ISO 21881:2019

Sterile packaged ready for filling glass cartridges

This document specifies the characteristics of sterile and ready for filling empty glass cartridges for injectable preparations, including the minimum requirements of materials, packaging systems and analytical test methods.

Cartouches en verre préremplissables sous emballage stérile

General Information

• Status: Published
• Publication Date: 17-Oct-2019
• ICS: 11.080.30 - Sterilized packaging
• Technical Committee: ISO/TC 76 - Transfusion, infusion and injection, and blood processing equipment for medical and pharmaceutical use
• Drafting Committee: ISO/TC 76/WG 2 - Rigid container systems and related accessories for parenterals and injectables
• Current Stage: 9092 - International Standard to be revised
• Start Date: 28-Oct-2024
• Completion Date: 13-Dec-2025

Overview

ISO 21881:2019 - Sterile packaged ready for filling glass cartridges - defines the minimum characteristics, materials and test methods for sterile, ready-for-filling glass cartridges for injectable preparations. The standard covers the product (glassware and closures), the sterile barrier and protective packaging systems, and the analytical/quality requirements needed to deliver cartridges that are washed, sterilized and presented for aseptic filling.

Key topics and technical requirements

• Scope and terminology: Definitions for cartridge components (plunger, disc, cap), packaging elements (nest, tub, tray, sealing lid, protective bag) and roles (manufacturer, customer).
• Quality system and testing: Testing within a formal quality management system; statistically based sampling plans and laboratory conditions (references to ISO 15378, ISO 2859-1 and ISO 3951 for quality/sampling best practice).
• Process steps: Requirements and process controls for washing, drying, lubrication, capping/crimping, plunger insertion, packaging and sterilization.
• Glassware requirements: Materials, dimensions, particle limits (visible and sub-visible), and bacterial endotoxin considerations.
• Packaging system design: Specifications for sterile barrier systems and protective packaging - including nest & tub (for automated filling) and tray configurations (for manual/semi-automated filling), insert liners, sealing lids and protective bags.
• Analytical and test methods: Normative and informative annexes include methods such as glide-force testing for lubrication (Annex D), closure system liquid leakage (Annex F), and sample preparation for endotoxin and particulate testing (Annex G).
• Labelling and traceability: Marking requirements for tubs/trays and information manufacturers must provide with sterile packaged cartridges.

Practical applications - who uses ISO 21881:2019

• Primary packaging manufacturers producing sterile, ready-for-filling glass cartridges.
• Pharmaceutical and biotech companies evaluating or sourcing cartridges for injectable drug products and clinical trial materials.
• Contract fill–finish sites that receive sterile packaged cartridges for aseptic or terminal filling.
• Quality assurance, regulatory and compliance teams performing supplier qualification, inspection, or audits of cartridge supply and packaging.
• Equipment and automation engineers who design filling lines that interface with nest/tub or tray packaging formats.

Why use this standard (benefits)

• Ensures consistent product quality and aseptic presentation at point-of-use.
• Harmonizes packaging configurations for automated and manual filling workflows.
• Provides validated test methods to assess particulates, endotoxin, lubrication and closure integrity.
• Supports supplier qualification, risk reduction and regulatory submissions by referencing recognized international requirements.

Related standards (selected)

• ISO 11607-1 (packaging for terminally sterilized medical devices)
• ISO 11608-3 (needle-based injection systems - finished containers)
• ISO 13926-1 (glass cylinders for pen-injectors)
• ISO 720, ISO 8871-1, ISO 10993-7, ISO 11138/11140 (sterilization & biological/chemical indicators)

Keywords: ISO 21881:2019, sterile packaged ready for filling glass cartridges, glass cartridges, injectable preparations, packaging systems, sterile barrier, analytical test methods, nest and tub, tray configuration.

Standards Content (Sample)

INTERNATIONAL ISO
STANDARD 21881
First edition
2019-10
Sterile packaged ready for filling glass
cartridges
Cartouches en verre préremplissables sous emballage stérile
Reference number
©
ISO 2019
© ISO 2019
All rights reserved. Unless otherwise specified, or required in the context of its implementation, no part of this publication may
be reproduced or utilized otherwise in any form or by any means, electronic or mechanical, including photocopying, or posting
on the internet or an intranet, without prior written permission. Permission can be requested from either ISO at the address
below or ISO’s member body in the country of the requester.
ISO copyright office
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Published in Switzerland
ii © ISO 2019 – All rights reserved

Contents Page
Foreword .iv
Introduction .v
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 1
4 Quality system . 3
4.1 General . 3
4.2 Testing . 3
5 Process description and requirements . 3
5.1 Washing . 3
5.2 Drying . 3
5.3 Lubrication . 3
5.4 Capping and crimping . 4
5.5 Plunger insertion . 4
5.6 Packaging . 4
5.7 Sterilization . 4
6 Requirements for glassware . 4
6.1 General . 4
6.2 Material . 4
6.3 Dimensions . 5
6.4 Particles . 5
6.4.1 Visible particles. 5
6.4.2 Sub-visible particles . 5
6.5 Bacterial endotoxin level . 5
7 Requirements for packaging system . 6
7.1 General . 6
7.2 Nest and tub configuration . 7
7.3 Tray configuration . 7
7.4 Nest . 7
7.5 Tub and tray . 8
7.6 Insert liner . 8
7.7 Sealing lid . 8
7.8 Protective bag . 8
7.9 Information to be provided by the manufacturer . 9
8 Marking of the tub or tray . 9
9 Labelling .10
Annex A (informative) Design of tub .11
Annex B (informative) Design of nest .12
Annex C (informative) Design of tray .13
Annex D (normative) Glide force test method to evaluate cartridge lubrication .14
Annex E (informative) Schematic illustrations of examples for the orientation of tubs or
trays within the protective bag .16
Annex F (normative) Closure systems liquid leakage .19
Annex G (informative) Sample preparation for endotoxin and particulate determination .21
Annex H (informative) Product and packaging configuration .25
Bibliography .28
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
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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
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.org/iso/foreword .html.
This document was prepared by Technical Committee ISO/TC 76, Transfusion, infusion and injection, and
blood processing equipment for medical and pharmaceutical use.
Any feedback or questions on this document should be directed to the user’s national standards body. A
complete listing of these bodies can be found at www .iso .org/members .html.
iv © ISO 2019 – All rights reserved

Introduction
In the last few years, following the more and more urgent request for ready for filling containers,
packaging manufacturers managed to offer to the pharmaceutical industry containers already washed
and sterilized. This category of products was born about 30 years ago with the appearance on the
market of ready for filling syringes.
Only recently, the sterilized sub-assembled ready for filling syringes have been standardized by
ISO 11040-4 and ISO 11040-7, including the corresponding packaging system. These two International
Standards define the performance requirements of the glass syringes and the related test methods, as
well as the ready for filling packaging system for these syringes, also including the test methods.
ISO 13926-1 specifies the design, dimensions, materials, performance and test methods for glass
cylinders used with pen-injectors for medical use.
Due to the increasing market presence of syringes ready for filling and the associated advantages of this
product for the pharmaceutical industry, the suppliers of packaging materials have started to develop
such systems of this type for cartridges.
The availability of two packaging configurations makes ready for filling glass cartridges suitable for
use both in clinical trials and in mass production. Nest and tub configuration has been conceived to
be used usually with automated filling machines, while tray configuration is usually suitable for small
batches filled manually or by means of semi-automated filling machines.
This duality of packaging configurations calls for a standardization of the production processes,
materials quality and analytical methods when launching these products on the market, in order to
avoid conceiving too highly customized processes.
INTERNATIONAL STANDARD ISO 21881:2019(E)
Sterile packaged ready for filling glass cartridges
1 Scope
This document specifies the characteristics of sterile and ready for filling empty glass cartridges for
injectable preparations, including the minimum requirements of materials, packaging systems and
analytical test methods.
2 Normative references
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 720, Glass — Hydrolytic resistance of glass grains at 121 °C — Method of test and classification
ISO 8871-1, Elastomeric parts for parenterals and for devices for pharmaceutical use — Part 1: Extractables
in aqueous autoclavates
ISO 10993-7, Biological evaluation of medical devices — Part 7: Ethylene oxide sterilization residuals
ISO 11138 (all parts), Sterilization of health care products — Biological indicators
ISO 11140 (all parts), Sterilization of health care products — Chemical indicators
ISO 11607-1, Packaging for terminally sterilized medical devices — Part 1: Requirements for materials,
sterile barrier systems and packaging systems
ISO 11608-3:2012, Needle-based injection systems for medical use — Requirements and test methods —
Part 3: Finished containers
ISO 13926-1:2018, Pen systems — Part 1: Glass cylinders for pen-injectors for medical use
3 Terms and definitions
For the purposes of this document, the following terms and definitions apply.
ISO and IEC maintain terminological databases for use in standardization at the following addresses:
— ISO Online browsing platform: available at https: //www .iso .org/obp
— IEC Electropedia: available at http: //www .electropedia .org/
3.1
cap
component which attaches the disc (3.3) to the cartridge
[SOURCE: ISO 11608-3:2012, 3.1]
3.2
customer
business entity which purchases sterile ready for filling cartridges and conducts further processing or
filling as appropriate
3.3
disc
component which seals the end of the container opposite the plunger (3.9)
[SOURCE: ISO 11608-3:2012, 3.5]
3.4
filling volume
90 % of the brimful capacity
[SOURCE: United States Pharmacopoeia Convention, USP <660>]
3.5
insert liner
foil to cover and protect the cartridges
3.6
manufacturer
business entity which performs or is otherwise responsible for the manufacturing of the cartridges
ready to be filled by the customer (3.2)
3.7
nest
plastic plate with a defined hole pattern for the placing of the cartridges
[SOURCE: ISO 11040-7:2015, 3.4, modified — “suspension of the syringe bodies” was replaced with
“placing of the cartridges”.]
3.8
packaging system
combination of the sterile barrier system (3.13) and protective packaging (3.10)
[SOURCE: ISO 11139:2018, 3.192]
3.9
plunger
elastomeric component which seals the back end of cartridge
3.10
protective packaging
configuration of materials designed to prevent damage to the sterile barrier system (3.13) and its
contents from the time of their assembly until the point of use
[SOURCE: ISO 11139:2018, 3.219]
3.11
protective bag
plastic bag or sealing around the tub (3.15) or the tray (3.14)
[SOURCE: ISO 11040-7:2015, 3.6, modified — “tray” was added as an additional configuration.]
3.12
sealing lid
microbial barrier material for sealing the tub (3.15) or the tray (3.14)
[SOURCE: ISO 11040-7:2015, 3.7, modified — “tray” was added as an additional configuration.]
3.13
sterile barrier system
minimum package that prevents ingress of microorganisms and allows aseptic presentation of product
at the point of use
2 © ISO 2019 – All rights reserved

3.14
tray
plastic container with optional supports to accommodate individual cartridges
3.15
tub
plastic container to accommodate the filled nest (3.7)
[SOURCE: ISO 11040-7:2015, 3.11]
4 Quality system
4.1 General
The testing hereunder described shall be carried out within a formal quality system.
NOTE ISO 15378 contains requirements for a suitable quality management system for primary packaging
materials for medicinal products.
4.2 Testing
4.2.1 Any suitable test system can be used, when the required accuracy (calibration) and precision
(gauge repeatability and reproducibility) can be obtained. In case the gauge is applied, repeatability
and reproducibility of the test apparatus shall be no greater than the range documented in test method
precision and bias statements or as established by industry round robin studies.
4.2.2 The sampling plans used for the selection and testing of sterile ready for filling cartridges or
components thereof shall be based upon statistically valid rationale at all process steps.
NOTE Examples of suitable sampling plans are given in ISO 2859-1 and ISO 3951 (all parts).
4.2.3 Unless agreed otherwise, testing shall be performed at ambient laboratory conditions.
5 Process description and requirements
5.1 Washing
5.1.1 Washing is the process intended to reduce particle, lubricant or any other contamination on the
bulkware cartridges after converting process steps.
5.1.2 Water used for final rinsing shall meet the specifications of water for injection (WFI) (see USP
and/or Ph.Eur).
5.2 Drying
Drying is an optional step to guarantee the absence of rinsing water after washing if heating is not
applied. The air shall be filtered using a filter with a pore size of maximum 0,22 µm.
5.3 Lubrication
The inner surface of the cartridges can be lubricated. Limit values of the amount of lubricant and the
required glide forces are subject to agreement between the manufacturer and the customer. Lubrication
of the inner surface of the cartridges is applied in order to improve gliding properties. This is usually
done by siliconization, with silicone emulsion followed by heat treatment.
Annex D specifies a suitable test method for the determination of the quality and consistency of the
lubrication using a glide force test.
5.4 Capping and crimping
5.4.1 Cartridges can optionally, upon customer request, be pre-capped with selected rubber
formulations. The rubber material that can be in contact with the injectable product shall meet applicable
requirements of ISO 8871-1. For additional regional or national requirements of pharmacopoeias, see
type I or type II requirements of Ph. Eur. 3.2.9, USP <381>.
5.4.2 The closure system shall provide an appropriate liquid leakage resistance when tested in
accordance with Annex F.
5.5 Plunger insertion
If required by the customer, as option of capping and crimping, plunger insertion can be performed
by the manufacturer. The rubber constituent shall meet applicable requirements of ISO 8871-1. For
additional regional or national requirements of pharmacopoeias, see type I or type II requirements of
Ph. Eur. 3.2.9, USP <381> and JP 7.03 that is applicable to volumes > 100 ml.
5.6 Packaging
5.6.1 Non-sterile glass cartridges already washed, shall be packed in plastic trays or nest and tub
configuration as agreed between the manufacturer and the customer. See Annex H.
5.6.2 For packaging systems for sterilized ready for filling cartridges, see Clause 7.
5.7 Sterilization
5.7.1 Sterilized ready for filling cartridges shall be sterilized according to a sterility assurance
−6
level (SAL) of 10 , using a suitable validated sterilization method (see e.g. ISO 11135, ISO 17665-1,
ISO 11137 (all parts) or ISO 14937).
5.7.2 The sterilization process shall not compromise the product safety and performance. Sterilization
compatibility of sterile barrier systems and packaging systems is assessed following the requirements in
ISO 11607-1.
NOTE Sterility testing is subject to national or regional pharmacopoeias, see the methods given in Ph. Eur.,
2.6.1, USP <71> and JP 4.06.
For ethylene oxide sterilization the requirements for residuals of ISO 10993-7 apply. See also
Reference [20].
6 Requirements for glassware
6.1 General
Cartridges shall be produced from glass with characteristics such as to be adequate to contain products
for injection.
6.2 Material
6.2.1 The material shall be colourless (cl) or amber (br) glass of the hydrolytic resistance grain class
HGA 1 in accordance with ISO 720.
4 © ISO 2019 – All rights reserved

6.2.2 Material requirements for hydrolytic resistance shall conform with ISO 13926-1. For additional
requirements, see the requirements for glass type Ι given in Ph. Eur. 3.2.1, USP <660> and in JP 7.01.
6.3 Dimensions
The dimensions of injection cartridges made of glass tubing should meet the requirements of
ISO 13926-1:2018, Figure 1 and Table 1. Dimension of cartridges for different applications not included
in ISO 13926-1 can be acceptable if agreed upon with the customer.
6.4 Particles
6.4.1 Visible particles
Sterilized cartridges ready for filling shall be manufactured by processes that reduce the risk of
particulate contamination.
NOTE Current pharmacopoeias identify visible particulates in injectables as undesirable, but they do not
define the size or put a limit on the allowable number for primary packaging materials. The manufacturer and
the customer can agree upon the size and number of visible particles and the test method.
6.4.2 Sub-visible particles
The particle-related specifications given in pharmacopoeias (e.g. Ph. Eur., USP, JP) do not apply to empty
containers but apply to final filled product. For sample preparation for particulate determination, see
Annex G.
NOTE 1 See also Ph. Eur. 2.9.19, Ph. Eur. 2.9.20, USP <788>, JP 6.06 as well as JP 6.07.
For sub-visible particles, the following limits apply for empty containers:
a) if determined by using the light obscuration particle count test (see USP <788> Method 1):
— particles ≥ 10 µm: 600 max. per container;
— particles ≥ 25 µm: 60 max. per container.
b) if determined by using the microscopic particle count test (see USP <788> Method 2):
— particles ≥ 10 µm: 300 max. per container;
— particles ≥ 25 µm: 30 max. per container.
NOTE 2 These limits are the 10 % of the USP <788> (small volume parenteral) limit values for filled containers
with a nominal volume of less than 100 ml (Test 1.B and Test 2.B).
6.5 Bacterial endotoxin level
6.5.1 For bacterial endotoxins, the limit value for cartridges shall be < 0,25 EU/ml considering the
filling volume. For sample preparation for endotoxin determination, see Annex G.
6.5.2 The cartridges ready for filling shall be processed to remove pyrogens to ensure that they are
suitable for their intended use. Such processes shall be validated for three log endotoxin reduction.
NOTE For rationale, see USP monograph on sterile water for injection according to USP <1231>.For testing,
see Ph. Eur., 2.6.14, method c), USP <85> and JP 4.01.
7 Requirements for packaging system
7.1 General
7.1.1 The packaging system intended to contain the ready for filling cartridges shall protect the
cartridges and their sterile barrier system during handling, distribution and storage, in order to maintain
the sterility and the functional and cosmetic characteristics over the claimed shelf-life.
NOTE Functional but also cosmetic defects determine a non-conforming product.
7.1.2 The materials, the sterile barrier system, and the packaging system that enable sterilization,
protect the product and maintain sterility until the point of aseptic filling, shall be in accordance with the
requirements of ISO 11607-1.
7.1.3 The packaging system shall have acceptable microbiological and particulate levels to support
the introduction of the sterilized cartridges into an aseptic filling environment and related designated
cleanrooms.
NOTE The introduction of sterilized packaged cartridges into an aseptic filling environment poses a risk of
microbiological and/or particulate contamination of the drug product.
7.1.4 Requirements should be agreed upon by the manufacturer and the customer.
7.1.5 Tubs, nests, lids, inserts, trays and protective bags shall allow general processing and aseptic
presentation of sterilized cartridges over their shelf-life. The process steps to be considered include, but
are not limited, to the following:
a) for tubs and trays including sealing lid and insert liner:
1) lid sealing and lid opening;
2) conveying;
3) nest/tray insertion and extraction;
4) stacking and destacking;
5) sterilization and decontamination.
b) for nests:
1) c
...