each dose setting.
k Actual k value, determined from the following equations:
act
Two-sided
 Ux− xL− 
() ()
Min ,
 
s s
 
 
One-sided
 xL−   Ux− 
() ()
   
s s
   
   
or
k Target k value, found from the look-up table in ISO 16269-6:2005 (Annexes D and E), or Annex B.
tar
DR Dialling resolution, the minimum dialling increment of the NIS.
a Absolute error, in millilitres, used to define the upper and lower specification limits for a pre-set dose
in absolute terms.
b Relative error, as a percentage, used to define the upper and lower specification limits for a pre-set
dose in relative terms.
TP The transition point volume, in millilitres, at which the upper and lower specification limits for V
set
change from absolute terms to relative terms (i.e. V where a and b are equal):
set
TP = (100 × a)/b
USL Upper specification limit for a given V .
set
LSL Lower specification limit for a given V .
set
RF Radio frequency
5 Requirements
5.1 General
Companies wishing to verify a NIS shall ensure that the system meets the requirements of this part of
ISO 11608. In addition, companies shall ensure that the appropriate components (e.g. needles and containers)
and features (e.g. electromechanical drive systems and automated functions) specified for use in the system
satisfy the relevant parts of ISO 11608.
5.2 System designations
Given the differences in device designs and containers (e.g. multi-dose, single dose with partial evacuation,
and single-dose with full evacuation), the following system designations are provided to clearly associate the
appropriate test and dose accuracy method with the injection system under consideration. Containers can be
either manufacturer-filled or user-filled.
Table 1 shows the various needle-based injector system designations.
4 © ISO 2012 – All rights reserved

ISO 11608-1:2012(E)
Table 1 — System designations
Multi-dose container Single-dose container
A B1
Needle-based injection device with replaceable container. Needle-based injection device with replaceable container.
Each container holds multiple doses, the size of which may Each container holds a single dose, whereby the entire
be fixed or variable (pre-set by the user). deliverable volume is expelled.
B2
Needle-based injection device with replaceable container.
Each container holds a single dose, whereby a portion of
the deliverable volume is expelled.
C D1
Needle-based injection device with integrated non- Needle-based injection device with integrated non-
replaceable container. replaceable container.
Each container holds multiple doses, the size of which may Each container holds a single dose, whereby the entire
be fixed or variable (pre-set by the user). deliverable volume is expelled.
D2
Needle-based injection device with integrated non-
replaceable container.
Each container holds a single dose, whereby a portion of
the deliverable volume is expelled.
5.3 Risk analysis requirements
The manufacturer shall conduct risk assessments in accordance with ISO 14971. These risk assessments shall
consider all aspects of the development, manufacture and intended use of the NIS for medical use. The NIS
shall conform to the usability requirements specified in IEC 62366.
5.4 Uncertainty of measurement and conformance with specifications
Measurement uncertainty shall be evaluated and expressed by the laboratory performing the test in accordance
with ISO/IEC Guide 98-3 (GUM).
Conformance with specifications is established in accordance with ISO 14253-1.
5.5 General design requirements
a) The container holder shall allow visibility of the deliverable volume. The manufacturer shall determine, by
risk analysis, if a residual scale is required and how much of the deliverable volume shall be visible.
b) With the exception of system designations B2 and D2, NISs shall be designed in such a way that they are
able to accurately deliver the entire labelled volume from the container for which they are designed.
c) NISs with system designation B1 where the container is user-filled shall be designed in such a way that they
are capable of delivering the maximum volume needed to fill the container, as specified in the labelling.
d) When the injection system requires the user to pre-set the dose, the injector shall provide an indication
of the dose that has been set. This information can be displayed in drug-specific units (e.g. millilitres,
milligrams, international units) or in a setting specified by the physician (e.g. number, letter, percentage) as
appropriate for the drug to be delivered. When the dose has been pre-set by the manufacturer, the dose
can be indicated by the device or the system labelling, as appropriate.
e) There shall be an indication of the pre-setting by visual and either tactile and/or audible means.
f) The NIS shall indicate, at least by visual means, that it is ready for injection.
ISO 11608-1:2012(E)
g) The state of the NIS, when ready to deliver a dose, shall be different from its state when the dose has been
delivered. The difference shall be visible.
h) The NIS shall indicate, by visual, audible or tactile means, or any combination of these, that the injection
stroke has been completed.
i) NISs with system designation D2 shall be designed in such a way that it is impossible to deliver the
remaining volume following the actuation and that it is impossible to reactivate the device.
j) Variable multi-dose NISs (system designations A and C) shall be designed so that they:
1) do not allow a larger dose to be pre-set than is left in the container, or
2) do not allow dose delivery if the pre-set amount exceeds the amount of medicinal product left in the
container, or
3) indicate the amount of medicinal product delivered, or
4) indicate the amount of medicinal product not delivered (of the pre-set dose).
k) Fixed multi-dose NISs shall not allow pre-setting of the dose if a volume that is insufficient for the full fixed
dose remains.
l) The NIS shall be designed to function with its specified needles. ISO 11608-2 provides guidance for needles.
m) The NIS shall be designed to function with its specified containers. ISO 11608-3 provides guidance
for containers.
n) If the NIS is an electromechanically driven injector, the requirements of ISO 11608-4 and ISO 11608-5
shall be fulfilled.
o) If the NIS contains electronic or electromechanical components and/or software, the requirements of
ISO 11608-4 shall be fulfilled.
p) To avoid inadvertent disabling of the NIS containing replaceable batteries, it shall not be possible to remove
the batteries unless two independent movements are applied.
q) If designed with small parts that might be swallowed, the NIS labelling shall include warnings preventing
access by children under the age of 3 years.
r) If the NIS contains batteries, it shall be designed to allow the user to determine the state of the power supply.
s) If the NIS contains software, the software shall be designed based on a life-cycle model in accordance
with IEC 62304. The NIS shall fulfil the applicable requirements of IEC 62304 including connection to
other equipment.
t) The risk analysis shall take into consideration the use of alarms, as appropriate, as described
in IEC 60601-1-11.
u) Adverse effects of the medicinal product contact with the NIS shall be assessed and mitigated through
risk assessment.
v) Biological requirements of the NIS shall be established in accordance with ISO 10993-1.
NOTE It is preferable that the design process incorporate environmentally conscious design (see IEC 60601-1-9).
w) Where requirements in this part of ISO 11608 provide a test method without acceptance criteria, the
manufacturer shall establish a specification and acceptance criteria appropriate for the intended use of the
device, using a risk-based approach (consistent with ISO 14971 and IEC 62366).
6 © ISO 2012 – All rights reserved

ISO 11608-1:2012(E)
6 Reagent and apparatus
6.1 General
Any suitable test system can be used, when the required accuracy (calibration) and precision (Gauge R&R)
can be obtained. The repeatability and reproducibility (Gauge R&R) of the test apparatus shall be no greater
than 20 % of the allowed tolerance range for any given measurement. For destructive test measurements,
the Gauge R&R shall be no greater than 30 % of the allowed tolerance range. At a minimum, the Gauge R&R
should cover ±2 standard deviations (thereby covering approximately 95 % of the variation).
EXAMPLE A measurement system with a measurement specification limit of ±0,01 ml (range of 0,02 ml) comes out of the
Gauge R&R with a Gauge R&R/tolerance range ratio of 20 %, which means that the Gauge R&R (4 standard uncertainties)
equals 0,02 ml/5 = 0,004 ml. The uncertainty of the measurement is ±2 standard deviations (GUM), which equals 0,002 ml.
All doses, V , delivered are recorded gravimetrically, G , (expressed in grams). These recordings are
set meas
converted to volumes, V , by using the density, r, (expressed in grams per millilitre) for the test liquid at
meas
environmental conditions. The following equation can be used to convert gravimetric measurements to volumetric:
V = G /r (1)
meas meas
6.2 Test liquid
The test liquid is the original medicinal product intended to be injected by the NIS, or a liquid with similar
physical properties.
6.3 Balance
The balance shall have a resolution of 1 % of the minimum dose delivery.
6.4 Test surface for free-fall testing
The test surface shall be made of smooth, hard, rigid steel of 3 mm thickness, backed by wood whose thickness
is greater than 10 mm.
7 Determination of dose accuracy
7.1 General
Determination of dose accuracy is a required element that shall be met by the NIS, as defined by the design
specifications. Where regulatory requirements are more stringent, or where the risk assessment dictates, the
dose accuracy acceptance criteria shall be adjusted to ensure the system meets them. If these regulatory
requirements are less stringent, then the manufacturer can include them in the risk assessment as justification
for widening the acceptance criteria.
Dose accuracy is determined by selecting and testing a variable number of NISs. The number depends on the
container and accuracy requirements for a given test. In the specific instance of user-filled single-dose needle-
based systems designed to fully empty the container, accuracy can be evaluated as dose-delivery efficiency.
In the instance of manufacturer-filled single-dose NISs designed to fully empty the container, accuracy can be
evaluated as the minimum deliverable dose (i.e. the labelled volume).
Assuming that the accuracy measurements are normally distributed (or can be transformed to normal) and
that each measurement is independent, the following methods enable accuracy measurements to be used
as the basis for determining a statistical tolerance interval for each V , i.e. an interval where there is a fixed
set
probability (confidence level) that the interval will contain at least a proportion (probability content, p) of the
true population from which the sample is taken. The statistical tolerance interval is two-sided or one-sided
(e.g. dose efficiency and minimum-deliverable-dose assessments) and the limits of the interval are called
“statistical tolerance limits” or “natural limits of the process”.
ISO 11608-1:2012(E)
Table 2 provides a summary, by system designation, of the subclauses that are required in order to complete
an assessment of dose accuracy.
Table 2 — Dose accuracy assessment matrix
System designation
Dose accuracy matrix
A B1 B2 C D1 D2
Determine doses needed 7.3.1 7.3.2 7.3.2 7.3.1 7.3.2 7.3.2
Determine accuracy limits 7.4.2.1 7.4.2.2 7.4.2.1 7.4.2.1 7.4.2.2 7.4.2.1
Determine last-dose accuracy limits (variable dose only) 7.4.3 N/A N/A 7.4.3 N/A N/A
Calculate last-dose error (variable dose only) 10.3 N/A N/A 10.3 N/A N/A
Calculate dose efficiency (user-filled only) N/A 7.4.4 N/A N/A 7.4.4 N/A
Calculate tolerance intervals 7.4.5 7.4.5 7.4.5 7.4.5 7.4.5 7.4.5
7.2 Dosing regions
For multi-dose containers, the dosing regions are as defined in Figure 1.
12 3
Key
1 front 1/3
2 middle 1/3
3 rear 1/3
Figure 1 — Schematic showing three divisions
NOTE 1 If the maximum dose setting is greater than one third of the labelled volume, the container can be divided into
two sections as opposed to three.
NOTE 2 The illustrated container design is an example. Different container designs require verification that all three
regions (full, half-way used and almost empty) perform predictably.
7.3 Dose settings
7.3.1 Multi-dose containers (system designations A and C)
7.3.1.1 Variable dose devices
a) Three dose sizes are used; V is equal to one of minimum (V ), midpoint (V ) and maximum (V ).
set min mid max
b) One dose of each V is taken from each container.
set
c) All replicate sequences are tested (V , V , V ; V , V , V ; etc.). Full details are given in Annex A.
min mid max max min mid
d) Dosing is designed such that V is delivered from the front 1/3, middle 1/3 and rear 1/3 divisions of the
set
container closure, as shown in Figure 1, or is uniformly sampled from regions representing the deliverable
volume of the container, as determined in the risk assessment.
8 © ISO 2012 – All rights reserved

ISO 11608-1:2012(E)
7.3.1.2 Fixed-dose devices
a) One dose size is used; V is equal to the fixed dose.
set
b) One dose is taken from each container.
c) Dosing is designed such that V is delivered from the front 1/3, middle 1/3 and rear 1/3 divisions of the
set
container closure, as shown in Figure 1, or is uniformly sampled from regions representing the deliverable
volume of the container, as determined in the risk assessment.
7.3.2 Single-dose containers (system designations B and D)
7.3.2.1 Complete evacuation
For system designations B1 and D1, one dose is used; V is equal to the delivered dose.
set
7.3.2.2 Partial evacuation
7.3.2.2.1 Variable dose devices
Three dose sizes are used; V is equal to minimum (V ), midpoint (V ) and maximum (V ).
set min mid max
7.3.2.2.2 Fixed dose devices
One dose size is used; V is equal to the pre-set dose.
set
7.4 Assessment
7.4.1 General
To pass the dose accuracy requirement, there shall be a 95 % confidence that at least the probability
content, p, of all doses delivered will fall within the proposed upper and lower specification limits for the three
dose settings (one dose setting in the case of fixed-dose systems).
To pass the minimum deliverable dose requirement (for system designations B1 and D1 with manufacturer-filled
containers), there shall be a 95 % confidence that at least the probability content, p, of all doses delivered are above
the lower specification limit, which is defined by the minimum deliverable dose specified by the drug labelling.
To pass the dose delivery efficiency requirement (for system designations B1 and D1 with user-filled containers),
there shall be a 95 % confidence that at least the probability content, p, of all delivery efficiencies are above the
lower specification limit for dose efficiency as determined from the risk assessment. Calculate dose delivery
efficiency in accordance with 7.4.4.
To pass the last-dose accuracy requirement (for system designations A and C), where the device allows setting
a dose greater than the remaining volume, there shall be a 95 % confidence that at least the probability
content, p, of all dose error calculations will fall within the proposed upper and lower specification limits for
allowable dose error.
Only one dose per injector can be used for each V for a given test.
set
Probability content, p, is defined by a specific test and is shown in Table 3.
7.4.2 Determination of dose accuracy limits
7.4.2.1 Two-sided dose accuracy limits (system designations A, C, B2, D2)
ISO 11608-1:2012(E)
Rule 1: Absolute error, a, expressed in millilitres, is equal to the minimum dialling resolution, DR, of the device
and is used when V is equal to or below the TP.
set
Rule 2: Relative error, b, expressed as a percentage, is equal to 5 % of V and is used when V is above
set set
the TP.
TP is equal to V where a and b are equal:
set
1 00 × α
TP =
β
Rule 3: For fixed-dose devices, the absolute error, a, is 0,01 ml if the fixed dose is below 0,2 ml and 5 % if the
fixed dose is above 0,2 ml.
EXAMPLE 1 For DR equal to 0,01 ml, a is 0,01 ml, b is 5 % and, therefore:
1 00 × 100,
TP = = 02, 0
EXAMPLE 2 For DR equal to 0,005 ml, a is 0,005 ml, b is 5 % and, therefore:
1 00 × 0,005
TP = = 01, 0
EXAMPLE 3 The upper and lower specification limits are calculated as follows:
If V ≤ TP, then:
set
U = V + a;
set
L = V - a.
set
If V > TP, then:
set
U = V + (b ⋅ V )/100;
set set
L = V - (b ⋅ V )/100.
set set
For system designations A, C, B2 and D2, if, according to the manufacturer’s risk assessment, the intended
dose sizes and accuracy requirements are more appropriately specified individually (i.e. rules 1, 2 and 3 are not
applied) rather than by absolute or relative ranges, the dose sizes tested and their specification limits shall be
specified in the labelling. In such a case, the specification limits can be no greater than the DR of the needle-
based system. For system designation D2, the dosing resolution requirement does not apply.
For system designations A and C, if, according to the manufacturer’s risk assessment, a specific dose is to be
treated differently from all other doses (e.g. first dose when the intended use of the system does not require
priming), then (after performing dose accuracy as described above) give special consideration when analysing
those specific data points:
a) each data point from the specific doses of a container shall satisfy t
...