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
Current Stage
6060 - International Standard published
Start Date
11-Sep-2019
Completion Date
18-Oct-2019
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ISO 21881:2019 - Sterile packaged ready for filling glass cartridges
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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 21881:2019(E)
ISO 2019
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ISO 21881:2019(E)
COPYRIGHT PROTECTED DOCUMENT
© ISO 2019

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Published in Switzerland
ii © ISO 2019 – All rights reserved
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ISO 21881:2019(E)
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

© ISO 2019 – All rights reserved iii
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ISO 21881:2019(E)
Foreword

ISO (the International Organization for Standardization) is a worldwide federation of national standards

bodies (ISO member bodies). The work of preparing International Standards is normally carried out

through ISO technical committees. Each member body interested in a subject for which a technical

committee has been established has the right to be represented on that committee. International

organizations, governmental and non-governmental, in liaison with ISO, also take part in the work.

ISO collaborates closely with the International Electrotechnical Commission (IEC) on all matters of

electrotechnical standardization.

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
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ISO 21881:2019(E)
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.
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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
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ISO 21881:2019(E)
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
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ISO 21881:2019(E)
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.
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ISO 21881:2019(E)

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

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.
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ISO 21881:2019(E)

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.
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ISO 21881:2019(E)
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) container insertion (nesting) and extraction (denesting);
2) filling;
3) plunger insertion;
4) capping and crimping;
5) stacking and destacking.
c) for protective bags:
1) sealing;
2) folding;
3) decontamination;
4) cutting and opening.
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ISO 21881:2019(E)

7.1.6 The packaging configuration including the arrangement of the product shall be agreed with the

customer to allow for adequate usability through the required processes.

NOTE The process steps described include those at the premises of the manufacturer and of the customer.

7.2 Nest and tub configuration

7.2.1 Ready for filling glass cartridges shall be packaged in a rigid plastic nest, which is placed within a

rigid plastic tub.

7.2.2 The nest shall maintain distance between the glass cartridges to reduce breakage during

transportation. Cartridge orientation shall be agreed upon between the manufacturer and the customer.

Depending on a particular cartridge’s dimensions, nests can contain different numbers and sizes of wells.

The tub shall maintain the nest in the correct position.

7.2.3 The cartridges shall be covered with a protective insert liner and the tub shall be sealed with a

sealing lid. The assembly shall be thermo-welded by heating the sealing lid. Once sealed, the tub and lid

assembly shall serve as a sterile barrier system to maintain sterility of the contents following sterilization

of the packaging system.
7.3 Tray configuration

7.3.1 Ready for filling cartridges shall be packaged directly into the tray that can be considered the

plastic support.

7.3.2 The tray can be equipped with some plastic insertions to guarantee the right orientation of the

cartridges and physical separation between the glass cartridges to reduce breakage during transportation.

The cartridge orientation shall be agreed upon between the manufacturer and the customer.

NOTE Depending on a particular cartridge dimension, trays can contain varying numbers of cartridges.

7.3.3 The cartridges shall be covered with a protective insert liner and the tray shall be sealed with

a thermo-welded sealing lid. Once sealed, the tray and sealing lid serve as a sterile barrier system to

maintain sterility of the containers, following sterilization of the packaging system.

7.4 Nest

7.4.1 For the nest, the following information should be provided (information on dimensions including

tolerances):
— external d
...

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