ISO 21882:2019

INTERNATIONAL ISO
STANDARD 21882
First edition
2019-10
Sterile packaged ready for filling
glass vials
Flacons 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
CP 401 • Ch. de Blandonnet 8
CH-1214 Vernier, Geneva
Phone: +41 22 749 01 11
Fax: +41 22 749 09 47
Email: copyright@iso.org
Website: www.iso.org
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 . 2
4.1 General . 2
4.2 Testing . 3
5 Process description and requirements . 3
5.1 Washing . 3
5.2 Drying . 3
5.3 Packaging . 3
5.4 Sterilization . 3
6 Requirements for glassware . 4
6.1 General . 4
6.2 Material . 4
6.3 Dimensions . 4
6.4 Particles . 4
6.4.1 Visible particles. 4
6.4.2 Sub-visible particles . 4
6.5 Bacterial endotoxin level . 5
7 Requirements for packaging system . 5
7.1 General . 5
7.2 Nest and tub configuration . 6
7.3 Tray configuration . 6
7.4 Nest . 6
7.5 Tub and tray . 7
7.6 Insert liner . 7
7.7 Sealing lid . 7
7.8 Protective bag . 8
7.9 Information to be provided by the manufacturer . 8
8 Marking of the tub or tray . 8
9 Labelling . 9
Annex A (informative) Design of tub .10
Annex B (informative) Design of nest .11
Annex C (informative) Design of tray .12
Annex D (informative) Schematic illustrations of examples for the orientation of tubs or
trays within the protective bag .13
Annex E (informative) Sample preparation for endotoxin and particulate determination .16
Annex F (informative) Packaging configuration .19
Bibliography .20
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 of the voluntary nature of standards, 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 www .iso
.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 8362-1 specifies the form, dimensions and capacities of bulkware glass vials.
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 started to develop
systems of this type for vials.
The availability of two packaging configurations makes ready for filling glass vials suitable to be used
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 21882:2019(E)
Sterile packaged ready for filling glass vials
1 Scope
This document specifies the characteristics of sterile and ready for filling empty glass vials 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 8362-1, Injection containers and accessories — Part 1: Injection vials made of glass tubing
ISO 8362-4, Injection containers and accessories — Part 4: Injection vials made of moulded glass
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
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
customer
business entity which purchases sterilized ready for filling vials and conducts further processing or
filling as appropriate
3.2
filling volume
90 % of the brimful capacity
[SOURCE: United States Pharmacopoeia Convention, USP <660>]
3.3
insert liner
foil to cover and protect the vials
3.4
manufacturer
business entity which performs or is otherwise responsible for the manufacturing of the vials ready to
be filled by the customer (3.1)
3.5
nest
plastic plate with a defined hole pattern for the placing of the vials
[SOURCE: ISO 11040-7:2015, 3.4, modified — “suspension of the syringe bodies” was replaced with
“placing of the vials”.]
3.6
packaging system
combination of the sterile barrier system (3.10) and protective packaging (3.7)
[SOURCE: ISO 11139:2018, 3.192]
3.7
protective packaging
configuration of materials designed to prevent damage to the sterile barrier system (3.10) and its
contents from the time of their assembly until the point of use
[SOURCE: ISO 11139:2018, 3.219]
3.8
protective bag
plastic bag or sealing around the tub (3.12) or the tray (3.11)
[SOURCE: ISO 11040-7:2015, 3.6, modified — “tray” was added as an additional configuration.]
3.9
sealing lid
microbial barrier material for sealing the tub (3.12) or the tray (3.11)
[SOURCE: ISO 11040-7:2015, 3.7, modified — “tray” was added as an additional configuration.]
3.10
sterile barrier system
minimum package that prevents ingress of microorganisms and allows aseptic presentation of product
at the point of use
3.11
tray
plastic container with optional supports to accommodate individual vials
3.12
tub
plastic container to accommodate the filled nest (3.5)
[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.
2 © ISO 2019 – All rights reserved

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 vials 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 vials 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 Packaging
5.3.1 Non-sterile glass vials, already washed, shall be packed in plastic trays or nest and tub
configuration as agreed between the manufacturer and the customer. See Annex F.
5.3.2 For packaging systems for sterilized ready for filling vials, see Clause 7.
5.4 Sterilization
5.4.1 Sterilized ready for filling vials shall be sterilized according to a sterility assurance level
−6
(SAL) of 10 , using a suitable validated sterilization method (see, e.g. ISO 11135, ISO 17665-1,
ISO 11137 (all parts) or ISO 14937).
5.4.2 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 [21].
6 Requirements for glassware
6.1 General
Vials 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.
6.2.2 Material requirements for hydrolytic resistance shall conform with ISO 8362-1 or ISO 8362-4.
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 vials made of glass tubing should meet the requirements of
ISO 8362-1:2018, Figure 1 or Figure 2 or Figure 3, as appropriate, and Table 1, or ISO 8362-4:2011,
Figure 1 or Figure 2, as appropriate, and Table 1 or Table 2, as appropriate. Dimension of vials for
different applications not included in ISO 8362-1 or ISO 8362-4 can be acceptable if agreed upon with
the customer.
6.4 Particles
6.4.1 Visible particles
Sterilized vials 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 material. 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 E.
NOTE 1 See also Ph. Eur. 2.9.19, Ph. Eur. 2.9.20, USP <788>, JP 6.06 and 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).
4 © ISO 2019 – All rights reserved

6.5 Bacterial endotoxin level
6.5.1 For bacterial endotoxins, the limit value for vials shall be < 0,25 EU/ml considering the filling
volume. For sample preparation for endotoxin determination, see Annex E.
6.5.2 The vials 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 endotox
...