ISO/DIS 11040-8

ISO/TC 76

Secretariat: DIN

Date: 2025-05-15

Prefilled syringes —

Part 8:
Requirements and test methods for finished prefilled syringes

DIS stage

Warning for WD’s and CD’s

This document is not an ISO International Standard. It is distributed for review and comment. It is subject to change without notice and may not be referred to as an International Standard.

Recipients of this draft are invited to submit, with their comments, notification of any relevant patent rights of which they are aware and to provide supporting documentation.

© ISO 2025

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Contents

Foreword

Introduction

Scope

Normative references

Terms and definitions

User requirements

Definition of intended use

Risk management

Application of usability engineering

System characterization

Critical dimensions

Description of components and materials

Description of the contents of the finished prefilled syringe

Functional performance requirements

General

Break-loose and extrusion forces

Flange breakage resistance

Front end closure pull-off forces and torques

Connectivity with small-bore connectors

Residual volume

Needle penetration force

Needle pull-out force

Sharps injury protection requirements

Liquid leakage resistance

Markings

Administration time with defined constant test force

Pharmaceutical requirements

General

Interactions between container closure system and contents (injectable product)

Biological hazards and microbiological requirements

Container closure integrity

Deliverable volume

Particles (visible and sub-visible)

Documentation

(normative) Test method for break-loose and extrusion forces of finished prefilled syringes

(normative) Test method for residual volume of finished prefilled syringes

(informative) Test methods for liquid leakage resistance of finished prefilled syringes

(informative) Test method for administration time with defined constant test force

(informative) Unintended plunger stopper movement of finished prefilled syringes

Bibliography

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.

The procedures used to develop this document and those intended for its further maintenance are described in the ISO/IEC Directives, Part 1. In particular the different approval criteria needed for the different types of ISO documents should be noted. This document was drafted in accordance with the editorial rules of the ISO/IEC Directives, Part 2 (see www.iso.org/directives).

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. Details of any patent rights identified during the development of the document will be in the Introduction and/or on the ISO list of patent declarations received (see www.iso.org/patents).

Any trade name used in this document is information given for the convenience of users and does not constitute an endorsement.

For an explanation on the meaning of ISO specific terms and expressions related to conformity assessment, as well as information about ISO’s adherence to the World Trade Organization (WTO) principles in the Technical Barriers to Trade (TBT) see the following URL: www.iso.org/iso/foreword.html.

The document was prepared by ISO/TC 76, Transfusion, infusion and injection, and blood processing equipment for medical and pharmaceutical use.

This second edition cancels and replaces the first edition (ISO 11040-8:2016), which has been technically revised.

The main changes are as follows:

• The entire document was revised for consistent use of terms and language.
• A basic statistical approach for design verification testing of functional performance requirements was included in the Clause and in Clause 6.1.
• Single Terms and definitions (Clause 3) were revised, deleted or included.
• The Definition of intended use (Clause 4.1) was revised for clarity.
• Break-loose and extrusion forces (Clause 6.2) was revised, and it was clarified to perform testing with the finished prefilled syringe as intended for use. The normative Annex A with the respective test method was introduced.
• The former clause for burst resistance was removed; parts of its contents were included in the revised clause for Liquid leakage resistance (Clause 6.10).
• Flange break resistance (Clause 6.3) was revised to include specification limits and a test method reference. It was clarified to perform testing with the finished prefilled syringe, with further instructions. Front end breakage resistance requirements were deleted.
• Front end closure pull-off forces and torques (Clause 6.4) was revised to clarify test methods and specification limits.
• Connectivity with small-bore connectors (Clause 6.5) was clarified to perform testing with the finished prefilled syringe as intended for use.
• Residual Volume (Clause 6.6) was clarified to perform testing with the finished prefilled syringe as intended for use. The normative Annex B with the respective test method was introduced.
• Needle penetration force (Clause 6.7) and Needle pull-out force (Clause 6.8) were revised to clarify test methods and specification limits.
• Liquid leakage resistance (Clause 6.10) was combined with parts of the contents of former clause for burst resistance and revised. The informative Annex C with the respective test methods was introduced.
• A new clause for Administration time with defined constant test force (Clause 6.12) was included. The informative Annex D with the respective test method was introduced.
• Where applicable, references to pharmacopoeias were included in the subclauses to Pharmaceutical requirements (Clause 7).
• The informative Annex E for Unintended plunger stopper movement of finished prefilled syringes was introduced.

A list of all parts in the ISO 11040 series can be found on the ISO website.

Introduction

Historically, injectable (parenteral) liquid pharmaceutical products have been mainly provided in primary containers (i.e. ampoules and vials) which required the liquid to be transferred into a hypodermic syringe and combined with the appropriate injection needle before administration. This procedure is not only time-consuming, but also presents a multitude of possibilities for contamination and use errors.

Over the past decades, the presentation of liquid pharmaceutical products in prefilled syringes for single use, many with staked needles, has become more prevalent. The simplicity of use that is provided not only benefits their use in the clinical setting, but also enables these to be used by lay users in a home setting.

The standardization of the requirements for prefilled syringes has been addressed by ISO/TC 76 in two ways:

• the specifications of the components of the prefilled syringe prior to filling are included in the previous parts of the ISO 11040 series;
• the requirements for the final prefilled syringe, presented to the user as a finished product, are addressed in this document.

Finished prefilled syringes can require marketing authorization as a medicinal product, in some regions as a combination product or as a medical device, depending on their contents and the intended use. The syringe plays a dual role in the finished prefilled syringe — as a container closure system and as a delivery device. Safety, functional performance and usability need to be considered, also in case of intended use in combination with pre-attached, co-packaged or cross-referenced additional components and/or devices. This document addresses the syringe and its contents as a system, with the intent to ensure the successful application for its intended use. In this context, the minimal configuration of a finished prefilled syringe is the syringe barrel filled with the intended contents (i.e. the injectable product) and closed with a front end closure and a plunger stopper (sealing the back end). Additional components (e.g. either attachment of a needle for single use or assembly of a plunger rod or both) may need to be added by the manufacturer or user to make it ready for administration by manual injection according to its intended use. Alternatively, such a finished prefilled syringe may be combined by the manufacturer or user with a device for administration by a needle-based injection system according to its intended use.

This document includes requirements for the design verification of the finished prefilled syringe’s functional performance requirements in accordance with its design specifications. The test methods and other aspects of testing described in this document are intended to verify the design at a confidence level of 95 %. They are not intended to stipulate acceptance criteria for lot release (e.g. acceptable quality limits, probability content, probability or other) in the context of manufacturing processes. Testing at component level can be sufficient for design verification of specific requirements if the influence of processing on the finished prefilled syringe can be ruled out.

There are other international and national standards and guidance publications and, in some countries, national regulations that are applicable to medical devices and medicinal products and combinations thereof. Their requirements might supersede or complement this document. Developers and manufacturers of finished prefilled syringes are encouraged to investigate and determine whether there are any other requirements relevant to the safety and functional performance or marketability of their products.

Prefilled syringes —

Part 8:
Requirements and test methods for finished prefilled syringes

This document is applicable to aseptically processed or terminally sterilized finished prefilled syringes (intended for single use only) based on components addressed in ISO 11040-4 or ISO 11040-6, together with a front end closure and a plunger stopper (sealing the back end), for parenteral preparations with focus on quality, functional performance and safety requirements, as well as relevant test methods.

Finished prefilled syringes which have undergone an additional preparation step by the user before injection (e.g. diluent-containing syringes that have been emptied for reconstitution and in which the reconstituted injectable product has been aspirated after reconstitution) are excluded from the scope of this document.

NOTE 1 This document can also be used as a guidance for other types, designs and/or sizes of finished prefilled syringes, e.g. dual chamber prefilled syringes.

NOTE 2 For finished prefilled syringes that are used in needle-based injection systems, see also references ISO 11608-1:2022^[1], ISO 11608-2^[2], ISO 11608-3^[3], ISO 11608-4^[4], ISO 11608-5^[5], ISO 11608-6^[6], ISO 11608-7^[7]).

NOTE 3 Attention is drawn to applicable national or regional regulations and pharmacopoeias such as Ph.Eur.^[1]1), USP^[2]2) or JP^[3]3).

NOTE 4 Finished prefilled syringes for parenteral preparations which are medical devices or which, according to the principal mode of action of the product (i.e. the means by which the product achieves its principal intended action), are borderline between medical devices and medicinal products fall within in the scope of this document, even if they are not always regulated as medicinal products.

The following documents are referred to in the text in such a way that some or all of their content constitutes requirements 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 7864, Sterile hypodermic needles for single use — Requirements and test methods

ISO 7886-1:2017, Sterile hypodermic syringes for single use — Part 1: Syringes for manual use

ISO 11040-4, Prefilled syringes — Part 4: Glass barrels for injectables and sterilized subassembled syringes ready for filling

ISO 11040-4:2024, Prefilled syringes — Part 4: Glass barrels for injectables and sterilized subassembled syringes ready for filling

ISO 11040-5, Prefilled syringes — Part 5: Plunger stoppers for injectables

ISO 11608-1:2022, Needle-based injection systems for medical use — Requirements and test methods — Part 1: Needle-based injection systems

ISO 23908, Sharps injury protection — Requirements and test methods — Sharps protection features for single-use hypodermic needles, introducers for catheters and needles used for blood sampling

IEC 62366-1, Medical devices — Part 1: Application of usability engineering to medical devices

ISO 11040-5, Prefilled syringes — Part 5: Plunger stoppers for injectables

ISO 11040-6, Prefilled syringes — Part 6: Plastic barrels for injectables

ISO 23908, Sharps injury protection — Requirements and test methods — Sharps protection features for single-use hypodermic needles, introducers for catheters and needles used for blood sampling

ISO 80369-1, Small-bore connectors for liquids and gases in healthcare applications — Part 1: General requirements

ISO 80369-7, Small-bore connectors for liquids and gases in healthcare applications — Part 7: Connectors with 6% (Luer) taper for intravascular or hypodermic applications

ISO 80369-20, Small-bore connectors for liquids and gases in healthcare applications — Part 20: Common test methods

For the purposes of this document, the following terms and definitions apply.

finished prefilled syringe

prefilled container closure system for parenteral preparations as marketed, including, e.g. filling with the intended contents and assembly of additional components, aseptic processing or terminal sterilization as applicable, and final packaging by the manufacturer (3.2)

manufacturer

natural or legal person holding the licence (e.g. marketing authorisation or other as applicable) for the injectable product with responsibility for the design, development, manufacture, packaging, and labelling of a finished prefilled syringe (3.1), before it is placed on the market or put into service, regardless of whether these operations are carried out by that person or on that person's behalf by a third party

needle-based injection system

injection system intended for parenteral administration of medicinal products using a needle or cannula and a multi-dose or single-dose container

[SOURCE: ISO 11608-1:2022, 3.15]

user

patient or health care giver (e.g. clinical personnel, doctor, lay person) who handles (e.g. prepares, applies, disposes of) the finished prefilled syringe (3.1)

The manufacturer shall define the intended use of the finished prefilled syringe. Aspects to be considered shall include the following:

• intended medical indication and criticality of administration, e.g. in emergency situations;
• patient population including their health status and the user profile;
• the route and frequency of administration and the target tissue;
• the use environment, e.g. clinical or home setting;
• additional components and/or devices (see 5.2.4) that are used for application, e.g. plunger rods/piston rods, finger flange extensions/backstops, sterile hypodermic needles, needleless small bore connectors, filters, tubing, vial adapters, needle-based injection systems;
• characteristics of the expected environmental conditions during transport, storage and use;
• operating principle if applicable, and interactions between user, environment and the finished prefilled syringe including additional components and/or devices, if applicable.

Manufacturers shall follow a risk-based approach during the design, development, manufacture and life cycle of the finished prefilled syringe like exemplarily described by ISO 14971^[8]. Risk management shall consider the intended use, interactions between container closure system and contents, and environmental conditions. This can result in product-specific requirements and test methods that differ from what is outlined in this document.

If the finished prefilled syringe is intended to be used in combination with pre-attached, co-packaged or cross-referenced components and/or devices, the manufacturer shall ensure that the whole combination, including the connectivity with other components and/or devices, is safe, usable and does not impair the specified functional performance of the single components and/or devices.

NOTE For risk management of manufacturing processes, see reference ^[9].

The usability of the finished prefilled syringe shall be considered and validated according to a process conforming to IEC 62366-1.

NOTE 1 For further information on usability engineering of medical devices, see reference ANSI/AAMI HE75^[10].

NOTE 2 The instructions for use are part of the user interface to be validated in the usability testing.

Critical dimensions shall be defined considering the intended use of the finished prefilled syringe. Particular attention shall be paid to, but not limited to, the following:

• interfaces with users;
• interfaces and connectivity with other components (e.g. needleless small bore connectors or sterile hypodermic needles);
• interfaces with other devices (e.g. sharps injury protection features or needle-based injection systems);
• plunger stopper position depending on the intended use (e.g. for manual injection or for use in needle-based injection systems) (see Figure 1).

Figure 1 shows examples of measuring the plunger stopper position for finished prefilled syringes.

Key

Figure 1 — Examples of measuring the plunger stopper position for finished prefilled syringes

The selected components and materials shall be suitable for the intended manufacturing processes (e.g. terminal sterilization process if applicable).

The interfaces with other components and/or devices (e.g. tubing or needle-based injection systems) shall be considered.

ISO 11040-4 and ISO 11040-6 shall apply.

The syringe barrel can include a staked needle. The needle dimensions including inner and outer diameters (gauge) and exposed needle length shall be consistent with the intended use, considering e.g. route of administration, use in needle-based injection systems and content properties.

ISO 11040-5 shall apply.

NOTE 1 The dimensional requirements of ISO 11040-5 are not applicable to barrier-coated plunger stoppers.

NOTE 2 The dimensional requirements of ISO 11040-5 apply to component level. Plunger stopper dimensions are different in compressed and uncompressed state.

Additional components and/or devices required for or supporting the intended use can include but are not limited to the following:

• plunger rods/piston rods;
• add-on finger flanges/backstops;
• sterile hypodermic needles with 6 % Luer conical fitting in accordance with ISO 7864;
• sharps injury protection features (integrated or combined with the finished prefilled syringe prior to use) in accordance with ISO 23908;
• other devices with small bore connectors with 6 % Luer conical fitting, for example
• filters;
• tubing;
• vial adapters.

Finished prefilled syringes can be used in needle-based injection systems if appropriately qualified. The interfaces with the relevant components and/or devices shall be considered.

Critical quality attributes of the contents shall be defined. Those relevant for interactions between container closure system and contents (injectable product) and/or affecting administration can include but are not limited to the following:

• viscosity;
• density;
• surface tension;
• pH;
• osmolality;
• filling volume including filling tolerances;
• head space volume and composition.

These quality attributes are temperature dependent and can change over time.

Based on the intended use (see 4.1) the manufacturer shall ensure that the finished prefilled syringe fulfils the corresponding functional performance requirements until the end of product shelf life. The finished prefilled syringe shall be tested in stability studies at time points up to the end of product shelf life. The tests described in clauses 6.2 to 6.12 should be considered but are not necessarily all inclusive.

NOTE For conducting stability studies, see reference ^[11].

The sampling plans for design verification testing should ensure a probability content level, determined to be appropriate by risk assessment, with a confidence level of 95 %. The confidence level of 95 % means that there is a 5 % risk of incorrectly concluding that the testing has demonstrated the reliability level based on the specific units in the testing sample. The reliability level is the reliability goal or target level of reliability that the product is expected to achieve. The confidence level of 95 % is the minimum confidence level commonly used. The typical choice of reliability level is 90 %, 95 % or 99 %, which is determined by the level of risk that can be accepted depending on the intended use of the product.

EXAMPLE If a process has achieved a 95 % confidence and a 99 % reliability, it has demonstrated with a 95 % confidence that at least 99 % of the units in the population are conforming to the requirements.

A sample size of 30 units is considered statistically significant as it fulfils the following criteria:

• The central limit theorem states that the distribution of sample means is normally distributed or transformed if the sample size is 30 units or more. This means that the mean value of a sample is close to the mean value of the population, regardless of the distribution of the data.
• The law of large numbers also states that the more data points a sample contains, the more accurate are the results. With fewer than 30 data points, it is difficult to draw reliable conclusions as there is not enough data to reduce variability and bias.
• In addition, a sample size of 30 units can provide a more complete picture of a histogram that reveals the underlying distribution of the data.

Specification limits for the functional parameters shall be defined based on the intended use. Testing at component level can be sufficient for design verification of specific requirements if the influence of processing on the finished prefilled syringe can be ruled out.

Break loose and extrusion forces testing shall be conducted with the finished prefilled syringe as intended for use (e.g. with attached needle or with assembled plunger rod). Finished prefilled syringes intended for administration by manual injection shall be assembled with the same plunger rod as for application according to the intended use (i.e. the plunger rod the product is placed on the market with); for those intended for administration by a needle-based injection system the plunger rod of the used injection system may be used if applicable, or an appropriate substitute plunger rod (e.g. of the used tensile and compression testing machine). For the tests, the temperature of the contents shall be as for application according to the intended use.

It shall be considered that the break-loose and extrusion forces can change over product shelf life depending on environmental conditions.

The finished prefilled syringe shall be tested according to Annex A for break-loose and extrusion forces with constant test speed. The test speed shall be defined based on the intended use, considering injection duration requirements with the impact of different syringe sizes, filling volumes, needle dimensions (in particular the inner diameter) as well as the content properties.

For flange breakage resistance, ISO 11040-4:2024, 5.4.4, including the stated specification limits as minimum requirements, applies. The specification limits may be adapted based on the intended use. The test method ISO 11040-4:2024, C.1 is applicable and is performed with the finished prefilled syringe. For this purpose, the tip cap or needle shield (or other front end closure) is removed from the finished prefilled syringe, the plunger stopper is manually depressed (i.e. the syringe emptied) and may remain in the syringe but the plunger rod is removed to allow the use of the loading pin required by the test method instead.

NOTE For finished prefilled syringes that are used in needle-based injection systems, the stated specification limits can be adapted to higher values depending on the intended use.

The following test methods apply:

• ISO 11040-4:2024, G3 Luer lock adaptor collar pull-off force; the specification limits of ISO 11040-4:2024, 6.5.3.5 apply
• ISO 11040-4:2024, G4 Luer lock adaptor collar torque resistance; the specification limits of ISO 11040-4:2024, 6.5.3.5 apply
• ISO 11040-4:2024, G5 Luer lock rigid tip cap unscrewing torque; according specification limits shall be defined based on the intended use
• ISO 11040-4:2024, G6 Pull-off force of the tip cap or the needle shield; according specification limits shall be defined based on the intended use

Additional small-bore connectors to be used in the fluid path of the finished prefilled syringe according to the intended use shall be tested for connectivity and leakage following ISO 80369-1, ISO 80369-7 and ISO 80369-20. The finished prefilled syringe with the intended contents shall be tested with the same additional small-bore connectors as for application according to the intended use (either pre-attached, co-packaged or cross-referenced).

Additionally, see ISO 11040-4 and ISO 11040-6 for testing Luer connectors/Luer lock adapters.

The residual volume (dead space) of the finished prefilled syringe shall be tested according to Annex B with the intended contents and in combination with additional components and/or devices as intended for use. For the test, the temperature of the contents shall be as for application according to the intended use. The residual volume can depend on the content properties (e.g. viscosity) and, for example, on the needle dimensions (in particular the inner diameter). It is determined, for example, to define a potential overfill for the manufacturing process in order to achieve the correct deliverable volume (see 7.5).

Needle penetration force for finished prefilled syringes with a staked needle shall be tested according to ISO 11040-4:2024, Annex F. The specification limits for needle penetration force stated in ISO 11040-4:2024, 6.5.2.4, apply as minimum requirements.

NOTE Terminal sterilization using moist heat can affect the, for example, silicone lubrication layer on the needle.

Needle pull-out force for finished prefilled syringes with a staked needle shall be tested according to ISO 11040-4:2024, Annex G.1. The specification limits for needle pull-out force stated in ISO 11040-4:2024, 6.5.2.6, apply as minimum requirements.

If the finished prefilled syringe has integrated sharps injury protection features (or is combined with a sharps injury protection device before use), it shall meet the requirements of ISO 23908.

The finished prefilled syringe should be tested in accordance with the procedures described in Annex C for liquid leakage resistance by applying an axial force to the plunger stopper through the same plunger rod as for application and under the same conditions according to the intended use, consistent with the maximum force generated during administration.

The finished prefilled syringe should be tested with the intended front end closure in accordance with the procedure for liquid leakage at the plunger stopper [Clause C.2].

When used for example in needle-based injection systems, significantly higher forces can act on finished prefilled syringes compared to manual injection, whereby the increased pressure in the syringe can lead to bursting under certain circumstances. Thus, the finished prefilled syringe should be tested in accordance with the procedure for burst resistance [Clause C.3] with an additional, irreversible sealing of the front end (i.e. replacing the front end closure). Test pressures and acceptance criteria shall be defined according to the requirements of the needle-based injection system with adding to the test pressure a safety margin of 20 %.

All graduation marks or indicator lines (e.g. preprinted directly on the syringe barrel or printed on a label) shall be verified to be as accurate as appropriate for the intended use.

NOTE If graduation marks or indicator lines are used (e.g. preprinted directly on the syringe barrel or printed on a label), ISO 7886-1:2017, Table 1, can be considered.

The administration of the injectable product is determined by the applicable time and required force. The administration time is of relevance when considering the capabilities of the intended users for manual injection or the functional force profile of the needle-based injection system. Applying a defined constant test force (or force profile if applicable) results in different injection speeds and administration times, which can be used to determine the suitability of the finished prefilled syringe for the intended use. Therefore, in addition to break-loose and extrusion forces (see 6.2), the finished prefilled syringe may be tested for characterization purposes in accordance with Annex D for administration time with a defined constant test force (or force profile if applicable).

Pharmaceutical requirements for injectable products are covered by national or regional regulations, standards such as pharmacopoeias and applicable guidelines. The container closure system shall be suitable for the intended contents (in terms of protection, safety, compatibility and functional performance), considering the intended use (e.g. transport, storage, administration). The tests in 7.2 to 7.6 shall be performed but are not necessarily all inclusive.

The contents of the finished prefilled syringe shall meet the specified quality attributes during transport, storage and use according to the manufacturer’s instructions throughout product shelf life. The impact of additional components and/or devices on the container closure system and contents during administration shall be considered.

The following aspects shall be considered but are not necessarily all inclusive:

• extractables and leachables migrating into the injectable product from components and the materials they are made of, e.g. glass, plastic, elastomer components (e.g. rubber), lubrication (e.g. free silicone), as well as from labels, but also residuals from forming, moulding, gluing, sterilization process, assembly process and the impurities and degradation products thereof;
• compatibility of the injectable product with container closure system components, e.g. loss of either assay or potency or both, adsorption, degradation, change of stability indicating quality attributes;
• effects of physical forces (e.g. shear or pressure) during administration on the quality of the injectable product.

NOTE Exemplary pharmacopoeial chapters for extractables and leachables testing are

• USP general chapters <1663> Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems and <1664> Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery Systems

Assessment of biological hazards shall be performed for the finished prefilled syringe following, e.g. ISO 10993-1^[12].

The container closure system shall maintain product sterility, achieved either by aseptic processing or by terminal sterilization, throughout product shelf life including transport and storage.

NOTE 1 See references ISO 13408-1^[13] for aseptic processing and ISO 17665^[14] for moist heat sterilization processes.

Sterility testing requirements are specified in applicable pharmacopoeias.

NOTE 2 Exemplary pharmacopoeial chapters for sterility testing are

• Ph.Eur. chapter 2.6.1. Sterility
• USP general chapter <71> Sterility Tests
• JP section 4.05 Sterility Test

Bacterial endotoxin limits are specified in pharmacopoeial requirements.

NOTE 3 Exemplary pharmacopoeial chapters for bacterial endotoxins testing are

• Ph.Eur. chapter 2.6.14. Bacterial endotoxins
• USP general chapter <85> Bacterial Endotoxins
• JP section 4.01 Bacterial Endotoxins Test

The container closure system sealing surfaces shall ensure integrity of the finished prefilled syringe throughout processing including filling, terminal sterilization if applicable, further manufacturing steps (e.g. assembly or packaging), transport and storage to ensure product sterility and to prevent leakage of the contents until the end of product shelf life.

A suitable container closure integrity test method (e.g. physical or microbiological) shall be qualified and validated to assess the finished prefilled syringe.

NOTE To account for unintended plunger stopper movement caused by air pressure changes, see Annex E.

The deliverable volume from the finished prefilled syringe shall conform to the specified or labelled volume when used according to the instructions for use for the finished prefilled syringe considering applicable pharmacopoeial requirements. Deliverable volume testing of the finished prefilled syringe shall be performed with additional components and/or devices required for or supporting the intended use if they can impact the delivery function.

NOTE 1 Exemplary pharmacopoeial chapters for deliverable volume testing are

• Ph.Eur. chapter 2.9.17. Test for Extractable Volume of Parenteral Preparations
• USP general chapter <697> Container Content for Injections
• JP section 6.05 Test for Extractable Volume of Parenteral Preparations

NOTE 2 For clarity, the deliverable volume is not to be equated with the dose accuracy. For finished prefilled syringes that are used in needle-based injection systems, see ISO 11608-1:2022 and the other parts of the ISO 11608 series for dose accuracy and further requirements (ISO 11608-2^[2], ISO 11608-3^[3], ISO 11608-4^[4], ISO 11608-5^[5], ISO 11608-6^[6], ISO 11608-7^[7]).

The limits for particulate contamination of the injectable product are specified in applicable pharmacopoeias.

NOTE Exemplary pharmacopoeial chapters for particles testing are

• Ph.Eur. chapters 2.9.19. Particulate contamination: sub-visible particles and 2.9.20. Particulate contamination: visible particles
• USP general chapters <787> Subvisible Particulate Matter in Therapeutic Protein Injections, <788> Particulate Matter in Injections, <789> Particulate Matter in Ophthalmic Solutions and <790> Visible Particulates in Injections
• JP section 6.06 Foreign Insoluble Matter Test for Injections and 6.07 Insoluble Particulate Matter Test for Injections

Test reports shall include

• the objective,
• the acceptance criteria or specification limits with a justification if not specified in the standard,
• the sample size with a justification if not specified in the standard,
• the test methods,
• a discussion of any deviations, and
• the test results including a discussion thereof and a conclusion.

1. 
   (normative)
   
   Test method for break-loose and extrusion forces of finished prefilled syringes
   1. Purpose

This test method is used to measure the break-loose and extrusion forces of finished prefilled syringes with constant test speed. It assesses the quality and consistency of the, for example, silicone lubrication within the inner syringe barrel in combination with the plunger stopper and with the intended contents. The quality and consistency of the lubrication performance can be dependent on the test speed used. Additionally, the test method considers other parameters that can affect the break-loose and extrusion forces of finished prefilled syringes, for example different syringe sizes, filling volumes, needle dimensions (in particular the inner diameter) and injection duration requirements, as well as the content properties.

• 1. Materials
     1. Finished prefilled syringes as intended for use and as marketed, numbers as required.
     2. Additional components and/or devices required for or supporting the intended use (see 5.2.4) as applicable.
  2. Apparatus
     1. Universal tensile and compression testing machine conforming with the following:
• test speed adjustable as defined;
• force range up to 50 N or as appropriate.

NOTE 1 The test method specifications of test speed and force range are depending on the contents and the intended use.

NOTE 2 According to ISO 11040-4:2024, typically, a test speed of 100 mm/min (similar to ISO 7886-1:2017) is used for testing the glide force of empty syringe barrels.

NOTE 3 According to USP <382>, an elution speed of 3 – 4 mm/s (180 – 240 mm/min) is considered generally suitable for testing finished prefilled syringes with volumes of <5 ml in the test for elastomeric component functional suitability in parenteral product packaging/delivery systems.

NOTE 4 A test speed within the range of 2 – 7 mm/s (120 – 420 mm/min) is considered generally suitable for testing the break-loose and extrusion forces of finished prefilled syringes to be used in needle-based injection systems (e.g. auto-injectors).

NOTE 5 Contents that must be injected slowly due to administered volume, viscosity, needle dimensions, route of administration or patient sensitivity, can be tested at other test speeds.

Whenever a test method requires a peak measurement a higher sampling rate (in Hz) will result in a more accurate result. Therefore, a sampling rate of 500 Hz is recommended for such tests. For all other tests, a sampling rate of minimum 100 Hz is recommended.

• • 1. Syringe support and syringe adaptor plates, if needed, appropriately sized for the finished prefilled syringe to be tested.
  1. Procedure
     1. Remove the tip cap or needle shield (or other front end closure) from the finished prefilled syringe.
     2. Attach any additional components and/or devices to the finished prefilled syringe as applicable for intended use.
     3. Place the finished prefilled syringe in the adaptor plate on the force-measurement instrument.
     4. Start the depression at the designated test speed.
     5. End the test when the plunger stopper comes into contact with the shoulder of the syringe barrel.
     6. Repeat the steps A.4.1to A.4.5for additional test samples.
     7. Record the maximum break-loose force. Record the maximum force in the extrusion force test region. The extrusion force test region is defined as the region between the break-loose until the sharp increase of the force at the end of the stroke. Exclude from the evaluation the region of an abrupt decrease of the force caused by extrusion of the air bubble (if present). See Figure A.1.

Key

Figure A.1 — Example illustrating friction forces regions

• 1. Test report or documentation

The test report or documentation shall include the following:

• maximum break-loose force in Newton (N);
• maximum extrusion force in the extrusion force test region in Newton (N);
• calculated average extrusion force in Newton (N);
• numbers of tested samples;
• any deviations or observations.

NOTE If the used testing equipment does not allow to save or print all setup parameters, traceability of all required parameters is given by additional documentation.

1. 
   (normative)
   
   Test method for residual volume of finished prefilled syringes
   1. Principle

The same syringe barrel as used for the finished prefilled syringe is weighed dry together with the plunger stopper and with additional components and/or devices as applicable for intended use. The syringe is filled with the intended contents and emptied by fully depressing the plunger stopper with the same plunger rod as for application according to the intended use and reweighed (together with the plunger stopper and with additional components and/or devices as applicable for intended use). The residual volume (dead space) is inferred from the mass of the contents remaining in the system, considering its density. The force applied during residual volume testing considering the plunger stopper compression should be consistent with the force generated during administration according to the intended use (applicable both for manual injection or for use in needle-based injection systems).

• 1. Materials
     1. Syringe barrels (including front end closures) and plunger stoppers as intended for use, numbers as required.
     2. Additional components and/or devices required for or supporting the intended use (see 5.2.4) as applicable.
     3. Intended contents (i.e. the injectable product) of known density, volume as required.
  2. Apparatus
     1. Balance with a resolution of 1 mg or better.
  3. Procedure
     1. Weigh (B.3.1) the empty system, i.e. the syringe barrel, including tip cap or needle shield (or other front end closure), together with the plunger stopper and with additional components and/or devices as applicable for intended use.
     2. Fill the syringe barrel to the intended filling volume with the intended content (B.2.3) and set the plunger stopper, taking care to prevent air bubbles.
     3. Remove the tip cap or needle shield (or other front end closure) from the finished prefilled syringe. Keep the front end closure for later weighing.
     4. Attach any additional components and/or devices as previously weighed (B.4.1) to the finished prefilled syringe as applicable for intended use.
     5. Expel the contents by fully depressing the plunger stopper with the defined force and according to the intended use, and wipe dry the outer surfaces of the finished prefilled syringe.
     6. Reweigh (B.3.1) the system, i.e. the finished prefilled syringe, together with the plunger stopper, the front end closure (B.4.3) and with additional components and/or devices as applicable for intended use.
  4. Calculation of results

Determine the mass, in grams (g), of content remaining in the system by subtracting the mass of the empty system (B.4.1) from the mass of the system after expulsion of the contents (B.4.6). Record this value as the residual volume (dead space) in millilitres (ml), considering the density of the intended contents at its temperature during testing.

• 1. Test report

The test report shall contain at least the following information:

• the identity of the materials (syringe barrels, plunger stoppers, contents, additional components and/or devices as applicable for intended use);
• the intended filling volume, in millilitres (ml), of the finished prefilled syringe;
• the density of the intended contents at its temperature during testing, in grams per millilitre (g/ml);
• residual volume (dead space), in millilitres (ml);
• date of testing.

1. 
   (informative)
   
   Test methods for liquid leakage resistance of finished prefilled syringes
   1. General

The finished prefilled syringe is designed to ensure that there is no leakage of the contents when the plunger stopper is under compression by the forces generated during processing including filling, plunger rod assembly process, and administration of the contents.

Liquid leakage at the plunger stopper testing (Clause C.2) is performed with the intended front end closure to confirm resistance of the finished prefilled syringe to leakage when the plunger stopper is under compression in such situations.

Burst resistance testing (Clause C.3) is performed to confirm a safety margin of the finished prefilled syringe against bursting under compression for situations of unintended high internal pressure (e.g. in cases of a clogged needle).

The correlation between the applied test force and the generated internal pressure in the syringe, that is determined by the nominal inner diameter of the syringe, can be calculated using Formula (C.1).

Formula (C.1)

where F is the test force in Newton (N), p is the target internal pressure in kilopascal (kPa) and A is the cross-sectional area of the syringe barrel in square millimetres (mm²).

NOTE Formula (C.1) is only applicable if the friction between the plunger stopper and the syringe barrel can be neglected.

• 1. Procedure for liquid leakage at the plunger stopper
     1. Set up the test as described in ISO 11040-4:2024, G.2 but using the finished prefilled syringe.
     2. Assemble the finished prefilled syringe intended for administration by manual injection with the same plunger rod as for application according to the intended use (i.e. the plunger rod the product is placed on the market with). For a finished prefilled syringe intended for administration by a needle-based injection system the plunger rod of the used injection system may be used if applicable, or an appropriate substitute plunger rod (e.g. of the used tensile and compression testing machine).

NOTE 1 The plunger rod can be inserted into or onto the plunger stopper.

NOTE 2 The plunger rod can be with or without thread.

Do not remove the tip cap or needle shield (or other front end closure) from the finished prefilled syringe.

• • 1. Apply a constant axial force to the plunger stopper based on the maximum internal pressure generated during application according to the intended use (i.e. administration by manual injection), or generally generating a test pressure up to 300 kPa.

NOTE Finished prefilled syringes that are used in needle-based injection systems (e.g. auto-injectors), can experience a higher axial force.

• • 1. Maintain the test pressure for 30 – 35 s.
    2. Examine the finished prefilled syringe for leakage at the back end (plunger stopper) and on the outside of the syringe barrel. Liquid found past the proximal rib or last seal of the plunger stopper is considered a failure. Leakage between the ribs is considered a failure if dose accuracy is impaired. Leakage on the outside of the syringe barrel is considered a failure of the finished prefilled syringe. Leakage at the front end is not considered a failure of the finished prefilled syringe in this test. In that case repeat the test with sealing the nozzle and ensuring that the seal is maintained during the test (for information see also C.3.2).
  1. Procedure for burst resistance
     1. Set up the test as described in ISO 11040-4, G.2 but using the finished prefilled syringe.
     2. For a finished prefilled syringe intended for administration by a needle-based injection system the plunger rod of the used injection system may be used if applicable, or an appropriate substitute plunger rod (e.g. of the used tensile and compression testing machine).

NOTE 1 The plunger rod can be inserted into or onto the plunger stopper.

NOTE 2 The plunger rod can be with or without thread.

Remove the tip cap or needle shield (or other front end closure) from the finished prefilled syringe. Using a suitable method and/or tool, seal the nozzle and ensure that the seal is maintained during the test. In the case of a staked needle, ensure that the needle lumen is blocked by a suitable method or tool.

• • 1. Apply a constant axial force to the plunger stopper based on the maximum internal pressure generated during application according to the intended use (e.g. administration by a needle-based injection system), with adding to the test pressure a safety margin minimum of 20 %.

WARNING — The syringe barrel can break during testing. Ensure adequate protection during testing on the universal tensile and compression testing machine.

• • 1. Maintain the test pressure according to the maximum required administration time during the intended use.
    2. Examine the finished prefilled syringe for breaks or leakage on the outside of the syringe barrel. Bursting, cracks, fractures or leakage on the outside of the syringe barrel are considered a failure of the finished prefilled syringe.

NOTE Leakage due to faulty sealing of the front end (C.3.2) is not considered a failure of the finished prefilled syringe.

• 1. Test report or documentation

The test report or documentation should include the following:

• assumed maximum internal pressure generated during application according to the intended use (with added safety margin if applicable) in kilopascals (kPa);
• applied pressure in kilopascals (kPa), or axial force in Newton (N);
• duration of maintaining the pressure in seconds (s);
• numbers of tested samples;
• numbers of passed/failed samples;
• any deviations or observations.

NOTE If the used testing equipment does not allow to save or print all setup parameters, traceability of all required parameters is given by additional documentation.

1. 
   (informative)
   
   Test method for administration time with defined constant test force
   1. Purpose

This test method is used to measure the administration time for finished prefilled syringes with applying a defined constant test force (or force profile if applicable), based on the intended use. It assesses the user interaction, considering the system variability concerning, for example, silicone lubrication within the inner syringe barrel in combination with the plunger stopper, the needle inner diameter and the viscosity of the intended contents. Controlling the required administration forces ensures that the user or the needle-based injection system can administer the contents in a reasonable time according to their capabilities or functional force profile and according to the intended use.

• 1. Materials
     1. Finished prefilled syringes as intended for use and as marketed, numbers as required.
     2. Additional components and/or devices required for or supporting the intended use (see 5.2.4) as applicable.
  2. Apparatus
     1. Universal tensile and compression testing machine conforming with the following:
• capable of maintaining a defined constant test force or a test force profile along the stroke, adjustable as defined;
• force range up to 50 N or as appropriate.

NOTE The test method specifications of test force are depending on the contents and the intended use.

Whenever a test method requires a peak measurement a higher sampling rate (in Hz) will result in a more accurate result. Therefore, a sampling rate of 500 Hz is recommended for such tests. For all other tests, a sampling rate of minimum 100 Hz is recommended.

• • 1. Syringe support and syringe adaptor plates, if needed, appropriately sized for the finished prefilled syringe to be tested.
  1. Procedure
     1. Remove the tip cap or needle shield (or other front end closure) from the finished prefilled syringe.
     2. Attach any additional components and/or devices to the finished prefilled syringe as applicable for intended use.
     3. Place the finished prefilled syringe in the adaptor plate on the force-measurement instrument.
     4. Start the depression at the designated constant test force or test force profile.
     5. End the test when the plunger stopper comes into contact with the shoulder of the syringe barrel.
     6. Repeat the steps D.4.1 to D.4.5 for additional test samples.
     7. Repeat the steps D.4.1 to D.4.5 with adapted constant test force or test force profile, as appropriate for the intended administration time.
     8. Record the administration time in seconds (s) for each constant test force or test force profile. See Figure D.1.

Key

Figure D.1 — Example of administration time measurement at constant test force

• 1. Test report or documentation

The test report or documentation should include the following:

• maximum administration time in seconds (s) for a given constant test force or test force profile;
• minimum administration time in seconds (s) for a given constant test force or test force profile;
• calculated average administration time in seconds (s);
• numbers of tested samples;
• any deviations or observations.

NOTE If the used testing equipment does not allow to save or print all setup parameters, traceability of all required parameters is given by additional documentation.

1. 
   (informative)
   
   Unintended plunger stopper movement of finished prefilled syringes
   1. General

The plunger stopper, as a container closure system component, is designed to ensure that the contents of the finished prefilled syringe remain entirely enclosed and its microbial contamination is avoided. Though, the plunger stopper is also designed to move in order to allow administration of the contents. This freedom of movement can pose significant risks with regard to container closure integrity and product sterility and, therefore, movement out of the sterile barrier zone shall be prevented.

Unintended plunger stopper movement can happen during environmental air pressure or temperature changes, content phase changes between liquid and frozen solid, and/or the plunger rod assembly process. It depends on different parameters including but not limited to gaseous head space volume, friction forces between syringe barrel and plunger stopper, the extent of the air pressure or temperature changes or the forces applied to the plunger rod.

The plunger stopper creates a sterile barrier zone through the design features at its distal and proximal ends that come into contact with the syringe barrel and are intended for sealing.

Key

Figure E.1 — Example of a sterile barrier zone provided by a plunger stopper

The plunger stopper movement should be within the range defined by the length of the sterile barrier zone L_SB in order to maintain container closure integrity and product sterility. For an example definition of the sterile barrier zone L_SB see Figure E.1.

NOTE 1 For injectable products that are stored frozen, special consideration can be needed to maintain container closure integrity and product sterility.

NOTE 2 In case of multiple plunger stopper movements caused by air pressure changes, special consideration can be required to maintain container closure integrity and product sterility.

The following calculation (Clause E.2, based on reference ^[15]) and testing (Clause E.3) are only relevant to instances where the plunger stopper has free backward movement during transport. If the finished prefilled syringe is assembled with other component(s) that restrict the free backward movement of the plunger stopper to less than the length of the sterile barrier zone L_SB the following calculations and testing may not be needed.

Plunger stopper movement of finished prefilled syringes may be verified through various test methods. When finished prefilled syringes are transported by means of certain modes of transport, the effects of air pressure changes can be tested by using a vacuum method simulating the transport conditions.

NOTE 3 Information about testing parameters using a vacuum method can be found, for example, in

• ASTM International D6653/D6653M-13, Standard Test Methods for Determining the Effects of High Altitude on Packaging Systems by Vacuum Method,
• International Air Transport Association (IATA) Packing Instruction 650.
  1. Theoretical calculation of plunger stopper movement caused by air pressure changes

A finished prefilled syringe can contain a gaseous head space (“air bubble”) depending on intended plunger stopper positioning. During transport at high altitudes, the air pressure-changes in relation to ground level can cause the plunger stopper to move due to either expansion or contraction of the air bubble or both.

In theory, the maximum amount of movement of the plunger stopper caused by changes in air pressure can be calculated on the basis of Boyle’s law, assuming that the temperature remains constant during transport and disregarding the friction between the plunger stopper and the syringe barrel. This can be expressed as

Formula (E.1)

where p₁ is the air pressure at condition 1, V₁ is the volume of the air bubble at condition 1, p₂ is the air pressure at condition 2, and V₂ is the volume of air bubble at condition 2.

Assuming the air bubble inside the syringe barrel has a cylindrical shape, the volume of the air bubble can be calculated with

Formula (E.2)

where V is the volume of the air bubble, L is the length of the air bubble and A is the inner cross-sectional area of the syringe barrel.

Since the inner cross-sectional area A can be regarded as constant for the syringe barrel, Formula (E.2) can be written as

Formula (E.3)

which can be transformed to

Formula (E.4)

where L₁ is the length of the air bubble at condition 1 and L₂ is the length of the air bubble at condition 2. The theoretical plunger stopper movement ∆L can be calculated as

Formula (E.5)

To maintain product sterility, the theoretical plunger stopper movement ∆L shall be less than the length of the sterile barrier zone L_SB. Therefore, the maximum air bubble length L_1max can be calculated as

Formula (E.6)

By controlling the air bubble length L₁ to be below the maximum air bubble length L_1max, and the air pressure (p₁, p₂) through the transport conditions, the theoretical plunger stopper movement ∆L can be controlled to be within the range defined by the length of the sterile barrier zone L_SB in order to maintain container closure integrity and product sterility.

Bibliography

[1] ISO 11608-1:2022, Needle-based injection systems for medical use — Requirements and test methods — Part 1: Needle-based injection systems

[2] ISO 11608-2, Needle-based injection systems for medical use — Requirements and test methods — Part 2: Double-ended pen needles

[3] ISO 11608-3, Needle-based injection systems for medical use — Requirements and test methods — Part 3: Containers and integrated fluid paths

[4] ISO 11608-4, Needle-based injection systems for medical use — Requirements and test methods — Part 4: Needle-based injection systems containing electronics

[5] ISO 11608-5, Needle-based injection systems for medical use — Requirements and test methods — Part 5: Automated functions

[6] ISO 11608-6, Needle-based injection systems for medical use — Requirements and test methods — Part 6: On-body delivery systems

[7] ISO 11608-7, Needle-based injection systems for medical use — Requirements and test methods — Part 7: Accessibility for persons with visual impairment

[8] ISO 14971, Medical devices — Application of risk management to medical devices

[9] ICH Q9 Quality Risk Management, see http://www.ich.org

[10] ANSI/AAMI HE75, Human Factors Engineering — Design of Medical Devices

[11] ICH Q1A Stability Testing of New Drug Substances and Products, see http://www.ich.org

[12] ISO 10993-1, Biological evaluation of medical devices — Part 1: Evaluation and testing within a risk management process

[13] ISO 13408-1, Aseptic processing of health care products — Part 1: General requirements

[14] ISO 17665, Sterilization of health care products — Moist heat — Requirements for the development, validation and routine control of a sterilization process for medical devices

[15] Kinney S, Wagner A, Phillips CW. A rational approach to determining the maximum allowable gas bubble inside a prefilled syringe to minimize stopper movement & protect product sterility. Drug Deliv Technol. 2009;9(2):42–47.

1. 1) See http://www.edqm.eu/. ↑

2. 2) See http://www.usp.org/. ↑

3. 3) See http://www.pmda.go.jp. ↑